The Beauty and the Beast: Aspects of the Autonomic Nervous System 1250886-1714/99 5.00 © 2000 Int. Union Physiol. Sci./Am.Physiol. Soc. News Physiol. Sci. • Volume 15 • June 2000 There are different methods to assess sympathetic nervoussystem (SNS) effects on the cardiovascular system in humans. Besides the assessment of endorgan responses such as blood pressure and heart rate, the most widely used meas- urements are plasma-norepinephrine (NE) assay, NE spillover technique, microneurographic recordings of postganglionic muscle and skin sympathetic nerves, and power spectrum analysis of blood pressure and heart rate variability. The tech- nique of microneurography allows a direct and continuous assessment of SNS activity (3, 13) and represents the only measure to detect small and short-lasting changes within the system. Superficial nerves such as the peroneal nerve are par- ticularly suitable for microneurography since their anatomic location allows the placement of a recording microelectrode. Sympathetic outflow is regulated in the brain stem and the medulla oblongata. Sympathetic nerves travel along the nerve column into ganglia, in which acetylcholine is respon- sible for transmission of activity from the pre- to the postgan- glionic adrenergic neurons innervating the heart and many other organs of the body. Depolarization of postganglionic sympathetic nerve fibers leads to increases in intracellular calcium in adrenergic nerve endings where NE is released The Beauty and the Beast: Aspects of the Autonomic Nervous System Roberto Corti, Christian Binggeli, Isabella Sudano, Lukas E. Spieker, René R. Wenzel, Thomas F. Lüscher, and Georg Noll Sympathetic nerve activity is altered and is a prognostic factor for many cardiovascular diseases such as hypertension, coronary syndromes, and congestive heart failure. Therefore, the selection of vasoactive drugs for the treatment of these diseases should also take into consideration their effects on the sympathetic nervous system. R. Corti, C. Binggeli, I. Sudano, L. E. Spieker, R. R. Wenzel, T. F. Lüscher, and G. Noll are in the Department of Cardiology, University Hospital Zurich, Switzerland. within the next decade. However, it is equally true that an enormous amount of research is still to be done before human therapy can be attempted. An essential side effect of develop- ing therapies in animal models will be a further understand- ing of retinal cell and molecular biology. For example, what is/are the role(s) of c-fos, does photoregeneration of rhodopsin by blue light occur under natural conditions in mammals, and do autophagy, the proteasome system, and apoptosis repre- sent means of adaptation to changing metabolic and environ- mental conditions? In this latter context, the apparent paradox of light eliminating photoreceptors might be resolved into a meaningful measure in those cases in which adaptation to bright light is required. The death of single cells might help the remaining ones to survive through the reduction of overall light sensitivity or photon absorption, respectively. We are supported by the Swiss National Science Foundation, Brupbacher Foundation Zürich, EMDO- and Hartmann Müller-Foundation, Zürich, SUVA-Research Foundation, Luzern, Switzerland, Grimmke-Foundation, Düsseldorf, Germany, and others. References 1. Enari, M., H. Sakahira, H. Yokoyama, K. Okawa, A. Iwamatsu, and S. Nagata. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391: 43–50, 1998. 2. Häcker, G., and D. L. Vaux. A chronology of cell death. Apoptosis 2: 247–256, 1997. 3. Hafezi, F., J. P. Steinbach, A. Marti, K. Munz, Z. Q.Wang, E. F. Wagner, A. Aguzzi, and C. E. Remé. The absence of c-fos prevents light-induced apop- totic cell death of photoreceptors in retinal degeneration in vivo. Nat. Med. 3: 346–349, 1997. 4. Hafezi, F., M. Abegg, C. Grimm, A. Wenzel, K. Munz, J. Stürmer, D. B. Far- ber, and C. E. Remé. Retinal degeneration in the rd mouse in the absence of c-fos. Invest. Ophthalmol. Vis. Sci. 39: 2239–2244, 1998. 5. Mancini, M., D. W. Nicholson, S. Roy, N. A. Thornberry, E. P. Peterson, L. A. Casciola-Rosen, and A. Rosen. The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling. J. Cell. Biol. 140: 1485–1495, 1998. 6. Miller, L. J., and J. Marx. Apoptosis. Science 281: 1301–1326, 1998. 