Recently, it has been reported that alpha-tocopherol analogues reduce infarct size in vivo in the rat and improve contractility upon reperfusion following global ischemia in isolated rat hearts. In the present study, we have thus investigated the effects of the hydrophilic alpha-tocopherol analogue MDL 74366 on nonenzymatic lipid peroxidation using a tissue homogenate method and reperfusion-induced arrhythmias following a local ischemia in isolated working rat hearts. Lipoperoxide (LPO) production was inhibited in a concentration-dependent manner in spontaneous as well as in induced peroxidations. The concentration resulting in a 50% inhibition (IC50) was around 2 microM. MDL 74366 treatment had no significant effect on baseline heart rate and cardiac output values. However, MDL 74366 decreased the incidence of reperfusion arrhythmias (ventricular tachycardia, VT; ventricular fibrillation, VF). The coincidence observed between the protective effect of MDL 74366 against tissue LPO formation and the preventive effect of this alpha-tocopherol analogue in the heart during the ischemia-reperfusion sequence confirms that vitamin E has beneficial effects against induced oxidative damage.