Effects of KRN2391, nicorandil and diltiazem on the changes in the electrocardiogram caused by endothelin-1 in anaesthetized rats.
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.
Harada
K
K
Pharmaceutical Research Laboratory, Kirin Brewery Co. Ltd., Gunma, Japan.
Miwa
A
A
Kaneta
S
S
Izawa
T
T
Fukushima
H
H
Ogawa
N
N
D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005117:Cardiac Complexes, Premature / Q000139:chemically induced / Q000503:physiopathology; D004110:Diltiazem / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects*; D004594:Electrophysiology; D016232:Endothelins / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008688:Methacholine Compounds / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000503:physiopathology
D016232:Endothelins; D008688:Methacholine Compounds; D011725:Pyridines; D014665:Vasodilator Agents; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; D009536:Niacinamide; D020108:Nicorandil; D004110:Diltiazem; D005905:Glyburide