Increased α CGRP potency and CGRP‐receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries

1 This study describes the effects of hypoxia on relaxing responses and cAMP production induced by the known vasodilator peptides: α CGRP, amylin (AMY) and adrenomedullin (AM) on isolated pig coronary arteries in vitro . 2 Hypoxic incubation increased the vasorelaxant effect of α CGRP (four‐fold; P <0.05), AMY (3.2‐fold; P <0.05), but not significantly for AM (two‐fold; NS). 3 Whereas hypoxia had no effect on arterial cAMP levels, it significantly potentiated the production of cAMP stimulated of α CGRP and AMY, but not of AM. 4 The antagonist α CGRP 8–37 also exerted an increased effect in hypoxia. The Schild plot‐derived p K B values revealed an increase in the apparent affinity of the antagonist for the CGRP 1 receptor from 7.0 to 7.2 under control conditions versus 8.0 in hypoxia. 5 Removal of endothelium, peptidase inhibitors, preincubation with the adenosine A 2A receptor antagonist CSC (10 −3   M ), the ATP‐sensitive K‐channel inhibitor glibenclamide (10 −5   M ), the cyclooxygenase inhibitor indomethacin (10 −3   M ) or NG ‐monomethyl‐ L ‐arginine (10 −4   M ) had no effect on the α CGRP‐induced vasorelaxation in hypoxia; neither did hypoxia influence the levels of CGRP and AM receptor mRNA. 6 We conclude that hypoxic incubation increases the relaxation and cAMP production induced by α CGRP and AMY in rings of porcine coronary arteries in vitro . A concomitant release of adenosine, a cyclooxygenase product, an endothelium‐derived substance, activation of vascular ATP‐sensitive K‐channels, peptidase inhibitors or changes in CGRP and AM receptor mRNA cannot account for the changes observed in hypoxia. Moreover, α CGRP 8–37 showed increased affinity at the CGRP 1 receptor during hypoxia, possibly due to a conformational change at the CGRP 1 receptor site.British Journal of Pharmacology (2005) 145 , 646–655. doi: 10.1038/sj.bjp.0706232