Protein kinase A (PKA) activation has been implicated in contributing to early phase ischemic preconditioning. We have recently found that during ischemia PKA activation causes inactivation of cytochrome c oxidase (CcO) and contributes to myocardial damage due to ischemia and reperfusion. It may be that -adrenergic stimulation during ischemia via endogenous catecholamine release activates PKA. Thus -adrenergic stimulation may mediate both myocardial protection and damage during ischemia. The current studies were designed to determine the role of the 1-adrenergic receptor (1-AR) in myocardial ischemic damage and ischemic preconditioning. Langendorff-perfused rabbit hearts underwent 30 minutes of ischemia by ligating the anterior coronary artery followed by two hours of reperfusion. Occlusion/reperfusion damage was evaluated by delineating the non-perfused volume of myocardium at risk and the volume of myocardial necrosis after 2 hours of reperfusion. In some hearts Ischemic preconditioning was accomplished by two 5-minute episodes of global low flow ischemia separated by 10 minutes before the coronary occlusion/reperfusion. Orthogonal electrocardiograms were recorded, and coronary flow was monitored by a drip-count. Also, three hearts from each experimental group were used to determine mitochondrial CcO and aconitase activities. We found that 2 hours of reperfusion following occlusion caused an additional decrease in CcO activity compared to that after 30 minutes of occlusion alone. Blocking the 1-AR during occlusion/reperfusion both reversed the depression in CcO activity and preserved myocardium at risk for necrosis. Similarly, mitochondrial aconitase activity exhibited a parallel response after occlusion/reperfusion as well as for the other interventions. Further, we found that classic ischemic preconditioning had no effect on CcO depression. However, blocking the 1-AR during preconditioning eliminated the cardioprotection. If the 1-AR was blocked after preconditioning the myocardium was preserved. Interestingly, in both of the latter cases the depression in CcO activity was reversed. Thus the 1-AR plays a dual role in myocardial ischemic damage. Our findings may lead to therapeutic strategies for preserving myocardium at risk for infarction especially in the setting of coronary reperfusion intervention.