7. Nir, I., and N. Agarwal. Diurnal expression of c-fos in the mouse retina. Brain Res Mol Brain Res 19: 47–54, 1993. 8. Portera Cailliau, C., C. H. Sung, J. Nathans, and R. Adler. Apoptotic pho- toreceptor cell death in mouse models of retinitis pigmentosa. Proc. Natl. Acad. Sci. USA 91: 974–978, 1994. 9. Raff, M. C., B. A. Barres, J. F. Burne, H. S. Coles, Y. Ishizaki, and M. D. Jacobson. Programmed cell death and the control of cell survival: lessons from the nervous system. Science 262: 695–700, 1993. 10. Remé, C. E., C. Grimm, F. Hafezi, A. Marti, and A. Wenzel. Apoptotic cell death in retinal degenerations. Prog. Retin. Eye Res. 17: 443–463, 1998. 11. Remé, C. E., F. Hafezi, A. Marti, K. Munz, and J. J. Reinboth. Light dam- age to retina and pigment epithelium. In: The Retinal Pigment Epithelium, Current Aspects of Function and Disease, edited by M. F. Marmor and T. J. Wolfensberger. Oxford, UK: Oxford University Press, 1998. 12. Rich, K. A., Y. Zhan, and J. C. Blanks. Aberrant expression of c-Fos accom- panies photoreceptor cell death in the rd Mouse. J. Neurobiol. 32: 593–612, 1997. 13. Susin, S. A., N. Zamzami, and G. Kroemer. Mitochondria as regulators of apoptosis: doubt no more. Biochim. Biophys. Acta 1366: 151–165, 1998. 14. Yoshida, K., K. Kawamura, and J. Imaki. Differential expression of c-fos mRNA in rat retinal cells: regulation by light/dark cycle. Neuron 10: 1049–1054, 1993. 15. Zhao, J., Q. Zhou, T. Wiedmer, and P. J. Sims. Level of expression of phos- pholipid scramblase regulates movement of phosphatidylserine to the cell surface. J. Biol. Chem. 273: 6603–6606, 1998. Downloaded from journals.physiology.org/journal/physiologyonline at Carnegie Mellon Univ (128.182.081.034) on April 5, 2021. from vesicles located in the nerve terminals. NE is the main neurotransmitter, although neuropeptide Y and ATP may also participate. The amount of NE and other neurotransmitters released is tightly regulated by negative feedback mecha- nisms involving the neurotransmitter itself (via presynaptic α2-adrenergic receptors), but also other mediators such as adrenaline, serotonin, histamine, acetylcholine, and many others (Fig. 1) (12). The effects of NE at the postjunctional level, i.e., vascular smooth muscle cells of blood vessels and myocytes of the myocardium, involve β-adrenergic receptors, as well as α1- and α2-adrenergic receptors. The former are involved in vasodi- latation (β2-adrenergic receptors), inotropy, and chronotropy (β1-adrenergic receptors), and the latter mediate vasocon- striction of the blood vessel wall. Of particular interest is the fact that SNS activity is very heterogeneous in the body. Indeed, the system is capable of activating certain organs but not others, depending on the pattern of activation and the physiological stimulus involved. Sympathetic fibers in the peroneal nerve innervate blood ves- sels in muscle tissue or the skin of the leg. Electrical activity within muscle and skin sympathetic nerve fibers can be iden- tified according to its characteristic pattern. The neurogram of muscle sympathetic activity (MSA), which significantly con- tributes to the regulation of peripheral vascular resistance, reveals spontaneous, intermittent, pulse-synchronous sympa- thetic bursts that increase during apnea. MSA can be stimu- lated by different maneuvers such as physical activity, mental stress, hypoxia, and unloading baroreceptors. During a cold pressor test, a massive increase in MSA occurs (3, 13). SNS and cardiovascular disease The sympathetic nerve fibers are ubiquitously distributed within the heart, the blood vessels, the kidney, and major peripheral baroreceptor sites, a finding that suggests a direct effect on fluid control, cardiac output, and peripheral vascu- lar resistances. In fact, SNS significantly regulates cardiovas- cular homeostasis (11), and SNS activity is altered in various forms of cardiovascular disease. Activation of the SNS plays an important role in the pathophysiology and the prognosis of cardiovascular disease such as hypertension, ischemic heart disease, and heart failure. Hypertension. In hypertension, hyperactivity of the SNS was postulated decades ago. It has been demonstrated that, partic- ularly in the early phases of the hypertensive process, the sym- pathetic drive is increased. In patients with borderline or mild hypertension, increased