To assess the effects of ethinyl estradiol on the incidence of death in ventricular fibrillation induced by isoproterenol in DOCA-salt pretreated rats we implanted male and female rats simultaneously with a 20 mg DOCA pellet and pellets containing either ethinyl estradiol or vehicle (wax). Rats drank saline after implantation. After 6 days rats were challenged with a single, sc dose of 150 micrograms of isoproterenol. The average daily dose of estradiol per rat was estimated on the basis of the quantity of pellet lost during 6 days. In male rats the average daily dose of 61.2 +/- 20.2 micrograms/rat of ethinyl estradiol decreased the incidence of mortality by 80%, from 73.3% (11/15) in vehicle treated to 13.3% (2/15) in estradiol treated rats. Death occurred within 19.2 +/- 8.0 minutes from the injection of isoproterenol and was due to ventricular fibrillation. Serum levels of magnesium and potassium were comparable in the two groups both before and after isoproterenol. Isoproterenol induced death in 9 of 11 DOCA-salt pretreated, ovariectomized rats within 22.3 +/- 9.8 minutes. Only 3 of 11 DOCA-salt ovariectomized rats receiving the average daily dose of 28.4 +/- 12.1 micrograms/rat of ethinyl estradiol died. None of 10 ovariectomized untreated rats died from isoproterenol challenge. Serum levels of magnesium and potassium were comparable in the estradiol and vehicle treated groups. The average daily dose of 2.8 +/- 0.42 micrograms/rat of ethinyl estradiol elicited uterine growth but did not influence the incidence of mortality, since 9 out of 16 and 10 out of 16 rats died following isoproterenol in vehicle and estradiol treated DOCA-salt ovariectomized rats. We conclude that only pharmacological doses of estradiol exert protective effects against DOCA-salt induced myocardial sensitization to isoproterenol and that this protection is not associated with relevant changes in serum potassium or magnesium.