The effect of L-arginine methylester (L-Arg-Me) was studied in the isolated heart of the guinea-pig perfused with hypoxic substrate-free medium for 30 min and subsequently reoxygenated with normal saline solution for 30 min. The administration of L-Arg-Me in basal conditions decreases dose-dependently heart rate without any changes in the myocardial structure. On the other hand, the administration of L-Arg-Me (5-10 mM) decreases ventricular arrhythmias, especially during reoxygenation; in fact ventricular fibrillation is abolished. L-Arg-Me treatment increases the recovery of normal electrical and mechanical activity at the end of reoxygenation and reduces the increase in basal tone. Treatment with 10 mM L-Arg-Me decreases lactate dehydrogenase (LDH) release in the effluent and lysosomal fragility in cardiac tissue, while it does not influence calcium gain. L-Arginine (L-Arg) does not mimic any of the effects of L-Arg-Me.