REGIONAL HEMODYNAMIC-EFFECTS OF HUMAN AND RAT ADRENOMEDULLIN IN CONSCIOUS RATS

1 Male, Long Evans rats were chronically instrumented with pulsed Dopp ler flow probes and intravascular catheters to permit assessment of th e regional haemodynamic responses to human and rat adrenomedullin, to compare the responses to human adrenomedullin to those of human alpha- CGRP in the absence and presence of the CGRP(1)-receptor antagonist, h uman alpha-CGRP [8-37], and to determine the involvement of nitric oxi de (NO)-mediated mechanisms in the responses to human adrenomedullin, relative to human alpha-CGRP. 2 Human and rat adrenomedullin (0.3, 1, and 3 nmol kg(-1), i.v.) caused dose-dependent hypotension and tachyca rdia, accompanied by increases in renal, mesenteric and hindquarters f lows and vascular conductances. At the lowest dose only, the hypotensi ve and mesenteric vasodilator effects of rat adrenomedullin were signi ficantly greater than those of human adrenomedullin. 3 Human alpha-CGR P at a dose of 1 nmol kg(-1) caused hypotension, tachycardia and incre ases in hindquarters flow and vascular conductance, but reductions in renal and mesenteric flows, and only transient vasodilatations in thes e vascular beds. These effects were substantially inhibited by human a lpha-CGRP [8-37] (100 nmol kg(-1) min(-1)), but those of human adrenom edullin (1 nmol kg(-1)) were not; indeed, the mesenteric haemodynamic effects of the latter peptide were enhanced by the CGRP(1)-receptor an tagonist. 4 In the presence of the NO synthase inhibitor, N-G-nitro-L- arginine methyl ester (L-NAME, 183 nmol kg(-1) min(-1)), there was onl y a slight, but significant, inhibition of the hindquarters hyperaemic vasodilator effect of human adrenomedullin, but not that of human alp ha-CGRP. 5 These results indicate that the marked regional vasodilator effects of human (and rat) adrenomedullin are largely independent of NO and, in vivo, do not involve CGRP(1)-receptors.