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 EXPERIMENTAL INVESTIGATION 
 
 OF THE 
 
 ACTION OF MEDICINES. 
 
 T. LAUDER BRUNTON, M.D., Sc.D., F.R.S. 
 
 MEMBER OF THE ROYAL COLLEGE OF PHYSICIANS ; ASSISTANT-PHYSICIAN AND 
 LECTURER ON MATERIA MEDICA AND THERAPEUTICS AT 
 
 ST. Bartholomew's hospital. 
 
 \Kepritited Jrom the British Medical Journal.] 
 
 LONDON : 
 J. & A CHy;RC;>13,Ll;, NEW BmiLiN(iTOis( STREET. 
 
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 EXPERIMENTAL INVESTIGATION OF THE 
 ACTION OF MEDICINES. 
 
 PART I. 
 
 CIRCULATION. 
 
 {Reprinted from tfte British Medical Journal, 1871.] 
 
 if dci tj 
 
EXPERIMENTAL INVESTIGATION OF THE 
 ACTION OF MEDICINES. 
 
 I.— The Standard of Health. 
 
 Modes of Investigation. — Pathology. — Pharmacology. — Life.— Condi- 
 tions of Health and Disease. — Effect of Drugs. — Direct and Indirect 
 Action. — Local and Remote Action. — Dose. — Modification of Dose. — 
 Cumulative Action. — Effect of Habit , Climate^ Fasting. — Form of 
 Administration. — Effect of Large and Small Doses. — Homoeopathy. — 
 Constitution and Idiosyncrasy. — Explanation of these from Experi- 
 ments on Animals. — Connection of Chemical Constitution and Physi- 
 ological Action. 
 
 Gentlemen, — The usual mode of investigating the action of a remedy 
 is to give it to a patient during an illness and observe what changes 
 occur in the symptoms after its administration. But it not unfrequently 
 happens that medicines are given without any distinct change in the 
 symptoms ensuing ; and, even when one does take place, we very often 
 cannot be sure that it is due to the medicine, and not to the course of 
 the disease or some other modifying cause. For, if the remedy and the 
 disease are both at work together, it is obviously impossible for us to 
 decide what part of the result is due to the one and what part to the 
 other, if we neither know what the course of the disease would have 
 been had the medicine been given, nor what action the medicine would 
 have had if the disease had not been present. Any attempt to investi- 
 gate the action of a remedy by giving it under such circumstances is 
 like that of a rifleman to learn shooting by practising only at dusk, 
 when he cannot see the butt, much less the bull's eye. He might go 
 on practising for ever in this way without making any improvement \ for, 
 when he missed, he would never know whether it was because he had 
 not seen the mark properly or had not aimed steadily at it. If he 
 wish to learn, he must practise by daylight, when he can clearly see 
 the mark, and can thus be sure that every miss is due to unsteady aim. 
 He will fire high or low, to one side or the other, as he finds neces- 
 
 B 
 
sary, and, by gradually correcting every error, his aim will at last be 
 sure. Should he then be called on to stand sentry on some dark night, 
 and shoot at some suspicious object without hitting it, he would know 
 that his failure was due to his not having seen the object distinctly, and 
 having consequently aimed in a wrong direction. And just as the 
 rifleman, before he stands sentry in the dark, must learn to shoot by 
 daylight, when he can note the effect of each alteration in the position 
 of his rifle on the course of the bullet, so ought we to investigate the 
 action of our remedies in circumstances and under conditions which we 
 know and can vary at will, marking the effect of each variation upon 
 their action till we thoroughly and exactly understand what it is, before 
 we proceed to give them in disease, when not only the conditions 
 under which they operate are at present in a great measure unknown, 
 but the effects they produce cannot be definitely ascertained from in- 
 sufficient knowledge of what the result would have been had they been 
 withheld. Of late years, it is true, vigorous efforts have been made to 
 determine what course diseases run when not interfered with by medi- 
 cines ; and, although it is often difficult to say what the sequence of 
 symptoms will be in any particular case, depending as it does not only 
 on the general course of the disease, but on individual peculiarities of 
 the patient and on the varying circumstances in which he is placed, we 
 may nevertheless ascertain with tolerable accuracy whether or not our 
 treatment is beneficial in a general way, even when we cannot deter- 
 mine its effects in detail. 
 
 Very inexact and very unsatisfactory as such a knowledge of medi- 
 cines as this necessarily is, it must for the present be our guide in prac- 
 tice in a large number of instances ; and our treatment at present and 
 for some time to come will be chiefly empirical, because our knowledge 
 of pharmacology, and perhaps still more of pathology, is not yet suffi- 
 ciently advanced. For there is hardly any disease in which we know 
 the exact nature of the morbid changes which are occurring, or the 
 precise organs or tissues which are their seats ; and, with some excep- 
 tions, we are but very imperfectly acquainted with the structures ou 
 which our remedies act, and the exact mode in which these are affected 
 by them. Day by day, however, our ignorance is diminishing ; and 
 we may hope that ere long rational treatment will to a great extent 
 supersede blind empiricism. It not unfrequently happens at present 
 that we meet with a case which bears a very close resemblance to 
 others which we have treated successfully, and which nevertheless 
 obstinately resists the remedies which we had previously found ser- 
 
viceable. Our failure astonishes and vexes us ; but we are ignorant of 
 its cause, and we can only select some other drug by guess and try it : 
 we cannot at once choose the one which will have the desired effect. 
 
 Pathology. — In order to choose a drug which will have the effect 
 that we desire to obtain, we must know where the morbid changes are 
 taking place, and what their nature is ; and we must be sure that our 
 medicine will act on the affected part, and in such a way as to counter- 
 act the disease. We must trace every symptom which we see, back to 
 its unseen source ; every flush on the cheek, every quickening of the 
 pulse, back to the vaso-motor or cardiac nerves, which have allowed 
 the capillaries to become dilated, and thus produced the redness, or 
 have permitted the heart to beat more rapidly than its wont. We 
 must then inquire what has produced this alteration in the nervous 
 system, and so on, till at last we discover, if possible, the hidden cause 
 of the mischief. We will then give that remedy which will act in the 
 proper way* on the part which we believe to be the seat of the morbid 
 process ; and, if the expected result does not ensue, we shall, at any 
 rate, have discovered what the pathology of the disease is not ; and, by 
 ti7ing a remedy which will act in a different way or on a different 
 structure, we may find out what it really is. 
 
 When I speak of the pathology of a disease, I do not mean those 
 obvious alterations in the structure of an organ which we meet with in 
 post mortetn examinations, but the so-called functional changes which 
 precede and are the cause of both them and the symptoms. For ex- 
 ample, the disorganisation of a man's liver by the presence of an 
 abscess, or of his kidneys by fatty degeneration, is not the disease from 
 which he suffered, any more than a field strewn with slain or crowded 
 with heaps of wounded is a battle. The disease was the alteration in 
 the nervous and vascular systems, and in the nutrition of tissues, which 
 we call the inflammatory process, and which produced the abscess and 
 degeneration, and the disturbance of the same systems to which these 
 lesions in their turn give rise ; just as an army may not only lose the 
 battle for want of the assistance which its slain and wounded would 
 have given, but its retreat may be embarrassed by their presence. 
 
 The insufficiency of present modes of treatment, and the urgent 
 necessity which exists for an accurate knowledge of pathology and 
 pharmacology, are shown by the manner in which any new remedy is 
 seized upon and applied in all sorts of cases, even in those where a 
 knowledge of the morbid processes going on, and of the action of the 
 remedy itself would at once have indicated that harm, and not benefit, 
 
must ensue from its application. It is unnecessary to discuss here the 
 manner in which pathology must be studied in order that an accurate 
 knowledge of it may be obtained : I may merely indicate as examples 
 the works of Cohnheim, Brown-Sequard, Sanderson, Stockvis, Strieker, 
 and many others. 
 
 Pharmacology. — In studying pharmacology, our first object is to 
 find out on what structures a remedy acts. For this purpose, it is of no 
 use to give it to a man either sick or well. We may do so in order 
 to find out what general symptoms it produces ; and from these symp- 
 toms we may guess at the structures affected ; but, in order to con- 
 vert our hypothesis into certainty, we must apply it to these struc- 
 tures or organs, and to them alone, and see whether the general result is 
 the same ; or we may prevent it from reaching them while it is applied 
 to all other parts of the body, and observe whether the effect is absent. 
 For this purpose, we cut off from one or other parts of the body the 
 supply of blood which carries the drug along with it, or we may so in- 
 jure the part that its function is abolished, and no action exerted upon 
 it can produce any effect. But it is impossible to do this in man, and 
 so we must have recourse to the lower animals, in which we can pro- 
 duce at will the conditions we desire. Although the administration of 
 medicine to a patient is really an experiment, we vary the conditions 
 in which it acts to so much greater extent in animals, that it is conve- 
 nient to call the latter mode of investigation the experimental method^ 
 and the former that of clinical observation. 
 
 Now pathology and pharmacology may go on hand in hand both in 
 teaching and study, but they must always be preceded by physiology ; 
 for, unless we know the processes which take place in the healthy 
 organism, it is impossible to understand the changes they undergo in 
 disease, or the effect of drugs upon them. I will, therefore, here say a 
 few words regarding the processes in which life consists, before pro- 
 ceeding to speak of the mode in which they may be modified by the 
 action of remedies. 
 
 Life. — We meet with life only in certain bodies composed of carbon 
 combined in a very complicated manner with oxygen, hydrogen, and 
 nitrogen j and it may, generally speaking, be said to be the power 
 which these bodies possess of assimilating to themselves other sub- 
 stances, of decomposing them, and of evolving energy, which is shown 
 in active motion, active growth, etc. Evolution of energy in this way 
 is the distinguishing mark of life. When we look at a grain of wheat, 
 an egg, or a dried wheel-animalcule, we are unable to say whether or 
 
s 
 
 not it is alive; it is only when it begins to evolve energy, either by 
 moulding other substances into conformity with its own constitution in 
 active growth, as in the seed or egg, or by active motion, as in the ani- 
 malcule, that we are able to decide the question. We cannot say how 
 these bodies originally came to possess their complicated constitution 
 and wonderful powers ; but the evolution of energy by which we re- 
 cognise the continued presence of life seems to be more intimately asso- 
 ciated with chemical affinity than with other forms of energy, such as 
 light, heat, or electricity. All these forms of energy modify the pro- 
 cesses which occur in living beings, both those which are chemical and 
 those which we term vital, and apparently in much the same degree ; 
 but whether they modify the vital only through the chemical, we are at 
 present unable to say. Instances may readily be found in which life 
 continues active, although one or other of the forces mentioned is not 
 supplied to the living body from without, and is only secondarily 
 present as a result of chemical changes going on within. Thus a seed 
 in the earth, a fungus in a cellar, or a proteus in its dark cave, live and 
 thrive without a ray of light; and the whale and walrus in the Arctic 
 seas are independent of any external heat, their temperature being only 
 maintained by combustion taking place within their own bodies. But 
 there seems to be no instance of vitality alone continuing active when 
 a stop has been put to the occurrence of chemical changes. Sometimes 
 both chemical and vital processes are suspended together for a time, as 
 in a grain of wheat or a rotifer when it is kept dry, or in an egg when 
 kept cool and coated with varnish to exclude air. So long as chemical 
 activity remains dormant, no other form of energy can awake the 
 latent vitality. Only when the conditions necessary for chemical trans- 
 formation of the proper kind and amount are supplied, does it again 
 become manifest. Thus light or heat may be applied in any amount or 
 any proportion to an egg, a seed, or a dried rotifer, and still they will 
 not grow or move if the air be withheld from the former or the moisture 
 from the two latter, which is essential for the production of chemical 
 changes within them. 
 
 Conditions of Health and Disease. — These changes of which 
 I have been speaking consist in the assimilation of certain sub- 
 stances, their decomposition within the organism, and the rejection of 
 waste products. A due proportion between these constitutes health. 
 Just as a fire can only be kept bright by raking out the ashes and sup- 
 plying fresh fuel as that in the grate burns away, so an organism can 
 only be kept healthy by removing the products of waste and supplying 
 
fresh nutriment as its tissues get decomposed during action. The con- 
 ditions necessary for this purpose are secured in the simplest forms 
 of life, such as the amoeba, by the little mass of protoplasm moving 
 about in a fluid which can supply the oxygen to keep up combustion 
 and evolve energy, and the nourishment necessary to replace the mate- 
 rial thus used up, and can at the same time remove the products of 
 waste. In higher organisms, the little masses of living material of 
 which they are composed, and which are for the most part fixed, are 
 nourished by a fluid in which they are bathed, fresh portions of it being 
 supplied by its constantly flowing over them, instead of their moving 
 like the amoeba through it. 
 
 It will simplify our conception of this subject if we fix in our mind's 
 eye one little mass of protoplasm or cell, and consider what changes 
 will be produced in it by different conditions. Any alteration in the 
 amount of the nutrient fluid, or in its composition, will necessarily pro- 
 duce a change in the nutrition of the living matter to which it is 
 supplied. If nutriment be withdrawn, the cell will begin to burn 
 away. If oxygen be withheld, (i) or the products of waste be not re- 
 moved, combustion will cease, and the cell will die. If nutriment or 
 oxygen be supplied in insufficient quantity, or the products of waste 
 only partially removed, the cell may adapt itself to the altered circum- 
 stances, and its nutritive and functional processes go on in the same 
 way, but to a less extent than before ; or they may become deranged — 
 that is to say, the cell becomes diseased. The limits within which 
 the cell can adapt itself to changes in nutrition are the limits of its 
 health. The higher animals, however, are no mere aggregation of 
 cells, each nourishing itself independently of the others ; for each cell 
 has its own peculiar function, each its special kind and amount of nou- 
 rishment ; and none must do either too much or too little work, none 
 must have too much or too little nourishment, or the nutrition and 
 functional activity of the body as a whole cannot be properly main- 
 tained. This delicate adjustment of the several parts to one another is 
 secured by means of the nervous system, which regulates at once the 
 activity of any organ, the quantity of nutritive fluid supplied to it, and 
 the amount of material it shall take up. The means by which it acts 
 are, its direct influence on the nutrition of cells themselves, (2) as is 
 seen in the salivary glands ;(3) or its indirect action through the circula- 
 tion in slowing or quickening the heart, which propels the blood, in 
 contracting or dilating the vessels which convey it to any part, or the 
 capillaries which allow the actual nutritive fluid or lymph to filter out (4) 
 
and bathe the tissues. Besides thus regulating the supply, it also regu- 
 lates the composition of the nutritive fluid by maintaining a due relation 
 between the activity of the body, the supply of new material by diges- 
 tion, and the separation of effete products by the excreting glands. 
 On account of this mutual dependence of all the parts of the body on 
 one another, if one gets wrong, it puts the others out of order. Thus a 
 sudden chill may act on the vaso-motor nerves, and cause contraction 
 of the vessels of the skin; and the blood they contain is thus thrown 
 back on the internal vessels, (5) and congestion and inflammation of the 
 kidneys ensue. In consequence of this, they no longer excrete as they 
 ought the effete products, which then accumulate in the blood, react on 
 the nervous system, and this again on the muscles ; and so the circle 
 goes on. In the case supposed, the renal arteries have not had power 
 to contract sufficiently to resist the increased pressure and prevent con- 
 gestion ; while in another they might have done so, only allowing so 
 much blood to pass as to increase secretion, and, by thus lessening the 
 fluid in the blood-vessels, to counteract the effect of vascular contrac- 
 tion in the skin, restore the normal pressure, and preserve health. 
 When all the organs are able to accommodate their nutrition and func- 
 tion to great alterations, we say the health is strong; but when they 
 can only do so to slight ones, we say the health is weak ; and when 
 this is the case with one organ alone, we say that it specially is weak. 
 
 Effect of Drugs. — The nutrition of a cell may not only be altered 
 by changes in its supplies of nutriment and oxygen ; but it may be modi- 
 fied or destroyed by the addition of certain substances to the nutrient 
 fluid. Thus a weak solution of alkali may increase or diminish the 
 rapidity of the changes which it undergoes, by hastening the removal of 
 waste products if they be acid, or retarding it if they be alkaline; while a 
 weak acid will have an opposite effect. Certain metallic salts may stop 
 them altogether by forming a firm compound with the substance of the 
 cell, while other bodies may enter into combination with it for a time 
 (possibly replacing some ordinary ingredient of its nutriment), again 
 passing out and leaving it in its primitive condition, but altering during 
 their stay its physical characters and functional properties. Such seems 
 to be the case with curare, which, when injected into the blood, para- 
 lyses the peripheral ends of motor nerves ; but, if life be preserved by 
 artificial respiration, the poison is excreted, and its effect passes off. 
 No change can be noticed in the nerve-fibres, either by the naked eye 
 or microscopically, during the paralysis ; and this was supposed to show 
 that great functional alterations may occur without any structural 
 
change. But this is not the case; for Kiihne (Strieker's Histology^ 
 Power's translation, vol. i, p. 221) has ascertained that, when the ends of 
 motor nerves in muscles are examined microscopically, their outline is 
 found to be more distinct during the action of the poison. It is possible 
 that the change in physical properties shown by this distinctness of out- 
 line may be only the indication of sonie more important alteration in 
 their chemical composition ; but, whether it be more chemical or phy- 
 sical, a change at any rate takes place ; and to this, I believe, we must 
 attribute the alteration in function. 
 
 Whatever be the composition of protoplasm, the substances which 
 are associated with it in the composition of different cells are at any 
 rate different; and, although the same nutritive fluid is supplied to 
 them, they do not all take out from it, or give out to it the same 
 substances in the same proportions, but some take up more of one 
 thing, and some more of another. And they do just the same with 
 drugs added to the nutritive fluid. Thus lime-salts naturally exist in 
 the blood, and are carried by it to every part of the body ; but, while 
 the bone-cells take them up in large amount, nerve-cells assimilate an 
 almost infinitesimal quantity. And if we feed an animal on madder, 
 which has an affinity for lime- salts, the bones become deeply stained, 
 while the nerves and fat retain their normal colour. (6) It is possible, too, 
 though experiments on this point are wanting, that a substance added 
 to the nutritive fluid may be taken up by two structures, but may have a 
 very different effect on the one from what it has on the other ; just as a 
 grain of sand, which would have no effect on the machinery of a loco- 
 motive, may totally stop the movements of a watch. We do not know 
 whether sulphocyanide of potassium and curare are taken up equally by 
 nerves and muscles or not ; but the former salt will paralyse the muscles 
 without affecting the nerves, while curare will paralyse the nerves, but 
 leaves the muscles intact. (7) 
 
 The cells composing one structure, then, take up and are acted on 
 by some drugs, and not at all by others; while other structures are 
 much affected by the very substances which had so little action on 
 the first. 
 
 Direct and Indirect Action. — When any drug is taken up by 
 a structure and acts upon it as curare on the ends of motor nerves, we 
 term this its direct action. But, as all parts of the body are dependent 
 on one another, some other structure may be affected, not by the action 
 of the drug upon it, but by that which it has exerted on the first part. 
 This is its indirect action. Thus, when curare has been given to an 
 
animal, it occasionally happens that the nerves going to the respiratory 
 muscles become paralysed before those which go to the extremities. (8) 
 The muscles of respiration then cease to act, the blood is no longer 
 arterialised, carbonic acid accumulates, and, by irritating the nerve- 
 centres, produce convulsions, which cease when the action of the poison 
 extends to other nerves. In this case neither the muscles, the blood, 
 nor the nerve-centres, are acted on directly by the curare. The muscles 
 will contract if stimulated, and, if the lungs be artificially supplied with 
 air, the blood will be arterialised as usual, the convulsions will cease, 
 and life may be preserved. The non-arterialisation of the blood, the 
 occurrence of asphyxial convulsions, and death, are thus due to the 
 indirect action of curare. 
 
 Local and Remote Action. — Before curare could reach the nerves 
 on which it acted directly, it was necessary for it to enter the circula- 
 tion, but it had no marked action on the spot whence it was absorbed. 
 Other substances, however, produce an effect on the spot to which they 
 are applied, and this may be independent of any effect which they pro- 
 duce after absorption. This is termed their local action. Thus strong 
 sulphuric acid taken into the stomach combines with its tissues and 
 forms a slough : this is its local action. But besides this, the irritation 
 in the stomach produces through the nervous system a weakening effect 
 on the heart, the circulation stops, and the person dies. It is not the 
 sulphuric acid which has found its way into the circulation and acted 
 on the heart, but the irritation in the stomach conveyed to it through its 
 nerves. This is the remote effect of the acid. 
 
 Dose. — The effect produced by any remedy depends on several con- 
 ditions. The first of these is the amount existing in the blood at any 
 given time, which we may call the actual dose, to distinguish it from 
 the usual dose administered by the stomach or otherwise, a part of 
 which may not be absorbed, but remain inert at the point of introduc- 
 tion. The action which a drug has on the body is not dependent on 
 its absolute amount, but on the proportion it bears to the body on which 
 it is to act, so that an amount which is a small dose for one person is a 
 very large one for another. (6) Thus if a grain of some active substance 
 be injected at the same time into the veins of a full-grown man and into 
 those of a boy of only half his weight, it will be distributed through twice 
 as much blood in the man as in the boy, and each tissue will only re- 
 ceive half so much of it. The dose of a drug must therefore be regu- 
 lated by the weight of the patient ; and thus women, being lighter, re- 
 quire a smaller amount than men, and children less than adults. Though 
 
 C 
 
it would be more exact, it is not always convenient, to weigh patients ; 
 but in experiments on animals the weight of the animal should always 
 be carefully ascertained, as well as the amount of the drug administered. 
 If a substance be injected into the veins, the whole of it mixes with the 
 blood and becomes active immediately, and the maximum effect is thus 
 at once obtained, and will again diminish as the substance is excreted. 
 But the case is different if it be injected subcutaneously, and still more 
 if it be given by the stomach or any other mucous cavity ; for as soon 
 as some of it is absorbed excretion begins, and thus part of the drug is 
 passing out of the blood while another part is being taken in. The 
 amount in the blood is, then, only the difference between that absorbed 
 and that excreted in a given time, and absorption may be so slow or 
 excretion so quick that there is never a sufficient amount of the sub- 
 stance in the blood to produce any effect. Thus Bernard found(7) that a 
 dose of curare which would certainly paralyse an animal when injected 
 into the veins or even subcutaneously, would have no effect when intro- 
 duced into the stomach; and Hermann(8) showed that this was due to 
 the kidneys excreting the poison as fast as it was absorbed from the 
 stomach, by tying the ureters, when the animal became paralysed as 
 surely as if the poison had been introduced at once into the veins, 
 though not so quickly. The more rapid the absorption, or the slower 
 the excretion, of any drug, the greater will be its effect. Thus the effect 
 produced by the same dose of a medicine will be in proportion to the 
 rapidity of its absorption from the different parts to which it has been 
 applied, unless the differences be so slight or the excretion so slow that 
 there has not been sufficient time for the removal of any considerable 
 quantity from the blood. On this account we must diminish the dose 
 of a medicine in order to obtain the same effect, according to the 
 rapidity of absorption from the place to which we apply it. Absorp- 
 tion is quickest from a serous membrane, then from intercellular tissue, 
 and lastly from mucous membrane. The vascularity and rate of absorp- 
 tion from intercellular tissue is greater on the temples, breast, and inner 
 side of the arms and legs, than their outer surfaces orback.(9) Itshouldnot 
 be forgotten that any drug introduced into the stomach but not absorbed 
 into the blood is as much outside the body as if it were in the hand, 
 for any effect it will have on the system, provided always it have no 
 local effect on the gastric walls. By the differences between absorption 
 and excretion under different circumstances or in different individuals, 
 the cumulative action of drugs, the effect of idiosyncrasy, habit, climate, 
 condition of body, as fasting, etc. , disease, and form of administration. 
 
can to a great extent, though not entirely, be explained ; but experi- 
 ments on some of these points are deficient, and the explanations now 
 given are to some extent theoretical. 
 
 Cumulative Action. — If a substance be naturally so slowly ex- 
 creted from the body that the whole of the dose in ordinary use is not 
 excreted before another is given, the amount present in the body will 
 gradually increase, just like the curare in Hermann's experiment, and 
 will produce an increasing or cumulative effect. Examples of this are 
 to be found in metallic preparations, such as those of mercury or lead, 
 which are excreted very slowly, or in some of the organic alkaloids, 
 such as digitaline, if given in sufficiently large and frequent doses. The 
 size of the dose and the frequency with which it must be repeated in 
 order to produce a cumulative effect will differ acccording to the rapidity 
 with which the drug is excreted ; for, if excretion be rapid, a larger 
 dose, or more frequent repetition, will be required. The long time 
 which elapses before a dose of opium takes effect on some individuals 
 is probably due to its being very slowly absorbed ; and the power of 
 one man to take, without apparent effect, an amount of alcohol or 
 opium which would intoxicate another, to its either being more slowly 
 absorbed from the stomach or intestine, or more quickly excreted by 
 the lungs, skin, or kidneys, so that the amount present in the blood at 
 any one time is never sufficient to produce toxic effects. If excretion from 
 the skin and lungs be stopped, as by going from a warm room into the 
 cold air outside, while alcohol is still being absorbed from the stomach, 
 the amount of it in the blood is increased just as with curare, (8) and 
 intoxication ensues. 
 
