Calcitonin Gene-Related Peptide Terminates Long-Lasting Vasopressor Responses to Endothelin 1 In Vivo

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 58; no. 1; pp. 99 - 106
• Main Authors: Meens, Merlijn J.P.M.T, Mattheij, Nadine J.A, Nelissen, Jelly, Lemkens, Pieter, Compeer, Matthijs G, Janssen, Ben J.A, De Mey, Jo G.R
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-07-2011; Lippincott Williams & Wilkins
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Arteries - drug effects; Arteries - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Calcitonin Gene-Related Peptide - pharmacology; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Disease Models, Animal; Endothelin-1 - pharmacology; Hypertension - physiopathology; Male; Medical sciences; Rats; Rats, Inbred WKY; Regional Blood Flow - drug effects; Vasoconstriction - drug effects; Vasodilator Agents - pharmacology; Hypertension; vasculature; Vascular resistance; Cardiovascular disease; Endothelin 1; Calcitonin gene related peptide; CGRP; ET
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.110.169128

Slow dissociation of endothelin 1 from its endothelin A receptors is responsible for the long-lasting vasoconstrictor effects of the peptide. We showed recently that calcitonin gene-related peptide selectively terminates long-lasting contractile responses to endothelin 1 in isolated rat mesenteric arteries. Here we assessed whether the antiendothelinergic effect of calcitonin gene-related peptide is vascular bed specific and may terminate long-lasting pressor responses to exogenous and locally produced endothelin 1 in vivo. Regional heterogeneity of the calcitonin gene-related peptide/endothelin A receptor cross-talk was explored in arteries isolated from various rat organs. Endothelin A receptor-mediated arterial contractions were terminated by calcitonin gene-related peptide in rat mesenteric, renal, and spermatic arteries but not in basilar, coronary, epigastric, gastric, splenic, and saphenous arteries. Endothelin A receptor antagonism only ended endothelin 1–induced contractions in spermatic arteries. In anesthetized rats, instrumented with Doppler flow probes to record regional blood flows, long-lasting pressor and vasoconstrictor responses to an intravenous bolus injection of endothelin 1 or big endothelin 1 were transiently reduced by sodium nitroprusside (NO donor) but terminated by intravenously administered calcitonin gene-related peptide. In conscious rats, calcitonin gene-related peptide but not sodium nitroprusside terminated prolonged (>60-minute) pressor responses to endothelin 1 but not those to intravenous infusion of phenylephrine. In conclusion, pressor responses to circulating and locally produced endothelin 1 that are resistant to endothelin receptor antagonism and NO can be terminated by a regionally selective effect of calcitonin gene-related peptide. Calcitonin gene related peptide receptor agonism may represent a novel strategy to treat endothelin 1–associated cardiovascular pathologies.