Synergism between low-dose nicorandil and neuropeptides on adenosine-induced vasodepression in rats

We hypothesized that the effect of nicorandil may be enhanced by interaction with naturally occurring vasodilators. To clarify this hypothesis, the effects of low-dose nicorandil alone and in combination with low doses of vasoactive intestinal polypeptide (VIP) or calcitonin gene-related peptide (CGRP) on adenosine-induced vasodepression were studied in rats. Intravenous (i.v.) bolus injections of adenosine (3-100 microg kg(-1)) elicited dose-dependent decreases in blood pressure, accompanied by slight decreases (except for 100 microg kg(-1)) in heart rate. Simultaneous i.v. infusion of either nicorandil (1 microg kg(-1) min(-1)) and VIP (0.003 microg kg(-1) min(-1)) or CGRP (0.1 ng kg(-1) min(-1)) significantly enhanced the adenosine-induced vasodepression, although each agent alone in the dose used had no effects on vasodepressor responses to adenosine. The potentiation of the effect of adenosine was not observed in the presence of 3,7-dimethyl-1-propargylxanthine (DMPX) (1 mg kg(-1), i.v.) or glibenclamide (20 mg kg(-1), i.v.). The present results suggest that low-dose nicorandil modifies the response to adenosine in interaction with low levels of endogenous neuropeptides such as VIP and CGRP, and that the reciprocal interaction is mediated partly through K(ATP) channel activation in vascular smooth muscle.