1. The effect of
KRN2391, a novel
vasodilator, on the changes of electrocardiogram caused by
endothelin-1 (ET-1) was studied in anaesthetized rats and compared with the effects of
nicorandil and
diltiazem. In addition, the effect of
KRN2391 on the action potential of guinea-pig papillary muscle was studied. 2. The intracoronary administration (i.c.) of ET-1 (5 micrograms) induced not only ST segment elevation of the electrocardiogram due to contraction of the coronary artery, but also arrhythmias involving
atrioventricular block (A-V block), ventricular premature contraction (VPC) and
ventricular fibrillation (VF), and resulted in death in most animals. However, the administration of
methacholine (3 micrograms, i.c.) produced ST segment elevation alone without developing arrhythmias. 3. Pretreatment with
intravenous administration of
KRN2391 (30 micrograms kg-1) inhibited the ST segment elevation and the development of arrhythmias induced by ET-1, and decreased the incidence of death. 4.
Nicorandil (1000 micrograms kg-1) prevented the ST segment elevation without suppression of the occurrence of VF.
Diltiazem (100 micrograms kg-1) suppressed both the ST segment elevation and the occurrence of VF but not other arrhythmias.
Nicorandil at 3000 micrograms kg-1 and
diltiazem at 300 micrograms kg-1 produced not only a suppression of ST segment elevation and VF incidence but also a decrease in the occurrence of arrhythmias. These doses of
nicorandil and
diltiazem produced a decrease in death in a dose-dependent manner. 5.
KRN2391 (10 and 30 micrograms kg-1),
nicorandil (1000 and 3000 micrograms kg-1) and
diltiazem (100 and 300 micrograms kg-1) significantly decreased mean blood pressure in a dose-dependent manner. Heart rate was decreased by
nicorandil (3000 microg kg-1) and
diltiazem (100 and 300 microg kg-1) but was not affected byKRN2391 (10 and 30 microg kg-1).6.
KRN2391 (30 microM) significantly shortened the action potential duration of guinea-pig ventricle at 50% and 90% repolarization (APD50 and APD90). The effect of
KRN2391 was inhibited by a K+channel blocker,
glibenclamide (30 microM).7. These results suggest that the occurrence of ST segment elevation 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-l-induced
heart disorders appear to be due to their direct actions on coronary vascular smooth muscle and the myocardium.