 Effect of Habit, Climate, Fasting, and Form of Adminis- 
 tration. — The effect of habit in lessening the action of drugs may be 
 due to increased power of excretion or diminished absorption ; and that 
 of a warm climate in increasing the action of narcotics, such as hyos- 
 cyamus, to their excretion being hindered by the diminution in the 
 amount of urine consequent on the increased cutaneous transpiration. 
 A medicine taken by a fasting person is generally more rapidly ab- 
 sorbed and has a greater effect than if the stomach be full, as is well 
 known in the case of alcohol. The form of administration has also an 
 effect on the rapidity of absorption. When a drug is given in a soluble 
 form in small bulk it is more quickly absorbed, and will have greater 
 effect than when given in an insoluble form or much diluted. So a 
 glass of brandy will have a greater and more rapid effect if taken raw 
 than if diluted with a large amount of water; for if three times its bulk 
 
of water have been added to it, the stomach must absorb four times as 
 much fluid before the same amount of alcohol could enter the blood- 
 circulation : at the same time the greater amount of water in the blood 
 increases excretion by the kidneys, and thus we have the actual dose 
 of alcohol diminished both by slower absorption and by quickened excre- 
 tion. It must not, however, be forgotten that the action of alcohol in 
 the blood is complicated by its local effect on the stomach, and this is 
 greater when it is given undiluted. 
 
 Large and Small Doses. — The effect produced by a small dose of 
 a drug is sometimes exactly the opposite of that produced by a large 
 one. We cannot say exactly why it is so ; but we very generally find 
 that any substance or any condition, whether it be acid or alkali, heat 
 or electricity, of which a moderate amount increases the activity of cells, 
 destroys it when excessive.(i) 
 
 HoMCEOPATHY. — This opposite action of large and small doses seems 
 to be the basis of truth on which the doctrine of homoeopathy has been 
 founded. The irrational practice of giving infinitesimal doses has of 
 course nothing to do with the principle of homoeopathy — similia similibus 
 curantur : the only requisite is that mentioned by Hippocrates, when 
 he recommended mandrake in mania ;(io) viz., that the dose be smaller 
 than would be sufficient to produce in a healthy man symptoms similar 
 to those of the disease. Now in the case of some drugs this may be 
 exactly equivalent to giving a drug which produces symptoms opposite 
 to those of the disease j and then we can readily see the possibility of 
 the morbid changes being counteracted by the action of the drug and 
 benefit resulting from the treatment. For example, large doses of 
 digitalis render the pulse extremely rapid, but moderate ones slow it. 
 In this instance its moderate administration when there is a rapid pulse 
 is homoeopathic treatment, and this has sometimes been beneficial. But 
 it is not proved that all drugs have an opposite action in large or small 
 doses, and homoeopathy, therefore, cannot be accepted as an universal 
 rule of practice. 
 
 Constitution and Idiosyncrasy.— Variations in the action of a 
 drug cannot be entirely explained, however, by the varying amount in 
 which it may be actually present in the circulation and acting on the 
 body. Another modifying element of great power is constitution. In 
 animals generally, we have certain arrangements for producing motion, 
 others for the regulation of these, and others, again, for supplying them 
 with the material necessary for the performance of their functions. But 
 the parts which enter into each of these are not equally developed in all 
 
13 
 
 animals ; in some one part preponderates ; in others, another. Even 
 in animals of different species, and in individuals of the same species 
 where the relative size of organs seems the same, differences nevertheless 
 exist ; and the presence of a few cells more or less in a ganglion, and a 
 few fibres more or less in a nerve, may alter to a very great extent the 
 action of any substance on the organism. When a medicine given to 
 one person produces an effect slightly differing from that which it 
 generally causes, the difference is said to be due to constitution ; when 
 its difference is great, it is said to be due to idiosyncrasy. Now, these 
 effects may be merely due to differences in absorption and excretion, as 
 has been already explained, or to the different relative development of 
 other parts, especially parts of the nervous system. It is easy to under- 
 stand the altered effect which may be thus produced, and to perceive 
 the ambiguity of such terms as "nervous stimulant", when we recollect 
 that different parts of the nervous system act exactly in the opposite 
 way to others ; and if anything should act on both of these, it will pro- 
 duce an opposite effect according as one or other part is more de- 
 veloped and more powerful. Thus the vagus nerve has the power of 
 rendering the heart's action slow, and the sympathetic of quicken- 
 ing it ; and any drug which irritates them both, will make the heart's 
 action slow if the vagus be more developed, or quicken it if the sym- 
 pathetic be stronger. Thus two horses of unequal strength, pulling in 
 opposite directions, may counterbalance each other ; but if both be 
 struck with a whip at the same moment, the power of the stronger 
 becomes evident, and he pulls the weaker after him. 
 
 A good example of this action is given by muscarin, an alkaloid 
 obtained from a poisonous mushroom, Agaricus muscarius. Pro- 
 fessor Schmiedeberg, of Dorpat,(ii) has shown that this alkaloid pro- 
 duces great irritation of the vagus nerve, so that in frogs the heart will 
 stand still for hours together. When given to dogs, it sometimes makes 
 the pulse slow, but sometimes it quickens it ; and one might therefore be 
 inclined to say that when it produces quickening it cannot be acting on 
 the vagus. But the explanation of this phenomenon is, that muscarin 
 does not act on the vagus alone, but has also an effect on the vaso- 
 motor nerves, producing dilatation of the vessels and diminution of the 
 blood -pressure in them. Now, lessened pressure acts as a stimulant to 
 the sympathetic, and quickens the heart. In this way, muscarin stimu- 
 lates both vagus and sympathetic, and the pulse is rendered quick or 
 slow according as the power of the one or other is greater in the par- 
 ticular dog to which it is given. In frogs, the blood -pressure has no 
 
u 
 
 great action on the heart, and in them the effect of the vagus is not in- 
 terfered with. 
 
 Another instance may be given where an apparent difference in 
 the effect of a drug on two animals may be removed by reducing 
 their organs to the same condition. In most animals, the slowing 
 action of the vagus on the heart is constantly exerted during health ; 
 and when it is cut the heart beats much faster. But in the rabbit, its 
 power is comparatively small, and the increased rapidity of the pulse 
 after its division is but slight. In most dogs, on the contrary, its power 
 is great, and, if it be cut, the heart beats very much quicker, and sends 
 more blood into the arteries, so as to raise the pressure in them. If 
 we measure the pressure of the blood in the arteries of a rabbit and of 
 a dog, and then cause them to inhale nitrite of amyl, we find that the 
 small vessels have become widened and allow the blood to pass easily 
 out of the arterial system into the veins, so that the pressure sinks con- 
 siderably in the rabbit, but it sinks only slightly in the dog. The effect 
 seems at first sight different; but when we examine it more closely, we 
 find that the heart of the dog is no longer beating slowly, but very 
 quickly, so as to keep up the pressure, notwithstanding the rapid flow 
 of blood through the widened vessels, while the heart of the rabbit was 
 going so fast before that it could not go much more quickly. If we cut 
 the vagi in the dog, so that the heart goes as quickly as in the rabbit 
 before it begins to inhale, the blood-pressure sinks during the inhala- 
 tion, just as it does in the rabbit. (12) 
 
 I have given these examples at length, because of their important bear- 
 ing on the question how far conclusions as to the action of medi- 
 cines on man may be drawn from those which they exert on the 
 lower animals. Now, the action of curare in paralysing the ends of 
 motor nerves is one of the simplest and least complicated examples that 
 we can take, as the very nature of its action prevents disturbances in 
 other systems from showing themselves ; and we find that it is exactly 
 the same in the Indian who accidentally wounds himself with his 
 poisoned arrow, in the game which he shoots, or in the frog on which 
 we experiment. 
 
 Motor nerves, the structure on which curare acts, are alike present 
 in all, and in all are its results the same. 
 
 And as we have seen that, in the lower animals, differences in the action 
 of drugs are produced by differences in the structure of the animal, and 
 that the former disappear when the latter are removed, we are, I think, 
 justified in concluding that, when the organs or structures on which a drug 
 
15 
 
 acts are similar in man and the lower animals, the action will be alike, 
 and that variations will be observed just in proportion to the difference 
 between his structure and theirs. But as it may be difficult or im- 
 possible to detect these differences except from their effects, we ought 
 to test our conclusions as to the action of remedies by giving them to 
 a healthy man, and observing whether their effects are such as we 
 have been led, from our experiments on animals, to expect. 
 
 Disease. — The different effects of a medicine in disease from those 
 produced by it in health may be partly due to differences in the dose 
 actually present in the blood from altered absorption and excretion, 
 and partly to the alterations produced by disease in other organs, 
 which may interfere with their direct, and probably to a much greater 
 extent with their indirect, action. But what the alterations in each dis- 
 ease, and the ways in which they will modify either the direct or 
 indirect action of remedies, really are, can only be determined by an 
 increased knowledge of pathology and by actual clinical observation. 
 
 Chemical Constitution and Physiological Action. — I have 
 spoken thus far only of the changes in the body and the various effects 
 which they produce; but I must not leave this subject without mentioning 
 the wide field of research which has been opened up by the remark- 
 able discovery made by Drs. Crum Brown and Fraser,(i3) of the relation 
 which exists between chemical constitution and physiological action. It 
 was known before that one drug would act only on one part of the body, 
 another on another part; but they have shown that changes in the 
 chemical composition of a drug may not only alter its action, but transfer 
 it to a different structure : so the addition of sulphate of methyl to 
 strychnia, brucia, or thebaia, causes them to act on the terminal 
 branches of motor nerves instead of on the spinal cord, while a similar 
 addition to other alkaloids removes some of their actions but leaves 
 others unchanged. Further researches of this kind may enable us to 
 determine what parts will be acted on by a drug after a definite change 
 has been effected in its chemical constitution ; and the progress of phy- 
 siological chemistry in ascertaining the composition and properties of 
 the tissues renders it not impossible that such knowledge may yet be 
 acquired as that spoken of by Locke in the following words. ** Did we 
 know the (mechanical) affections of the particles of rhubarb, hemlock, 
 opium, and a man, as a watchmaker does those of a watch, whereby it 
 performs its operations, and of a file, which by rubbing on them will 
 alter the figure of any of the wheels, we should be able to tell before- 
 hand that rhubarb will purge, hemlock kill, and opium make a man 
 
i6 
 
 sleep." And even though our knowledge should never reach this extent, 
 the rapid advances which it has made of late years, the power of altering 
 the chemical composition of the organic alkaloids, and along with it 
 their physiological action, which we now possess, and the fact that one 
 of them (conia) has already been made synthetically, (14) incline us to be- 
 lieve that we may by and bye make substances which will produce the 
 physiological effects which we desire, and that a future lies before thera- 
 peutics of which at present we can hardly dream. 
 
17 
 
 II. — Action of Drugs on Protoplasm : General Directions 
 FOR Experimental Investigation. 
 
 Modes of Experimenting. — Caution. — Action of Drugs on Protoplasm. — 
 Action on Vibriones and Bacteria. — Contagium Vivum. — Action on 
 Fungi; on Fermentatiott ; on Putrefaction ; on Oxidation ; on White 
 Blood Corpuscles; on Inflammation. — Action of Gases. — Steps of an 
 hivestigation. — Administration of Drugs. — Observation of Effects. — 
 Interpretation of Results. — Minimum Fatal Dose. — Various Channels 
 of Administration. — Excretion. — Mode of securing Animals. — Instru- 
 ments required. — Mode of making Cannula: ^ T-tubes, and Pens. — Nar- 
 cotising Animals. — Action of Narcotics. — Introduction of Cannulce into 
 Vessels. — Injectioji of Fluids. — Division and Irritation of Nerves. — 
 Artificial Respiration ; in Mammals ; in Frogs. — Administration of 
 Gases or Vapours. 
 
 Gentlemen, — In experimenting on the effect of drugs, our great ob- 
 ject must be to localise their action — to be able to say with certainty, 
 This is the organ on which this medicine acts, and such and such is the 
 action which it exerts upon it. There are two ways in which this 
 might be done. 
 
 1. We might give the medicine to animals of all kinds, from those 
 consisting of one simple cell upwards to the highest forms of life, and 
 mark how its action became modified as we advanced farther and farther 
 from the simple mass of sarcode, and organ after organ became differ- 
 entiated and developed. Unfortunately, however, the knowledge of 
 comparative anatomy and physiology which is required to interpret 
 the effects that we might thus obtain is so great, and possessed by so 
 few, that this method is at present of little use. 
 
 2. We might take a highly organised animal, not very unlike man in 
 its general structure, and, by operative procedures, allow the medicine 
 to act now on one and now on another part of the body, but never on 
 all at once, till we find out those parts for which it has a particular 
 affinity. 
 
 This second method is the one which we chiefly employ, but some- 
 times we may very conveniently use them both, as in the case of pro- 
 toplasm, the physical basis of life. 
 
 D 
 
i8 
 
 Caution. — As I intend not only to describe the ways in which ex- 
 periments on the action of medicines are to be performed, but also to 
 give examples of the conclusions drawn by various observers from the 
 experiments which they have made, ' and of the way in which these 
 conclusions have been applied, I take this opportunity of strongly 
 warning you, once for all, that you must distinguish very carefully be- 
 tween the observations actually made by any one and the conclusions 
 which he draws from them. Observations on the effect of a drug may be 
 correct, and yet the theory of its mode of action be erroneous; and both 
 of these may be right, and still the proposed application of it to a dis- 
 ease may be valueless from ignorance of its real pathology. All ob- 
 servations, too, are not to be taken as facts : they must be confirmed 
 by frequent repetition either by the first observer himself or by others 
 before they can lay claim to this title. Their value depends to a great 
 extent on the observer, and is in proportion to his power of seeing cor- 
 rectly what is before him, and the exactness of his description of what he 
 he has seen. Perhaps erroneous statements are due in great measure to 
 the results of experiments not being noted at the time when they were 
 done, but written down from memory some time afterwards. When this 
 is the case, they lose in a great measure their claim to the name of ob- 
 servations, and they become merely thoughts or ideas of the observer. 
 All experiments should be noted down at the time when they are performed ; 
 and if they are not, the time which elapsed before they were written 
 should be stated, that future workers may know what value to attach 
 to the observation, and not be put to the unnecessary trouble of dis- 
 proving it if it be erroneous. Before beginning an investigation, it is 
 convenient to write out the questions which we propose to ourselves, 
 and to note down what experiments will be necessary to answer them. 
 We are thus less likely to make experiments at random, and to waste 
 time without coming to any certain conclusion. 
 
 Action on Protoplasm. — We may study the action of drugs on 
 protoplasm either in unicellular organisms like the Infusoria, in cilia, in 
 white blood- corpuscles, or in those minute bodies — bacteria and vibriones 
 — to which attention has of late been so much directed, and which, de- 
 spite their minuteness, possess so much importance from their power of 
 producing fermentation and decomposition in dead organic matter, and 
 not improbably of causing disease in living beings. For the purpose of 
 studying it in Infusoria, we prepare an infusion of hay some days before 
 we wish to experiment, and a solution in water of the drug which we 
 wish to investigate. We then heat a piece of glass tubing in the middle. 
 
19 
 
 draw it out and cut it across, so as to obtain two little pipettes, which 
 will deliver drops of nearly equal size. From one of these we let fall 
 a drop of infusion of hay on a glass slide, and examine it under a low 
 power of the microscope without a covering glass. We then let fall a 
 drop of the solution of our drug upon it, mix the two drops well with 
 a glass rod, and again examine them microscopically to see whether or 
 not the infusorial animalcules are still moving. If they be moving, and 
 continue to do so for some time, we prepare a stronger solution of the 
 drug ; but if they have completely stopped when we looked, we make 
 a weaker one, and again mix a drop with one of hay-infusion, repeating 
 the experiment till we have got a solution of such a strength that a slight 
 movement of the animalcules can be observed just after mixing the 
 drops, but ceases almost immediately, and cannot be brought back by 
 adding water. We can then compare the action of different drugs by 
 observing of what strength the solution of each must be, in order to pro- 
 duce precisely this effect. ( 1 5) 
 
 Professor Binz of Bonn has found in this way that certain substances, 
 such as common salt, chlorate, chloride and bromide of potassium, alum, 
 etc., appear to stop the movements of infusoria by altering the amount 
 of water which they contain, as strong solutions cause them to shrivel 
 at first, and then to swell up and become motionless. Weaker ones 
 make them swell likewise ; but their effect at first is different, as they 
 do not shrivel up the animals, but, on the contrary, render their move- 
 ments more lively. 
 
 Other substances kill them in a way which we do not understand, 
 stopping the movements at once without producing any apparent 
 change in the animal's body to account for it. The most active of these 
 substances are chlorine, bromine, corrosive sublimate, iodine, per- 
 manganate of potash, and creasote. After these comes quinine, less 
 powerful than they, but far more so than other organic alkaloids. Even 
 strychnia, so fatal to higher animals, has barely one-fourth the power 
 over these lower organisms which is possessed by quinine, a substance 
 which is dangerous to mammals only in such large doses that we are 
 accustomed to look upon it as a remedy, but hardly at all as a poison. 
 
 Action on Vibriones and Bacteria. — If a piece of boiled meat 
 or white of egg be allowed to lie in water for a few days, or a little of 
 Pasteur's solution be exposed in a glass, the fluid becomes milky, and 
 vibriones and bacteria are formed in large numbers. Pasteur's solution 
 is made by dissolving ten grammes of sugar, five decigrammes of tar- 
 trate of ammonia, and one decigramme of yeast-ash, in one hundred cubic 
 
cmtimetres of water ; or a little white of egg may be added to the hay- 
 infusion, when the infusoria soon disappear, and it remains full of bac- 
 teria and vibriones.(i5) A drop may now be taken, diluted with another 
 drop of water, and the action of drugs on vibriones examined in the 
 same way as on infusoria. 
 
 In this way it is found that the same substances which kill infu- 
 soria also prove destructive to vibriones and bacteria : and if they 
 kill these organisms when outside the animal body, they should do 
 likewise when they are inside, and thus cure diseases which may be 
 caused by their presence. Now, bacteria have been said to be the 
 cause of malignant pustule, and they are at all events frequently pre- 
 sent in large numbers in the blood of animals affected by it, and 
 their destruction can hardly fail to be advantageous. We are, there- 
 fore, not at all surprised to learn that Bouley and the French Com- 
 mission found {Compt. Rend. Ixviii, 82) that, while all animals which 
 they inoculated with this disease died when left to themselves, four 
 recovered out of five to which they had given carbolic acid, and that 
 other cases treated in the same way by others gave a like favour- 
 able result. The striking correspondence between the effect actually 
 produced on the disease and that which we would expect from its 
 action on bacteria, which we suppose to be the cause of it, seems 
 also to be an evidence of the truth of the hypothesis that bacteria are 
 the cause of the disease, and that carbolic acid cures it by killing 
 them. Before we accept this as a fact, however, we should test it by 
 adding to one portion of the blood of a diseased animal, carbolic acid 
 in the same proportion as it was likely to be present in the blood of 
 the one cured, and comparing it with another portion to which none 
 had been added, and see whether the amount was sufficient to have 
 any action on the bacteria. If it were not sufficient, we should have 
 to look for some other action of the acid to explain its effect. 
 
 As cases of malignant pustule or other diseases in which bacteria and 
 vibriones are found in the blood happily do not present themselves every 
 day, Binz(i6) produced fever in dogs artificially by injecting infusion of 
 hay or putrid animal matter into their veins, and then tested the action of 
 quinine by injecting it either at the same time or shortly afterwards. 
 The quinine diminished the effect of the infusion, but not to the extent 
 which he expected ; and this he thinks due to the infusion not containing 
 vibriones alone, but gases and other products of decomposition, whose 
 action would not be affected by quinine. Whether this be so or not, 
 must be decided by further experiments. He believes also that hay-fever 
 
21 
 
 is due to vibriones; and he cured Helmholtz, who had suffered from it 
 for several years, by injecting a solution of quinine into his nostrils. 
 
 Action on Fungi. — When spores of the ordinary penicillium or 
 mould -fungus are thrown into Pasteur's fluid or syrup, they grow and 
 develope new spores. Two portions must be taken, and the drug to be 
 tested added to one and none to the other, and the amount of it neces- 
 sary to prevent the formation of spores must be noted. If carbolic acid, 
 corrosive sublimate, or very strong solutions of quinine, be added to 
 them, their growth is prevented. 
 
 Action on Fermentation. — As butyric fermentation depends on 
 the presence of vibriones( 1 7) and alcoholic on the yeast-fungus, we should 
 expect that substances which kill these would prevent fermentation. 
 To test this, two glass-tubes or flasks are filled with a mixture of milk- 
 water, grape-sugar, and chalk (from which carbonic acid will be set free 
 by the lactic acid formed), or with a solution of grape-sugar or yeast. 
 To one of them a certain amount of the substance to be tested is added, 
 and both are then inverted over mercury and kept in a warm place for 
 several days. The amount of gas developed is then measured ; and, if 
 the addition of the substance have hindered the production of gas, we 
 know that it has hindered fermentation in the same proportion. It 
 has thus been found that quinine, amounting to y^ot'^ V^^^ o^ ^^^ mixture, 
 completely stopped the development of vibriones or the production of 
 gas ; and other substances have a similar effect. 
 
 As many cases of indigestion, acidity, flatulence, vomiting, and sum- 
 mer diarrhoea, more especially in children fed by hand, are most pro- 
 bably due to the fermentation of starchy and saccharine food caused by 
 vibriones, (1 8) Binz thinks that creasote, quinine, etc., are serviceable in 
 their treatment by stopping this. As it is the local action that is 
 wanted, the longer the medicine remains in the intestine before being 
 absorbed, so much the better will its effect bej and thus the greater benefit 
 derived from bark than quinine in some such cases might be explained. 
 
 Action on Putrefaction. — The antiputrescent action of drugs is 
 tested by putting a square of boiled white of egg into each of two ves- 
 sels containing water and setting them in the sun. To the liquid in one 
 vessel the drug is added, and the rapidity with which the edges of the 
 square of white of egg on it become decomposed and soft is noted and 
 compared with that in the other vessel. Instead of white of egg, a piece 
 of meat or bread may be used. The relative power of different drugs in 
 stopping putrefaction does not always correspond to the ideas which 
 we would be inclined to form ; for who would think that quinine would 
 
22 
 
 be more powerful than such antiseptics as creasote, chloride of lime, or 
 arsenic ? and yet such is said to be the case. So powerful is quinine, 
 that a piece of meat placed in a solution of a per cent, of the sulphate, 
 with a little dilute acid, remained in summer without decomposition till 
 the fluid was dried up. (19) 
 
 Action on Oxidation. — If fresh leaves of lettuce or dandelion are 
 triturated with five or ten times their weight of water, with free access 
 of air, the fluid filtered, and fresh guaiac tincture added to it, a blue 
 colour is produced, showing that ozone is present in it. (20) To test the 
 action of a drug on the formation of ozone, two portions of the filtered 
 fluid are put in test-glasses, and the drug added to one. Both are allowed 
 to stand for one or two hours, with occasional shaking, fresh guaiac 
 tincture is dropped cautiously into both, and by the greater or less depth 
 of blue produced in each fluid we judge of the amount of ozone present 
 in each. In this way it is found that quinine diminishes or stops the 
 formation of ozone in these fluids, and at the same time the little proto- 
 plasma-granules with which they abound are rendered motionless and 
 altered in appearance. There seems to be some connection between 
 these protoplasma-granules and the formation of ozone, as the stoppage 
 of the one runs parallel with the alteration in the other. 
 
 Quinine seems to have the power of diminishing oxidation within the 
 body as well as out of it, since when injected into the blood it lessens 
 the excretion of urea and diminishes the temperature both in health and 
 disease during life, and hinders its rise after death ;(2i) and this action is 
 apparently not due to nervous centres regulating temperature, or to 
 changes in the circulation allowing quicker cooling by the skin. 
 
 Action on White Blood-Corpuscles. — To examine this, we take 
 a drop of blood from the finger, put it on the under surface of a thin 
 glass, and lay it over the opening in Strieker's warm stage (Strieker's 
 Histology ; New Sydenham Society's Translation^ p. 13), and examine 
 it with a high power of the microscope, such as Ross's -^-^ or Hartnack's 
 No. 10, at a temperature of 98° F. After satisfying ourselves that the 
 white corpuscles are in active motion, we take a solution of the drug in 
 fresh serum, or in half per cent, solution of common salt ; mix a drop of 
 it with the blood and examine again. Or we may use Max Schultze's 
 warm stage, which consists of a flat piece of bi-ass covering the stage of 
 the microscope, and having a long arm projecting at each side and a 
 thermometer in front. When a lamp is placed under one or both arms, 
 they conduct the heat to the middle part on which the object lies, and 
 thus warm it to any desired temperature. The drop of blood must be 
 
23 
 
 placed on a piece of glass three and a half inches long and two and a 
 half broad, which is then laid on the warm stage. (22) The drop is next 
 covered by a thin glass, and over all is put the lower part of a lamp- 
 cylinder, through whose upper end the tube of the microscope slides, and 
 round whose interior is put a piece of moist blotting-paper to prevent 
 evaporation from the blood. The drug is applied as with Strieker's 
 stage. Solutions of corrosive sublimate and veratria, even in very mi- 
 nute quantity, stop the movements of the white blood-corpuscles, but 
 neither is so active as quinine. Strychnia is rather less powerful than 
 any of these, and many otljer alkaloids much less so. 
 
