Vol. 298, Issue 2, 551-558, August 2001

Functional Role of -Calcitonin Gene-Related Peptide in the Regulation of the Cardiovascular System

You-Tang Shen, Tamara J. Pittman, Pamela S. Buie, David L. Bolduc, Stefanie A. Kane, Kenneth S. Koblan, Robert J. Gould and Joseph J. Lynch, Jr.

Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania

It remains unknown whether the extent of vasoactive response to exogenous calcitonin gene-related peptide (CGRP) varies among different regional vascular beds. It is also unclear whether endogenous CGRP plays a functional role in regulating basal vascular activity. To address these two issues, experiments were conducted in 27 anesthetized rats instrumented with a carotid flow probe and catheters in a jugular vein, left ventricle (LV), and femoral artery, and in 6 conscious dogs, chronically instrumented with LV pressure gauge, aortic and atrial catheters, and ascending aortic, coronary, carotid, and renal flow probes. In both species, administration of human -CGRP (0.1-0.5 µg/kg, i.v.) induced a dose-dependent peripheral vasodilation that was completely abolished by pretreatment with -CGRP[8-37] (30 µg/kg/min, i.v.), a competitive antagonist of CGRP receptors. Regional blood flow measured by the radioactive microsphere technique in rats showed that the -CGRP (0.3 µg/kg, i.v.)-induced increase in blood flow was greater (p < 0.05) in the heart (+53 ± 16%) than in the brain (+14 ± 6%). In the presence of -adrenergic receptor blockade with propranolol, however, the increases in blood flow in these two vascular beds were identical. In conscious dogs, -CGRP (0.3 µg/kg, i.v.) produced similar increases in coronary (+24 ± 6%), carotid (+26 ± 3%), and renal (+26 ± 6%) blood flow, which were different from the patterns induced by other vasodilators; at an equivalent level of reduction in mean arterial pressure and total peripheral resistance, -CGRP increased coronary and carotid blood flow significantly less (p < 0.05) than adenosine or nitroprusside. Unlike -CGRP, adenosine and nitroprusside, as expected, induced pronounced differential blood flow changes in these vascular beds. Neither systemic hemodynamics nor regional blood flow distribution was altered by the administration of a pharmacological blocking dose of -CGRP[8-37] in the two species. Thus, we conclude that endogenous -CGRP does not play an important role in cardiovascular regulation under normal, resting conditions, although exogenous -CGRP induces a marked, comparable vasorelaxation in different regional vascular beds.