K-OPENING ACTION CONTRIBUTES TO THE PREVENTIVE EFFECTS OF NICORANDIL ON U46619-INDUCED VASOCONSTRICTION OF CANINE LARGE CORONARY-ARTERIES IN-VIVO( CHANNEL)

The antispasmogenic effects of nicorandil on epicardial coronary arter y vasoconstriction were compared with those of a K+ channel opener, cr omakalim, and a nitrovasodilator, nitroglycerin, in open-chest dogs. I ntracoronary administration of U46619 (0.5-1.0 mu g), a stable thrombo xane A(2) analogue, reduced the external diameter of the left circumfl ex coronary artery with no marked alterations in systemic hemodynamics . This U46619-induced vasoconstriction of large epicardial coronary ar teries was dose-dependently prevented by the intracoronary infusion of nicorandil (1-10 mu g/kg/min), cromakalim (0.03 mu g/kg/min) and nitr oglycerin (1 mu g/kg/min). After pretreatment with glibenclamide (3 mg /kg, i.v.), an ATP-sensitive K+ channel blocker, these effects of nico randil and cromakalim were inhibited significantly, whereas the respon se to nitroglycerin remained unchanged. Nicorandil (3 mu g/kg/min), cr omakalim (0.03 mu ug/kg/min) and nitroglycerin (1 mu g/kg/min) increas ed coronary blood flow. However, the inhibitory effects of each drug o n the U46619-induced vasoconstriction were not influenced by the parti al occlusion of the left circumflex coronary artery, which kept corona ry blood flow constant. This indicates a direct antispasmogenic effect of K+ channel openers, which is independent of that mediated by the r esponse to flow. Furthermore, our results suggest that, by this effect , nicorandil protects large coronary arteries from U46619-induced vaso constriction.