ADRENOMEDULLIN MEDIATES VASODILATION VIA CGRP(1) RECEPTORS

Adrenomedullin is a recently discovered 52 amino acid polypeptide with potent hypotensive activity. The peptide possesses 21% homology with the amino acid sequence of human calcitonin gene-related peptide-alpha (hCGRP-alpha). In I-125-hCGRP-alpha receptor binding experiments using membranes from human neuroblastoma cells (SK-N-MC) adrenomedullin is a potent competitor with a K-i of 0.37 nM. In SK-N-MC cells hCGRP-alpha and adrenomedullin concentration-dependently increase cAMP levels with -logEC(50) values of 9.65 and 7.75, respectively. Both responses were attenuated in the presence of 30 nM CGRP[8-37], a CGRP(1) receptor antagonist. In isolated rat hearts, perfused at constant flow, bolus infusion of adrenomedullin (1 to 100 nM) resulted in a concentration-dependent, pronounced and long-lasting vasodilation with an approximate EC(50) of about 3 nM. This effect was markedly attenuated in the presence of 100 nM CGRP[8-37]. In this model, bolus infusion of hCGRP-alpha (0.01 to 100 nM) evoked a comparable vasodilation with an approximate EC(50) of 0.5 nM. This effect was also potently inhibited in the presence of CGRP[8-37]. These results suggest that adrenomedullin-mediated vasodilation is linked to the activation of CGRP(1) receptors in the coronary vascular system.