 Action on Inflammation. — During inflammation, the white blood- 
 corpuscles are very active, and crawl through the walls of the capillaries 
 in much greater numbers than usual. It is, therefore, interesting to 
 inquire what will be the effect on this of any drug that stops their mo- 
 tions. For this purpose we curarise a frog and lay it on a large plate 
 of cork with a hole at one side, (23) and another piece of cork half an inch 
 high at the other. We fix the body of the frog to the raised piece, open 
 its abdomen with a pair of scissors, draw out the intestines, and fasten 
 the mesentery with very fine pins over the hole. In an hour and a half 
 or two hours afterwards, white corpuscles come rapidly out of the vessels 
 and wander over the field. We may then inject our drug into the circula- 
 tion or apply it locally to the mesentery. 
 
 Binz states that, when he injected quinine into the circulation, the 
 number of corpuscles in the vessels became diminished, and they ceased 
 to wander out, while those already out continued to wander further, so 
 that, instead of being evenly distributed over the field, they left a clear 
 space round the outside of the vessel, in which few were to be seen. 
 If, on the other hand, it be applied locally, the corpuscles which are 
 already out stop moving, while those in the vessel continue to migrate, 
 and thus, instead of a clear space, a dense accumulation of corpuscles 
 forms round the vessel. In order to produce this effect, 1^5 000 to Voooo^^ 
 of the animal's weight of quinine is necessary ; and, if it were given to a 
 man weighing 150 lbs., in order to stop the exit of corpuscles from the 
 vessels in such a disease as peritonitis, three or four drachms of the 
 medicine would require to be given within a short time. Binz's obser- 
 vations as to the effect of quinine on the white corpuscles have been 
 confirmed by Martin, (24) but have been denied by Schwalbe, (25) so that 
 farther investigations on this point are very desirable. 
 
 Action of Gases. — This is examined by putting the cells to be ex- 
 amined on Strieker's warm stage, and bringing the gas into contact with 
 
24 
 
 them in the manner described by him (Strieker's Histology, Sydenham 
 Society's edition, p. 8). 
 
 Steps of an Investigation.— The animals which we chiefly use in 
 experiments are frogs, rabbits, guinea-pigs, and dogs. In investigating 
 the action of a drug, we examine — 
 
 1. What the symptoms are which a large dose produces. 
 
 2. Taking the most prominent symptom, we inquire {a) On what organ 
 does the production of this symptom depend ? ((5.) How has it been 
 affected by the drug? (<r.) Has this affection been primary or secondary ? 
 
 3. We examine other organs which we think may have been also 
 affected. 
 
 Administration of Drugs. — To examine the general effect of a 
 drug, we weigh the animal and then give it a large dose in our first ex- 
 periment, in order to get exaggerated symptoms. It may be given by 
 the mouth or by subcutaneous injection. In frogs, the substance may 
 be injected either under the skin of the back or into the abdominal 
 cavity. In rabbits, etc., it is most conveniently injected under the skin 
 of the flank. In guinea-pigs, the abdominal parietes are very thin ; and, 
 if we wish to compare experiments with different doses, care must be 
 taken not to push the point of the syringe into the abdominal cavity, as 
 the absorption will be then more rapid, and the same dose produce a 
 greater effect. If we wish to give the medicine by the mouth, we either 
 put it well back on the root of the tongue and then hold the animal's 
 jaws together till we think it has swallowed it, or we put a perforated 
 cork between its teeth, push an elastic catheter through the hole in the 
 cork down the oesophagus into the stomach, and inject the drug in solu- 
 tion through the catheter. Orfila used to introduce the drug into an 
 opening in the oesophagus, which he then ligatured to prevent vomit- 
 ing 5(26) but since subcutaneous injection was introduced this method is 
 rarely employed^ 
 
 Observation of Effects. — After the drug has been administered, 
 we allow the animal to move freely about, but prevent frogs from escap- 
 ing by covering them with a large bell-jar. We then see whether the 
 animal is restless or disinclined to move ; whether its movements are 
 perfectly performed or unsteady ; whether or not its legs seem weak and 
 paralysed, or convulsive movements or involuntary twitchings be pre- 
 sent ; whether its heart-beats or pulse, and respirations, are quick or 
 slow, strong or weak ; whether there is vomiting or purging diuresis ; 
 salivation; or dryness of the mouth; flow of tears, or dry conjunc- 
 tiva ; and whether the pupil be contracted or dilated. If the animal 
 
25 
 
 seem asleep, we pinch it to ascertain if reflex action continue after 
 voluntary motion is gone ; and if respiration cease, we ascertain if the 
 heart still continue to beat. As soon as possible after death, we open 
 the animal and see if the heart still be beating. If it have stopped, we 
 note whether its cavities are full or empty, its walls flaccid or firm, 
 and try whether it will still contract or not on pinching or scratch- 
 ing it, or on irritating it by an electric current. We observe whether 
 the veins are turgid or empty, the lungs pale or congested, the stomach 
 and intestines quiet or in active peristaltic movement, the spleen large 
 or contracted, the bladder full or empty j and the urine may be tested 
 for sugar. 
 
 Interpretation of Results. — If we find in the course of these 
 experiments that voluntary motion is increased or lessened, we may 
 naturally conclude that the activity of the cerebrum is increased or 
 diminished, unless the increase of motion should depend on pain, or its 
 diminution on impairment of the motor apparatus. Unsteady move- 
 ments, paralysis or convulsions, impaired reflex action on pinching, 
 or stoppage of respiration before the heart, point to the spinal cord, to 
 the nerves, or to the muscles; while quick or slow, strong or weak 
 pulse, or stoppage of the heart before the respiration, point to the 
 vaso-motor system or cardiac nerves ; increased or diminished secretion, 
 to secreting nerves ; and full or empty bladder, and diminished or in- 
 creased peristalsis, to the motor nerves of the bladder or intestine. We 
 then try the effect of a small dose, and note in what respects it differs 
 from that of a large one. We thus ascertain in a general way what 
 the organ is, which is chiefly acted on by any drug, and afterwards 
 proceed to investigate the nature of the action by a farther series of ex- 
 periments. 
 
 Minimum Fatal Dose. — If the drug be poisonous, we then try to as- 
 certain the minimum fatal dose. For this purpose we weigh an anitnal 
 and inject into it a dose which we think will not prove fatal, wait a short 
 while, and then inject more till death is produced. We then reckon 
 how much of the drug has been injected for every pound weight of the 
 animal. We take another animal, and inject into it at once a quantity 
 which will be somewhat smaller for its body-weight than that given to the 
 first. The reason why a somewhat smaller quantity should be taken is, 
 that some time was allowed in the former experiment for the excretion 
 of part of the poison between each dose. If this amount prove fatal, 
 we must give a still smaller quantity to another animal ; but, if not, we 
 must give more till we find the smallest quantity which will kill. 
 
 E 
 
26 
 
 Various Channels of Administration. — The next point to be 
 determined is, whether the effects are the same when given by the mouth 
 or rectum, or other mucous surfaces, as by subcutaneous injection. If 
 we should find, as Bernard did with curare, that a substance which is 
 active when injected subcutaneously or into a vein, has no effect when 
 introduced into the mouth, rectum, eye, or bladder, we must determine 
 whether this is due to want of absorption or to decomposition of the 
 drug by the secretions with which it becomes mixed. This is done by 
 mixing it with these secretions, such as urine or gastric juice, allowing 
 it to stand some time at the temperature of the body, and then injecting 
 the mixture subcutaneously, and observing whether the usual effect is 
 produced or not ; or by ligaturing the ureters to prevent excre- 
 tion. 
 
 Excretion. — Lastly, we examine in what manner it is excreted 
 from the body. As most solids are excreted by the kidney, we generally 
 restrict this process to evaporating the urine, or testing it either chemi- 
 cally or by injecting some of the extract into another animal. 
 
 Mode of Securing Animals.— In order to determine in an exact 
 manner what organs or parts are affected, we are obliged to make use 
 of apparatus of various kinds ; and, before these can be applied to an 
 animal, it must be prevented from moving. Frogs are fastened to a 
 frog-board by a piece of cord with a noose at the end, slipped over 
 each elbow and ankle. The frog-board may consist of a piece of 
 mill-board about nine inches long by three inches broad, with four 
 slits at the sides to keep the cords in position, 'Or of a piece of 
 wood the same size, and from a quarter to half an inch thick, with 
 holes, through which the cords are passed. They may be fastened by 
 simply tying them together or by sticking a small wooden pin into each 
 hole, or by four screws, such as are used by fastening the wires of gal- 
 vanic batteries, placed in the edges of the board. The last way is, I 
 think, the most convenient. Rabbits are best secured by Czermak's 
 holder and board (shown in fig. i). The best cord is strong window- 
 cord. The one end should be flattened with a hammer, and turned over 
 so as to make a small loop, whose two sides are then firmly bound toge- 
 ther with waxed thread. Through this loop the other end is passed, 
 and the noose thus made is ready to be drawn tight at any moment. 
 The other end of the cord should be cut to a point and also bound with 
 waxed thread to prevent the strands unravelling. The rabbit is placed 
 on the board, the nooses slipped over the legs and drawn tight, and the 
 ends of each cord passed through the screw which will be nearest it 
 
27 
 
 when the animal lies on its back. The rabbit is then turned over, and 
 the cords drawn through the screws and fastened. The bar h is then 
 put between its teeth, and the screw / turned till ^and g fit tightly over 
 
 Czermak's Rabbit Holder and Board, a. The board, b. A bent piece of iron 
 forming the upper part of the board, c. An open space through which in- 
 struments can be introduced from below to divide the spinal cord. It is 
 generally covered by an iron plate, d is an upright rod fixed by a screw into 
 a slit in b. _/ is a forked rod, which can be moved back or forward, up or 
 down, by the nut e. The forks are hollow, so that the ends of the holder can 
 be passed into them and fastened by the screw / h is a bar which passes 
 behind the incisor teeth of the rabbit, g and g' are two bent bars which pass 
 under the chin and over the nose of the animal, and are brought together by 
 the screw /. From the upper end of ^' hangs a screw, which passes between 
 two projections on g, and has a mother-screw k. The screw k works against 
 the projections on g, and draws the ends of ^' and g together. These press 
 on the rabbit's nose and under jaw and keep the teeth firmly locked over the 
 rod h. 7n m are screws for fixing the cords which confine the legs. They 
 are a remarkably convenient sort, consisting of an outer part with a horizontal 
 hole, and an inner ring with a stalk on which a milled screw plays. When 
 the milled head is at the top of the stalk, the inner ring and outer holes cor- 
 respond, and the cord can then be easily pushed through ; but when the milled 
 head is turned, the stalk and ring are drawn up and the cord nipped between 
 it and the outer part. The cords may either be fastened directly in the screw 
 or passed first through one of the holes in the edge of the board. The board 
 should be covered with a large pad of India-rubber stuffed with horsehair, 
 and there should be another round pillow to put under the animal's neck. 
 
 its muzzle, and the projecting ends of ^ fixed into the ends ofy^ Dogs 
 may be fastened by Bernard's holder (fig. 2a), or by a simple bar of 
 iron put behind their canine teeth. A piece of cord is first tied round 
 the upper jaw, the bar put into the mouth, and the two jaws tied firmly 
 over it. A split strap may be used instead of the cord. I have had a 
 bar made with a hole at each end, into which a fork of steel passes, and 
 is secured by a screw. The fork may then be fastened by a nut to an 
 upright rod, as in Czermak's holder (fig. 2b). Cats and guinea-pigs may 
 be fastened by Czermak's holder. For guinea-pigs, a little padding must 
 be placed between g and g' in order to make them catch the head. A 
 simple bar and cord may also be used for rabbits, cats, and guinea-pigs, 
 as well as for dogs. 
 
Instruments Required. — The instruments which we generally re- 
 quire for operations are — sponges, one pair of large scissors and one small 
 pair, cutting well at the points, scalpels, forceps, small bull-dog forceps 
 
 Fiq.jr 
 
 A is Bernard's dog-holder, a is a metal ring, within which a bent piece of metal, 
 i, is moved up and down by the screw c. A is a straight piece, which is 
 fastened by a screw to a, and can be moved nearer to or farther from a corre- 
 sponding piece at d. These two pieces lie under the lower jaw of the dog ; 
 the bent piece i> is screwed down on its nose, and the strap i buckled behind 
 its head, which is thus firmly fixed. It may be moved back or forward by 
 sliding the rod d through the nut e, or up and down by moving e on y, which 
 is a strong iron rod fastened to a table or board by the screw ^._ 
 
 B. Brunton's holder for dogs or rabbits. A loop of cord is tied round the 
 upper jaw, the bar / passed behind the canine teeth of the dog or cat or in- 
 cisors of the rabbit, and the two jaws then tied together to prevent its slip- 
 ping out. This mode of fastening animals has been long used, and my modi- 
 cation simply consists in the addition of the forked bar X:. After i is fastened 
 in the mouth, the forked ends of k are pushed through holes in /, and 
 fastened by the screws m. k may then be fastened to an upright bar by 
 means of a nut in the same way as Bernard's or Czermak's holder. 
 
 with smooth points, blunt hooks, a small aneurism-needle, flattened 
 sidewise and with a rounded point (fig. 3 g), ligatures, finder (a kind of 
 probe set in a handle to open up the lumen of a divided vessel), 
 syringe, cannulae, a piece of card, small whalebone-probe, and one or two 
 swine's bristles. As these are very apt to be mislaid during an opera- 
 tion, I find it convenient to have a small wooden tray about three-quar- 
 ters of an inch deep, with thin upright sides, and divided into com- 
 partments, one for each kind of instrument. It is advisable, also, to 
 have an extra instrument or two of each sort. 
 
29 
 
 Way of Making Cannul^e. — Cannul^e for injecting into vessels 
 may be made of metal (fig. 3 c) or of glass. Glass ones can be easily 
 made of any size required by heating a piece of glass-tubing over the 
 flame of a blow-pij)e, and drawing it out in the middle, as represented 
 by the dotted line (fig. 3D.) It is then heated at a and slightly drawn 
 out, so that a bulging piece is left between a and c ; it may then be 
 heated and very slightly drawn out at b, then cut with a three-cornered 
 file at c, and the point ground obliquely off on a hone. If the point be 
 at all sharp, its edges may be rounded in a gas-flame. When the 
 cannula is introduced into a vessel, a ligature at a prevents it from 
 coming out : it may be connected with a syringe or with any piece of 
 apparatus by a piece of India-rubber slipped over the other end and tied 
 at b. A cannula for connecting an artery with a kymographion may 
 either be of this sort, or may be made of metal of the shape shown in 
 fig. 3 A. As it is difficult to hold it with forceps, it should be put on a 
 piece of wood or whalebone of the shape shown at B. This both holds 
 it firmly, and the point entering the vessel allows the cannula to 
 be more readily pushed on into the lumen. A few notches on the side 
 of the cannula prevent the vessel and ligature with which it has been 
 tied from slipping off the end. By means of the little ear at ^, it can 
 be tied to the tube, on to which it is fitted. 
 
 Mode of making Cannula, T-tubes, and Pens. — Cannuloe 
 for the trachea are made by closing one end of a tube, directing a small 
 blow-pipe flame against a point in its side till it is quite soft, and then 
 suddenly blowing into it. The soft part expands into a thin bulb, 
 which is scraped off, and a hole remains in the side of the tube. The 
 object of this hole is to allow the air to escape during expiration. In- 
 stead of a hole in the cannula, one may be cut in the side of the India- 
 rubber tube to which it is connected ; but this is more apt to be acci- 
 dentally closed. The tube is then drawn out into the form seen at 
 Fig. 4 A, cut off at both ends, and one end ground obliquely off on a 
 sandstone with some water. 
 
 A knob may be made at the ends of other cannulse for various pur- 
 poses, by heating the end and striking it against a piece of glass or iron, 
 or by heating the end in a flame, continuing to blow steadily through 
 the tube while you do so. 
 
 T-tubes are made by blowing a hole in the side of one tube, in the 
 same way as for a respiration-cannula ; and then putting the heated end 
 of another tube over it while the first is still hot, so that the two stick 
 together. The joint must then be annealed by heating it in an ordi- 
 
30 
 
 nary gas-flame, reducing the size of the flame gradually, so that the 
 glass may cool very slowly. 
 
 Pens for use with a kymographion are made by drawing tubes to a 
 point, as shown in Fig. 3, e and f ; and grinding the point on a fine 
 hone, and rounding it, if necessary, in the flame. 
 
 A is a metal cannula with an ear e, by which it can be fastened to any tube con- 
 nected with its large end. b is an instrument for introducing a into a vessel. 
 It consists of a piece of metal tubing, with a pointed piece of wood at one 
 end, over which a is put. The point projects through the smaller opening in 
 A, so as to enter the lumen of the vessel readily, c is a metal cannula which 
 fits on the end of a syringe for injecting fluids into vessels. D is a glass 
 cannula. The dotted line shows the original tube drawn out in the blowpipe- 
 flame ; the darker line shows the finished cannula, e and f are two pieces of 
 glass tubing drawn out to make pens. They may be attached by pieces of 
 cork to any writing apparatus. G is an aneurism-needle. 
 
 Narcotising Animals. — Narcotics cannot be given in all cases to 
 animals on which we experiment, as their action must to a certain 
 extent complicate that of the drug which we wish to investigate. We 
 cannot use them when we are observing what are the general symptoms 
 which a medicine produces. But, when we are investigating its action 
 on particular organs, we may often use them, not only with safety, but 
 with advantage, when they have no action on the particular organ which 
 we are studying, or so little that its disturbing influence is more than 
 compensated by the diminished muscular action, and consequent ease 
 in performing the experiment, which narcotics produce. 
 
 It is almost unnecessary to say that, in all cases which admit of it, 
 narcotics should be used, as we have no right to inflict any unnecessary 
 pain, although we may be justified in taking the lives of the lower 
 animals in order to preserve the more valuable life of man, either by 
 
31 
 
 supplying him with food by means of those killed in the slaughter- 
 house, or by obtaining the knowledge which shall enable us to cure dis- 
 ease by means of those killed in our experiments. The narcotics which we 
 use are opium and chloral. Chloroform is inadmissible, as its adminis- 
 tration generally seems to cause dogs more pain than the experiment 
 itself, and rabbits are very easily killed by it. 
 
 A convenient form of giving chloral is a solution containing half a 
 grain in i minim or I gramme in two cubic centimetres of water. The 
 dose for a frog is 2 to 5 centigrammes, or about i to 5 drops. The dose 
 for guinea-pigs is about 1 2 minims of this solution for an animal half 
 a pound weight; and more or less may be given, according to the 
 weight of the animal, 18 minims being given to one weighing three- 
 quarters of a pound, and 24 to one weighing a pound. About the 
 same proportion of dose to weight may be employed for rabbits. 
 
 Opium may be given in the form of laudanum, or of solution of 
 acetate or hydrochlorate of morphia. Much as it is used, the proper 
 dose for different animals has not been exactly determined. We do not 
 often employ it to narcotise guinea-pigs or rabbits, but frequently for 
 dogs. The dose for a medium sized dog is about 40 minims or 2^ 
 cubic centimeti-es of laudanum, or 2 drachms of liquor morphise, which 
 is equal to i grain or 5 centigrammes of morphia. This dose is for in- 
 jection into a vein : when injected subcutaneously, rather more should 
 be given. If the dog be above or below middle size, the dose must be 
 proportionately increased or diminished. We must be careful not to 
 give too much opium to old dogs, or they will die. Opium is pre- 
 ferred by some to morphia, as producing more certain narcosis, and 
 being less likely to produce the excitement and hypersesthesia which 
 sometimes follow the administration of morphia. 
 
 W^hen we wish to render the animal absolutely motionless, or to 
 observe what effect any drug will produce after the motor nerves have 
 been paralysed, we give curare. Small doses of this remarkable sub- 
 stance paralyse the motor nerves of muscles, but leave the vagi and 
 vaso-motor nerves unaffected. Large doses of it seem also to cause 
 paralysis of the vagi. It affects the blood -pressure to a certain extent, 
 moderate doses contracting the vessels and raising the pressure, while 
 large ones lower it. The dose of curare for a frog is about i to 5 
 drops or more of a solution of i part in 1000. The dose varies with 
 the size of the frog and the purpose for which we wish it. If we wish 
 to observe the circulation microscopically, we must not give too large a 
 dose, or the heart may stop. To rabbits, ^ to i cubic ccutiuietre or 8 
 
32 
 
 to 15 minims, and to dogs, 4 to 6 cubic centimetres or i to 2 drachms, 
 of such a solution, may be given,* 
 
 Definite rules cannot be laid down as to the experiments in which 
 narcotics may or may not be used. The experimenter himself must 
 judge in each case whether their action is likely to disturb that of the 
 drug to be experimented on or not. For this purpose, he must know 
 the action which the narcotics themselves produce ; and I will, there- 
 fore, mention in a few words what that of each is. 
 
 Action of Narcotics. — Chloral acts on the brain, producing deep 
 sleep, during which there is no sensation or voluntary motion. The 
 reflex function of the spinal cord is first increased and then diminished 
 in frogs ; in guinea-pigs and rabbits, it is diminished for thermal irrita- 
 tions, but not for tactile ones — pinching producing reflex action, but 
 burning or pricking none. It leaves the motor nerves, vagus, and 
 muscles unaffected j but diminishes the activity of the respiratory 
 nervous centre, rendering the breathing slow ; and of the cardiac gan- 
 glia, somewhat weakening the heart. It lessens the blood-pressure and 
 temperature, probably by dilating the vessels at the surface as the ear of 
 a rabbit becomes hot and its vessels dilated, while the general tempera- 
 ture is falling. (27) 
 
 Opium is a mixture of several alkaloids, some of which are purely 
 narcotic, while others produce tetanus, just like strychnia, and others 
 partake of both characters. This is the case with morphia, in which, 
 however, the narcotic qualities predominate. In small doses it first 
 slightly increases, and then diminishes the irritability of motor and 
 sensory nerves, and the reflex action of the cord, the irritability of 
 the vagus (ends and central roots) and the musculo-motor apparatus 
 of the heart, and the temperature. If the dose be large, those functions 
 may be at once lessened. The blood-pressure varies, but is generally 
 raised. (28) 
 
 The advantage of giving either a narcotic or the drug to be investi- 
 gated by injection into a vein rather than subcutaneously is, that the 
 action is immediate, and we know that the whole of the dose has 
 taken effect; whereas, after subcutaneous injection, a part may remain 
 for some time in the cellular tissue before it enters the blood and 
 becomes active. The most convenient vein is the external jugular. In 
 dogs, however, it is sometimes more convenient to inject the narcotic 
 into a vein which runs obliquely across the outside of the hind knee- 
 
 * Curare may be obtained from Messrs. Hopkin and Williams, New Cavendish 
 Street, London ; or from Bruckner and Lampe, Leipzig. 
 
33 
 
 joint. Before injecting, we must introduce a cannula into the vein ; 
 and the introduction of a cannula into a vessel is an operation on 
 the proper performance of which the success of many an experiment 
 depends. 
 
 Introduction of Cannula into Vessels. — First, the hair must 
 be cleanly clipped or shaved away, and loose hairs removed by a moist 
 sponge. The skin, subcutaneous cellular tissue, and cutaneous muscles, 
 are divided with a scalpel, and any bleeding vessels are twisted or liga- 
 tured. If the vessel lie deep, the muscles are separated from each 
 other by the finger of the operator, or by a blunt aneurism-needle, and 
 any unyielding connective tissue may be cut by a pair of scissors. That 
 surrounding the vessel itself should be separated from it by the aneurism 
 needle. A closed pair of forceps may be pushed under the vessel and 
 then opened. This both raises it from its bed, and lays bare a con- 
 siderable part of its course. A couple of ligatures are now caught 
 between the jaws of the forceps and drawn through. The proximal 
 end of the exposed part of the vessel is now compressed by a pair of 
 smooth-pointed bulldog-forceps, or a ligature laid in a simple slipknot; 
 one ligature is firmly tied round the distal end, and the second ligature 
 is tied in a loop round the middle, but is not drawn tight. A small 
 piece of calling card, about an eighth of an inch broad, is then slipped 
 under the vessel, so that it may rest on it and remain steady ; its walls 
 are then snipped by a sharp-pointed pair of scissors just on the distal 
 side of the loop. The finder, or aneurism-needle, may be introduced 
 so as to make the opening more distinct, and, if necessaiy, this may be 
 enlarged by the points of the forceps being introduced, and then sepa- 
 rated. One lip of the divided vessel is seized by the forceps, the 
 cannula introduced, and the loop drawn tight over it so as to tie it 
 firmly into the vessel. The cannula is then filled by a small glass 
 pipette with the fluid to be injected, the syringe is fitted on, the bull- 
 dog forceps removed, and the requisite amount injected. The bulldogs 
 are again put on, and the syringe removed. 
 
 Injection of Fluids into Vessels. — First, we prepare the solu- 
 tion to be injected in a test or a watch-glass, and see that the syringe 
 is in working order. The most convenient is one for subcutaneous in- 
 jection, with a glass barrel and a graduated piston. On the piston-rod 
 a small nut screws up and down, so that it can be set to any figure on 
 the rod, and thus prevents it from being any further pushed in, so as 
 to allow the exact amount required to be given at once, but prevent 
 the accidental injection of more than this amount. The end of the 
 
 F 
 
34 
 
 barrel must either fit directly into a cannula of the shape shown in fig. 
 3 C, or it may be adapted to a glass cannula by tying a small piece 
 of India-rubber tubing to the cannula. The cannula is then intro- 
 duced into the vessel as already described. A fine pipette must be at 
 hand, made by drawing a piece of glass tubing to a point, and by 
 this the cannula, or cannulse with the attached India-rubber tubing, 
 must be carefully filled with the fluid, so that no air-bubbles remain. 
 The syringe is then connected to it, the slip-knot of the ligature un- 
 tied, or the bulldogs compressing the vessel in front of the cannula 
 removed, and the necessary amount injected. The slip-knot is then 
 re-tied, or the bulldogs replaced, if a second dose is to be given. If 
 no more is to be injected, the vessel may be firmly ligatured. 
 
