Calcitonin gene-related peptide-dependent vascular relaxation of rat aorta: An additional mechanism for nitroglycerin

Abstract

We investigated the involvement of calcitonin gene-related peptide (CGRP) in the vasodilatory mechanism of action of nitric oxide (NO) donors. The functional role of CGRP in NO donor-induced vasodilation of isolated rat aortic rings was determined by incubating these drugs with and without CGRP 8–37, a selective CGRP receptor antagonist. CGRP 8–37 (0.63 μM) induced rightward shifts in the vasodilatory concentration–response curves for nitroglycerin (NTG), Piloty’s acid (PA), and SIN-1 (linsidomine). The ec 50 values for NTG, PA, and SIN-1 were increased by 8.3-, 5.2-, and 2.3-fold, respectively ( P < 0.05). The release of CGRP from rat aorta in response to NTG and PA was measured specifically by radioimmunoassay. Thirty-minute incubations of NTG or PA with rat aorta induced 189.5 and 214.6% increases, respectively, in CGRP release when compared with the control ( P < 0.05). The concentration–response curves of sodium nitroprusside (SNP), S-nitroso-acetylpenicillamine (SNAP), tetranitromethane (TNM), diethylamine NO complex (DEA-NO), and diethylenetriamine/nitric oxide adduct (DETA NONOate) were not inhibited significantly by CGRP 8–37 co-incubation ( P > 0.05). NO donors also were incubated with aortic strips, and NTG and PA alone induced significant formation of hydroxylamine, a NO - metabolite (232.4 and 364.9%, respectively, P < 0.05). These results indicate that only NTG and PA, and to a lesser extent SIN-1, stimulate the release of CGRP from the rat aorta, which subsequently contributes to the vasodilatory activity of these agents. The hydroxylamine formation suggests a possible link between NO - generation and CGRP release from the vascular wall.