Calcitonin gene‐related peptide and human epicardial coronary arteries: presence, release and vasodilator effects

Abstract

1 In the present study, the levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (-LI) in human cardiopulmonary tissue were determined in combination with studies on CGRP-LI release from the left anterior descending coronary artery (LAD) and functional effects of CGRP on coronary arterial tone.2 The highest levels of CGRP-LI were found in the LAD followed in declining order by the bronchus, right atrium, pulmonary artery, lung and left ventricle. 3 Exposure to capsaicin evoked a clear-cut increase in CGRP-LI outflow, suggesting release from isolated large specimen of the LAD. This release was Ca2"-dependent and was markedly attenuated by incubation with the mitochondrial Ca2+-inhibitor, ruthenium red. Exposure to potassium also released CGRP-LI in a Ca2 +-dependent fashion from the LAD. 4 In functional experiments on human epicardial coronary arteries with an inner diameter of 0.4 to 0.8 mm, human CGRP alpha and beta relaxed the potassium-precontracted arteries equipotently. Substance P (SP) also relaxed these precontracted arteries but the relaxation could be prevented by incubation with methylene blue, an inhibitor of endothelium derived relaxing factor (EDRF)-mechanisms, which did not influence the effect of CGRP. 5 Capsaicin evoked a ruthenium red-sensitive relaxation of the potassium-precontracted arteries. However, ruthenium red did not affect the relaxations induced by CGRP or SP. Furthermore, the capsaicin effect was not influenced by methylene blue. 6 It is concluded that CGRP-LI is present in human cardiopulmonary tissue and can be released upon exposure to high concentrations of capsaicin as well as potassium. CGRP causes relaxation of arteries independently of EDRF activation and closely resembles the vasodilator effects of capsaicin. This supports the view that the coronary vasodilatation observed upon sensory nerve activation is mediated by CGRP. Ruthenium red inhibits capsaicin-induced CGRP-LI release and functional effects and may thus serve as an experimental tool in evaluating the function of capsaicin-evoked stimulation of peripheral nerve terminals.

Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials

“…cardiovascular system (196)(197)(198)(199) and the presence of i-CGRP in perivascular nerves (1), taken together with the potent vasodilatory activity of CGRP (237-256), suggest that this peptide may play a major role in regulating peripheral vascular tone and controlling blood flow in various organs (12). The highest concentrations of i-CGRP in human cardiopulmonary tissues are found in the left anterior descending artery, whose relaxation is independent of activation of endothelium-derived-relaxant factor (EDRF) nitric oxide (251). Direct infusion of CGRP into large coronary arteries, including the left anterior descending artery, did not cause a change in blood pressure or heart rate, although it significantly reduced coronary artery resistance and increased coronary blood flow (256)(257)(258)(259).…”

“…Spasm of coronary arteries may occur in association with atheromatous disease, in isolation, or in combination with variant or Prinzmetal's angina (425). In vitro studies have shown that CGRP can rapidly relax human epicardial coronary arteries that have been previously constricted with serotonin (423). Like nitrates, CGRP also relaxes human coronary arteries directly, without mediation of endothelium-derived growth factors (537).…”

“…CGRP may also directly affect capacitance blood vessels and lead to peripheral vasodilation and reduced vascular resistance (23)(24)(25)(26)(27)(28)(246)(247)(248)(249)(250)(251)(252)(253). Indeed, CGRP has been suggested as a therapeutic agent to treat systemic arterial hypertension (452,453).…”

“…The bioassays used to measure the potency of CGRP include cAMP generation (344-347), a rat aortic strip relaxation assay (239-241), inotropic and chronotropic effects on the rat heart (215, 406), assays of cardiovascular functions including changes in mean arterial blood pressure in whole animals (240-244), and direct blood flow measurements (250)(251)(252)(253)(254)(255)(256), including Doppler techniques and xenon clearance assays in rabbit skin, and others (132, 133, 247, 405).…”

Changes in calcitonin gene‐related peptide, atrial natriuretic peptide and brain natriuretic peptide in patients undergoing coronary artery bypass grafting

“…The increase in CGRP levels cannot be explained by the lack of a pulmonary circulation during CPB, as there was no significant difference between arterial and venous levels. The coronary arteries contain 10 times more CGRP than peripheral arteries [25]. However, as their blood flow constitutes only 5% of cardiac output, the peripheral arteries can be thought of as the main production site of CGRP [26].…”