SCH 79797, a selective PAR1 antagonist, protects against ischemia/reperfusion-induced arrhythmias in the rat hearts

OBJECTIVE: Thrombin is implicated in the genesis of arrhythmias and activation of thrombin receptors exacerbated ventricular arrhythmias following coronary artery ligation. The present study was designed to investigate the possible protective effect of the protease-activated receptor-1 antagonist, SCH79797 against ischemia and reperfusion arrhythmias in the rat heart. MATERIALS AND METHODS: Healthy male Wistar rats (250-350 g) were anesthetized with urethane. Coronary artery ligation was performed for 5 minutes followed by 10 minutes reperfusion. Rhythm disturbances were monitored throughout the ischemia and reperfusion periods. Drugs injected were SCH79797 dihydrochloride (6.25, 12.5, 25 and 100 mu g/kg), glibenclamide (5 mg/kg) and N-nitro L-arginine methyl-ester hydrochloride (25 mg/kg). The control group was injected with dimethylsulfoxide (0.1 ml). RESULTS: SCH79797 dihydrochloride reduced the number of premature contraction, prevalence and duration of ventricular tachycardia, prevalence and duration of ventricular fibrillation during both the ischemic and reperfusion periods in a dose-dependent manner. There is a trend for N-nitro L-arginine methylester hydrochloride to increase all parameters of arrhythmias in SCH79797 dihydrochloride (25 mu g/kg) treated rats, but glibenclamide (5 mg/kg) significantly (p < 0.05) increased these parameters. CONCLUSIONS: SCH79797 dihydrochloride induced an antiarrhythmic effect in the anesthetized rat. This protective effect could possibly be mediated by activation of nitric oxide synthase and/or of ATP-sensitive potassium channels.