Interaction of endothelial eccrine mechanisms and human adrenomedullin on vascular resistance in canine bone

Adrenomedullin is a novel peptide known to be one of the most potent vascular smooth muscle relaxing agents in vivo. The aim of this study is to investigate the effect of adrenomedullin in relation to nitric oxide, prostaglandins and endothelium-derived hyperpolarized factor (EDHF). A 0.1- ml bolus of 1 nmol human adrenomedullin is a potent inhibitor of the pressor response to exogenous norepinephrine infusion in an ex vivo canine tibia perfusion model for a duration of at least 70 min (P < 0.005). This attenuation of vascular smooth muscle contraction occurs even when nitric oxide production is blocked by N(G)-monomethyl-L-arginine acetate (L-NMMA) infusion and EDHF is blocked by tetraethylammonium infusion, although the effect is of shorter duration (at least 10 min). Indomethacin as well does not affect the suppression of norepinephrine-induced vascular smooth muscle contraction. Based on these data, human adrenomedullin has both nitric oxide- and EDHF-dependent mechanism as well as a nitric oxide- and EDHF-independent mechanism.