EFFECTS OF ADRENOMEDULLIN AND CALCITONIN-GENE-RELATED PEPTIDE ON CONTRACTIONS OF THE RAT AORTA AND PORCINE CORONARY-ARTERY

1 Effects of adrenomedullin and alpha-calcitonin gene-related peptide (CGRP) on the contractions and cytosolic Ca2+ concentrations ([Ca2+](i )) of the rat aorta and porcine coronary artery were investigated. Cha racteristics of the receptors mediating the effects of adrenomedullin and alpha-CGRP were also investigated. 2 Adrenomedullin and alpha-CGRP caused a concentration-dependent relaxation in the rat aorta contract ed with noradrenaline. The IC50 values for adrenomedullin and alpha-CG RP were 2.4 nM and 4.0 nM, respectively. The relaxant effects of these peptides were abolished by removal of the endothelium and significant ly attenuated by an inhibitor of nitric oxide synthase, N-G-monomethyl -L-arginine (L-NMMA, 100 mu M), but not by a cyclo-oxygenase inhibitor , indomethacin (10 mu M). 3 Adrenomedullin and alpha-CGRP increased th e endothelial [Ca2+](i) in the rat aorta with endothelium, whereas the y did not change [Ca2+](i) in the smooth muscle. 4 An antagonist of th e CGRP(1) receptor, CGRP (8-37), antagonized the relaxant effects of a lpha-CGRP and the beta-isoform of CGRP (beta-CGRP) but not those of ad renomedullin in the rat aorta. 5 In the porcine coronary artery contra cted with U46619, adrenomedullin and alpha-CGRP caused a concentration -dependent relaxation with an IC50 of 27.6 and 4.1 nM, respectively. R emoval of the endothelium altered neither the IC50 values nor the maxi mal relaxations induced by adrenomedullin or alpha-CGRP. When the arte ry was contracted with high K+ solution (72.7 mM), these peptides caus ed a small relaxation. 6 Adrenomedullin and alpha-CGRP increased cycli c AMP content and decreased the smooth muscle [Ca2+](i) in the porcine coronary artery. 7 CGRP (8-37) significantly antagonized the relaxant effects of adrenomedullin and alpha-CGRP in the porcine coronary arte ry. However, it had little effect on the relaxations induced by the be ta-isoform of CGRP (beta-CGRP). 8 These results suggest that in the ra t aorta, adrenomedullin and alpha-CGRP increase the endothelial [Ca2+] (i), activate nitric oxide synthase and release nitric oxide, without a direct inhibitory action on smooth muscle. In the porcine coronary a rtery, in contrast, adrenomedullin and alpha-CGRP directly act on smoo th muscle, increase cyclic AMP content, decrease the smooth muscle [Ca 2+](i) and inhibit contraction. The rat aortic endothelium seems to ex press the CGRP receptor which is sensitive to alpha-CGRP, beta-CGRP an d CGRP (8-37) and the adrenomedullin specific receptor. The porcine co ronary smooth muscle, in contrast, seems to express two types of CGRP receptor; one of which is sensitive to alpha-CGRP, CGRP (8-37) and adr enomedullin and the other is sensitive only to beta-CGRP.