 Division and Irritation of Nerves. — The nerve must be laid 
 bare, and separated from the surrounding connective tissue in the same 
 way as a vessel, especial care being taken never to seize the nerve 
 itself with the forceps. Blood must be removed by a sponge 
 squeezed quite dry, and the nerve must on no account be touched with 
 water. If we wish to remove any adhering clot, or if the nerve hap- 
 pen to get dry through long exposure, it may be moistened with a 
 little saliva or serum. A director is then pushed under the nerve, or 
 we raise it up by a ligature passed below it, so as to secure the 
 adjoining vessels from injury, and we then divide it by a pair of 
 scissors. Very often we wish to have the nerve prepared for section 
 some time before we actually divide it. We then pass the ligature 
 under it and tie the two ends together, so as to prevent the ligature 
 from being pulled from below the nerve, and thus form a loose loop 
 by which we can at any moment raise and divide the nerve. 
 
 Nerves may be irritated by pinching, the application of strong saline 
 solutions, or heat j but generally we use Pulvermacher's galvanic for- 
 ceps, which are made of alternate wires of copper and zinc, and dipped 
 in acetic acid, or, still oftener, the interrupted current from Du Bois 
 Reymond's induction coil. The most convenient electrodes for this pur- 
 pose consist of two wire points, about a quarter to half an inch long, and 
 an eighth to a quarter of an inch apart. They may either be set in an 
 ivory handle, or they may be simply fixed in a piece of glass tubing 
 by means of cement or sealing-wax, or simply pushed through a piece 
 of cork. 
 
 Artificial Respiration in Mammals. — Artificial respiration is 
 chiefly used to keep an animal alive after it has been poisoned with 
 curare, for the purpose of rendering it perfectly still during an experi- 
 
35 
 
 ment ; or after the thoracic cavity has been opened for observation or 
 experiment on the viscera it contains. It is performed by introducing 
 a cannula into the trachea, and inflating the lungs by means of a bel- 
 lows connected with it by India-rubber tubing. 
 
 A is a glass cannula for artificial respiration, large enough for a small dog. A 
 hole for the exit of expired air is seen in the side. B a metal one for a 
 rabbit. The hole for expiration is at the top, and not visible in the figure. 
 The lower part of the cannula can be turned round upon the upper at a joint 
 about one-third of the way from the top, not marked in the figure. The tube 
 which conveys air can thus be brought from the side instead of the front. 
 
 To introduce the cannula, an incision is made in the middle line 
 below the cricoid cartilage through the skin and cutaneous muscles; 
 the larger muscles lying along the side of the trachea are separated 
 from it by an aneurism-needle or the handle of the knife, and a strong 
 ligature is passed under it by an aneurism-needle or forceps, care 
 being taken to avoid the veins which lie close to its posterior wall. A 
 round or oval piece must then be cut out of the front of it by the 
 scissors or knife, and the cannula introduced, and tied firmly in by the 
 ligature. 
 
 "When the knee-shaped metal cannula is used, it is advisable to push 
 the heel of the cannula into the trachea, so that the tube lies quite in 
 its lumen. After the cannula has been tied into the trachea, the ends 
 of the ligature may be fastened round the upright bend of the knee, to 
 ensure that it do not slip out. The bellows may be simply held in 
 the hand, or fastened to the under side of a table by means of a piece 
 of board screwed to its upper side and larger than the bellows itself, so 
 that there is a rim of board all round. A few screws passed through 
 this projecting rim into the under side of the table hold the bellows 
 
36 
 
 fast. A small pulley (one used for window-blinds will do) is then 
 screwed into the under side of the table, and a cord passed over it. 
 One end of the cord is fastened to a piece of board a foot and a half or 
 two feet long, which serves as a treadle ; and the other end to the under 
 board of the bellows, so that it may be drawn up when the treadle is 
 pressed down by the foot. A weight must be attached to the under 
 board of the bellows, in order to draw it down again after it has been 
 raised. The respiration is kept regular by depressing the treadle in 
 accordance with the beat of a metronome set to beat the proper 
 number in a minute. 
 
 The apparatus may be rendered more complete by the introduction 
 between the bellows and trachea of a valve which will allow the air to 
 pass readily towards the trachea, but hinder its return. Such a valve 
 may be readily made by passing two pieces of glass tubing through the 
 cork of a wide-mouthed bottle, and partially filling it with mercury or 
 
 water. The tube nearest the bellows must descend nearly to the 
 bottom of the bottle, while the other just passes through the cork. 
 The air from the bellows passes easily through the mercury or water in 
 
37 
 
 which the end of one tube dips; but any attempt to return simply 
 raises the mercury in the tube. If water be used, the tube must be 
 longer, so that it may contain a column of water sufficiently high to 
 afford the necessary resistance to the return of the air. This sort of 
 valve is termed Muller's valve. (Fig. 5, v.) 
 
 Artificial Respiration in the Frog. — Although the frog can live 
 perfectly well for some time without breathing, it maybe desirable in some 
 experiments to employ artificial respiration. A cannula for this purpose 
 is best made by heating the end of a glass tube about one-eighth of an 
 inch in diameter (more or less, according to the size of the frog), and 
 then suddenly pressing it down on a metal plate, so that a broad rim is 
 formed round the end. The sides of the larynx are seized by two artery 
 forceps, the cannula introduced, and tied firmly in. A Richardson's 
 spray-producer, from which the tubes have been removed, is then con- 
 nected to it and used as a bellows. 
 
 Introduction of Gases or Vapours into the Lungs. — Gases 
 or vapours may be introduced into the lungs either by simple inhalation 
 or by artificial respiration. For the inhalation of a gas, a conical bag of 
 oilskin, India-rubber, or bladder, must be made to fit the snout of the 
 animal, and connected with a bag, bladder, or gas-holder containing 
 the gas. Or a tube may be put into the trachea and connected with the 
 gas-holder. 
 
 For the inhalation of a vapour, a cone of strong paper or cardboard 
 may be used, the wide end being put over the muzzle, and the liquid, 
 the vapour of which is to be inhaled, dropped on a piece of blotting-paper 
 and put on the small end. Or the whole cone may be made of blot- 
 ting-paper. 
 
 Many different kinds of apparatus have been used for the artificial 
 respiration of gases, among which may be mentioned the ingenious in- 
 strument of Thiry(29) and the beautiful respiration-pump of Ludwig. 
 The simplest method probably is to have the gas in a bag, connected by 
 means of the bottle or Muller's valve with the tracheal cannula. The 
 gas may then be forced into the lung at intervals, by alternately com- 
 pressing and relaxing the bag. 
 
 Air may be loaded with vapour of any kind of fluid before it is sent 
 into the lungs, by either mixing the fluid with the water in the bottle- valve, 
 or by emptying out the water and putting a little of the fluid alone on the 
 bottom of the bottle. Pure air or air loaded with vapour may be sent 
 into the lungs alternately by the arrangement shown in fig. 5. A 
 stream of air is sent from the bellows through the India-rubber tube s, 
 
38 
 
 and divided into two by the T-tube t'. When the clip x is removed, 
 and x' put on, the air passes straight through to the tracheal cannula z. 
 If X be now put on, and x' removed, the air passes through v, and be- 
 comes loaded with the vapour of any fluid placed in the bottle. 
 
 The alternation may be effected still more rapidly and conveniently 
 by a stopcock which I have had made for this purpose. Two tubes, C 
 and c', pass from its sides, and two others, D and d', from its bottom. 
 The interior is perforated with three holes. Two of these, E and e', are 
 L-shaped, and one (f) passes straight through from side to side. When 
 the handle b is in a line with c and c', their lumen corresponds 
 with that of the hole f, and air passes straight through. When 
 B is transverse, the hole e corresponds with c and d, and e' with c or 
 d', so that air passing in through c' passes down through d', and may 
 pass up through D and out at c. When b is neither in a line with c 
 nor yet transverse, but half-way between, the holes in the interior do 
 not correspond with those on the exterior of the stopcock, and no air 
 can pass at all, and it may thus be used for experiments on asphyxia. 
 When such experiments are made, the hole in the tracheal cannula 
 must be carefully stopped with white wax. By means of the screw G 
 the stopcock may be fastened to the rod E of the rabbit-hold in fig. i. 
 The tubes d and d' may either be attached by pieces of India-rubber 
 tubing to tubes of a bottle such as v, or they may be themselves passed 
 through the cork and a small piece of glass-tubing long enough to reach 
 the bottom of the bottle attached to d'. By then simply turning the 
 stopcock, pure air may be passed direct to the lungs through c', F, and 
 C, or it may be loaded with vapour by passing it through d' into the 
 bottle, and then up through D and C to the lungs. 
 
39 
 
 III.— Artificial Circulation : Investigation of Blood- 
 Pressure. 
 
 Artificial Circulation of Blood. — Circulation of Warm and of Cold 
 Blood. — Fever. — Mode of Conducting Artificial Circulation. — Appli- 
 cation of this Method to Pharmacological Investigations. — Schema of 
 the Circulation. — Circulation in the Living Body. — Importance of the 
 Arterial Elasticity. — Arterial Tension or Blood-Pressure. — Oscilla- 
 tions in it produced by the Heart and Respiration. — Causes of Varia- 
 tion in the Blood-Pressure. — Influence of Nerves upon it. — Cardiac 
 Ganglia. — Inhibitory Nerves of Heart. — Quickening Nerves of Heart. 
 Vaso-motor Nerves. — Vaso-inhibitoty Nerves. — Action of Counter- 
 irritants. — Tabular View of the Causes of altered Pulse-Rate and 
 Blood-Pressure. — Application of this to Pathology. — Experimental Ex- 
 amination of Blood-Pressure. — Forms of Manometer. — Kymogra- 
 phion. — Mode of Using the Kymographion. — Reduction of the Kymo- 
 graphion Tracings. — Mode of Recording Experiments. — Graphic 
 Method of Representing Experiments. 
 
 Artificial Circulation of Blood.— A constant supply of arterial 
 blood to all parts of the body is necessary to preserve their vitality ; 
 and if the supply to any part be cut off by stopping its circulation, that 
 part will die. Thus, if the circulation be stopped in an arm or leg by 
 tying its arteries, or through their becoming plugged by emboli, morti- 
 fication, or death of the part, ensues ; and if the heart cease to beat, and 
 the circulation be thus stopped in all parts of the body, they all die. 
 But, if we supply arterial blood artificially to any one part, we may 
 keep it alive at least for a certain time after the rest of the animal is 
 dead ; and the muscles may be made to contract, (30) the lungs to excrete 
 carbonic acid,(3o) the lymphatics to pour forth lymph, (31) and the 
 excised liver to secrete bile, (32) for hours after the rest of the animal 
 has been consigned to the dust-bin. 
 
 Circulation of Warm and Cold Blood. — For this purpose, 
 blood may be used either at the temperature of the room or of the 
 body ; but these have not exactly the same effect, and experiments 
 made with blood at one temperature must not be compared indiscrimi- 
 nately with those made with blood at another. Professor Ludwig, to 
 
40 
 
 whom we owe this method, has discovered by its means the curious 
 fact that the muscles of a warm-blooded animal may be artificially en- 
 dowed with the properties of those of a cold-blooded one. (33^) Those of a 
 frog or other cold-blooded animal retain their irritability, and contract, 
 when stimulated, for a long time after they have been removed from 
 the body ; while those of warm-blooded animals quickly lose theirs, 
 and will no longer contract on the application of a stimulus, no matter 
 how powerful it may be. But if the muscle of the warm-blooded 
 animal be quickly cooled by passing a stream of cold blood through its 
 vessels immediately after it has been excised from the body, and before 
 it is stimulated, it will retain its irritability for a long time, and respond 
 to stimuli applied again and again, like that of the cold-blooded frog. 
 
 Fever. — In the same way, by supplying the heart of a mammal 
 with cold blood, it may be made to resemble that of a frog or turtle ;(33) 
 while, on the other hand, if the heart of a frog be supplied with warm 
 blood, it will become like that of a mammal ; and, if the temperature be 
 still further raised, the quick and weak beats of fever are produced. (34) 
 
 Mode of Conducting Artificial Circulation. — When we 
 wish to pass blood, at the ordinary temperature of the room in which 
 we are working, through any organ, we defibrinate the blood of the 
 animal itself from which the organ has been obtained, or the blood of 
 an animal of the same species j dilute it somewhat with salt solution of 
 I per cent. 5(35) and put it into a flask with two necks, one of which is near 
 the bottom of the flask, as seen at A, Fig. 6. We then introduce a 
 cannula into the principal artery of the organ, and ligature, if neces- 
 sary, the smaller arteries and branches ; fill it carefully with blood by 
 means of a fine pipette, so that no air-bubble remains in it, and connect 
 it with the lower neck of the flask. By then simply raising the flask, 
 the blood flows out of it through the cannula into the vessels, and out 
 again by the veins, from which it may be collected, shaken with air, 
 and used over again. As the lips of the divided veins are sometimes 
 apt to fall together and hinder the exit of blood, it is advisable to put a 
 cannula into them as well ; and great care must be paid to the 
 adjustment of these, in order that they may be fairly in a line with the 
 lumen of the vein, and not form an angle with it, which would present 
 an obstruction to the flow of blood from it. 
 
 For the purpose of passing a stream of blood at the temperature of 
 the body, we use the same apparatus ; but the flask containing blood 
 (e, Fig. 6) is then placed in a water-bath, kept constantly heated to 
 98 deg. F. As this prevents us from conveniently raising the flask 
 
4t 
 
 high enough to obtain the pressure required to carry on the circulation, 
 we supply the want by compressing the air in the upper half of the 
 flask, E, by means of two other bottles, A and C, containing mercury 
 or water. On raising A, the fluid which it contains runs into C, and 
 compresses the air in its upper half; and, as this communicates with 
 E by an India-rubber tube, the pressure is freely transmitted to it, 
 and exerted on the surface of the blood which it contains. 
 
 Fiq, S. 
 
 A and c. Bottles containing mercury or water, b. Wooden blocks, by which a 
 may be raised to the required height. If water be used, it is easier to suspend 
 it from a pulley in the ceiling, so as to get sufficient pressure, d is a mano- 
 meter, to estimate the pressure in c and E. e is a bottle containing blood. 
 F is a small stand to raise the bottle E from the bottom of G, as it is otherwise 
 apt to become too warm, and the bottom of the bottle cracks, or the blood is de- 
 composed. G. A tin water-bath. Atone side of it, is a trough with hollow 
 sides, into which the warm water freely passes, and in which the organ to be 
 experimented on may be laid, h is an iron stand supporting G. i is a Mitscher- 
 lich's burner, k is a thermometer, by which the temperature of the water- 
 bath is examined. L. Bunsen's gas regulator, as modified by Geissler. This 
 apparatus consists of a wide glass tube w, divided into two parts by a sep- 
 tum, from the middle of which a tube runs down nearly to the end of w. The 
 upper part is filled with mercury, which, of course, runs down the inner tube, 
 and fills the bottom of w, compressing the air in it. A perforated cork z is 
 then put into the upper part of w, and the tube y pushed through the hole in 
 its centre. Inside Y, and shorter than it, is a .second tube x, and the two are 
 sealed to one another at their upper ends. The tube Y is then connected to 
 a gas pipe, and x to Mitscherlich's burner, by India-rubber tubing. So long 
 as Y is not pushed so deeply into w that the point of x dips into the mercury, 
 the gas enters through y, passes down between y and x, comes up again 
 through X, and goes to the burner. The apparatus is now set by dipping it 
 into the water-bath, and heating the water to 98 deg , or any other tempera- 
 ture desired, and then pushing Y down till the point of x is just covered by 
 the mercury. The passage of gas through it is at once stopped, and the 
 flame would go out, were it not that a very small hole in the side of x admits 
 just enough gas to keep it alive. As the flame gets low, the temperature of 
 the water-bath above it diminishes : the air and mercury in w contract and 
 leave the end of x open, so that the gas again passes freely to the burner, and 
 the flame becomes larger. The water-bath now regains its former tetnpera- 
 ture, the air and mercury expand, the end of x is again closed, and again the 
 flame becomes small. By this apparatus, a water-bath may be kept for a very 
 long time without varying more than half a degree. 
 
 Application of thls Method to Pharmacological Investi- 
 gations. — Besides its use in the experiments of Ludwig and his pupils 
 
 G 
 
42 
 
 on the secretion of bile and the formation of lymph, this method has 
 been used by Cyon to show that urea is formed in the liver ;(36) but, so far 
 as I know, no experiments on the action of medicines have yet been 
 made by its means. It may seem, then, a strange thing that I should 
 mention, in a course of experimental pharmacology, a mode of research 
 which as yet has only been tried in physiology ; but the good service it 
 has already done the physiologist, and the splendid promise it gives to 
 us, are, I think, a sufficient excuse. For we can thus take two similar 
 organs, or two parts of the same organ, and supply them with the 
 same blood, at the same temperature and the same pressure — in short, 
 we may put them under exactly the same external conditions ; but to the 
 blood supplying the one we may add any drug whose action on the organ 
 we wish to test. We can analyse the blood flowing into, and that flowing 
 from, the substance of the organs before and after the experiment, the 
 lymph produced, or the secretion poured forth ; and by comparing the 
 results when the drug was added with those obtained when it was 
 withheld, we may, I think, gain such a knowledge of its action as 
 could be got in no other way. 
 
 Schema of the Circulation. — In the living body, a constant 
 stream of blood is kept up in the vessels, in exactly the same way that 
 a constant current of air is produced in Richardson's spray-apparatus. 
 By removing the glass or metal tube from one of these, and attaching 
 a nozzle wiih a small stopcock to the India-rubber tube in its stead, we 
 obtain a very good schema of the circulation ; and, by imitating on it 
 the changes which occur in the heart and vessels, we may form a 
 much clearer idea of them than we could otherwise do. The India- 
 rubber ball will represent the heart; the elastic bag, surrounded by 
 netting, will represent the elastic aorta and larger arteries ; and the 
 stopcock, which regulates the size of the aperture through which the 
 air escapes, will represent the small arteries and capillaries, whose con- 
 traction or dilatation regulates the flow of blood from the arteries into 
 the veins. If we turn the stopcock so as to present some resistance to 
 the escape of air, and then compress the India-rubber ball, very little 
 air will issue from the stopcock even while we are squeezing the ball ; 
 the greater part of it goes to distend the bag ; and, when we cease to 
 compress the ball, no air at all comes out from the stopcock. At the 
 next squeeze, the bag becomes a little more distended ; and a little air 
 issues from the stopcock, not only while we are compressing the ball, 
 but even when we relax our grasp. At each squeeze of the ball, the 
 elastic bag becomes tighter, till it is so tense, and contracts so strongly 
 
43 
 
 on the air inside, that it can press all the extra amount of air forced 
 into it when the ball was compressed, out through the stopcock, during 
 the time when the ball is relaxed. When this is the case, every time 
 we squeeze the ball we see the bag become a little fuller, and air issue 
 more quickly from the nozzle. At each relaxation, while the ball is re- 
 filling, the bag gets a little slacker, and the air passes out of the nozzle 
 a little more slowly, but never stops entirely. During the time the ball 
 is filling, the valves between it and the bag and nozzle are closed, and 
 cut it off from any connexion with them. All this time, then, the 
 stream of air from the nozzle must be entirely independent of the ball; 
 it is produced by the contraction of the elastic bag, and by it alone. 
 The bag may be stretched, and the tension of its walls increased in 
 consequence, in two ways : first, by working the ball more quickly ; 
 second, by lessening the opening of the nozzle, and thus hindering the 
 passage of air through it. One trial will, I think, be enough to show 
 you how much easier it is to alter the pressure by changing the size of 
 the nozzle than by any alteration in the working of the ball, and thus 
 convince you that alterations in blood-pressure probably depend much 
 more on alterations in the lumen of the small arteries than on changes 
 in the action of the heart. 
 
 But our schema, as it at present exists, is not a perfect representa- 
 tion of the heart and vessels ; for it draws its air from an inexhaustible 
 reservoir, the atmosphere, and is not obliged each time to use that 
 amount alone which it had previously driven through the nozzle ; while 
 the heart can only use the blood which has been forced by it through 
 the capillaries and returned to it by the veins. In order to make our 
 schema complete, we must connect its two ends by tying them into a 
 bladder or large thin caoutchouc bag (such as is used, after inflation, as 
 a toy for children), so that the air shall pass into it from the nozzle 
 and be sucked out of it by the elastic ball. This will represent the 
 veins. If we then repeat the experiment just described, we shall find 
 that, when we begin to work the ball and stretch the elastic bag repre- 
 senting the arteries, the bladder, representing the veins, becomes 
 empty and collapsed ; and just in proportion as we fill the bag do we 
 empty the bladder. If we now stop, the air will gradually escape from 
 the bag to the bladder, till both are equally filled as they were at first. 
 
 Circulation in the Living Body. — The phenomena of the cir- 
 culation in the heart and vessels are very much the same as in the 
 spray-producer. When the heart stands still (as when the vagus is 
 strongly galvanised), the blood flows from the arteries into the veins 
 
44 
 
 till they are nearly full and the pressure inside both is about the same. (37) 
 If the heart now begin to beat, it forces blood into the elastic aorta 
 and arteries at each systole, and distends them, just like the elastic bag 
 of the spray-producer j while at the same time it takes blood from the 
 veins, and they become empty in proportion as the arteries become 
 full. At every diastole, the elasticity of the distended aorta causes it 
 to contract on the blood it contains, and keeps it flowing on through 
 the capillaries till another systole occurs. During the diastole, the 
 heart is completely shut off from the aorta by the sigmoid valves (just 
 as the ball of the schema was shut off from the elastic bag), and the 
 blood is kept flowing during this time by the elastic contraction of the 
 aorta and large arteries. In general, the diastole is longer than the 
 systole ; so that for the greater part the circulation is carried on by the 
 elasticity of the arteries, and not directly by the heart. The arteries 
 become distended by the heart, just as the elastic bag was by the ball, 
 and press more and more on the blood in them (so that it would spout 
 higher and higher, if one of them were cut), till they are able during 
 the diastole to press the same amount of blood through the capillaries 
 into the veins as had been pumped into them during the systole. The 
 more these are stretched, the greater is the pressure they exert on the 
 blood they contain ; and the amount of this is termed the arterial ten- 
 sion or blood-pressure. These two terms mean the same thing, and we . 
 use one or other just as the fancy strikes us. At each systole, the fresh 
 supply of blood pumped in by the heart stretches them more ; that is, 
 the arterial tension rises. During each diastole, the blood escapes into 
 the wide and dilatable veins, and the arteries become relaxed ; that is, 
 the arterial tension falls. 
 
 Besides the oscillations which take place in the blood-pressure at 
 each beat of the heart, a rise and fall in the form of a long wave occurs 
 at each respiration. The wave begins to rise just after inspiration has 
 begun, reaches its maximum just after the beginning of expiration, and 
 then begins to fall again till a new wave succeeds it. (38) The heart-beats 
 are generally quicker during inspiration, and slower during expiration. 
 
 The blood-pressure thus oscillates up and down at each heart-beat 
 and rises and falls with each respiration, and the average between the 
 highest and lowest points is called the mean arterial tension or mean 
 blood-pressure. 
 
 Causes of Variation in the Blood-Pressure. — The pressure 
 of blood in the arteries depends on two circumstances: first, the 
 amount of blood pumped into them in a given time ; and second, on 
 
45 
 
 the amount that flows out of them into the veins in the same time. If 
 more be pumped in, or if less flow out, it will rise ; if less be pumped 
 in, or if more flow out, it will fall. It may, therefore, be raised — i. 
 By the heart beating more quickly ; 2. By a larger amount of blood 
 being sent into the aorta at each beat ; 3. By contraction of the small 
 vessels. It may be lowered — i. By the heart beating more slowly; 2. 
 By the heart sending out less blood at each beat ; 3. By dilatation of the 
 small vessels, allowing the blood to flow more quickly into the veins ; 
 4. By contraction of the pulmonary vessels, or obstruction to the 
 passage of blood through them. 
 
 The influence on the pressure exerted by the amount of blood sent 
 out by the heart at each beat, and by the number of beats, to a certain 
 extent, though by no means completely, counteract each other ; for, 
 when the heart is going quickly, it has not time to fill completely, 
 and so sends out Kttle blood, at each beat ; but, when going slowly, 
 it becomes quite full during each diastole, and sends out a larger 
 quantity of blood at each contraction. 
 
 It must be remembered that we measure the blood-pressure in the 
 systemic arteries ; and, before the blood can get into them from the 
 veins, it must come through the pulmonary vessels. Any contraction 
 of the lumen of these vessels, by lessening the entrance of blood into 
 the systemic arteries, will cause the pressure in them to fall. 
 
 Influence of Nerves on Blood-Pressure. — Both the quick- 
 ness of the heart's beat and the contraction of the arteries are regulated 
 by the nervous system ; and it is generally by acting on different parts 
 of it that drugs alter the blood-pressure, though they may also do so by 
 acting on the muscular walls of the heart and arteries themselves. The 
 parts of the nervous system chiefly concerned in regulating the circula- 
 tion are : 
 
 I. The cardiac ganglia which lie in the walls of the heart, and are, in 
 all probability, the cause of its rhythmical action. 
 
