We have previously reported that α2-adrenoceptor stimulation enhances adenosine-induced coronary vasodilation. In the present study, we tested the hypothesis that α2-adrcnoceptor activity exerts beneficial effects on myocardial ischemia through augmentation of vasodilatory effects of released adenosine. In open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the carotid artery. Propranolol was infused into the bypass tube to exclude the metabolic effects of norepinephrine. When clonidine (0.24 μg/kg/min i.e.) was infused for 10 minutes after reduction of coronary blood flow by partial occlusion of the bypass tube, coronary blood flow was increased by 43% from 27 ± 1 ml/100 g/min despite no changes in coronary perfusion pressure (38 ± 5 mm Hg) and a slight decrease in adenosine release. Both fractional shortening and lactate extraction ratio of the perfused area were significantly improved (fractional shortening, 1.8 ± 1.0 to 10.9 ± 1.5%, p<0.001; lactate extraction ratio, −57.8 ± 6.5 to −31.9 ± 2.4%, p<0.005). Identical results were observed in the denervated hearts, indicating that the beneficial effect of clonidine is not attributed to the prevention of norepinephrine release from the sympathetic nerve terminals. The beneficial effects of clonidine were prevented by yohimbine, an α2-adrenoceptor blocking agent. An adenosine receptor antagonist, 8-phenyltheophylline, also prevented the beneficial effects of clonidine, indicating that these beneficial effects are mediated by effects of adenosine. Furthermore, the extent of augmentation of coronary flow in the ischemic heart was coincided with that of augmentation of exogenous adenosine-induced hyperemic flow (40%) by clonidine. Production of cyclic AMP in the coronary artery during myocardial ischemia was augmented by clonidine. In 12 other dogs, myocardial ischemia was produced by intracoronary embolization of microspheres (15 μm in diameter). Clonidine enhanced (39%) the hyperemic coronary flow and improved both fractional shortening and lactate extraction ratio. Thus, we conclude that α2-adrenoceptor stimulation can ameliorate myocardial ischemia mainly due to enhancement of vasodilatory effects of adenosine released from the ischemic myocardium.