Recent clinical and experimental studies have suggested that antioxidant supplements might actually have harmful as well as beneficial effects in the setting of cardiovascular disease. The mechanisms underlying the beneficial effects of the various antioxidants are poorly understood in humans. Reperfusion-associated myocardial injury, and particularly the phenomenon of stunning, is important because it occurs in clinical settings and may condition the prognosis after short ischemic insult. We studied the effects of chronic (3 months) alpha-tocopherol supplementation with a large oral dose (500 mg daily) on myocardial contractility (stunning) and ventricular arrhythmias in a dog model of short ischemia followed by reperfusion. Twenty dogs were randomized to either an alpha-tocopherol supplemented or a control group. After 3 months, dogs were anesthetized and underwent a 20-min coronary artery occlusion followed by reperfusion. Myocardial regional blood flow was measured by the radioactive microsphere technique and myocardial contractility by sonomicrometry. Plasma alpha-tocopherol was measured by high-performance liquid chromatography in all dogs. Twelve dogs (seven supplemented and five controls) developed ventricular fibrillation at reperfusion, showing no difference between groups. Hemodynamic parameters, blood flow in the ischemic area (collateral flow), and area at risk were similar in the two groups. Regional systolic segment shortening in the ischemic area was similar during ischemia and reperfusion in both groups, representing 41 +/- 15% (mean +/- SEM) of baseline contractility in controls and 51 +/- 8% in supplemented dogs after 150 min of reperfusion. Plasma alpha-tocopherol level was higher in supplemented than in controls (19.1 +/- 1.6 and 6.9 +/- 0.6 mg/L; p < 0.001). Thus a long-term large dose of alpha-tocopherol had no significant effect on postischaemic ventricular arrhythmias and dysfunction (myocardial stunning) in this canine model. These data suggest that if alpha-tocopherol supplementation might be useful to improve the prognosis of coronary patients, it is likely not by interfering with the stunning phenomenon.