Recent studies in several animal models have suggested that estrogen, given for the short term, may protect ischemic myocardium. Our objective was to test the effect of exogenous estradiol on the development of myocardial necrosis. Twenty minutes before coronary occlusion, rabbits were given an IV bolus of either 17 beta-estradiol, a form of the hormone that stimulates the estrogen receptor (10 micrograms) or 17 alpha-estradiol, a natural form of the hormone lacking estrogenic effects (1 mg), or vehicle. Regional myocardial blood flow (RMBF) was measured after treatment and during occlusion and reperfusion, and heart rate and blood pressure were monitored throughout. All rabbits underwent 30 minutes of coronary artery occlusion and 4 hours of reperfusion. Estradiol levels were 6 +/- 2 pg/ml in untreated rabbits, 392 +/- 78 pg/ml in rabbits given 17 beta-estradiol, and 413 +/- 68 pg/ml in rabbits given 17 alpha-estradiol. The size of the ischemic region was similar in all groups, but rabbits treated with 17 beta-estradiol developed significantly less necrosis than did control rabbits (0.33 +/- 0.04 vs 0.53 +/- 0.05 of the area at risk; p < 0.05), whereas rabbits treated with 17 alpha-estradiol did not (0.43 +/- 0.03; p = NS vs control group). Heart rate, systemic pressure, and RMBF were comparable among groups throughout the protocol. In conclusion, 17 beta-estradiol exerts a protective effect on ischemic myocardium, reducing infarct size. This beneficial effect is not associated with an increase in myocardial blood flow or alteration in hemodynamics. Because 17 alpha-estradiol did not affect infarct size, the cardioprotective effect of 17 beta-estradiol is probably receptor mediated.