The present study has examined the effects and the possible mechanisms of a single dose of simvastatin on the severity of arrhythmias resulting from a 25 min occlusion and reperfusion of the left anterior descending coronary artery in anaesthetized (chloralose and urethane) dogs. The control animals (n=16) were given the solvent of simvastatin by slow (over 5 min) intracoronary (ic.) injection just prior to the occlusion. Twenty-six dogs were treated with simvastatin (0.1 mg/kg) by the same route, both in the absence (n=15) and in the presence (n=11) of l-NAME. This latter was administered (5 mg/kg, ic.) either alone (n=12) or 10 min before the simvastatin treatment. The severity of ischaemia (epicardial ST-segment, inhomogeneity) and ventricular arrhythmias (ventricular premature beats [VPBs], ventricular tachycardia [VT] and fibrillation [VF]), plasma nitrite/nitrate levels, myocardial superoxide production and eNOS activity were assessed. Compared with controls simvastatin significantly reduced the number of VPBs (289±34 vs. 94±25) and the episodes of VT (5.6±1.3 vs. 0.3±0.2), the incidence of VT (88% vs. 20%) and VF (56% vs. 0%) during occlusion and increased survival (0% vs. 33%) on reperfusion. There were also less marked ischaemic changes in the simvastatin-treated dogs than in the controls. Simvastatin preserved eNOS activity and nitric oxide (NO) bioavailability during occlusion and attenuated superoxide production following reperfusion. All these effects of simvastatin (except for the protection against VF) were reversed by l-NAME. We conclude that simvastatin given just prior to ischaemia/reperfusion reduces the severity of arrhythmias. This effect involves both NO-dependent and NO-independent mechanisms.