Functional role of alpha-calcitonin gene-related peptide in the regulation of the cardiovascular system.
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 alpha-CGRP (0.1-0.5 microg/kg, i.v.) induced a dose-dependent peripheral vasodilation that was completely abolished by pretreatment with alpha-CGRP[8-37] (30 microg/kg/min, i.v.), a competitive antagonist of CGRP receptors. Regional blood flow measured by the radioactive microsphere technique in rats showed that the alpha-CGRP (0.3 microg/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 beta-adrenergic receptor blockade with propranolol, however, the increases in blood flow in these two vascular beds were identical. In conscious dogs, alpha-CGRP (0.3 microg/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, alpha-CGRP increased coronary and carotid blood flow significantly less (p < 0.05) than adenosine or nitroprusside. Unlike alpha-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 alpha-CGRP[8-37] in the two species. Thus, we conclude that endogenous alpha-CGRP does not play an important role in cardiovascular regulation under normal, resting conditions, although exogenous alpha-CGRP induces a marked, comparable vasorelaxation in different regional vascular beds.
Shen
Y T
YT
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. youtang_shen@merck.com
Pittman
T J
TJ
Buie
P S
PS
Bolduc
D L
DL
Kane
S A
SA
Koblan
K S
KS
Gould
R J
RJ
Lynch
J J
JJ
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013045:Species Specificity; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D009599:Nitroprusside; D015740:Calcitonin Gene-Related Peptide; D000241:Adenosine