ANALYSIS OF RESPONSES TO HUMAN SYNTHETIC ADRENOMEDULLIN AND CALCITONIN-GENE-RELATED PEPTIDES IN THE HINDLIMB VASCULAR BED OF THE CAT

Vasodilator responses to human adrenomedullin (hADM), a newly discover ed hypotensive peptide, human calcitonin gene related peptide-alpha (h CGRP-alpha) and hCGRP-beta, which share structural homology with hADM, were compared in the hindlimb vascular bed of the cat under constant flow conditions. Injections of hADM (0.003-1 nmol), hCGRP-alpha, and h CGRP-beta (0.003-0.3 nmol) into the perfusion circuit caused dose-rela ted decreases in hindlimb perfusion pressure. Vasodilator responses to hCGRP-alpha and hCGRP-beta were similar in potency and duration, and the doses of hCGRP-alpha and hCGRP-beta required to reduce hindlimb pe rfusion pressure 40 mm Hg (ED40 mm Hg) were significantly lower than t he ED40 mm Hg for hADM. The duration of the hindlimb vasodilator respo nses to hCGRP-alpha and hCGRP-beta were significantly longer than the duration of the response to hADM, Amylin, a peptide that shares struct ural homology with ADM and with CGRP, had no significant effect on hin dlimb perfusion pressure when injected in doses up to 1 nmol. Decrease s in hindlimb perfusion pressure in response to hADM, hCGRP-alpha, and hCGRP-beta were not altered by L-N-5-(1-iminoethyl)-ornithine (L-NIO) in a dose of the nitric oxide synthase inhibitor that decreased the v asodilator response to acetylcholine or by the cyclooxygenase inhibito r, meclofenamate, in a dose that decreased the vasodilator response to arachidonic acid. The present data demonstrate that hADM, hCGRP-alpha , and hCGRP-beta have potent, but relatively short-lasting, vasodilato r activity, and that vasodilator responses are not dependent on the re lease of nitric oxide or vasodilator prostaglandins in the hindlimb va scular bed of the cat.