Receptors mediating CGRP-induced relaxation in the rat isolated thoracic aorta and porcine isolated coronary artery differentiated by hα CGRP8-37

Abstract

1. Receptors mediating CGRP-induced vasorelaxation were investigated in rat thoracic aorta and porcine left anterior descending (LAD) coronary artery and anterior interventricular artery (AIA), using CGRP agonists, homologues and the antagonist hα CGRP8-37. 2. In the endothelium-intact rat aorta, hα CGRP, hβ CGRP, rat β CGRP and human adrenomedullin caused relaxation with similar potencies. Compared with hα CGRP, rat amylin was about 25 fold less potent, while [Cys(ACM2,7)] hα CGRP and salmon calcitonin were at least 1000 fold weaker. 3. Hα CGRP8-37 (up to 10-5 M) did not antagonize responses to hα CGRP, hβ CGRP or rat β CGRP (apparent pK(B) < 5). Peptidase inhibitors did not increase either the effect of hα CGRP or [Cys(ACM,2,7)] hα CGRP, while hα CGRP8-37 remained inactive. Endothelium-dependent relaxation produced by hα CGRP was accompanied by increases in cyclic AMP and cyclic GMP, that were not inhibited by hα CGRP8-37 (10-5 M). 4. In porcine LAD and AIA, hα CGRP produced relaxation in an endothelium-independent manner. Hα CGRP8-37 competitively antagonized hα CGRP responses (pA2 6.3 and 6.7 (Schild slope 0.9 ± 0.1, each), in LAD and AIA, respectively). In LAD artery, hα CGRP-induced relaxation was accompanied by increases in cyclic AMP that were inhibited by hα CGRP8-37 (10-7-10-5 M). 5. In conclusion, the antagonist affinity for hα CGRP8-37 in porcine coronary artery is consistent with a CGRP1 receptor, while the lack of hα CGRP8-37 antagonism in rat aorta could suggest either a CGRP receptor different from CGRP1 and CGRP2 type, or a non-CGRP receptor.