 II. Inhibitory nerves^ which render the heart's action slow, and, if irri- 
 tated very strongly, may stop its beating altogether, and produce still-stand 
 in diastole. The inhibitory fibres have their origin or roots in the 
 medulla, and proceed in the vagi to the heart. In man and in dogs, 
 they are normally in constant action; and, after they are cut or 
 paralysed, the heart beats in the dog three or four times a§ quickly, and 
 in man twice as quickly, as before. In rabbits and cats, they act less, and 
 their division only makes the heart go one-half or one-fourth faster. (39) 
 A drug may irritate them, and render the heart's action slow — 
 
46 
 
 1. By acting directly on {a) their roots in the medulla, {b) their 
 fibres, if) their ends in the heart ; 
 
 2. Indirectly, through its action on other parts, producing (a) in- 
 creased blood-pressure, or {b) accumulation of carbonic acid in the 
 blood, both of which act as irritants to the vagus-roots 5(40) 
 
 3. Reflexly, through irritation of sensory nerves, (41) irritation of the in- 
 testines, (42) of the sympathetic nerve, (43) of the depressor, (44) or of the 
 vagus of the other side. (45) Reflex irritation is only likely to be caused 
 by drugs having a powerful local action. 
 
 Drugs may also paralyse the inhibitory fibres, and thus quicken the heart. 
 
 III. Quickening Nerves. These belong to the sympathetic system. 
 They have their origin in the brain or medulla, pass down through the 
 cervical part of the spinal cord to the last cervical and first dorsal 
 ganglion (which are often united), and thence through the third branch 
 of the ganglion to the heart. (46) Quickening fibres are said by some to 
 run also in the cervical part of the sympathetic cord. (47) Unlike the 
 vagus, the quickening nerves are not normally in constant action. (48) 
 They may be irritated — 
 
 1. By the direct action of drugs upon them. 
 
 2. Indirectly by the drugs producing a diminished blood-pressure, 
 which acts as a stimulus to them. (49) 
 
 IV. VasO'tnotor Nerves^ which cause the smaller arteries, and pro- 
 bably also the capillaries, to contract. These belong to the sympa- 
 thetic system ; and the most important of them are the splanchnics, 
 which produce contraction of the intestinal vessels. As these vessels 
 can, under certain circumstances, hold all the blood in the body, the 
 influence of the splanchnics over the blood- pressure is very great ;( 50) and 
 division of these can lower it, or stimulation of them increase it very 
 much. The centre of the whole vaso-motor system, however, seems to 
 be in the medulla oblongata; (51) and it is generally in constant action, 
 keeping up a certain amount of contraction or tone in these vessels. 
 Its activity may be increased, and the vessels made to contract — 
 
 1. By direct irritation of the centre. 
 
 2. By reflex irritation through {a) the cervical sympathetic{52), {b) the 
 vagus, when the brain is intact, and the animal not narcotised (53), («r) 
 sensory nerves. (54) When the medulla is separated from the rest of the 
 body by dividing the spinal cord at the atlas, it can, of course, no 
 longer exert any influence over the vessels ; and they consequently 
 become dilated throughout the whole body, and the blood-pressure 
 sinks very low. If the lower end of the divided cord be then irritated. 
 
47 
 
 the vaso- motor nerves which pass through it from the medulla to the 
 body are stimulated, and the blood-pressure rises. 
 
 V. Vaso-inhibitory nerves. Irritation of these nerves is conducted to 
 the vaso-motor centres, and acts on them in such a way as to cause a 
 reflex dilatation of the small vessels, either (i) throughout the whole 
 body, or (2) in one particular part of it. 
 
 1. The chief nerve which causes dilatation throughout the whole 
 body is one which runs from the heart to the medulla, and is called, 
 from its power of diminishing blood-pressure, the depressor nerve. (55) 
 Its fibres seem to be included in the vagus in the dog; but in the rabbit 
 it generally runs separate from the heart to the level of the thyroid car- 
 tilage ; here it divides into two so-called roots, one root going to the 
 superior laryngeal, and the other to the vagus nerve. These are 
 generally called roots, though, as the nerve conveys impressions from 
 the heart to the brain, they are, physiologically, really branches. There 
 seem to be also depressor fibres in the vagus itself ;(56) but this nerve con- 
 tains fibres of many kinds, and, among others, some which cause con- 
 traction of the vessels and rise of blood-pressure— hence called pressor- 
 fibres.(57) The former seem to act on the vaso-motor system through the 
 medulla itself, while the latter affect it through a centre in the brain, 
 so that, when the brain is perfect, irritation of the central end of the 
 vagus causes increased contraction of the vessels and raised blood - 
 pressure ; but, when the brain is removed or its functions abolished 
 by opium, it causes dilatation of vessels and diminished pressure. (58) 
 
 2. When a sensory nerve is irritated, the action of the vaso-motor 
 centre is suspended in the part supplied by the nerve, and in those 
 which immediately adjoin it, so that their vessels become dilated, while 
 at the same time contraction of the vessels in other parts of the body 
 is produced. The blood-pressure is thus increased generally, and pro- 
 duces in the locally dilated vessels a very rapid stream of blood. This 
 fact was first discovered, and its importance in therapeutics indicated, 
 by Ludwig and Loven.(59) 
 
 Action of Counterirritants. — The application of an irritant, 
 whether mechanical, chemical, or thermal, injures the tissues of the 
 part to which it is applied ; and what better means of removing the in- 
 jury and restoring health could be imagined than a copious supply of 
 blood, and the removal of every hindrance to its free flow which con- 
 traction of the vessels might present ? 
 
 Experiments are still wanting to decide how far the vascular dilata- 
 tion will extend in the neighbourhood of the irritated part when more 
 
48 
 
 or less powerful irritants are applied, or which the vessels are (if any) 
 which especially contract, when certain others dilate ; so that at presenr, 
 when we apply a mustard plaster to the chest to relieve bronchitis, we 
 are unable to say with certainty whether the relief is due to a more 
 full flow of blood through the vessels of the bronchi, or to contrac- 
 tion of their lumen diminishing congestion, or (though this is unlikely) 
 to some unknown action independent of the vessels altogether. The 
 experiments of Sinitzin, however (detailed by a recent writer in the 
 British Medical Journal, 187 i, p. 535), which show that ulcers of 
 the cornea, eyelids, and lips, occurring after division of the fifth nerve, 
 rapidly heal when dilatation of the vessels of these parts is produced 
 by extirpation of the superior cervical ganglion, render it in the highest 
 degree probable that it is to the increased flow of blood that healing is 
 due. (60) As a general rule, too, the vascular dilatation seems to extend 
 more widely the stronger the irritant applied ; and we may thus see how 
 a strong irritant, or one applied over a large extent of surface, may 
 prove beneficial in a deep-seated inflammation when a weak one or one 
 applied to a small surface has no effect. 
 
 For convenience of reference, I have put together the causes of alter- 
 ation in the blood-pressure in the following table. 
 
•r -r: -r; o s- i» <u g a> 
 
 i: i: I: c -^ > > ° ."s 
 
 I— I (—(I— II— iP-iP*K^U'LJ 
 
 
 
 !3 2 
 
 pn 
 
 PQ 
 
 pq 
 
 •psitsuiTuitp sq X-Eui 3.inss3jd-poo][g; 'pastjojoui 9q Xbut ajnss3id-poo|g; 
 
 H 
 
so 
 
 Application to Pathology.— The brief sketch of the circulation 
 which I have given, will enable you to understand and appreciate the 
 meaning of the changes produced in our circulation by any drug, and 
 to explain the facts we may meet with in the course of an investigation. 
 I may remind you that the alterations in the pulse-rate and blood-pres- 
 sure which we meet with in disease, as well as those produced by drugs, 
 are due to some one or other of the causes mentioned in the previous 
 table ; and whenever you meet with a quick, slow, weak, or irregular 
 pulse, you must try to find out to which of these causes it is due, in 
 order that you may be able to apply scientifically the proper remedy. 
 
 Experimental Examination of Blood-Pressure : Forms of 
 Manometer. — As the life and health of the body and of the organs 
 comprising it depend on the supply of blood to them — and this, as we 
 have already seen, is closely associated with the arterial pressure — the 
 observation of the effects of drugs on it naturally forms one of the 
 most important parts of an investigation into their action. The first to 
 measure the blood -pressure was Hales, who simply connected a glass- 
 tube with an artery, and noted the height to which the blood rose in it. 
 Poiseuille improved upon this method by substituting a bent tube, par- 
 tially filled with mercury, for the straight tube, and estimating the pres- 
 sure from the difference in the level of the mercury in the two limbs. 
 A solution of carbonate or bicarbonate of soda was introduced into the 
 tube between the mercury and the blood in order to prevent its coagu- 
 lation. The bent tube, partly filled with mercury, is called a haemady- 
 namometer, or, more generally, a manometer. The height of the mer- 
 cury is read off from a scale fixed behind the tube. Usually both limbs 
 of the tube are of equal diameter, and the blood-pressure is then ascer- 
 tained by doubling the height of the mercury in one limb above zero 
 and subtracting a fraction, which varies with the specific gravity of the 
 solution of soda used. The height must be doubled, because the mer- 
 cury descends as much below zero in the one limb as it rises above it 
 in the other ; and a fraction of the whole is subtracted for the additional 
 weight of the column of soda solution, which enters one limb as the 
 mercury rises in the other. 
 
 A very simple manometer, which will show the mean blood-pressure 
 as well as the maximum and minimum between which it oscillates, may 
 be made by passing two straight glass-tubes about sixteen inches Jong 
 through the cork or India-rubber stopper of a small wide-mouthed bottle, 
 and fixing behind them a graduated cardboard scale. The lower end 
 of one tube must be nearly closed in the blow-pipe flame, and both 
 
51 
 
 pushed down till they almost touch the bottom of the bottle. A third 
 bent tube is inserted into the stopper, reaching only to its under sur- 
 face, and a piece of India-rubber tubing is attached to its upper end for 
 the purpose of connecting it with the artery. Some mercury is then 
 poured into the bottle, so as to stand a little above the ends of the 
 tubes, and both it and the India-rubber tube are filled with a saturated 
 solution of bicarbonate of soda and connected with the artery. The 
 mercury rises and falls in the open tube with every pulsation ; but in the 
 one with the constricted end the resistance to its movement is so great 
 that it can only rise and fall slowly, so that, before its upward oscilla- 
 tion has had time to show itself, its descent has begun, and vice versdb. 
 The upward and downward oscillations thus balancing each other, the 
 mean pressure only is shown. 
 
 The oscillations in the unconstricted tube are so rapid that it is im- 
 possible for the eye to follow them exactly; and this difficulty led Lud- 
 wig to conceive the idea of making them register themselves by means 
 of a slender rod swimming on the surface of the mercury, and bearing 
 at its upper end a pen which moved up and down on a piece of paper 
 fixed on a revolving cylinder. The vertical height of the tracing thus 
 produced showed the blood-pressure, while the horizontal distance from 
 one point to another on it indicated the time between them. 
 
 This instrument is called a kymographion ; and in devising it, Ludwig 
 introduced for the first time into physiology that method of self-regis- 
 tration which is now generally applied to all kinds of vital pheno- 
 mena, and has already done much to render our knowledge exact. 
 That form of it which is used by Traube and made by Sauerwald of 
 Berlin is shown in fig. 7. It consists of a metal cylinder (/) supported 
 on a wooden frame (y), and caused to revolve at a steady rate by clock- 
 work and pendulum (/ and u). The manometer is fixed to the wooden 
 frame and connected with the artery by tubing of lead and India- 
 rubber. On the mercury in one limb floats a rod or swimmer of glass, 
 to whose upper end is attached a glass pen {g), which registers the 
 movements of the mercury on the revolving cylinder. 
 
 The disadvantage of the mercurial manometer is, that it does not 
 give the true form or extent of the variations of blood-pressure, the 
 inertia of the mercury causing it to oscillate above and below the true 
 value. We may, however, obtain the true form of each oscillation along 
 with the mean pressure by connecting the artery at the same time with 
 the manometer and one of Marey's sphygmoscopes and levers (fig. 6, 
 X and y) by means of a Y-tube, one end of which is connected to d and 
 
52 
 
 A. Ludwig s Kymographion. «'. The manometer. Instead of one simple bent 
 glass tube, it consists of two tubes fixed on a piece of wood, and joined by a 
 piece of metal b, which may be unscrewed for cleaning the tubes. <r is a tube 
 of soft lead, for connecting the manometer with the artery. One end of it is 
 
53 
 
 screwed to the manometer, and the other is attached to a stopcock d. d is a. 
 stopcock attached to c, and may be connected with the tube b in the artery 
 by a piece of India-rubber tubing. It is bored in a T-shape. and is perforated 
 in the centre by an additional perpendicular hole, into which is put a hollow 
 plug ^. y is a flask containing saturated solution of bicarbonate of soda, and 
 connected by India-rubber tubing with e. When the clip on the India-rubber 
 tube just above e is removed, and the stopcock turned longitudinally, soda 
 solution will flow into c as well as out of d. By turning it transversely, the 
 opening towards c may be closed, and soda will then only run out through d. 
 This is done when we wish to wash out the cannula with soda without altering 
 the level of the mercury in a. g^ is a glass pen attached to the top of a glass 
 rod or swimmer, which rests on the surface of the mercury in a. h is a thread 
 of unspun silk, with a small weight attached to it. It rests against the pen g, 
 and keeps it constantly applied to the paper without impeding its movements. 
 i is an iron wire, from which the thread h is suspended, j is the wooden frame 
 bearing the clockwork and revolving cylinder, k are three screws to level the 
 frame. / is the clockwork, in is an upright, and « a horizontal bar, which 
 support a pivot o. / is a metal cylinder, which carries the paper. ^ is a small 
 metal bar for holding the paper on the cylinder. It is hinged to the lower 
 edge of the cylinder, and caught by a spring at its upper edge. It lies in a 
 hollow in the cylinder, so that its outer surface does not project above it. 
 When a new paper is to be put on, the spring catch at the upper end of q is 
 raised, q pulled out, the old paper removed, and the edges of the new one 
 placed under q. It is then pushed down, its upper end is caught by the spring, 
 and the paper is securely held, r is a catch for stopping the movement of the 
 clockwork, s and s' are two weights to drive the clockwork. ^ is a rack for 
 winding up the weight j'. u is a pendulum, with a movable bob, to regulate 
 the motion of the clockwork and cylinder. By moving the bob up or down, 
 the motion may be made quicker or slower, z/ is a pencil stuck through a 
 piece of cork, and fastened to the upright m, so as to draw a line on the paper 
 at the same level as g, when there is no pressure on the mercury in the tube. 
 The blood-pressure is estimated by the height of the curve traced by g, above 
 the zero line thus drawn, y is one of Marey's tympana, which is supported on 
 a movable rod z, and may be used for registering either the respiration or the 
 form of the pulse-wave. It consists of a shallow cup of metal, over whose top 
 a piece of India-rubber is tightly stretched. A metal tube passes into the in- 
 terior of the cup, and a light lever lies over the upper surface of the India- 
 rubber, and is firmly connected with it. When air is blown into the interior 
 of the cup, the India-rubber bulges and raises the lever; when air is sucked 
 out, it becomes depressed and draws the lever down. When used to register 
 the respirations, it is simply connected with a tube in the trachea of the 
 animal, or with a mask fitted before its nose. As the piece of India-rubber 
 stretched over jj* is thin, it would be blown out, and perhaps burst, by the 
 pressure, if we were to connect it directly with the artery. One of Marey's 
 sphygmoscopes is, therefore, introduced between them, when we wish to 
 measure the blood-pressure. The sphygmoscope consists of a little bag 
 of strong India-rubber, enclosed in a piece of glass tubing, connected with 
 the tympanum. The bag is filled with soda solution, and connected with 
 the artery. Each time that the pressure rises in the artery, the bag 
 becomes distended, and forces some of the air out of the glass tube 
 into the tympanum, and raises the lever ; and when the pressure diminishes, 
 the bag collapses again, and the lever falls, x is a modification of this, designed 
 by my friend Dr. Burdon Sanderson. Instead of a bag enclosed in a tube, it 
 consists of a metal box, across the interior of which a septum of strong India- 
 rubber is stretched. One side of the box is filled with soda solution, and con- 
 nected with the artery ; the other with air, and connected with the tympanum. 
 7f is a piece of lead tubing for connecting the sphygmoscope x with the tube 
 in the artery. 
 
 B is a forked tube of German silver or brass for connecting the artery with the 
 kymographion. « is a cannula, which is inserted into an artery (see fig. 3A) ; 
 ^ is a small ring soldered to it, by which it may be tied to the rings e on b, to pre- 
 vent it from slipping off"; e and e are two rings soldered to b. By means of liga- 
 tures passed through these, b may be fastened to the skin or hair of the animal 
 to prevent its being displaced by any sudden movement. The oblique limb of 
 B may be connected to Kd alone by a piece of India-rubber tubing, or to both 
 A d and a w at the same time hy means of a Y glass tube and India-rubber 
 tubing. Another piece of India-rubber tubing is attached to the straight 
 limb d, and closed by a clamp or clip. When a clot forms, the clip is taken 
 off, and the clot removed, the tube washed out by a stream of soda solu- 
 tion, and the clip again replaced. 
 
 c is the tracing-pen (see fig. 3&). It is stuck horizontally through a piece of 
 
54 
 
 cork : another small piece of glass tubing, about three-fourths of an inch long, 
 closed at its upper end, and about one-twelfth of an inch in diameter, or just 
 wide enough to admit the end of the swimmer, is stuck vertically into the 
 same piece of cork 
 
 the other to w. In order to obtain the mean pressure we turn the stop- 
 cock (<?), till on blowing through it only a slow rise and fall of the mer- 
 cury can be produced, but no sudden oscillation. On then connecting 
 it with the artery the mercurial column shows the mean pressure, while 
 the sphygmoscopic lever registers each oscillation 
 
 Besides this form there are various others on the same principle, some 
 of which have cylinders which wind off a continuous roll of paper from 
 a bobbin, so that a tracing may be taken uninterruptedly for an hour 
 or two without renewing the paper. In order to avoid the inconve- 
 niences of the mercurial manometer, Fick has constructed one (Fig. 8) 
 in which the pressure is not measured by the movements of a column 
 of mercury, but by those of a bent hollow tube (a) fixed at one end and 
 
 Fi<j,S 
 
 Fick's spring kymographion. a is a flat tube of German silver, fixed at one 
 end B, to a piece of board d. The other end c is freely movable, e is a tube 
 connecting a with the artery, f is a lever made of reed, connected to c. g is 
 the writing point, moved up and down by f, and kept perpendicular by 
 another short lever above. The tube a is filled with alcohol, and the tube E 
 with a soda solution ; and b is then connected with the artery. Whenever the 
 pressure rises, the tube A tends to straighten itself, but it is firmly fixed at the 
 end B, and so the end c alone moves upwards, and pushes up the lever f and 
 the writing point G. Whenever the pressure relaxes, the tube bends back 
 again to its original shape, and the point G consequently again descends. The 
 tracing is taken by allowing g to rest against a revolving cyUnder, covered 
 with a piece of paper, which has been smoked either over a gas flame or a 
 paraffin lamp. 
 
55 
 
 free at the other. The tube is filled with alcohol, and its fixed end 
 connected with an artery. At every rise of pressure this tube tends 
 to straighten itself, and this motion of the free end is communicated 
 by it to a lever (f) and writing-point (g), which records it on a smoked 
 cylinder. 
 
 The advantage of this form of kymographion is, that it gives the 
 exact form, duration, and extent, of each pressure- variation. Its dis- 
 advantage is, that the tracings it gives are on a small scale, so that it 
 is not so well adapted for showing small oscillations of pressure like 
 those at each heart-beat in the rabbit, although it answers admirably 
 for dogs. Another disadvantage is, that the tracing must be taken 
 on smoked paper, and this is more troublesome to manage than white 
 paper and ink. 
 
 Mode of using the Kymographion. — The kymographion must 
 first be rendered perfectly level by the screws, K K (fig. 7). The upper 
 part of the outer tube of a and the tube c, the India-rubber tube connect- 
 ing it with B, and B itself, are then filled with soda solution and the clip 
 at e put on. A fresh sheet of paper is put on/, the pen (^) filled with ink, 
 and the pencil {v) adjusted at the same level. A piece of cotton-thread 
 should be drawn through the pen, so that the end projects just beyond 
 the pen's point ; this makes the pen write better. The animal is next 
 fixed, a vein exposed for injecting, the cannula (a) introduced into an 
 artery in the way already described, the blood being prevented from 
 entering the cannula by a clip placed on the artery. A drop of carbonate 
 of soda solution is placed in the cannula (a), the tube (b) fitted into it 
 and tied to it by a thread through the ears, b and c. Two other threads 
 through e and e fasten the tube (b) to the skin or hair of the animal. The 
 flask {J) is raised several feet above the apparatus, and the clip at e 
 opened, so as to make the pressure in the manometer and tubes nearly 
 equal to that of the blood in the vessels so as to prevent the blood from 
 filling the tubes. It must not be greater, or the carbonate of soda will 
 pass into the vessels and produce convulsions. The clip at e is then 
 replaced and that on the artery removed, the cylinder set in motion, and 
 a tracing of the normal blood-pressure taken. 
 
 The dmg in solution is now injected into a vein and a fresh tracing 
 taken. At the time the injection is begun a cross should be made on 
 the tracing opposite the pen of the kymographion, and a o should be 
 made when the injection is finished. The time at which these were 
 made should be noted on a separate piece of paper, and afterwards 
 copied on to the tracing itself. Instead of putting each time on a 
 
56 
 
 fresh piece of paper, two or three may often be taken on one paper by 
 having two or three exactly similar glass pens of the form shown filled 
 with inks of different colours. Each is stuck through a small piece of 
 cork, and into the under side of the cork a small glass tube is put, 
 which will just fit the top of the swimmer. By simply dropping the 
 glass tube on the end of the swimmer the pen is in its place at once, 
 and can be changed with great facility. A small sable brush may 
 also be substituted for the glass pen. 
 
 After the experiment has gone on for some little time, a clot is apt 
 to form in the cannula. When this is the case the clip must be re- 
 placed on the artery, the stopcock (d) turned transversely, so as to keep 
 the mercury at the same height, the, clip on the India-rubber tube of 
 d B and at <? A removed, and the tube washed out by a stream of car- 
 bonate of soda. Any clot in the cannula is removed by a spill of twisted 
 paper, by a hog's bristle, or by a piece of whalebone. The whalebone- 
 probes are most convenient, as they can be made of any size. A single 
 jet of blood should now be allowed to escape from the artery, so 
 as to make sure that there is no clot in it, the tube again washed 
 out with carbonate of soda, the clips at ^ B and e A replaced, that on 
 the artery removed, and the stopcock turned and tracings taken as 
 before. 
 
 Reduction oif the Kymographion Tracings. — It is not only 
 impossible to publish the tracings as they are taken from the kymo- 
 graphion for the benefit of others, but it is extremely difficult to draw 
 any except very general conclusions from them for one's self. Before 
 they can be of much use they must be reduced to tables, or, what is 
 still better, the tables themselves may be graphically represented. In 
 making the tables we must first fix the time at which the different parts 
 of the tracing were made. The time when the tracing was begun and 
 when the injection was made must be noted down at the time in a 
 separate note-book, or, still better, on the tracing itself. In the first 
 tracing it is convenient to take the time when the injection was made, 
 as a starting-point from which to reckon the other periods. 
 
 Beginning at this point, then, we divide the abscissa or zero line into 
 parts corresponding to five seconds each, or any other period we think 
 convenient. If the circumference of the cylinder be sixty millimetteSy 
 and it revolve once in a minute, each five millimetres of paper will cor- 
 respond to five seconds' revolution. 
 
 Secondly, we must ascertain the blood-pressure at different times. 
 At the point where the injection took place, we draw from the 
 
57 
 
 tracing a perpendicular to the abscissa, and. another, five, ten, or 
 fifteen seconds fiirther back. The mean pressure is most readily and 
 exactly got by means of a planimeter; but, as this is an expensive instru- 
 ment and possessed by few, we usually employ ruder methods. The first 
 is to determine the square superficies of the irregular figure contained by 
 the abscisse, the two perpendiculars, and the curve, and then divide it 
 by the length of the abscissa : this gives the mean height of the pres- 
 sure-curve. The size of the figure is ascertained by placing over it a 
 piece of tracing-paper or glass ruled in square millimetres, and counting 
 the number of squares contained in it. Volkmann cuts the figure exactly 
 out in paper of uniform texture and weighs it. By then comparing its 
 weight with that of a square of given size, the superficies of the figure 
 is easily ascertained. The second method is still simpler, and, though 
 not so exact, takes much less time, and is, therefore, frequently em- 
 ployed. It consists in drawing a straight line from one perpendicular 
 to the other along the curve, so as to cut the pulse- and respiration- 
 waves as nearly as possible in their middle, and leave as much of their 
 surface above as below it. We then measure the height of this line 
 above the abscissa, double it, and subtract from it the fraction of the 
 whole, which represents the column of carbonate or bicarbonate of 
 soda solution which entered one limb of the manometer and pressed 
 on the mercury in it as the mercury rose in the other limb. For a 
 solution of carbonate of specific gravity 1018, this fraction will be 
 about ^ of the whole. 
 