cardiac β-adrenergic and vascular α- adrenergic drive has been documented by selective receptor blockade. The evidence from pharmacological studies is in line with the slightly increased plasma levels of NE in young sub- jects with mild hypertension. These findings were confirmed by experiments that showed an increase of NE spillover in the heart and the kidney of hypertensives in particular. Further- more, using the technique of microneurography it has been clearly demonstrated that resting MSA is increased in patients with borderline hypertension (1). In addition, an exaggerated blood pressure response to mental stress has been demon- strated in patients with essential hypertension. In normotensive offspring of hypertensive parents, we found that the MSA response to mental stress is more pronounced than in offspring News Physiol. Sci. • Volume 15 • June 2000126 FIGURE 1. Regulation of vascular smooth muscle cell tone by sympathetic nervous system (SNS). Release of neurotransmitters, norepinephrine (NE), neuropep- tide Y (NPY), and ATP at sympathetic nerve endings is influenced by several substances acting on presynaptic receptors. Thus acetylcholine (ACh), histamine, sero- tonin (5-HT), and dopamine can inhibit (–) release of NE. NE itself can inhibit its release by acting on presynaptic α2-receptors. Vasoactive substances such as epi- nephrine and angiotensin II can increase (+) release of NE by activating presynaptic receptors. On smooth muscle cells, NE can stimulate α1-receptors, causing contraction, and α2-receptors, causing relaxation; ATP acting on P receptors induces relaxation, whereas NPY can induce constriction. Downloaded from journals.physiology.org/journal/physiologyonline at Carnegie Mellon Univ (128.182.081.034) on April 5, 2021. of normotensive parents, but resting MSA is comparable (Fig. 2) (9). Thus it is now clear that in offspring of hypertensive par- ents in which resting blood pressure is still normal, MSA is abnormally stimulated during mental stress (9). It is possible that early on in the disease process the SNS is only activated abnormally during episodes of increased stress and that resting MSA is increased during development of high blood pressure, whereas at later stages of hypertension SNS activity may again become normal, although the values may still be too high for the level of blood pressure of these patients. Coronary artery disease. In patients with coronary artery disease, the SNS and its activity may be important as triggers for acute coronary syndromes in general and sudden death in particular. Indeed, abnormal SNS activity as assessed by heart rate variability greatly determines prognosis in patients after myocardial infarction (5). Heart failure. In heart failure, the SNS is markedly activated (4, 6), probably because of an activation of baroreflex mech- anisms to compensate for low blood pressure and decreased perfusion of vital organs as a consequence of abnormal left ventricular function. This activation of SNS may initially lead to an increase in cardiac output, but in severe heart failure SNS-mediated increase in peripheral vascular resistance fur- ther deteriorates cardiac function and may actually be harm- ful. In the vasodialator-heart failure trial study, patients with the highest levels of plasma NE had the poorest prognosis (2). This suggests that indeed in heart failure the degree of acti- vation of the SNS may be an important prognostic variable. Modulation of sympathetic nerve activity by cardiovascular drugs The efficacy of cardiovascular drugs primarily depends on their action on blood vessel wall and myocardium. However, some of the beneficial effects of the drugs in the circulation, i.e., vasodilatation and stimulation of myocardial contractil- ity, may be overcome at least in part by their effects on neu- rohumoral regulators. Various drugs are used to treat patients with cardiovascu- lar disease, e.g. β-blockers, calcium antagonists, ACE- inhibitors, and nitrates. Indeed, certain drugs may be very efficacious antihypertensive or vasodilator agents yet activate the SNS, and others inhibit it (7). Given the important prog- nostic relevance of SNS activity in patients with cardiovascu- lar disease, understanding the effects of these vasoactive drugs on the SNS may have great clinical relevance. Calcium