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The effects of intravenous propranolol (2 mg/kg) on myocardial ischemic injury in relation to the influence of delay in therapy on gross infarct size (GIS) were determined in 39 closed-chest anesthetized dogs in which the left anterior descending coronary artery (LAD) was occluded at a fixed distance from its origin by a balloon catheter. Precordial ECG maps. hemodynamic variables and serum CK levels were monitored for 24 hours. After 24 hours, we estimated GIS from the measured areas of ischemic discoloration in serial sections of the left ventricle (LV). In nine dogs, propranolol administration was started before LAD occlusion, in another nine 3 hours and in 10 others 6 hours after occlusion; the remainder (n = 11) served as controls. In the dogs pretreated with propranolol, the GIS (14.0 ± 4.0 g or 10.0 ± 2.0% of LV weight) was 53% smaller (p < 0.01) than in the controls (29.0 ± 2.0 g or 22.0 ± 1.0% of LV weight); those given propranolol 3 hours after occlusion had 28% smaller (p < 0.05) GIS (19.0 ± 2.0 g or 15.0 ± 2.0% LV weight) than the controls. However, GIS in the dogs receiving propranolol 6 hours after occlusion (24.0 ± 3.0 g or 19.0 ± 3.0% of LV weight) was not significantly different from that in the controls. The beneficial effect of propranolol on GIS was accompanied by corresponding directional changes in the precordial ST-segment elevation and in the rate of decline of the R-wave amplitude of the ECG. Propranolol reduced the heart rate and cardiac output for 5-6 hours in pretreated dogs; in dogs given propranolol 3 and 6 hours after occlusion, heart rate was reduced for 3-4 hours, but the cardiac output remained low for the remainder of the 24 hours. The data in these studies indicate that the beneficial effect of propranolol on GIS varies inversely with the delay in drug administration after LAD occlusion, and that no effect is apparent when propranolol infusion is begun 6 hours after occlusion.