REGIONAL DIFFERENCES IN THE VASORELAXANT EFFECTS OF NICORANDIL AND AMLODIPINE ON ISOLATED PORCINE CORONARY-ARTERIES

The vasorelaxant effects of nicorandil, a K+-channel opener, and amlod ipine, a dihydropyridine-type Ca2+-channel blocker, were investigated on partially and maximally K+-depolarized ring preparations from the p orcine left anterior descending coronary artery. By comparing vascular responses in the proximal and distal parts of the epicardial segment, the scope of the study was to evaluate regional differences in the ac tion of nicorandil and amlodipine. Nicorandil (10(-7)-10(-4) M) shifte d the K+ concentration-response curves to the right and depressed the maximal contractile responses in a concentration-dependent manner, con sistent with K+-channel opening and secondary non-K+-channel opening m echanisms of action. Nicorandil had a significantly more potent relaxa nt effect in the proximal compared to the distal arterial rings contra cted with 85 mM K+. Pretreatment with methylene blue (10(-5) M) did no t significantly influence the regional difference in the action of nic orandil. Amlodipine (10(-9)-10(-6) M) had a significantly more potent and effective inhibitory and relaxant effect than nicorandil under the same conditions. In contrast to nicorandil, the effect of amlodipine was more prominent in the distal compared to the proximal vessel rings . The cumulative addition of extracellular Ca2+ exhibited a more poten t contractile response in the distal rather than in the proximal rings . Nicorandil totally and amlodipine partly eliminated the contractile responses to the lowest concentration of Ca?+. The inhibitory effect o f amlodipine on the contractile responses to higher Ca2+ concentration s was more pronounced than that of nicorandil. The results show that t here are regional differences in the responsiveness of porcine coronar y arteries to Ca2+, nicorandil and amlodipine. Our findings indicate t hat the regional difference in nicorandil-induced vasodilation was cau sed neither by the K+-channel opening nor by the nitrate-like mechanis m of action, but could be due to a direct Ca2+-influx blocking effect of the drug. (C) 1998 Elsevier, Paris.