INTERACTION OF HUMAN ADRENOMEDULLIN(13-52) WITH CALCITONIN-GENE-RELATED PEPTIDE RECEPTORS IN THE MICROVASCULATURE OF THE RAT AND HAMSTER

1 Adrenomedullin (ADM), a recently discovered circulating hypotensive peptide, shares limited sequence homology with the sensory nerve-derived vasodilator, calcitonin gene-related peptide (CCRP). This study compared the vasodilator effect of sequence 13-52 of human adrenomedullin (ADM(13-52)) With that of human alpha CGRP (CGRP), in the microvasculature of the hamster cheek pouch and rat skin in vivo. 2 Single arterioles (20-40 mu m diameter) in the hamster cheek pouch were visualised by intravital microscopy and video recording, and measured by image analysis. Both ADM(13-52) (1 pmol-0.4 nmol) and CGRP (0.1 pmol-1 nmol) evoked dose-related increases in the diameter of preconstricted arterioles (n = 6). ADM(13-52) (ED(50) 14 pmol) was 20 fold less active than CGRP (ED(50) 0.71 pmol). The kinetics of onset and decline of vasodilator responses to both peptides were similar, with vasodilator responses to both peptides reaching a maximum at ca. 2 min, and reversing after 10-15 min (n = 5-7). The submaximal increase in blood flow evoked by ADM(13-52) was significantly inhibited (P<0.05; n = 6) by the CGRP(1) receptor antagonist, CGRP(8-37), at a dose (300 nmol kg(-1), i.v.) that we have previously shown to inhibit significantly equivalent vasodilator responses to CGRP in this preparation. 3 In experiments measuring changes in local blood flow in rat skin by a (133)xenon clearance technique, intradermal injection of both ADM(13-52) (3-300 pmol) and CGRP (0.1-30 pmo1) evoked dose-related increases in local blood flow. ADM(13-52) (ED(50) 27 pmol) was 17 fold less potent than CGRP (ED(50) 1.6 pmol) (n = 6). The submaximal increase in blood flow evoked by both peptides was significantly inhibited (P<0.02; n = 5) by CGRP(8.37) (100 nmol kg(-1), i.v.). 4 We conclude that ADM13-52 is a potent vasodilator in the microvasculature of the hamster and rat in vivo. It mediates its vasodilator effect by arteriolar dilatation and this effect is due, at least in part, to the stimulation of CGRP(1) receptors.