Calcitonin gene-related peptide (CGRP)-induced cyclic AMP, cyclic GMP and vasorelaxant responses in rat thoracic aorta are antagonized by blockers of endothelium-derived relaxant factor (EDRF)

Abstract

The mechanism of CGRP-induced vasodilation in rat thoracic aorta was investigated using antagonists of the classical endothelium-derived vasorelaxant factor (EDRF) and comparisons with acetylcholine-induced vasodilations. The CGRP-induced relaxations of isolated rings of rat thoracic aorta were completely dependent on the presence of endothelium and were associated with increases in the levels of both cyclic AMP and cyclic GMP, the same as in our previous study using rat abdominal aorta. Maximum relaxations to CGRP, which represented 40–50% reversal of the norepinephrine-induced contractions, occurred with 100 nM CGRP. Addition of acetylcholine (ACh, 1 μM) to aortic rings, which were already maximally relaxed to CGRP, caused further relaxation to 100%, suggesting that CGRP may use a mechanism (or pool of EDRF) different from that of ACh. Both CGRP- and ACh-induced relaxations of aorta were significantly inhibited by the EDRF blocking agents, hemoglobin (10 μM), methylene blue (10 μM), and nordihydroguaiaretic acid (NDGA, 10 μM). In fact, hemoglobin and NDGA were more effective as inhibitors of CGRP-induced relaxations than ACh-induced relaxations. Hemoglobin, methylene blue and NDGA also inhibited the CGRP-induced increases in both cyclic AMP and cyclic GMP levels. On the other hand, indomethacin, a cyclo-oxygenase inhibitor, did not alter CGRP-induced vasorelaxations or increases in either cyclic AMP or cyclic GMP levels, suggesting that prostaglandins are not involved. Therefore, CGRP-induced vasodilations in rat thoracic aorta appear to involve EDRF, leading to cyclic GMP elevations in smooth muscle and ultimately vasorelaxations. However, another previously undescribed mechanism, which involves EDRF-dependent and indomethacin-resistant elevations of cyclic AMP levels, is triggered by CGRP in thoracic aorta. This novel EDRF-dependent cyclic AMP response may contribute to the CGRP-induced vasodilation in rat thoracic aorta.