 Passing along the curve taken after the drug has been injected, we 
 note the place where any change in pressure has occurred, and here we 
 draw another perpendicular and proceed as before. Thirdly, we obtain 
 the number of pulsations and respirations in a minute by counting the 
 pulse- and respiration-waves between each two perpendiculars, and 
 reckoning from the time between them what the rate of pulse or respir- 
 ation will be in a minute. As the rate of both may change several 
 times in a minute, and a calculation of this sort would lead to consider- 
 able error, we not unfrequently take fifteen seconds as the unit of time 
 instead of a minute. 
 
 The way in which the numbers thus obtained may be tabulated, is 
 shown by the following examples of supposititious experiments. These 
 examples have been made by piecing together several experiments of 
 Von Bezold, and show generally the action of atropine, but must not be 
 regarded as accurate descriptions of any one experiment. Even when 
 a continuous roll of paper is employed, instead of several separate 
 
 I 
 
58 
 
 pieces, it is often convenient to divide it by lines, and tabulate each part 
 separately, just as when separate pieces of paper are used. 
 
 Mode of Recording Experiments. 
 
 Experiment /, November 5, i8 . 
 
 Young rabbit. Weight 1540 grammes. Jugular vein exposed and 
 one cubic centimetre of tincture of opium, containing two grammes in 
 twenty-five cubic centimetres, injected into it. Cannula in the left carotid. 
 Animal otherwise uninjured. 
 
 Tracing I. 
 Tracing begun 2.39. p.m. .. 
 Injection begun 2.39. 15. .. 
 „ ended 2.39.25. .. 
 
 At 2.39.35 
 
 At 2.40.0 
 
 Tracing II. 
 At 2.40.30 
 
 u 
 
 
 <h 
 
 g 
 
 % 
 
 , t 
 
 .3 
 
 t 
 
 6^ 
 
 1i 
 
 J 
 fS 
 
 
 
 78 
 
 60 
 
 23 
 
 
 78 
 
 60 
 
 23 
 
 
 80 
 
 63 
 
 18 
 
 lOS. 
 
 «3 
 
 65 
 
 19 
 
 35s. 
 
 «7 
 
 70 
 
 20 
 
 i-S 
 
 92 
 
 92 
 
 22 
 
 Remarks. 
 
 2^ milligrammes of sul- 
 phate of atropine, dis- 
 solved in 2 cubic cetiti- 
 fnelres of water, injected 
 into the jugular vein to- 
 wards the heart. 
 
 Experiment II, November 9, 1 8 . 
 Old rabbit. Weight, 1 764 grammes. Jugular vein exposed. Animal 
 not narcotised. Cannula in the left carotid. Animal otherwise unin- 
 jured. 
 
 Tracing I. 
 Tracing begun 3.50.0 p.m. 
 Injection begun 3.50.10.. , 
 
 At 3.50.13 
 
 Injection ended 3.53.1s.. 
 At 3.51.0 
 
 Tracing II. 
 At 3.58.0 
 
 s . 
 
 
 i 
 
 § 
 
 ^ s 
 
 6 
 
 c 
 
 tj 
 
 
 
 
 
 
 
 S5 
 
 1 
 
 
 
 92 
 
 64 
 
 26 
 
 
 92 
 
 64 
 
 26 
 
 
 73 
 
 
 
 .. 
 
 73 
 
 70 
 
 24 
 
 45s. 
 
 72 
 
 70 
 
 26 
 
 7-45 
 
 78 
 
 68 
 
 25 
 
 Remarks. 
 
 cejitigranimes of sul- 
 phate of atropine, dis- 
 solved in 2 cubic centi- 
 metres of water, injected 
 into the jugular vein to- 
 wards the heart. 
 
 Graphic Method of Representing Experiments. — In looking 
 over a column of figures such as the tables we have now obtained, it 
 is by no means easy to see at once what it really indicates ; and it is 
 still more difficult when we have to compare several tables together. 
 For this reason it is of great advantage to convert the tables into 
 curves, from which the result of any experiment can be learned at a 
 
59 
 
 glance, and the points of resemblance, or difference in the results of a 
 whole series compared with the greatest ease. 
 
 To obtain these graphic curves, we reverse the process by which we 
 formed our tables. We first take a piece of paper ruled in squares, 
 and on it we draw a horizontal line or abscissa, and then a perpendicu- 
 
 Fig. 9. 
 
 r^ 
 
 100 
 
 ^ 
 
 lar to one or both ends, and number the spaces along both the abscissa 
 and the perpendicular or ordinate. Those along the abscissa represent 
 periods of time to which we may assign any value which is convenient, 
 seconds, minutes, hours, or multiples of these. The numbers along 
 the ordinate may represent blood-pressure, pulse-rate, number of respir- 
 ations, or degrees of temperature ; and we may describe curves repre- 
 senting all of these on the same paper, distinguishing them from one 
 another by the use of different coloured inks. Fig. 9 represents gra- 
 phically the tables of blood -pressure and pulse-rate in Experiments i 
 and II. We begin the pressure- curve by making a dot on the first 
 perpendicular, at a height corresponding to the number 78. Passing 
 along horizontally from this for a space corresponding to fifteen seconds 
 to the abscissa, we make another dot ; and at ten seconds further, at a 
 height corresponding to 80, we make a third dot, and so on. We 
 then connect the dots by lines, and thus obtain the curves we wish. 
 
IV. — Determination of the exact Structures through which 
 Drugs affect the Heart and Vessels. 
 
 Comparison of the Effects of Drugs on different Animals in different 
 Doses. — Mode of detei'mining the Exact Cause of Symptoms. — 
 Mode of raising Blood-pressure. — Modes of counting the Beats 
 of the Heart. — Causes of Quickened Ptdse. — Direct Stimulation 
 of the Sympathetic. — Stimulation of Cardiac Ganglia. — Paralysis 
 of the Vagus-roots and Fibres, and of its ends in the Heart. — Causes 
 of Slozo Pulse. — Irritation of Vagus-roots. — Mode of supplying the 
 Head and Body with different kinds of Blood. — Indirect B^ritation of 
 Vagus-roots through the Blood-pressure : mode of lowering and rais- 
 ing it. — Reflex Irritation of Vagus- roots, — Indirect Irritation through 
 the Respiration. — Irritation of Vagus-fibres. — Increased Conducting 
 Poiver of Fibres. — Stimulation of Vagus- ends, — Paralysis of the Sym- 
 pathetic. — Paralysis of the Cardiac Ganglia. — Part of the Ganglionic 
 Apparatus Aflected. — Nervous System in the Heart. — Motor Ganglia. 
 — Stimulating Ganglia. — Inhibitory Ganglia. — Connecting Apparatus. 
 — Action of Drugs on the Inhibitory Apparatus — Nicotia, Muscaria. 
 — Antagonism of Atropia and Physostigma : bearing of this on Thera- 
 peutics. — Paralysis of Co-ordinating Apparatus. — Paralysis of the 
 Muscular Fibres of the Heart. — Blood-pressure : mode of determining 
 whether changes in it are dzie to alterations in the Heart or Vessels. — 
 Elimination of the Action of the Heart: Division of its Nerves. — 
 Irritation of Vagus. — Ligature of Aorta. — Artificial Circulation ; in 
 Mammals, in the Frog. — Observation of Vessels. — Action on Vaso- 
 motor Centre ; on Vascular Walls. — Influence of ths Action of Parts 
 surrounding the Vessels upon the?n. — Action of the Pulmonary Circu- 
 lation on the Blood-pressure. — Use of the Sphygmograph. 
 
 Comparison of the Effects of Drugs. — Before proceeding to 
 examine separately the different structures through which a drug may 
 act on the blood-pressure, it is advisable to compare the effects which 
 it produces on animals of different kinds, such as dogs and rabbits, as 
 well as the action of larger and smaller doses on animals of the same 
 kind. Continuing to take as an example the action of atropia, ad- 
 mirably investigated by Von Bezold, we find the following results. (6 1) 
 
 With a small dose of atropia injected into the jugular vein towards 
 the heart : 
 
6i 
 
 The blood-pressure rises in both rabbits and dogs : 
 
 The pulse becomes quick, rising in rabbits from 256 to 288 ; in 
 
 dogs, from 80 to 240. 
 With a larger dose : 
 
 The blood-pressure, in both rabbits and dogs, falls at first and 
 
 afterwards rises to the normal. 
 The pulse becomes quick in both. 
 With an additional dose : 
 
 The blood-pressure in rabbits falls very low as the poison reaches 
 
 the heart ; afterwards rises ; and falls again below the normal. 
 The pulse becomes slower, and then quicker. 
 With a very large dose : 
 
 The blood-pressure sinks instantly in both rabbits and dogs. 
 The pulse in rabbits becomes slower and weaker, and then stops ; 
 
 in dogs, it becomes quick. 
 
 This comparison between the effects which atropia produces in different 
 animals, and in large and small doses in the same animal, shows us that 
 it sometimes raises and sometimes lowers the blood -pressure, but that 
 it always quickens the pulse, except when a large quantity of the poison 
 is introduced at once into the heart of the rabbit. On consulting 
 the table already given (British Medical Journal, June 3rd, 
 page 583), it will be seen that quickening of the heart may be 
 due to stimulation of the sympathetic, either directly by the drug or in- 
 directly by diminution of the blood -pressure ; to stimulation of the car- 
 diac ganglia ; or to weakening or paralysis of the vagus. Any one of 
 these conditions may cause quickened pulsation ; and, in order to de- 
 termine which of them really does it, we must test each one of them 
 separately by farther experiment. 
 
 Mode of determining the exact Cause of Symptoms. — The 
 plan which we follow is this : we suppose for the time being that the 
 cause which we are testing is the true one, and consider what effects it 
 will produce under certain conditions. We then supply these condi- 
 tions experimentally, and see whether or not the results we obtain cor- 
 respond with those which we should find if our supposition were cor- 
 rect. So in the present instance we first ask. Is the quickening of the 
 pulse due to indirect stimulation of the sympathetic roots by diminished 
 blood-pressure or not ? We suppose for the moment that it really is so, 
 and we consider that if we raise the blood-pressure we shall remove the 
 cause of quickening and bring the pulse down again to its normal rate. 
 We then proceed to raise the pressure, and see whether or not the pulse 
 is rendered slow, as we expect it to be. In the case of atropia, a special 
 
62 
 
 experiment is not necessary for this purpose, as we have seen that small 
 doses do not lower but raise the blood-pressure, at the same time that 
 they quicken the pulse ; consequently the quickening cannot be due to 
 indirect stimulation of the sympathetic. Other drugs, however, such as 
 nitrite of amyl, even in small doses, lower the blood-pressure at the 
 same time that they quicken the pulse ; and in their case we must raise 
 the blood-pressure artificially. 
 
 Mode of Raising Blood-pressure. — This may be done either by 
 injecting a sufficient quantity of the defibrinated blood of another animal 
 of the same species, warmed to 98 deg. Fahr., into the carotid or crural 
 artery towards the heart, or by compressing the aorta. The aorta may 
 be either compressed by the thumb of the operator, or by a narrow pad 
 of cork laid over it and pressed upon it by a tourniquet, of which the 
 strap has been passed round the animal's body. 
 
 Mode of Counting the Beats of the Heart.— Now, if we wish 
 to determine the blood-pressure at the same time with the pulse-rate, 
 we may count the latter from the oscillations which each beat of the 
 heart produces in the tracing of the kymographion, or from the sphyg- 
 moscope attached to it ; but this is not always necessary, and we may 
 wish to ascertain the pulse-rate without going to the trouble of opening 
 an artery and using a manometer. We may do this in three ways — I. 
 By feeling the pulse in one of the large arteries, such as the crural, with 
 the finger ; 2. By listening to the beats of the heart with a stethoscope ; 
 3. By the motion of a needle stuck into the ventricles. For this pur- 
 pose a fine harelip-needle is inserted at the point where the apex 
 beats, and is pushed upwards into the substance of the ventricle. At its 
 upper end it may have either a knob, or a loop to which a thread can 
 be attached, and a barb at the point will prevent it from changing its 
 position in the heart when traction is made upon it. In rabbits, the 
 point where the needle should be inserted is in about half an inch to 
 the left of the sternum in the third intercostal space, and the length of 
 the needle used should be about three inches. Various means have 
 been proposed for counting the oscillations more readily than can be 
 done by simply watching the movements of the needle itself. (62) The 
 knob of the needle may be allowed to strike against a wineglass, and 
 the pulsations may thus be counted by the ear ; or a needle without a 
 knob may be used, and a rice-straw with a piece of bright- coloured paper 
 attached to it may be slipped over it, so that its vibrations, amplified by 
 the long straw, and made more visible by the bright- coloured paper, 
 may be readily counted by the eye. 
 
63 
 
 A convenient way of registering the oscillations on an upright cylinder 
 is one devised by Professor Strieker. One of Marey's cardiographic 
 levers is fixed on a rod close to the side of the animal and some distance 
 above it, and a small piece of cork attached to the lever. One end of 
 a fine thread is then fastened to the needle, and its other end pulled 
 through a slit in the cork till it is sufficiently tight to make the lever 
 vibrate with each movement of the needle ; it is then fastened by twist- 
 ing it round the lever, or by a little sealing-wax. If the lever be not 
 raised several inches above the needle, it is pulled too much to a side 
 and not sufficiently downv/ards to give a good tracing. The tracing 
 may be taken either on plain paper with a glass-pen or camel's hair- 
 brush attached to the lever by a piece of cork, or with a dry point on 
 smoked paper. Instead of a vertical cylinder a horizontal one may be 
 used, and is perhaps still better. In this case the lever should be nearly 
 on a level with the needle, and not raised much above it. 
 
 Is THE Quickening of the Pulse due to direct Stimulation 
 OF THE Sympathetic ? — If so, the injection of the drug should cause 
 an increase in the pulse-rate after the vagi have been divided as well as 
 when they are intact. We, therefore, divide the vagi, inject the drug 
 into the veins, and see whether or not the pulse-rate is increased. On 
 doing this with atropia it is found that the pulse becomes slower rather 
 than quicker, showing that the drug does not stimulate the quickening 
 nerves of the heart. The increased rapidity of the pulse which it pro- 
 duces when the vagi are intact is, therefore, not due to this cause. 
 
 Is the Quickening due to Stimulation of the Cardiac Gan- 
 glia ? — The experiment just mentioned shows that it is not, for if it 
 were, injection of atropia should cause quickening after division of the 
 vagi. Supposing, however, that it had caused quickening, the question 
 whether the acceleration was due to the ganglia or the sympathetic 
 would have to be decided by dividing all the nerves going to the heart 
 with a platinum- wire heated by electricity, (63) and then injecting the 
 drug, or by applying it to the heart of the frog in a way which I shall 
 afterwards describe. If it quickened the beats of a heart thus separated 
 from all other nerves, it could only do so by acting on the cardiac 
 ganglia themselves. 
 
 Is THE Quickening due to Paralysis of the Vagi ? — The ex- 
 clusion of the other causes leads us to believe that it is due to this ; 
 but, in order to avoid the possibility of error, we must try to confirm 
 our conclusion by other experiments ; and, moreover, we have still to 
 find out which part of the vagus is affected — its roots, its fibres, or its 
 ends in the heart. 
 
64 
 
 Are the Vagus-roots Paralysed by the Drug ?— We are en. 
 abled to answer this question by our knowledge of the fact, that poisons 
 only act on the parts to which they are carried by the blood, and that 
 when introduced into the circulation they do not reach every part of 
 the body at once, but are carried on with the blood-stream first to one 
 part and then to another, and will reach a part near the point where 
 they were introduced before one which is farther off. Thus if we inject 
 a drug into the carotid it will be carried direct to the head, and will act 
 on the medulla oblongata and the roots of the vagus before it reaches 
 the heart ; but if we inject it into the jugular vein it will reach the heart 
 and act on the vagus- ends in it before it reaches the roots in the medulla. 
 If atropia paralyse the vagus-roots, then its injection into the carotid 
 towards the head should be followed by rapidity of the pulse more 
 quickly than its injection into the jugular j but if it act on the vagus- 
 ends in the heart, the pulse should become rapid more quickly after 
 injection into the jugular vein towards the heart than after injection into 
 the carotid. On testing this experimentally, it is found that, when 
 atropia is injected into the jugular vein towards the heart, the pulse at 
 once becomes quick, even before the injection is finished ; but, when it 
 is injected into the carotid towards the head, the pulse is not quickened 
 for a quarter of a minute or more, or, in other words, till the poison 
 has had time to pass through the capillaries of the head and go through 
 the veins to the heart. This, then, shows that it is the vagus- ends in 
 the heart, and not the roots in the medulla, that are paralysed by it. 
 
 Are the Vagus-fibres Paralysed? — From the rapidity with which 
 paralysis of the vagus occurs after atropia reaches its ends, we have 
 already come to the conclusion that the ends are the part affected rather 
 than the roots or fibres ; but it is well to substantiate our conclusion by 
 further experiment. We divide the vagus and galvanise its peripheral 
 extremity. If we do this to a normal vagus, the heart will beat more 
 slowly or stand still altogether ; but if either the fibres or ends of the 
 nerve have been paralysed, no change will be produced in the heart's 
 rhythm by the application of galvanism to its trunk, and this we find to 
 be the case after the administration of atropia. But this experiment 
 does not enable us to decide which part of the nerve is paralysed — the 
 fibres or the ends, for in either case the effect would be the same. We 
 may do this, however, by observing the effect which irritation of the 
 vagus-trunk produces on such of its fibres as do not go to the heart. If 
 it were the fibres which were paralysed, we should expect that those 
 which go to the heart would not be the only ones affected, but that 
 those going to other parts would be paralysed likewise. 
 
65 
 
 I have hitherto spoken of the vagus as if it were a simple nerve contain- 
 ing only inhibitory fibres for the heart, but it is really a most compli- 
 cated bundle, containing centripetal fibres having probably no fewer than 
 eleven different functions, and centrifugal ones having nine or ten ;{6^) 
 so it is little wonder that it has long been a puzzle to physiologists, and 
 even yet its functions are not completely investigated. Among these 
 fibres are some which produce contraction of the oesophagus and muscles 
 of the larynx ; and if we find that irritation of the vagus continues to 
 produce contractions in these parts after it has ceased to render the heart's 
 action slow, as is the case after injection of atropia, we conclude that its 
 fibres are not paralysed. Dr. Rutherford has shown(65) that the best 
 mode of observing the effects of irritation of the vagus on the muscles of 
 the larynx, is to open it in front and place the animal in such a position 
 that the light may be reflected from the inner surface of the arytenoid 
 cartilage, as the slightest movements can then be readily detected. In 
 this way it is found that atropia produces complete paralysis of the car- 
 diac branches of the vagus, while the motor fibres supplying the mus- 
 cles of the larynx remain unaffected ; and we are therefore forced to con- 
 elude that it acts not on the fibres but on the ends in the heart. A 
 more direct method is to apply the drug dissolved in an indifferent 
 fluid, such as half per cent, solution of chloride of sodium, to the vagus 
 itself, and then to irritate the nerve above this point. This may be 
 done by dropping the solution on the nerve after placing a piece of 
 gutta-percha tissue below it, so as to keep the fluid from reaching the 
 tissue below and being absorbed. If the drug paralyse the fibres the 
 irritation which is applied to the nerve above the part which is moist- 
 ened by the solution will not be conveyed by the paralysed part of the 
 nerve, and will consequently have no effect on the heart. 
 
 How DOES A Drug render the Heart's Action Slow? — We 
 have now gone over the experiments which are necessary to determine 
 what the structure is through which a drug quickens the heart's action, 
 and we have now to consider those which we require when investigating 
 the action of a drug which renders it slow. It may do so by irritating 
 the vagus-roots, fibres, or ends ; by increasing their excitability, so that 
 they act more strongly when stimulated ; or by paralysing the sympa- 
 thetic, the cardiac ganglia, or the muscular substance of the heart itself. 
 
 Does it act by irritating the Vagus-roots? — In order to 
 answer this question, we divide both vagi and then inject the drug. 
 We thus separate the heart from the vagus-roots and deprive them of 
 any influence over it, so that, if they have been the cause of slowness of 
 
 K 
 
66 
 
 the pulse in previous experiments, it will not occur in this ; but if the 
 slowness have been due to other causes it will, with one or perhaps 
 two exceptions, be noticed in this experiment just as it would had the 
 vagi been intact. These exceptions, which we will consider afterwards, 
 are increased excitability of the vagus-fibres and ends. The vagus-roots 
 can only act on the heart through the medium of the fibres and ends ; 
 if the drug itself should affect these structures, its action on the heart 
 may be much altered or even destroyed. If the vagus-ends be para- 
 lysed, the roots can exert no more action on the heart than they can 
 after we have cut through the trunks ; and if the excitability of the 
 ends be increased, the power of the roots over the heart will be greatly 
 augmented, so that the heart's action may be made slow without there 
 being any actual irritation either of the roots or ends. In order, then, 
 to find out what effect the drug has on the vagus-roots themselves, we 
 must inject it into the carotid, so that it may reach them before it reaches 
 the fibres or ends ; and note what change occurs in the pulsations 
 of the heart immediately after the injection. Any change which occurs 
 immediately is due to the effect of the drug on the roots themselves ; 
 and, by comparing the number of pulsations at this time with that 
 which is found a quarter of a minute or so afterwards, when the drug 
 has reached the vagus-ends, we may discover whether their excitability 
 has been increased or diminished. Thus, in the experiment already men- 
 tioned for ascertaining whether or not the vagus -roots are paralysed by 
 atropia, we find that, when we inject it into the carotid, we get immediate 
 slowness of the pulse, showing that the vagus-roots are irritated by the 
 drug ; but whenever it gets round to the heart it paralyses the vagus- 
 ends, and the slowness at once disappears. If we were to keep the 
 head alive by supplying it with an artificial stream of blood containing 
 atropia,. and prevent any of the poisoned blood from reaching the heart, 
 the slowness might be continued indefinitely. 
 
 Mode of supplying the Head and Body with different kinds 
 OF Blood. — In his researches on respiration, (66) Hering employed 
 a method of this sort, at one time supplying the brain with blood loaded 
 with^carbonic acid while the blood of the body was richly arterialised, 
 and at another sending arterial blood to the brain while respiration 
 was stopped and the blood circulating in the body was intensely venous. 
 For this purpose he opened the thorax and tied the left carotid and 
 innominate close to the aorta, and the vena cava superior close to the 
 heart in a cat ; he then introduced one cannula into the innominate 
 artery, and another into the vena cava, and injected dog's blood, defi- 
 
(>7 
 
 brinated and warmed, into the innominate artery, while he allowed it to 
 flow out by the vein. 
 
 In atropia, we have an example of a drug which acts on more than 
 one part at once, and whose action on one part completely neutralises 
 the effect which its action on the other would produce. In the case of 
 others, however, we have the action on the different parts strengthening 
 each other, as in veratria, which, like atropia, stimulates the vagus- 
 roots, (67) but, instead of paralysing the ends, increases their sensibility, 
 and thus greatly augments the effect which the excited roots would 
 have exercised over the heart, even had the ends remained unaltered. 
 
 Are the Vagus-roots irritated directly by the Drug or 
 
 INDIRECTLY THROUGH INCREASED BlOOD-PRESSURE ? — Along with 
 
 the slow pulse, produced by the injection of atropia into the carotid, a 
 rise occurs in the blood-pressure ; and how are we to determine whether 
 the irritation of the vagus-roots is due to this increase, or to the direct 
 action of the drug itself ? This is a question very difficult to solve in 
 the case of atropia, on account of the rapidity with which the vagus- 
 ends are paralysed and all influence of the root over the heart destroyed. 
 In the case of other drugs, however, where time is allowed, the ques- 
 tion might be settled by diminishing the blood -pressure and seeing 
 whether or not the slow pulse returned to its normal rate, and then 
 raising it again and observing whether the pulse again became slow. 
 
 Mode of Lowering and Raising the Blood-pressure. — The 
 blood-pressure may be lowered by opening a large artery, such as the 
 carotid or crural, and allowing the blood to flow out into a vessel 
 warmed to 98 deg. Fahrenheit, and again raised by injecting the warm 
 blood back into the artery. Or we may adopt Ludwig and Asp's 
 plan, (68) of inserting into the central end of the carotid a straight tube 
 with a stopcock in its middle, and the moist bladder of a small animal, 
 well emptied of air, tied to its free end. When the stopcock is opened, 
 the blood rushes from the carotid into the bladder, and the tension in 
 the arteries is diminished ; but, when we press the blood out of the 
 bladder back into the arteries, the tension on them is again increased. 
 
