CHARACTERIZATION OF VASCULAR EFFECTS OF CALCITONIN GENE-RELATED PEPTIDE

Abstract

Calcitonin gene-related peptide (CGRP) is a 37 amino acid transcript of the calcitonin gene. We used an isolated, perfused rabbit ear artery preparation to study the vascular effects of CGRP. The peptide produced a concentration-dependent inhibition of the constrictor responses to electrical stimulation or phenylephrine administration. The inhibitory effect of CGRP was not altered by disruption of the endothelium or by the presence of methylene blue or ibuprofen. Incubation with CGRP resulted in a marked increase in arterial cAMP levels, with no significant changes on cGMP levels.The ear arteries exhibited a gradual loss of sensitivity to CGRP, both to its inhibitory effect on nerve-induced vasoconstrictions and to its stimulatory effect on cAMP production. The time course for onset of the vasodilatory effect and the stimulatory effect on cAMP accumulation was similar. Furthermore, the EC for vasodilation and for cAMP accumulation were approximately the same. These findings show that the vascular effects of CGRP are associated with an increase in cellular cAMP concentrations.CGRP was more potent than vasoactive intestinal peptide (VIP) and parathyroid hormone (PTH) in inhibiting neurovascular transmission (EC : CGRP = 1.5 nM, PTH = 30 nM, and VIP = 40 nM). The inhibitory effect of PTH and VIP decreased during prolonged exposure to these peptides (desensitization). Arteries desensitized to one of these peptides exhibited decreased sensitivity to any of the other peptides, suggesting an interaction through adenylate cyclase.CGRP effects were also studied in the presence of various vasoconstrictors. Histamine, angiotensin II, or phenylephrine did not alter the inhibitory potency of CGRP on nerve-induced vasoconstrictions. However, 5-hydroxytryptamine or clonidine significantly reduced the inhibitory effect of CGRP on nerve-induced vasoconstrictions and the stimulatory effect of CGRP on tissue cAMP production.The ear artery possessed significant CGRP immunoreactivity (465 pgm CGRP/mg protein). In addition, perfusion effluent samples collected during field stimulation of the periarterial nerves possessed significantly more immunoreactivity than the samples collected before or after stimulation.These results show that CGRP is present in the rabbit ear artery where it acts as a potent vasodilator, with an action mediated through cAMP production. Its release from stimulated nerves suggests a physiological role in regulating peripheral resistance.