Receptors mediating CGRP-induced relaxation in the rat isolated thoracic aorta and porcine isolated coronary artery differentiated by h(alpha) CGRP(8-37).
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 h(alpha) CGRP(8-37). 2 In the endothelium-intact rat aorta, h(alpha) CGRP, h(beta) CGRP, rat beta CGRP and human adrenomedullin caused relaxation with similar potencies. Compared with h(alpha) CGRP, rat amylin was about 25 fold less potent, while [Cys(ACM2,7)] h(alpha) CGRP and salmon calcitonin were at least 1000 fold weaker. 3 H(alpha) CGRP(8-37) (up to 10(-5) M) did not antagonize responses to h(alpha) CGRP, h(beta) CGRP or rat beta CGRP (apparent pKB <5). Peptidase inhibitors did not increase either the effect of h(alpha) CGRP or [Cys(ACM,2,7)] h(alpha) CGRP, while h(alpha) CGRP(8-37) remained inactive. Endothelium-dependent relaxation produced by h(alpha) CGRP was accompanied by increases in cyclic AMP and cyclic GMP, that were not inhibited by h(alpha) CGRP(8-37) (10(-5) M). 4 In porcine LAD and AIA, h(alpha) CGRP produced relaxation in an endothelium-independent manner. H(alpha) CGRP(8-37) competitively antagonized h(alpha) CGRP responses (pA2 6.3 and 6.7 (Schild slope 0.9+/-0.1, each), in LAD and AIA, respectively). In LAD artery, h(alpha) CGRP-induced relaxation was accompanied by increases in cyclic AMP that were inhibited by h(alpha) CGRP(8-37) (10(-7)-10(5 )). 5 In conclusion, the antagonist affinity for h(alpha) CGRP(8-37) in porcine coronary artery is consistent with a CGRP1 receptor, while the lack of h(alpha) CGRP(8-37) antagonism in rat aorta could suggest either a CGRP receptor different from CGRP1 and CGRP2 type, or a non-CGRP receptor.
Wisskirchen
F M
FM
Department of Pharmacology, University College London, Gower Street, London WC1E 6BT.
Gray
D W
DW
Marshall
I
I
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine
D009712:Nucleotides, Cyclic; D010446:Peptide Fragments; D011480:Protease Inhibitors; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide