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 jg) 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 jig, i.c.)produced ST segment elevation alone without developing arrhythmias.3 Pretreatment with intravenous administration of KRN2391 (30 1g kg-') inhibited the ST segment elevation and the development of arrhythmias induced by ET-1, and decreased the incidence of death.4 Nicorandil (1000 tLg kg-') prevented the ST segment elevation without suppression of the occurrence of VF. Diltiazem (100 pg kg-') suppressed both the ST segment elevation and the occurrence of VF but not other arrhythmias. Nicorandil at 3000 jig kg-' and diltiazem at 300 tg kg-' 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 ig kg-'), nicorandil (1000 and 3000 ig kg-') and diltiazem (100 and 300 fig kg-') significantly decreased mean blood pressure in a dose-dependent manner. Heart rate was decreased by nicorandil (3000 Igkg-') and diltiazem (100 and 300 gkg-') but was not affected by KRN2391 (10 and 30 Ag kg-').6 KRN2391 (30pjM) significantly shortened the action potential duration of guinea-pig ventricle at 50% and 90% repolarization (APD50 and APD%0). The effect of KRN2391 was inhibited by a K+ channel blocker, glibenclamide (301iM). 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.
1 The relaxant mechanisms of action of KRN2391, a novel vasodilator, and nicorandil on epimyocardial coronary artery (2.5-3.0 mm outer diameter) and mid-myocardial coronary artery (0.8-1.0 mm outer diameter) were investigated in porcine isolated coronary arteries. In addition, the vasorelaxant responses of KRN2391 and nicorandil were compared with those of nitroglycerin and cromakalim, a K+ channel opener, in epi-and mid-myocardial coronary arteries. 2 Nitroglycerin showed a more potent relaxant effect on epi-myocardial coronary arteries than on mid-myocardial coronary arteries, whereas cromakalim produced greater relaxation responses in midmyocardial coronary arteries. There was no difference between epi-and mid-myocardial coronary arteries in terms of the relaxant effect of KRN2391 and nicorandil. 3 Relaxation induced by KRN2391 in epi-and mid-myocardial coronary arteries was inhibited by oxyhaemoglobin, a pharmacological antagonist of nitrovasodilators, and glibenclamide, a pharmacological antagonist of K+ channel opening drugs. However, the inhibitory effect of glibenclamide on KRN2391-induced relaxation was greater in mid-myocardial coronary artery than in epi-myocardial coronary artery. 4 Relaxation induced by nicorandil was inhibited by oxyhaemoglobin alone in epi-myocardial coronary arteries and by both oxyhaemoglobin and glibenclamide in mid-myocardial coronary arteries. 5 In epi-and mid-myocardial coronary arteries, relaxation induced by cromakalim was inhibited by glibenclamide but not by oxyhaemoglobin, whereas relaxation induced by nitroglycerin was inhibited by oxyhaemoglobin but not by glibenclamide. 6 These results suggest that KRN2391 and nicorandil exhibit a dual mechanism of action acting partly as a nitrate and partly as a K+ channel opener. The mechanism of action of these drugs depend on the segment of coronary artery studied. Furthermore, the dual mechanism of action of KRN2391 and nicorandil seems to contribute to the equipotent relaxant effect between epi-and mid-myocardial coronary arteries.
The present study was performed to determine whether KRN2391 (N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethanesulphonate), a novel vasodilator, shows different effects on porcine isolated coronary arteries of different sizes. The vasodilating effects of KRN2391 on porcine large (2.5-3.0 mm outer diam.) and small (0.8-1.0 mm) coronary arteries were also compared with those of cromakalim, nicorandil, nifedipine, nitroglycerin and adenosine. The relaxant effects of these drugs were examined in coronary arteries contracted by 25 mM KCl. Nitroglycerin caused greater relaxation in large vessels than in small vessels. In contrast, adenosine, nifedipine and cromakalim caused greater relaxation in small vessels. However, there was no difference between large and small vessels in the relaxing effects of KRN2391 and nicorandil. These unique features of KRN2391 and nicorandil appear to be beneficial in ischaemic heart disease.
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