In the rabbit heart, acute ethanol exposure followed by washout before ischemia exerts a preconditioninglike effect. However, if alcohol is still present during ischemia, all preconditioning-related cardioprotection is abolished. The present follow-up study investigated the dose-response relationships of both the beneficial and detrimental effects of acute ethanol exposure. In the isolated rabbit heart either 2.5-, 5-, 10-, 20-, or 50-mmol/L ethanol was given as a 5-minute pulse followed by washout before 30 minutes of regional ischemia and 2 hours of reperfusion. Isolated rabbit hearts were also preconditioned with 5 minutes of global ischemia followed by 10 minutes of reperfusion (PC) before onset of 30 minutes of regional ischemia. This latter protocol was combined with a 35-minute infusion of ethanol at concentrations of either 5, 10, 20, or 50 mmol/L, starting 5 minutes before the onset of the 30-minute period of ischemia. Infarct size was determined with triphenyltetrazolium staining. No protection was seen with a 5-minute infusion of 2.5-mmol/L ethanol (29.9 +/- 1.6% of risk zone infarcted), and minimal protection was evident with the 5-mmol/L dose (25.4 +/- 3.4% infarction). In all other groups infarct size was significantly reduced (17.9 +/- 3.2, 18.4 +/- 3.5, and 16.8 +/- 3.4%, respectively, versus 33.0 +/- 3.0% in control group, P < 0.05). In the presence of 10-, 20-, or 50-mmol/L ethanol, infarct size following PC was not different from control (24.3 +/- 2.5, 28.4 +/- 4.3, and 39.0 +/- 4.0%, respectively, versus 28.5 +/- 2.5%). Thus the presence of alcohol during ischemia inhibited protection induced by preceding preconditioning ischemia. Only in the PC group exposed to 5-mmol/L ethanol was infarct size significantly smaller than in the control group (6.4 +/- 2.5%, P < 0.005). Thus both protective and antiprotective effects of alcohol were dose dependent with similarly low threshold doses in in vitro rabbit hearts. Since it might be impossible to find a dose of ethanol that would be protective if administered shortly before ischemia, ethanol should be removed before that ischemia to protect myocardium.