channel blockers are potent vasodilators acting directly on vascular smooth muscle cells. These drugs are widely used for the treatment of hypertension and angina pectoris. In secondary prevention after myocardial infarction, calcium antagonists did not have beneficial effects on car- diovascular events and survival, particularly in patients with heart failure. This could be due to either negative inotropic effects or a baroreceptor-mediated activation of the SNS (2). Dihydropyridines such as nifedipine also have important effects on the SNS in healthy human subjects. Oral adminis- tration of short-acting nifedipine leads to a marked increase of MSA and NE plasma levels (Fig. 3). The degree of activa- tion of MSA is comparable to a cold pressor test (which is the most potent stimulus of sympathetic nerve activity). Most interestingly, nifedipine remains a very important stimulus for SNS activity even in the presence of a cold pressor test (14). This finding indicates that with short-acting dihydropy- ridines, the peripheral and cardiac portions of the SNS are highly activated and remain responsive to these stimulatory maneuvers. Indeed, the potent vasodilator effects under acute conditions together with the negative inotropic effects of the drug may lead to marked activation of the baroreflex News Physiol. Sci. • Volume 15 • June 2000 127 FIGURE 2. Muscle sympathetic activity (MSA) in peroneal nerve at rest and during mental stress in normotensive offspring of normotensive (left) and hypertensive (right) parents. Increase of MSA during mental stress is more pronounced in offspring of hypertensive parents. BP, blood pressure; HR, heart rate. Modified from Ref. 9. Downloaded from journals.physiology.org/journal/physiologyonline at Carnegie Mellon Univ (128.182.081.034) on April 5, 2021. and in turn an increase in heart rate and SNS activity. It is conceivable that such effects are less pronounced with a more slowly acting form of nifedipine. The nifedipine gas- trointestinal therapeutic system (GITS), which is a slow- release form of nifedipine, indeed does not significantly change heart rate even under acute conditions, suggesting that the baroreflex is less activated. However, in the per- oneal nerve, a marked activation of MSA can still be docu- mented (Fig. 3) (14). This suggests that a slower onset of vasodilatation as it occurs with slow-release nifedipine does not lead to a generalized sympathetic nerve activation and does not significantly increase sympathetic outflow to the heart. Nevertheless, sympathetic outflow to peripheral mus- cles is still activated under these conditions. Whether such effects also occur during chronic treatment with nifedipine remains to be demonstrated. Due to its different pharmacological profile, verapamil is associated with a decrease rather than an increase in heart rate even under acute conditions. During chronic therapy in patients with hypertension, verapamil lowers rather than increases plasma NE. Although studies with microneurography have not been performed yet, there is indirect evidence that verapamil affects the SNS differently from dihydropyridines (10). Angiotensin-converting enzyme (ACE) inhibitors also act as vasodilators, inhibiting the formation of the vasoconstrictor peptide angiotensin II. ACE inhibitors tend to lower heart rate in normotensive subjects, although they do slightly decrease blood pressure. These drugs not only improve symptoms in patients with left ventricular dysfunction and/or congestive heart failure but also reduce acute coronary events and death. Experimentally, angiotensin II stimulates SNS activity by activating specific binding sites in the brainstem and, at presynaptic levels, it increases the release of NE from sym- pathetic nerve endings (Fig. 1). These mechanisms could explain the increased MSA observed in patients with reno- vascular hypertension, characterized by a high plasma level of angiotensin II. After administration of captopril in healthy volunteers, MSA remained constant despite a significant decrease in diastolic blood pressure (Fig. 4) (8). These find- ings are in line with the observation that in rat model of renal hypertension lisinopril and losartan had no influence on splanchnic sympathetic nerve activity despite a reduction in blood pressure. This effect on SNS activity