Nicorandil, its denitrated metabolite, SG-86 and naturally occurring vasodilators synergistically interact on adenosine-induced vasodepression in rats: special reference to adrenomedullin.

Abstract

To investigate synergistic effects among nicorandil, its main metabolite, SG-86 and endogenous vasodilators such as adrenomedullin (ADM), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP), the effects of ADM, VIP and CGRP as well as nicorandil and SG-86 alone, and their low-dose combination were examined on adenosine-induced vasodepression in anesthetized rats. Single bolus i.v. injections of adenosine (3-100 micrograms/kg) caused a dose-dependent reduction of arterial blood pressure, accompanied by slight decreases (except for 100 micrograms/kg) in heart rate. i.v. infusion of nicorandil (10 micrograms/kg/min), SG-86 (100 micrograms/kg/min) ADM (1 ng/kg/min), VIP (30 ng/kg/min) or CGRP (1 ng/kg/min) alone, or the low-dose combination of either nicorandil (1 microgram/kg/min), and SG-86 (10 micrograms/kg/min) or either nicorandil or SG-86 and endogenous vasodilators, significantly potentiated the vasodepression produced by bolus i.v. adenosine, but not that by bolus i.v. acetylcholine (0.1 microgram/kg). The observed enhancement did not occur in the presence of glibenclamide (20 mg/kg i.v.). The present results indicate that nicorandil, SG-86 and endogenous vasodilators reciprocally interact, partly in link with KATP channels in vascular smooth muscle.