 Are the Vagus-roots Irritated Reflexly from some other 
 part of the Nervous System ? — There are two ways of deciding 
 this : the first is to inject the poison in such a manner that it shall 
 reach the vagus-roots before it reaches the other nervous structures 
 through which we suspect it to act reflexly ; the second is to remove 
 these nervous structures themselves, or to destroy their function by means 
 of some other poison. Thus, if we think that atropia, when injected 
 
68 
 
 into the carotid, acts on the medulla through the cerebrum, we may either 
 remove the latter, or abolish its function by opium or chloral. The 
 application of irritating vapours, such as ammonia or tobacco-smoke, to 
 the nasal mucous membrane of a rabbit, produces still-stand of the 
 heart. We ascertain that this is due to irritation of the vagus by cut- 
 ting it and finding that the vapour then has no effect ; and we next de- 
 cide that the irritation is conducted to the nervous centres through the 
 trigeminus and not through the olfactory nerve, by observing that 
 section of the former likewise prevents the action of the vapour on the 
 heart, while section of the latter does not affect it. (69) 
 
 Are the Vagus-roots Irritated indirectly by the Drug 
 IMPAIRING Respiration, and thus allowing Carbonic Acid to 
 accumulate in the Blood ? — In the experiment just mentioned, we 
 have ascertained that the vagus is irritated, and that irritation is con- 
 ducted to the nerve-centres through the trigeminus, but we do not 
 know that the irritation is directly reflected from the trigeminus to the 
 vagus. It might be due to irritation of the vagus-roots by carbonic acid, 
 which has accumulated in the blood from impeded respiration ; for the 
 irritating vapour applied to its nose causes the rabbit to close its nos- 
 trils and stop breathing for a while if the trigeminus be intact, but when 
 it is cut no irritating impression can be conveyed to the brain, and so 
 no closure of the nostrils takes place, either voluntarily or reflexly. The 
 rabbit, therefore, continues to breathe freely ; no carbonic acid accu- 
 mulates in the blood, and no irritation of the vagus occurs. Other 
 drugs, such as strychnia and curare, etc., impede respiration — not by 
 causing closure of the nostrils and consequent obstruction to the pas- 
 sage of air to the lungs, but by acting on the muscles and nerves and 
 diminishing the respiratory movements. Strychnia does this by pro- 
 ducing tetanic contraction of the respiratory muscles, curare by para- 
 lysing them, and chloral by diminishing the excitability of the respira- 
 tory nervous centre. In all such cases, in order to ascertain that indirect 
 irritation of the vagus from impeded respiration is not the cause of the 
 slowing of the pulse, we insert a cannula into the trachea and begin 
 artificial respiration ; we then note the rate of the pulse and blow the 
 irritating vapour into the nostrils, or inject the drug into the veins, and 
 see whether or not the pulse is rendered slow, taking care to keep up 
 artificial respiration all the time. If the drug cause convulsive move- 
 ments which interfere with the proper performance of artificial respira- 
 tion, curare should be given so as to prevent their occurrence, and the 
 experiment should be again repeated. 
 
69 
 
 Are the Vagus-fibres Irritated ? — To ascertain this we apply 
 the drug dissolved in an indifferent fluid, such as a solution of half per 
 cent, of chloride of sodium, or serum, to the nerve, and notice whether 
 any change occur in the heart-beats. Care must be taken that the 
 solution of the drug be not applied in too concentrated a solution, as it 
 might then have an irritant action, which it could not have if it reached 
 the part through the circulation and became diluted by the blood be- 
 fore reaching the nerve, and false conclusions might thus be arrived at. 
 
 Is their Conducting Power Increased, so that the Roots 
 CAN Act through them on the heart more readily and 
 POWERFULLY ? — If their conducting power be increased, other stimuli 
 as well as those from the roots will act more powerfully on the heart. 
 We therefore divide the vagi and apply a stimulus to the peripheral end 
 of one or both by irritating them with one of Du Bosi Reymond's in- 
 duction-coils, and note at what distance from the primaiy coil the se- 
 condary one must stand in order to produce stoppage or slowness of the 
 heart; we then apply the drug to the nerve below it and again irritate. 
 If the excitability of the nerve be increased, stoppage or slowness should 
 be produced when the distance between the primary and secondary coils 
 is greater — that is, when the current is weaker than before. It is gene- 
 rally assumed that the fibres are not likely to be affected, and these 
 experiments are rarely performed. 
 
 Are the Vagus-ends Excited ?— We may test this in the same 
 way as the action on the roots, by injecting the drug at one time into 
 the jugular and at another into the carotid. If. it increase the excita- 
 bility of the ends without affecting the roots, we should find it produce, 
 when injected into the jugular vein, an immediate slowing of the pulse, 
 which does not become greater in a quarter of a minute afterwards, when 
 the drug has reached the roots. When injected into the carotid, no slow- 
 ness should occur till sufficient time has elapsed for it to pass round to 
 the heart. If it increase the excitability of both roots and ends, imme- 
 diate slowness should occur, whether it be injected into the jugular or 
 carotid, and this should become more marked after fifteen or twenty 
 seconds. If, like physostigma, it increase not only the excitability of 
 the vagus-ends, but that of the quickening centre in the head, injection 
 into the jugular should be followed by immediate slowing, which would 
 become less marked when the drug reached the head, and injection 
 into the carotid by an immediate quickening, which would become less 
 or give place to slowness when the drug reached the heart. 
 
 At first sight one might think that, after time had been allowed for 
 
70 
 
 the drug to pass round the circulation and be applied both to the vagus- 
 roots and ends, its action on the heart would be the same whether it 
 had been originally injected into the jugular or into the carotid ; but 
 this is not the case, for that organ towards which the drug was injected 
 gets a larger dose, and its action is more strongly excited than that of the 
 other. Thus when physostigma is injected into the carotid, the quick- 
 ening centres are stimulated and the pulse-rate rises ; and, although the 
 pulse falls somewhat after the vagus-ends have also been acted on, it 
 nevertheless continues above the normal, the stimulation of the vagus- 
 ends not being able to counteract the still more excited quickening 
 centres. When it is injected into the jugular, the vagus-ends get the 
 largest dose j and, although the pulse, which is at first made very slow, 
 may afterwards become quicker when the drug reaches the brain ; 
 it nevertheless does not reach the normal rate, the quickening cen- 
 tres being unable to counteract the more strongly excited vagus. I 
 the vagus be then cut, however, the pulse becomes quicker than it 
 would have done had no physostigma been given; or, if the vagi be first 
 cut and the drug injected, the pulse is quickened at once. (70) One 
 might think that, since the drug acts on the vagus-ends, its action should 
 remain after the nerves themselves have been divided ; but since it is 
 by increasing the excitability of the ends that it acts, if we separate 
 these ends from the roots, and thus remove their normal stimulus, their 
 increased excitability can have but little effect. In order to measure 
 the amount of increase in the excitability of the nerves, we divide the 
 vagi and irritate them by an induction-coil, noting the strength of 
 current required to produce still-stand or slowness of the heart before 
 and after injection of the drug into the veins. 
 
 Is THE Sympathetic Paralysed ? — This is tested by cutting the 
 vagi and dividing the spinal cord between the first and second cervical 
 vertebrae, so as to exclude the action of those centres in the head which 
 quicken the heart and raise the blood -pressure ; the drug is then in- 
 jected, and the sympathetic irritated by an induced current and the 
 pulse counted. If it be quickened by the irritation, the sympathetic is 
 not paralysed. 
 
 Are the Cardiac Ganglia Paralysed ? — To see whether or not 
 the nervous structures contained in the heart itself are acted on by a 
 drug, we must separate it from all other nerves passing to it from 
 without, and prevent its being acted on by anything other than the 
 drug, such as altered blood-pressure or temperature. This is done in 
 mammals by dividing the vagi, the sympathetic cord, the depressor, and 
 
 i 
 
71 
 
 the spinal cord between the first and second cervical vertebrae. The 
 heart is thus separated from the quickening and retarding centres, so that 
 any alteration in its beats must be due to the nerves contained in its 
 walls, or the muscular fibre of these walls themselves ; at the same 
 time the vessels are separated from the vaso-motor centre, and the heart 
 is thus protected from the effects of any change in the blood-pressure, 
 except the generally unimportant ones produced by the action of the 
 drug on the vascular walls. The number and amplitude of the heart's 
 contractions are then registered by a needle placed in the ventricle, and 
 the blood-pressure by the manometer ; poison is injected into the jugular, 
 and the tracings taken afterwards are compared with those taken before. 
 If we find that the heart-beats have become slower and weaker, while 
 the pressure they have to overcome has not been increased, we may 
 conclude that the motor nerves or the muscular substance of the heart 
 have become paralysed. If the blood- pressure have risen, blood should 
 be allowed to flow from an artery till it falls to its previous level, and 
 then tracings should be taken with the needle for comparison with the 
 previous ones. 
 
 The action of drugs on the heart can be studied still better in the 
 frog than in mammals, as the heart of the former can be completely 
 separated from the body, so that the drug can be applied to it alone. 
 After its removal it continues to pulsate just as before, and, conse- 
 quently, any action of the drug on the rhythm or force of its beats can 
 be very easily noticed. The usual way of making experiments on this 
 subject formerly was to take out the heart and lay it in a solution of the 
 poison, or, what was better, to take two glasses containing solution of 
 chloride of sodium (half per cent.) and add a little of the drug to one 
 of them. A frog's heart was then laid in each, and the beats of the 
 poisoned compared with those of the unpoisoned one. Both of these 
 plans are inferior to that of Ludwig, who supplies the heart with serum 
 so as to keep it as nearly as possible in a normal condition, and at- 
 taches to it a manometer, so that it may itself register the number and 
 form of its beats, and give more exact indications than could be ob- 
 tained by merely looking at it. The apparatus which he and Cyon first 
 used, and which is figured in his Arbeiten for 1866, has been consi- 
 derably modified by Dr. H. P. Bowditch, and is shown in fig. 10, It 
 consists of a bent glass tube (c c' c"), which is supported by a glass 
 plate (d). The frog's heart (a) is connected to the ends of this tube by 
 means of India-rubber tubing and two glass cannula, one of which (b) 
 is tied into the vena cava and the other (b') into the aortic bulb. The 
 
72 
 
 tube has three openings, each of which is furnished with a three-way 
 glass stopcock. By means of one of these (c) it can be filled with serum 
 
 Fi^.lO. 
 
 Fig. lo.— Dr. H. P. Bowditch's apparatus for experiments on the heart of the 
 frog. A is the frog's heart, b is a cannula tied into the vena cava, and b' one 
 into the aortic bulb, c, c', and c" are three glass stopcocks. By c fresh serum 
 is supplied, by c' old serum is let out, and c'' allows the communication between 
 the bent tube b c' b' and the manometer M to be opened or shut at will. D is a 
 glass plate through which the bent tube b c' b' passes, e is a rod ending in a 
 ring into which d is fitted, f is a nut by which the whole apparatus can be 
 moved up and down on the stand G. h is a T-tube. j and j' ' are two clips to 
 stop the flow of serum from K or k'. k and k' are two fountain -bottles for supply- 
 ing serum to the heart. K contains pure, and k' poisoned serum. L and l' are 
 bent tubes which convey the serum out of k and k'. m is a small manometer. 
 N is the pen or point which swims on the mercury. The horizontal part is made 
 of glass ; the vertical rod of esparto grass, with a small piece of sealing-wax at its 
 lower end. The tracing may be made with ink, or with a dry point on smoked 
 paper, p is a small weight which hangs by a piece of unspun silk from a bent 
 wire, and keeps the pen resting on the paper, q is the revolving cylinder, r is 
 the clockwork, which is provided with one of Foucault's regulators, s is a table, 
 which can be raised or lowered at pleasure, and fixed at any height by the 
 screw T. V is an India-rubber tube through which the serum is emptied from x. 
 X is a graduated tube into which the serum is allowed to pass after it has circu- 
 lated some time, y is an India-rubber tube, which is generally closed by a clip, 
 but is opened when the apparatus is to be filled, or when we wish to let down 
 the mercury to zero, in order to draw an abscissa, w is a glass vessel, which 
 fits tightly to the under side of d, and protects the heart from external irritation. 
 Into the two holes seen in d, tubes may be fitted air-tight, and the heart made 
 to pulsate in an atmosphere of any sort of gas.* 
 
 * This apparatus is made by Geisler, Blume's Hof, Berlin. Mr. Hawksley, of 
 Blenheim Street, Oxford Street, has adapted a bobbin and rollers to the revolving 
 cylinder figured above, so that it will carry a continuous roll of paper, and may be 
 conveniently used instead of the kymographion shown in Fig, 7. The instruments 
 which I have already described as necessary for experiments, may be obtained from 
 him or from Oswald Hornn, Schiller Strasse, Leipzig. 
 
73 
 
 from a reservoir (k or k'), and the stopcock may be so turned as to allow 
 serum to enter the part of the tube above it, the part below it, or both 
 together, or the communication with K may be shut off while the lumen 
 of the tube remains open. By c', the serum which has been already used 
 is allowed to escape, when a fresh supply is given, and c" allows the 
 tube to communicate with a manometer (m), on the mercury in which 
 a fine pen floats and registers its oscillations on a revolving cylinder (q). 
 Each time the heart contracts, it drives the serum with which it is filled 
 out of the ventricle, round the tube, and back through the vena cava 
 into the auricle, and at the same time raises the mercurial column in 
 M. The height of the curve traced by the pen depends very much on 
 the amount of serum which the heart contains, being very much higher 
 when the heart is full ; and it must, therefore, be equally filled each 
 time, or very different tracings will be obtained. For this purpose I 
 use, as reservoirs for the serum, fountain-bottles, in the mouth of which it 
 always stands at the same level, and, consequently, always fills the heart 
 at the same pressure. One of them (k) is filled with pure serum, 
 and the other (k' ) with serum to which a certain amount of the drug to 
 be tested has been added. 
 
 For the purpose of introducing the cannula into the heart, the brain 
 and cord of the frog are destroyed by a piece of wire, and the animal 
 fixed on its back to a board. A v-shaped incision, with its apex at the 
 lower end of the sternum, and its limbs extending upwards and 
 outwards towards the fore-arms, is then made in the skin, and the flap 
 turned back or cut off. The sternum is then removed in a similar way. 
 The pericardium is next opened, the cut being made while the heart is 
 contracted, so as to avoid injuring it. The apex of the heart itself is 
 then turned upwards, and two ligatures are passed underneath a small 
 vein which runs from its posterior surface to the pericardium. The 
 ligatures are tied, and the vein is cut between them. The pericardium 
 must now be removed entirely from the heart, and the vena cava 
 superior and the right branch of the aorta tied. The vena cava inferior 
 is carefully isolated ; a ligature is passed under it ; a short and wide 
 cannula tied into it, and another into the left branch of the aorta. 
 The heart is then cut away from the body. Both cannulae are filled 
 with serum, and connected by India-rubber tubing to the ends of the 
 tube c c'c", care being taken to exclude air-bubbles. The end of the 
 manometer nearest c is filled with serum by opening the clip at Y, and 
 allowing all the air and a little serum to escape. The clip is then re- 
 placed, and the heart allowed to beat once or twice, with the stopcock 
 
 L 
 
74 
 
 c and the clip j freely open, so that it may become full of fresh serum. 
 The stopcock c is then turned so as to cut off the tube c c' c'' from all 
 communication with k ; and tracings are then taken, an abscissa or 
 zero-line being drawn under each. The heart is next supplied with 
 poisoned serum from k', and the tracings which it gives are compared 
 with the normal ones. By slightly turning the stopcock c, a greater 
 or less resistance may be opposed to the circulation of fluid, and the 
 effects thus imitated which contraction or relaxation of the vessels 
 would produce in the living animal. 
 
 Another apparatus has been invented by Ludwig, and used by Coats 
 in his research on the vagus,(7i ) in which there is no circiJation, the serum 
 being simply forced out of the ventricle at each systole, and falling 
 back at each diastole. It gives, however, very good tracings of the 
 number and form of the heart-beats, and is extremely well adapted for 
 observations on the effects of drugs on the vagus. Its consists of a 
 manometer, e, and a reservoir, a, with which the frog's heart is con- 
 nected by two cannulse, D and D. The frog's heart is prepared by 
 destroying the brain and spinal cord, removing the sternum and fore 
 legs, but leaving a large flap of skin, S, to cover the heart with, and 
 then introducing a cannula into the vena cava and aorta, as in the 
 former experiment. Instead of then cutting out the heart, the liver and 
 lungs are removed, and the stomach is cut through the middle ; and a 
 glass tube, sealed at both ends, and as thick as the cesophagus will 
 admit, is pushed through it till one end projects at the mouth and the 
 other from the cut end of the stomach. The vagus is thus clearly dis- 
 played ; and, in order to isolate it more perfectly, all other nerves 
 should be cut away, as well as a part of the pharynx, so that no soft 
 parts may touch it from its exit from the bone to the place where it 
 crosses the aorta. From this point to the heart, it should be left un- 
 touched ; and the jugular vein should not be tied, so as to leave it un- 
 disturbed. The glass tube, j, is then fixed firmly in a holder, L, and 
 the cannulse, D and d', connected with the reservoir, a, and the mano- 
 meter, E. Instead of the reservoir a shown in the figure, it is perhaps 
 better to use two fountain-bottles. The apparatus is used just like that 
 shown in Fig. lo ; and the heart should in this case also be filled so 
 full that a certain tension exists within it even during diastole. The 
 amount of this is shown by the height of the diastolic curve above the 
 zero-line. When the vagus is irritated, the tension during the diastole 
 sinks ; but, if its inhibitory fibres be paralysed by atropia, which leaves 
 its quickening ones unhurt, irritation has then the opposite effect, and 
 
Fig. II.— Ludwiff and Coats' frog-heart apparatus, a is a reservoir for senim. 
 B. A stopcock to regulate the supply to the heart, c. A piece of caoutchouc 
 
76 
 
 tubing connecting A and D. d. A glass cannula in the vena cava inferior. 
 r>'. Another in the aorta, e. A manometer, f. A piece of tubing closed by a 
 clip, to allow of the escape of serum, g. A fine pen, floating on the mercury in e. 
 H. The frog's heart, j. A sealed glass tube passed through the oesophagus 
 K, and firmly held by a holder l. m. A nut which allows l to be moved up 
 and down. N. A second holder to support a. p. A stand with upright rod. 
 Q. A flap of skin to cover the heart and prevent drying, v. The vagus. 
 
 the tension during the diastole becomes greater and greater till the 
 heart may stand still in firm contraction. (72) 
 
 What Part of the Ganglionic Apparatus in the Heart is 
 AFFECTED ? — In dealing with this part of the subject, we tread on very 
 unstable ground, for here pharmacology has almost run ahead of phy- 
 siology; and even with our physiological knowledge of the nervous 
 structures of the heart a great deal of speculation is mixed. We know 
 that the heart contains ganglia scattered through its substance, but 
 found in the greatest numbers in the septum between the auricles and 
 in the auriculo- ventricular groove of the frog's heart,(73) in which they 
 have been chiefly investigated. As the heart, long after it has been 
 separated from the body, or the apex after it has been cut off frona the 
 ventricle, will still continue to beat rhythmically, the cause of the con- 
 tractions must be contained in itself ; and we assume the cause in each 
 part to be the cardiac ganglia, and suppose that they are connected by 
 some apparatus which keeps them working harmoniously together, as 
 the different parts of the heart all contract in a definite order so long 
 as it is uninjured. Their action may be rendered slow or quick by 
 nerves passing to them from without, both the retarding and the quick- 
 ening nerves being contained in the vagus in the frog {74) ; while in mam- 
 mals the retarding ones are found in the vagus, (75) and the quickening 
 ones chiefly in the third branch of the ganglion stellatum (76) (or first 
 dorsal generally joined to the last cervical), although some may also be 
 found in the vagus. (77) 
 
 Some physiologists consider that the function of all the ganglia is 
 simply to keep up rhythmical movements in the heart. (78) Others hold 
 that only some of them, found chiefly in the venous sinus and ventricle, 
 have this function (79); while others are inhibitory, and restrain the action 
 of the former. (80) These inhibitory ones exist chiefly in the septum be- 
 tween the two auricles. (81 ) The reason of this supposition is that, when 
 the venous sinus is separated from the rest of the heart, it conti- 
 nues to pulsate ; but the auricles and ventricles stand still. When the 
 ventricle is cut off from the auricles, it begins to beat again, but the 
 auricles do not ; so that it would seem as if the motor apparatus in the 
 venous sinus and ventricles together could overcome the inhibitory 
 
71 
 
 apparatus in the auricles, and keep the heart going ; but that this is too 
 strong for the motor ganglia in the ventricle alone, and will not let 
 them go on till they are separated from it, or till it becomes exhausted, 
 which it seems to do after a little, and then botli auricles and ventricles 
 begin anew. The physiologists who hold the simpler view, say that 
 this stoppage is only due to the irritation of the vagus-fibres which run 
 along the venous sinus, and that the renewed cardiac contractions are 
 simply due to the irritation passing off. (82) The pharmacologist, however, 
 is not contented even with the more complicated of these mechanisms, 
 but demands a still more elaborate nervous apparatus in order to explain 
 the action of poisons on the heart. (83) The necessity for this has been 
 clearly shown, and a plan of the nerves drawn up, by Professor 
 Schmiedeberg. I have endeavoured to represent the supposed nature 
 of this apparatus in the accompanying diagram. It consists of a 
 ganglion, M, which keeps up a rhythmical contraction of those muscu- 
 lar fibres of the heart to which it is connected by the fine nervous fila- 
 ments, E. This ganglion is connected by an intermediate apparatus 
 with an inhibitory ganglion, I, which can retard or stop the muscular 
 contractions which M produces ; and by another apparatus, c, with 
 another ganglion, Q, which quickens the contractions, i is connected 
 by an intermediate apparatus. A, with the retarding fibres, v, of the 
 vagus, and D with the quickening nerves, s, of the heart. 
 
 Fig. 12. — Diagram of the hypothetical nervous apparatus in the heart. M. Motor 
 ganglion, i. Inhibitory ganglion. Q. Quickening ganglia, v. Inhibitory fibres ; 
 and s, quickening fibres from the head. A, a', b, and c, intermediate apparatus* 
 E. Fibres passing from the motor ganglia E, to the mnscular substance F. For 
 simplicity's sake, only one set of motor ganglia has been represented, but other 
 similar ones are to be supposed to be present in other parts of the heart, and so 
 connected with this set that they all work in unison. It must be remembered 
 that this diagram is purely hypothetical : but if this be carefully borne in mind, 
 the sketch will be found of service in remembering and comparing the action of 
 different poisons on the heart. 
 
 Inhibitory Ganglia of Heart.— We have hitherto included 
 under the terms vagus-ends all the inhibitory apparatus in the heart j 
 
78 
 
 but, when we begin to experiment with the heart alone, we find that 
 poisons which such experiments as have already been described would 
 lead us to class together, as acting on the vagus -ends, really act on very 
 different parts of the cardiac nervous system. Thus nicotia, when in- 
 jected into the blood after the vagi and cord have been divided, renders 
 the pulse slow; but this soon gives way to quickening; or, if the dose be 
 large, quickening may occur at once; and, if we then irritate the vagus, 
 we find that we cannot render the heart beats slow any more than we 
 can after poisoning by atropia.(84) We thus see that, after the irritation 
 which nicotia first occasions in the vagus-ends has passed off, it para- 
 lyses them ; and we might thus be inclined to think that they acted on 
 the same structures. But, if we give nicotia to a frog, and instead of 
 irritating the vagus, we irritate the venous sinus, still-stand of the 
 heart is at once produced ; while, if atropia be given, and the 
 venous sinus then be irritated, the pulsations are not slowed at all 
 — showing us that there is some inhibitory apparatus in the venous sinus 
 which has been paralysed by atropia, but left untouched by nicotia. We 
 may substantiate this conclusion by another and extremely useful method 
 of investigation — viz., by administering another poison, and seeing how 
 its action is affected by each of the other two. If we allow a little mus- 
 caria to reach a frog's heart, its beats become slower and slower, and at 
 last cease altogether ; the ventricles remaining widely distended, just as 
 they would do if the vagus were strongly galvanised. If nicotia be 
 then injected into the frog or mixed with the serum supplying an excised 
 heart, no alteration is observed ; and, if nicotia be injected before the 
 muscaria, the latter poison stops the heart just as usual, although the 
 nicotia may have so paralysed the vagus that no irritation whatever 
 applied to its trunk could act on the heart. But, if atropia be used in- 
 stead of nicotia, the effect of the muscaria is at once destroyed, and the 
 heart, which was standing quite still, immediately begins to beat. (85) 
 If the atropia be applied first, and muscaria given afterwards, it has no 
 effect. Hence we see that nicotia has paralysed some part of the inhi- 
 bitory apparatus farther away from the motor ganglia than that on 
 which muscaria acts, while atropia has acted either on the same part as 
 muscaria, or on some other one which lies between it and the motor 
 ganglia. 
 
 Now, as the inhibitory effect produced by muscaria is not developed 
 all at once, but goes on slowly increasing till it makes the heart stand 
 still in diastole, it seems probable that its stimulating action is exerted 
 on a ganglion, rather than on a nerve-fibre ; and we therefore suppose 
 that it acts on the inhibitory ganglion 1.(86) As the action of nicotia is 
 
79 
 
 exerted on something farther from the heart than i, our first idea is, 
 that it must be the nerve- fibres v. But, on applying nicotia to the 
 trunk of the vagus, after fixing the heart in Coats' apparatus, we find, 
 on irritating the nerve above the point, that it still conducts impressions 
 and causes stoppage of the heart. We are thus led to suppose the exist- 
 ence of an intermediate apparatus on which nicotia acts ; but, whether 
 or not this intermediate part simply consist of nerve-fibres less protected 
 from the poison than those in the trunk, we cannot say. As atropia de- 
 stroys the action of muscaria, it may act like muscaria on I ; but the fact 
 that muscaria does not destroy that of atropia would lead me to refer the 
 action of the latter to a part between i and M, which is represented by B. 
 Of what nature this part is, we know nothing; but that such a part exists, 
 is rendered all the more probable by the mutual antagonism of atropia 
 and physostigma. Although this latter poison renders the vagus very 
 sensitive, so that the power of any irritation applied to its trunk to stop 
 the heart is immensely increased, (87) yet it has not the extraordinary 
 power of producing stillstand of the heart possessed by muscaria. Unlike 
 muscaria, however, it has the power of removing the paralysis of the 
 vagus produced by atropia ; and, though an additional dose of atropia 
 will again cause paralysis, a second dose of physostigma will again 
 remove it. (88) This difference of action between muscaria and physo- 
 stigma seems to show that they act on different nervous structures ; 
 while the mutual power that atropia and physostigma possess to neu- 
 tralise each other's effects, indicates that atropia acts on the same 
 structure as physostigma, and consequently on a different one from 
 muscaria. 
 