could explain the favorable effects of ACE inhibitors on the prognosis of patients with heart failure in whom activation of the SNS is an important prognostic factor. Hence, ACE inhibitors and possibly angiotensin II receptor antagonists may be particu- larly efficacious in blunting or even inhibiting the untoward effects of the SNS in patients with cardiovascular disease. Similar reduction of blood pressure is achieved with nitrates, but these drugs are associated with marked activa- tion of the SNS. Earlier studies demonstrated that intravenous administration of nitrovasodialators is associated with a marked increase in MSA. In healthy subjects, an acute oral administration of isosorbide dinitrate causes a marked increase in MSA (Fig. 4) and heart rate and has little effect on blood pressure. Indeed, this effect of the nitrates may be partially responsible for the clinically observed tolerance, or rather pseudotolerance, since the baroreflex-mediated News Physiol. Sci. • Volume 15 • June 2000128 FIGURE 3. MSA expressed as bursts/min (left) and heart rate (right) before and after oral nifedipine [5 mg, 10 mg, and GI theraputic system (GITS) of 60 mg] or placebo. bpm, Beats per minute. Modified from Ref. 14. FIGURE 4. Change in resting MSA 90 minutes after oral administration of placebo, 6.25 mg captopril, and 40 mg isosorbide dinitrate (ISDN). A signifi- cant increase in MSA was observed in subjects who received placebo. Increase in MSA after ISDN was more pronounced compared with placebo. In subjects treated with captopril, MSA did not change. *P < 0.05 vs. placebo; #P < 0.05 vs. ISDN. Modified from Ref. 8. Downloaded from journals.physiology.org/journal/physiologyonline at Carnegie Mellon Univ (128.182.081.034) on April 5, 2021. News Physiol. Sci. • Volume 15 • June 2000 129 activation of the SNS in part blunts the vasodilator effects of these drugs in the intact organ (8). Centrally acting drugs, i.e., clonidine and α-methyl-DOPA, have been used for the treatment of hypertension for a long time. It has been postulated that this antihypertensive effect is due to a central inhibitory effect on the SNS. Moxonidine belongs to a new generation of centrally acting drugs that activate I1-imida- zoline receptors in the brain stem. The oral administration of moxonidine in healthy volunteers and hypertensive patients leads to a significant decrease of systolic and diastolic blood pressure, NE, and MSA (15). This demonstrates that the I1-imida- zoline receptor agonist moxonidine reduces blood pressure in untreated hypertensive subjects through the reduction in central sympathetic outflow (15). This effect may be beneficial not only in hypertensives but also in patients with heart failure. Clinical Implications In conclusion, it is clear that sympathetic activity is an important prognostic factor in patients with cardiovascular disease and in heart failure in particular. Its true importance, however, has been revealed more recently though new tech- niques allowing precise assessment of its activity and its con- trol over cardiovascular functions in the intact organism. Recent data suggest that activation of the SNS during men- tal stress may precede the increase in resting activity present in early stages of hypertension. These data suggest that respon- siveness as well as activity of the SNS may play an important role in the development of hypertension. Hence, the effects of drugs on this important regulatory system should be more thoroughly investigated since this may have important impli- cations for the effects on the prognosis of these patients. In regard to calcium antagonists, it appears that the effects of cal- cium antagonists on SNS activity depend on pharmacokinet- ics of these drugs as well as their genuine pharmacological properties. Activation of the SNS is most pronounced with short-acting dihydropyridines and less so with long-acting preparations of these drugs. These properties of certain cal- cium antagonists deserve further investigation to elucidate their clinical implications. ACE inhibitors, besides their favor- able influence on hemodynamics, seem to lower SNS activity, an effect that may contribute to the beneficial effects on the prognosis of patients with impaired left ventricular function. 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