Transmural creatine kinase activity was determined 5 hours after acute occlusion of the left anterior descending coronary artery in 27 open chest anesthetized dogs. In seven dogs, propranolol, 2 mg/kg, was given intravenously over a 10 minute period 10 minutes after occlusion. In 10 dogs, nitroglycerin, 300 microgram/min, was infused intravenously for 1 hour 10 minutes after occlusion. Methoxamine, 300 to 500 microgram, was administered to return blood pressure and heart rate to prenitroglycerin levels. In untreated dogs, there was a distinct transmural gradient of creatine kinase activity in the ischemic region from subepicardium to subendocardium: nonischemic subepicardium 1,187 +/- 50 international units (IU)/g versus ischemic subepicardium 1,054 +/- 46 IU/g and nonischemic subendocardium 1,170 +/- 53 IU/g versus ischemic subendocard;um 766 +/- 42 IU/g, respectively. Administration of propranolol did not affect the transmural creatine kinase gradient after 5 hours of occlusion. In contrast, nitroglycerin plus methoxamine significantly (P less than 0.05) decreased subendocardial creatine kinase depletion after 5 hours of occlusion (776 +/- 42 versus 978 +/- 47 IU/g). These findings demonstrate the unique capability of nitroglycerin plus methoxamine to protect the subendocardium during ischemic insult.