key: cord-0743215-e3t9zx74 authors: Skaria, Tom; Wälchli, Thomas; Vogel, Johannes title: CGRP Receptor Antagonism in COVID-19: Potential Cardiopulmonary Adverse Effects date: 2020-10-22 journal: Trends Mol Med DOI: 10.1016/j.molmed.2020.10.005 sha: c39a2714c8619db8532efa410371ddf71ee58d83 doc_id: 743215 cord_uid: e3t9zx74 Recently, the US FDA has authorized a drug repurposing trial with calcitonin gene-related peptide (CGRP) receptor antagonists to reduce lung inflammation in coronavirus 2019 (COVID-19). However, the well-established cardiopulmonary protective effects of CGRP raise concerns about the safety of antagonizing CGRP in COVID-19. Awareness regarding potential cardiopulmonary adverse effects may enable their early detection and prevent illness from worsening. trials evaluating the efficiency of anti-CGRP therapy were conducted in migraineurs without any pre-existing cardiovascular diseases such as systemic hypertension or stroke. This has raised concerns about the potential adverse effects of long term anti-CGRP therapy in hypertension and stroke because inhibition of endogenous CGRP worsens ischemic stroke and causes heart failure in systemic hypertension in preclinical models [1, 2] . Accordingly, pharmacotherapy by a systemically administered longlasting αCGRP-analog reduced elevated systemic blood pressure and consequently improved cardiac function in murine models of hypertension and heart failure [3] . In humans, αCGRP administration delays the onset of myocardial ischemia upon exercise in patients with stable angina pectoris and enhances cardiac function in patients with congestive heart failure ( Table 1 ) (cf. discussions in [1, 3] ). Apart from the clinical use of CGRP antagonists in migraine prophylaxis, most recently, the FDA has provided authorization for initiating a Phase II, randomized trial of a small molecule CGRP receptor antagonist, originally advancing to Phase III development for acute treatment of migraine, to reduce severe lung inflammation, impending oxygen desaturation, acute respiratory distress syndrome, need for supplemental oxygenation, artificial ventilation, or death in hospitalized COVID-19 patients ii . The rationale supporting the repurposing of a small molecule CGRP receptor antagonist in COVID-19 treatment seems to be the stimulatory effects of CGRP on production of proinflammatory cytokines, including IL-6, and polarization of T cell response towards T helper (Th)17-based responses in various types of cultured cells and animal models studied in the absence of viral infection [4] . Inhibiting endogenous CGRP 46 signaling has been shown to attenuate respiratory malfunction in ovine models of 48 burn and smoke inhalation and mice models 49 of acid-induced lung injury [5, 6] . Severe alve- [13, 14] . Additionally, 120 circulating CGRP concentrations are 121 reduced in pulmonary hypertensive patients 122 and rats with hypoxia-induced PH, in 123 correlation with the rise in pulmonary artery 124 pressure. Reduced CGRP concentration 125 may permit unopposed action of vasocon-126 strictors such as endothelin-1. Although 127 cells attempt to simultaneously upregulate 128 CGRP receptor expression and thus in-129 crease CGRP binding to counteract the effects of decreased peptide bioavailability, this adaptive mechanism is not effective in restoring the dilatory potential of CGRP in pulmonary vasculature [14] . Rather, increasing endogenous CGRP concentrations by infusion of CGRP analogs and gene therapy (intratracheal administration of adenoviral vector encoding CGRP) are capable of inducing pulmonary vasodilation, reducing elevated total pulmonary resistance, and preventing PH and RV remodeling in chronic hypoxic rats. Furthermore, CGRP protects also against pulmonary vasoconstriction induced by endothelin-1, angiotensin II, and the nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester [13] . In addition, the wellestablished positive inotropic effect of CGRP [3] alone may enhance pulmonary hemodynamics by regulating RV function. What do these studies tell us about the potential cardiopulmonary risks associated with the use of CGRP receptor antagonists in COVID-19 patients? In COVID-19 patients with PH, CGRP receptor antagonist therapy may exacerbate: (i) existing PH and RV remodeling, thus accelerating the transition to RV heart failure; and (ii) vasoconstriction that may further amplify intravascular coagulopathy and lung infarcts. Moreover, it generates the question whether there exists a correlation between circulating CGRP concentrations and PH, which may predict such adverse Blood pressure normalizationindependent cardioprotective effects of endogenous, physical activity-induced alpha calcitonin gene-related peptide (alphaCGRP) in chronically hypertensive mice Anti-migraine calcitonin generelated peptide receptor antagonists worsen cerebral ischemic outcome in mice A novel alpha-calcitonin generelated peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure Could CGRP antagonists be helpful in the fight against COVID-19? Role of calcitonin gene-related peptide (CGRP) in ovine burn and smoke inhalation injury Calcitonin gene-related peptide mediates acid-induced lung injury in mice Lipopolysaccharide induces calcitonin gene-related peptide in the RAW264.7 macrophage cell line The neuropeptide calcitonin gene-related peptide inhibits TNF-alpha but poorly induces IL-6 production by fetal rat osteoblasts A potent and selective calcitonin gene-related peptide (CGRP) receptor antagonist, 11 Circulating levels of calci-202 tonin gene-related peptide (CGRP) are lower in COVID Targeted blocking of gene 210 hypoxic rats