The alpha 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found. Therefore we designed a study to determine if yohimbine was protecting ischemic myocardium via antagonism of alpha 2-adrenoceptors. In isolated globally ischemic rat hearts, the effects of two structurally distinct classes of alpha 2-adrenoceptor antagonists, the indole alkaloids (yohimbine and rauwolscine) and the imidazolines (idozoxan and tolazoline) were investigated. Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release. The structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In contrast, idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic activity.