 Antagonism of Atropia and Physostigma. — Atropia and phy- 
 sostigma are thus physiological antidotes to each other ; and Fraser has 
 shown that a dose of physostigma large enough to kill an animal may 
 be given to it with impunity, if atropia be administered along with it ; 
 and that the animal may be afterwards destroyed by a small dose given 
 alone. (89) It is true, they do not completely counteract each other's 
 action, each one seeming to produce several effects, some of which, and 
 these the most deadly, are neutralised by those of the other drug, 
 while others are not so neutralised ; and, if enormous doses be ad- 
 ministered, those active effects which are not neutralised may become 
 so powerful as to cause death, although they are comparatively unim- 
 portant when the dose is small. (90) 
 
 Importance of this in Therapeutics.— Nevertheless, within cer- 
 tain limits these poisons do antagonise each other most successfully ; 
 
8o 
 
 and this observation seems to me to have a most important bearing on 
 the treatment of such diseases as have their origin in morbid matter in- 
 troduced into the system, for it shows that it is not always necessary to 
 eliminate a poison in order to remove its effects, but that it may be 
 neutralised and rendered innocuous while still present in the organism ; 
 and seems to indicate that, for the treatment of zymotic diseases, we 
 should seek to discover such remedies as will counteract the effects of 
 the poisons on which they depend, and not merely endeavour to 
 quicken their elimination. 
 
 Action of Various Drugs on the Inhibitory Apparatus. — 
 From experiments which he has made on the excised hearts of frogs 
 with Ludwig and Coats' apparatus, Boehm(9i)has come to the conclusion 
 that conia paralyses the terminal filaments of the vagus ; nicotia the in- 
 termediate structure between them and the inhibitory ganglia ; and that 
 others, such as atropia, hyoscyamia, daturia, physostigmia, aconitia, del- 
 phinia, and veratria, diminish or destroy the irritability of the inhibitory 
 ganglia themselves. It is rather extraordinary to find physostigmia in 
 this list ; and it would thus seem that the pure alkaloid which Boehm 
 used had a different action from the tincture used by Von Bezold, un- 
 less it be that the result depends simply on a difference in the amount 
 of the poison used. 
 
 Accelerating Ganglia in the Heart. — We infer the presence 
 of quickening ganglia in the heart, from the effects produced by irri- 
 tating the vagus after its inhibitory power has been destroyed by the 
 administration of nicotia or atropia. When irritation is then applied 
 to the nerve, it no longer produces retardation, but, on the contrary, a 
 decided acceleration of the cardiac pulsations. This shows that the 
 vagus contains fibres which quicken the heart, and that these are un- 
 affected by the drugs which have paralysed the others. The quicken- 
 ing, however, does not take place till some time after the application 
 of the irritant ; and, if it be applied only for a short time, no accelera- 
 tion may take place till after its removal ; but, after it does occur, it 
 remains for a considerable time. If we irritate the heart directly, 
 instead of irritating the nerve, its beats are quickened at once, and the 
 acceleration does not last long after the irritation is discontinued. This 
 shows that, when we stimulate the quickening nerves, we do not act 
 directly on the motor ganglia M (Fig. 12), as we do when we irritate the 
 heart itself, or as we should do if the quickening fibres ended directly in 
 them ; and we therefore infer the existence of the accelerating ganglia 
 Q between the quickening nerves s and the motor ganglia m. (92) The ac- 
 
celerating apparatus seems to be stimulated by veratria ; for we find 
 that the cardiac pulsations are increased by its administration to mam- 
 mals in which the spinal cord, vagi, sympathetics, and depressors, have 
 all been divided, or when it is applied to the excised heart of a frog (93. ) 
 
 Is Quickening of the Excised Heart due to Paralysis of 
 Inhibitory OR Stimulation of Accelerating Ganglia? — It is' 
 possible that the quickening may be due to paralysis of the inhibitory 
 ganglia in the heart, and not to stimulation of the quickening ganglia. 
 This can be decided by paralysing the inhibitory ganglia by means of 
 atropia, before applying the poison to be tested — e.g:^ veratria. If the 
 latter poison exercise a stimulating action on the quickening ganglia, 
 it will quicken the heart after atropia has been applied. If it simply 
 paralyse the inhibitory ganglia, it will have no further effect after their 
 power has been destroyed by atropia. In the diagram, I have figured 
 intermediate structures c and d between the quickening nerves and 
 ganglia, so as to correspond with those of the inhibitory apparatus ; but 
 whether they really exist or not, we cannot at present say. 
 
 Is THE Co-ordinating Apparatus of the Cardiac Ganglia 
 PARALYSED ? — Regarding this apparatus we know almost nothing. 
 When the heart is dying, its rhythm is often disturbed, and two or 
 three contractions of the auricles may occur for every contraction of the 
 ventricle. When laudanum is poured into the heart, the rhythm is 
 quite reversed ; for after each pause the ventricle contracts first, and con- 
 traction of the auricle follows it (94). Digitalis and some other poisons 
 cause peristaltic movements in the ventricle ; and occasionally some 
 spots in the ventricle continue to pulsate while the rest of it remains 
 firmly contracted and motionless (95). These effects are probably due to 
 disturbance of the apparatus which connects the different motor ganglia 
 in the heart and causes them to work in unison. 
 
 Are the Muscular Fibres of the Heart paralysed ? — We 
 test this by applying an irritant to them directly, and seeing whether or 
 not they contract. If the motor ganglia be uninjured, the application 
 of an irritant generally produces a rhythmic contraction of the whole 
 heart ; but, if they be paralysed while the muscular fibre is healthy, the 
 irritation only causes a local contraction of the part to which it is 
 applied. 
 
 Blood-Pressure. — The blood-pressure depends on two things — i, 
 the activity with which the heart pumps the blood into one end of the 
 arterial system ; 2, the rate at which it flows out at the other end into 
 the veins. The rate is regulated by the small arteries and capillaries, 
 
 M 
 
82 
 
 which dilate and contract so as to quicken or slow it. The power of 
 contraction is denied to the capillaries by many physiologists ; but 
 Strieker has, I think, conclusively shown that they do possess it (96). 
 
 The rapidity with which the blood flows through them does not 
 depend entirely on the width of the capillaries, but also on the pressure 
 on the arteries which is forcing the blood into them. The higher this 
 is, the more rapidly does the blood flow ; and in proportion as it dimi- 
 nishes, does the current become slower. From this circumstance we 
 can judge of the force of the heart-beats from the form of the curve 
 which we obtain with the sphygmoscope. When the heart contracts 
 with great force, it drives the blood out of the ventricle into the arte- 
 ries so quickly that there is no time for much to escape from the capil- 
 laries while the systole lasts ; and so the tension rises high. This in- 
 creased tension makes the blood run quickly out of the capillaries, and 
 we have a fall of pressure, rapid at first, but gradually becoming slower 
 as the tension diminishes. This is shown in Fig. 13. When the heart 
 
 F^g- 13 
 
 contracts less forcibly, it sends in the blood more slowly, and there is 
 time for a greater quantity to escape by the capillaries during the 
 systole ; and the tension does not rise so high. From the tension being 
 lower, th« outflow of blood is not so quick ; and the pressure therefore 
 sinks more gradually than in the former case. This is represented in 
 Fig. 14. Both of these figures were obtained by connecting a sphyg- 
 
 Fig. 14. 
 
 
 BHHJIHHH! 
 
 ■ 
 
 I^^I^SH^HB 
 
 I 
 
 BHHBHMI 
 
 I 
 
 moscope with a schema of the circulation such as I have already de- 
 scribed, and compressing the India-rubber ball which represented the 
 heart with greater or less force and suddenness ; care being taken, how- 
 ever, to empty it completely each time, so that the amount of air sent 
 out should always be alike. 
 
S3 
 
 As variations in the blood- pressure may be due to alterations in the 
 activity of the heart or the size of the capillaries, or to both together, we 
 cannot say when it is due to the one and when to the other, unless we 
 can keep one of them constant while we allow the other to alter, or 
 unless we examine them both separately. 
 
 Elimination of the Action of the Heart.— We may keep the 
 action of the heart tolerably constant, and thus ascertain with consider- 
 able exactitude the action of any drug on the exit-tubes — whether they 
 be arterioles or capillaries matters not — by separating the heart from 
 the nerve-centres, and then injecting the drug into the circulation. 
 
 Division of Cardiac Nerves. — This separation can be effected 
 to a considerable extent by dividing the sympathetics, vagi, and de- 
 pressors in the neck ; but it is done much more effectually by dividing 
 the nerves near their entrance into the heart by a fine wire heated by 
 means of a galvanic battery (97). 
 
 As poisons generally produce their most marked effects on the heart 
 of mammals through the nervous centres whose connexion with the 
 heart we have thus severed, alterations in the blood-pressure will be 
 due to changes in the vessels, except in so far as the drug may have 
 affected the cardiac muscle or gangUa. But, just as we obtained the 
 most exact results when we examined the heart altogether apart from 
 the blood-vessels, so we shall probably come to the most satisfactory 
 conclusions regarding the vessels by observing them apart from the 
 heart. You will remember that, during the diastole, the circulation is 
 carried on entirely independently of the heart by the pressure of the 
 blood in the arteries ; and, if we can prolong the diastole sufficiently, 
 we shall be able to tell whether the vessels are dilated or contracted by 
 simply seeing whether the pressure sinks quickly or slowly. 
 
 If we prevent any blood from being pumped into the aorta by the 
 heart, the arterial system will come to resemble a bottle with a hole in 
 it, from which the fluid which it contains is running. The larger the hole, 
 the more quickly will it run out and the bottle become empty, and vice 
 versd ; and, in the same way, the more dilated the capillaries are, the 
 quicker will the blood run out of them into the vein, and the pressure 
 sink in the arteries ; the more contracted the capillaries are, the more 
 slowly will the blood flow through them, and the more gradual will be 
 the fall of pressure. In the case of many poisons, we may do this by 
 irritating the vagi before poisoning, and seeing how quickly the pressure 
 falls while the heart is standing still ; and then repeating the experi- 
 ment after injecting the poison. If the pressure fall more quickly in 
 
84 
 
 the second case, we know that the vessels have become dilated ; and if 
 more slowly, that they have contracted (98). Of course, only those parts 
 of the tracings in which the pressure has been the same are to be com- 
 pared with each other ; but, if we stop the heart long enough, we can 
 always get parts in both which are capable of comparison. 
 
 "When the poison paralyses the vagus, as atropia does, this method 
 fails ; and then we must open the thorax, perform artificial respira- 
 tion, and put a ligature round the aorta. 
 
 Artificial Circulation in Mammals. — As an animal quickly 
 dies when the aorta is ligatured, it is better to carry on artificial 
 circulation by a syringe through a cannula inserted into the aorta, 
 as Hering (99) has done in his researches on the connexion be- 
 tween arterial movement and respiration. After the blood has cir- 
 culated once, it may be defibrinated, shaken with air, warmed to 
 40 deg. Cent., and reinjected. Instead of using a syringe, the can- 
 nula in the aorta may be connected with the nozzle M, Fig. 6, and 
 the blood put in the flask 3. It can thus be kept at a constant 
 
 Fij, 6, 
 
 temperature more easily than when a syringe is employed. The 
 pressure may be alternately increased and diminished so as to imitate 
 the beats of the heart by raising and depressing the flask A. This 
 may be done by passing a string over a pulley, and attaching one 
 end to the flask and the other to a treadle worked by the foot. Warm 
 blood has the disadvantage, that it undergoes change and becomes 
 decomposed quickly; and cold blood may, therefore, be sometimes 
 preferred. When cold blood is employed, only the flask which con- 
 tains the blood is necessary ; and it may be raised or lowered in the 
 same way as the other. 
 
85 
 
 Artificial Circulation in Frogs.— Artificial circulation maybe 
 kept up in frogs by simply inserting^ a cannula into the aorta, and allow- 
 ing blood to flow into it from a raised reservoir, as done by Rollett (lOo). 
 By using two, as in the experiments on the frog's heart, normal blood 
 may be allowed first to circulate through the vessels; and, the web 
 being put under the microscope, their diameter may be measured; and 
 then poisoned blood may be allowed to flow through them, and any 
 change in their diameter noticed. 
 
 Observation of Vessels.— The parts best adapted for observing 
 changes in the size of vessels in mammals are the ear in rabbits and the 
 mesentery. When the mesentery is chosen for observation, the abdo- 
 minal parietes should be divided ; but the peritoneum should not be 
 opened, as changes in the diameter of the mesenteric vessels may be 
 observed through it, and they are thus protected from the disturbing 
 element which the irritation produced by the access of air to them 
 would introduce into the experiment. The vessels in the rabbit's ear 
 are readily measured by a micrometer used with one of Briicke's mag- 
 nifiers, which is simply a telescope with an extremely short focus. The 
 ear should be held up so as to allow the light to shine directly through 
 it, and the magnifier placed horizontally. 
 
 The area of the capillaries may be lessened, and the flow of blood through 
 them retarded in two ways ; i, by contraction of their walls ; 2, by 
 pressure exerted on them from without. They may be made to contract 
 by irritation, i, of the vaso-motor centres, 2, of the vaso-motor nerves, 
 or, 3, of their muscular walls ; and pressure may be exerted from without 
 by the motions of muscles or of organs composed of involuntary mus- 
 cular fibre such as the intestines. The movements of respiration also, 
 as already mentioned, exercise an important influence on the pressure. 
 
 Elimination of Respiration and Muscular Movement. — 
 The influence both of respiration and of muscular movement may be 
 eliminated by giving the animal curare, and keeping up artificial re- 
 spiration, before beginning to experiment with the drug whose action 
 we wish to examine. 
 
 Elimination of Vaso-motor Centre.— For the purpose of ascer- 
 taining w^hether the drug has acted on the vascular walls or on the vaso- 
 motor centre, we divide the vaso-motor nerves going to a part before 
 injecting it, and see whether it acts as it would have done had they 
 been undivided. Thus, when we are observing the rabbit's ear, we 
 divide the sympathetic in the neck ; and, when looking at the mesen- 
 tery, we cut the splanchnics before the injection, and see whether the 
 
86 
 
 vessels contract or dilate as we have previously seen them do under 
 influence of the poison in animals in whom the nerves were intact. 
 
 For the purpose of ascertaining whether the drug acts on all the ves- 
 sels in the body in the same way that it does on those of the ear or 
 mesentery, we first cut the vagi, sympathetics, and depressors ; and 
 then divide the spinal cord between the occiput and atlas, or atlas and 
 axis, so as to sever the connexion between the vaso-motor centre and 
 vessels, and begin artificial respiration. We next note the blood- 
 pressure, inject the poison, and see what alterations it produces. Expe- 
 riments may also be made by irritating the vagvis or ligaturing the 
 aorta. 
 
 Action of Surrounding Parts.— It sometimes happens, as in 
 the case of physostigma, that the drug produces no contraction in the 
 vessels of the ear or mesentery when their nerves are cut — a fact which 
 shows that it acts on them through the vaso-motor nerves, and not 
 directly on their walls ; and nevertheless, when injected into a vein 
 after the cord has been cut, it may cause the blood-pressure to rise very 
 considerably. At first sight, this would seem to indicate that the drug 
 acted on the walls of some vessels in the body, if not on those of the 
 ear or mesentery, directly, and not through their vaso-motor nerves. 
 On examination, however, it is found that the obstruction to the flow 
 of blood through the capillaries does not depend on their contraction, 
 but on the occlusion of a large number of them in the intestine by spas- 
 modic contractionof the intestinal walls in which they are imbedded (loi). 
 
 Influence of the Pulmonary Capillaries. — It has lately been 
 pointed out by Holmes (102) that when a drug such as ergot, which acts 
 on the walls of the vessels and causes them to contract, is injected into 
 the jugular vein, it has to pass through the pulmonary capillaries before 
 it reaches the systemic ones j and, by contracting them, it will lessen 
 the amount of blood sent into the aorta from the left ventricle, and will 
 at first produce a fall in the arterial pressure, succeeded by a great rise 
 when time has elapsed for the drug to reach the systemic capillaries and 
 cause them likewise to contract. 
 
 Use of the Sphygmograph. — For a description of the sphygmo- 
 graph and the mode of applying it, we must refer to the special works 
 on that subject, such as those of Marey and Sanderson. The indica- 
 tions which it gives are the following. I. The greater or less pressure 
 which is requisite to compress an artery and stop its pulsations enables 
 us to estimate approximately the amount of pressure within it. The 
 amount of pressure and the rapidity of the pulse help us to form con- 
 
 / 
 
87 
 
 elusions regarding the motor and inhibitory apparatus of the heai^t, in 
 the same way as in the experiments, already mentioned, though, of 
 course, to a much more limited extent and with much less cer- 
 tainty. 3. The form of the curve, like those in Figs. 13 and 14, shows, 
 in the same way as those of the sphygmoscope, Figs. 13 and 14, the 
 rapidity with which the pressure falls during the diastole ; and from 
 this curve and the amount of blood-pressure we can judge of the size of 
 the capillaries. 
 
APPENDIX. 
 
 Artificial Circulation through Isolated Organs. — In order to study 
 the effects of alterations in the blood, and the action of various poisons 
 upon the walls of the vessels themselves, with entire exclusion of the 
 nervous system, Ludwig and Mosso have Icept up artificial circulation 
 in the kidney and the liver. In removing these organs great care is 
 taken not to wound them, and the diaphragm is removed along with 
 the liver. In experimenting on the kidney large dogs were employed. 
 The carotids were first opened, and blood allowed to flow until convul- 
 sions began. The artery was then closed for some time, during which 
 the blood was defibrinated and part of it put into a flask, so as to be 
 ready to wash out all the coagulable blood from the kidney. The 
 carotids were now opened a second time, and as much blood as possible 
 got from them by pressure on the abdomen, etc. As soon as the 
 animal became insensible the abdomen was opened, the renal artery 
 was then compressed just above its bification, so as to prevent any air 
 getting into it, and a glass cannula was introduced into the main artery; 
 another cannula was put into the renal vein. All the small vessels which 
 communicate with adjacent parts were ligatured, and the kidney was 
 then removed. Before connecting the cannula in the renal artery with 
 the apparatus for artificial circulation, it was carefully filled by means 
 of a fine pipette with defibrinated blood, and the utmost care em- 
 ployed to prevent any air bubbles from getting into the vessel. After 
 the communication between the renal artery and the flask has been 
 opened, it sometimes happens that blood does not flow until a consider- 
 able time has elapsed, owing apparently, to a tetanic contraction of the 
 vessels in the kidney. 
 
 After the blood has begun to flow it does not do so in an equable 
 stream, as it would do through glass tubes, but its velocity is alternately 
 greater and less, owing to periodic contractions of the walls of the 
 renal vessels, independently of any nervous influence. If the circula- 
 tion is arrested for some time and then allowed to go on, the rapidity is 
 
much greater after than before the stoppage, but it gradually falls again 
 to normal. Blood containing much carbonic acid and little oxygen 
 {erstickungsblut ), causes the vessels to contract, and the stream to be- 
 come slow ; while blood containing much oxygen and little carbonic 
 acid causes them to dilate. When different sorts of blood are allowed 
 to circulate after each other through the kidney, and each successive 
 kind contains less CO2 than the one preceding it, the rapidity of 
 the flow from the vein goes on increasing ; or, as it might be 
 expressed, each kind of blood in this series seems to diminish the 
 amount of contraction of the vascular walls which the greater amount 
 of COj in the preceding kind had occasioned. The order would be 
 this — suffocation — blood — venous — arterial — apnceic, /. e., saturated with 
 oxygen, by agitation with air. This dilatation, however, was only tem- 
 porary. 
 
 When nicotine was mixed with blood in the proportion of i to 10,000 
 it seemed, at first, to cause contraction of the vessels, for it produced a 
 diminution in the flow of blood, and also in the size of the kidney ; 
 but both soon return to the normal. One per cent, of nicotine, on the 
 contrary, seems to cause immediate dilatation of these vessels, for it 
 immediately causes an increase in the velocity of the current and the 
 size of the kidney. The increased velocity is not to be entirely 
 ascribed to contraction of the vessels, for a solution of nicotine of this 
 strength alters the blood, and will diminish the friction in the vessels. 
 
 Atropia has a powerful action, and different doses of it produce dif- 
 ferent effects. In the proportion of I in 100,000 it causes diminished 
 rapidity in the flow of blood and in the volume of the kidney, but 
 both soon return to their normal. One in 10,000 causes diminished, 
 followed by increased rapidity, but this soon disappears. One in 5,000 
 soon kills the kidney, but before doing so causes first, diminution, and 
 then acceleration of the current through it. Chloral hydrate first 
 causes diminished and then greatly increased velocity, but it also 
 has a very peculiar action on the vessels, increasing the rhyth- 
 mical contractions in them when they are present, and causing them to 
 appear when they were previously absent. 
 
 The shocks of an induction coil, or Faradaic currents, do not alter 
 the velocity of the circulation, but constant currents do. During the 
 time they are passing, both the rapidity of the current, and the size of 
 the kidney increase, and after the irritation ceases they diminish. 
 When the circulating blood contains a small quantity of chloral, this 
 action is altered. At first, when the chloral has not altered the current 
 
much, it becomes slightly diminished during the irritation, and slightly 
 increased after its removal. When the chloral has acted longer and 
 increased the velocity of the current to five or six times its normal, no 
 alteration is noticed during the application of the current, but a still 
 further increase occurs after its removal. 
 
 After the kidney has been removed from the body for twenty-four 
 hours, and kept in a cool place, its vessels still retain their irritability, 
 but small doses of chloral in such a kidney only cause contraction, and 
 larger doses of 0.3 to 0.5 per cent, are requisite to induce dilatation. 
 The effect is not due to the action of the chloral on the blood, for it is 
 produced when the blood is replaced by serum. One of the most 
 extraordinary things about the action of chloral is that, in the dead 
 kidney, instead of increasing the rapidity of the current, or leaving it 
 unaltered, chloral greatly diminishes it — exactly the opposite to its effect 
 on the living organ. When the blood used in the artificial circulation 
 is saturated with carbonic acid chloral no longer produces any effect on 
 the vessels, so its action would seem to be abolished by this gas. 
 
 Induction of Ancesthesia — At page 3 1 I have stated that chloro- 
 form is inadmissible as a narcotic, as its administration seemed to cause 
 dogs so much pain, but farther experience has shown me that this state- 
 ment is incorrect. Chloroform can be readily administered to all 
 animals by placing them under a glass bell jar, along with a sponge or 
 piece of blotting-paper, saturated with the ansesthetic. The advantage 
 of the glass jar is, that the movements of the animals can be distinctly 
 seen, and they can be removed immediately on their becoming insen- 
 sible, thus avoiding the danger to which they would be exposed by 
 longer inhalation of air saturated with the vapour. The vapour being 
 heavier than air sinks to the bottom of the jar, and when the animal 
 falls unconscious, the air it then respires is much more heavily charged 
 with the vapour than that which it breathed while still erect. On 
 account of the density of chloroform vapour, anaesthesia is more quickly 
 produced when the bell jar has an opening at the top which can be 
 plugged with cotton wool saturated with chloroform, than when the 
 sponge is laid at the bottom of the' jar ; as in the former case the vapour 
 falling down is more rapidlyjdiffused through the air of the jar than in 
 the latter. Instead of a bell jar a deep milk pan may be used, the 
 rabbit or cat being placed in it, and the top covered by a towel 
 stretched tightly over it. The chloroform is sprinkled on the toweL 
 Ancesthesia is thus rapidly induced, but care must be taken not to 
 
allow the animal to remain too long in the vessel. For large dogs an 
 inverted packing-case or box, without the lid, may be used instead of a 
 bell jar. 
 
 After the animals have been rendered insensible and the operation 
 has been begun, the anaesthesia may be kept up by putting a piece of cloth 
 round the animal's nose and pouring chloroform upon it, a drop or two 
 at a time, as often as is necessary. In this way less chloroform is re- 
 quired, and there is not so much danger of killing the animal by giving^ 
 it the vapour in too concentrated a form. 
 
 Instead of keeping up the anaesthesia by the continued administration 
 of chloroform, it is often more convenient to open a vein and inject 
 opium or chloral. 
 
 In operations on the abdominal viscera in dogs, e.g.^ in making gas- 
 tric fistulae, death sometimes occurs from shock, although the animals 
 are completely under the influence of chloroform. For such operations 
 ether is preferable, as it increases rather than diminishes the power of 
 the heart. If given in the same way as chloroform, however, much time 
 and a very large quantity of ether are required to produce anaesthesia. 
 Professor SchifFhas found, however, that it can be readily done by pouring 
 a quantity of ether into a bladder, and holding this tightly around the 
 dog's muzzle so that it respires ether vapour almost pure. As dogs do 
 not like to be tied down, the muzzle shown at Fig. II, p. 28, should be 
 put on, and the operator sitting on a low stool should put the dog's 
 fore paws on his knee, and hold them with one hand, while with the 
 other arm passed round the dog's body he restrains its movements, and 
 an assistant holds the bladder with ether over the dog's nose. 
 
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