Adrenomedullin synergistically interacts with endogenous vasodilators in rats: a possible role of K(ATP) channels

To examine synergistic interactions among naturally occurring vasodilators, we investigated the effects of i.v. infusion of adrenomedullin (ADM) alone and in combination with low-dose vasoactive intestinal polypeptide (VIP) or calcitonin gene-related peptide (CGRP) on adenosine-induced vasodepression in rats. I.v. infusion of the combination of low-dose ADM (0.1 ng kg(-1) min(-1)) and VIP (3 ng kg(-1) min(-1)), as well as that of ADM (1 ng kg(-1) min(-1)) alone, significantly enhanced the vasodepressor responses to bolus i.v. doses of adenosine (3-100 microg kg(-1)), but not those to acetylcholine (0.1 microg kg(-1)). The observed potentiation did not occur in the presence of glibenclamide (20 mg kg(-1) i.v.), an antagonist of K(ATP) channels. Simultaneous i.v. infusion of low-dose ADM and CGRP (0.1 ng kg(-1) min(-1)) failed to enhance the effects of adenosine as well as acetylcholine. In the whole-cell voltage clamp experiments using single cells of the rat mesenteric artery, ADM (10(-11)-10(-7) M) as well as CGRP (10(-11)-10(-7) M) produced increases of inward current in a concentration-dependent manner. The ADM-induced current was not affected by iberiotoxin, a specific blocker of large conductance Ca2+-activated K+ channels, but suppressed markedly by glibenclamide and CGRP(8-37), a selective antagonist of CGRP1 receptors. From the results, we conclude that several naturally occurring vasodilators involving ADM synergistically interact, probably in link with K(ATP) channels, and furthermore that ADM may act, in part through CGRP1 receptor activation.