EFFECTS OF KRN2391, NICORANDIL AND DILTIAZEM ON THE CHANGES IN THE ELECTROCARDIOGRAM CAUSED BY ENDOTHELIN-1 IN ANESTHETIZED RATS

1 The effect of KRN2391, a novel vasodilator, on the changes of electr ocardiogram caused by endothehn-1 (ET-1) was studied in anaesthetized rats and compared with the effects of nicorandil and diltiazem. In add ition, the effect of KRN2391 on the action potential of guinea-pig pap illary muscle was studied. 2 The intracoronary administration (i.c.) o f ET-1 (5 mug) induced not only ST segment elevation of the electrocar diogram due to contraction of the coronary artery, but also arrhythmia s involving atrioventricular block (A-V block), ventricular premature contraction (VPC) and ventricular fibrillation (VF), and resulted in d eath in most animals. However, the administration of methacholine (3 m ug, i.c.) produced ST segment elevation alone without developing arrhy thmias. 3 Pretreatment with intravenous administration of KRN2391 (30 mug kg-1) inhibited the ST segment elevation and the development of ar rhythmias induced by ET-1, and decreased the incidence of death. 4 Nic orandil (1000 mug kg-1) prevented the ST segment elevation without sup pression of the occurrence of VF. Diltiazem (100 mug kg-1) suppressed both the ST segment elevation and the occurrence of VF but not other a rrhythmias. Nicorandil at 3000 mug kg-1 and diltiazem at 300 mug kg-1 produced not only a suppression of ST segment elevation and VF inciden ce but also a decrease in the occurrence of arrhythmias. These doses o f nicorandil and diltiazem produced a decrease in death in a dose-depe ndent manner. 5 KRN2391 (10 and 30 mug kg-1), nicorandil (1000 and 300 0 mug kg-1) and diltiazem (100 and 300 mug kg-1) significantly decreas ed mean blood pressure in a dose-dependent manner. Heart rate was decr eased by nicorandil (3000 mug kg-1) and diltiazem (100 and 300 mug kg- 1) but was not affected by KRN2391 (10 and 30 mug kg-1). 6 KRN2391 (30 mum) significantly shortened the action potential duration of guinea- pig ventricle at 50% and 90% repolarization (APD50 and APD90). The eff ect of KRN2391 was inhibited by a K+ channel blocker, glibenclamide (3 0 mum). 7 These results suggest that the occurrence of ST segment elev ation and arrhythmias induced by ET-1 are due to a dual direct action on both coronary vascular smooth muscle and myocardium. Therefore, the protective effects of KRN2391, nicorandil and diltiazem on ET-1-induc ed heart disorders appear to be due to their direct actions on coronar y vascular smooth muscle and the myocardium.