Irreversible ischemic myocardial cell injury developes in an increasing number of cells as the duration of coronary occlusion is prolonged. The present study quantitates myocardial necrosis produced by 40 minutes, 3 hours, or 6 hours of temporary circumflex coronary occlusion (CO) followed by 2 to 4 days of reperfusion, or by 24 or 96 hours of permanent circumflex ligation in pentobarbital anesthetized open chest dogs. After 40 minutes of ischemia, myocyte necrosis was subendocardial but with increasing duration of coronary occlusion, irreversible injury progressed as a wavefront toward the subepicardium. Transmural necrosis was 38 +/- 4% after 40 min, 57 +/- 7% after 3 hours, 71 +/- 7% after 6 hours and 85 +/- 2% after 24 hours of ischemic injury. These results document the presence of a subepicardial zone of ischemic but viable myocardium which is available for pharmacologic or surgical salvage for at least three and perhaps six hours following circumflex occlusion in the dog.

The effect of propranolol on the severity of myocardial necrosis following 40 minutes of temporary coronary artery occlusion was assessed in dogs. The circumflex coronary artery was occluded 1-2 cm from the aorta in open-chest dogs anesthetized with sodium pentobarbital. One group of dogs was untreated and a second group received propranolol (5.0 mg/kg, iv) 10 minutes prior to the occlusion. After 40 minutes the clamp was removed and arterial perfusion was restored. Dogs which survived this procedure were killed 2-5 days later for gross and histologic assessment of the necrosis. The relative area of necrosis (percent of fibers involved) in the posterior papillary muscle of each heart was quantified from stained histologic sections prepared from serial longitudinal slices of each posterior papillary muscle. Dogs treated with propranolol showed significantly less necrosis than did untreated controls, but the mechanism of the drug's action remains unknown. During coronary artery occlusion, propranolol-treated dogs exhibited somewhat lower heart rates, systolic blood pressures , and S-T segment elevations than did untreated dogs. However, none of these latter differences between groups was significant. KEY WORDS infarction heart quantification of infarct size ventricular fibrillation cell death ^8-receptor blockade S-T segment elevation • In the past few years much attention has been directed toward various therapeutic interventions which slow or prevent the development of myocar-dial cell death following an acute coronary artery occlusion. Sommers and Jennings (1) have suggested that propranolol in some way alters the course of ischemic injury.-They observed that 17 of 31 untreated dogs subjected to a 20-minute temporary occlusion of the circumflex coronary artery showed foci of necrosis 24-48 hours later. Only 3 of 30 similar dogs treated prophylactically with proprano-lol showed any necrosis. The 20-minute occlusion, however, induced relatively mild injury even without treatment, since it caused only small islands of cell death in about half of the untreated dogs. The present study was undertaken to provide a more severe test of propranolol's efficacy against myocardial ischemic injury. A 40-minute period of temporary circumflex coronary artery occlusion was chosen for study; injury induced by this method causes necrosis in 100% of dogs in the absence of protective therapy, and the characteristics of this model have been described in considerable detail (2, 3). The posterior papillary muscle is in the center of the lesion and is the site of maximum, most predictable injury. The proportion of muscle fibers which become necrotic can readily be quantified and in a previous series of dogs was about 55% of the posterior papillary muscle projecting above the endocardial surface of the ventricle (4). Thus this model provides an appropriate injury in which either beneficial or deleteri-ous interventions can be observed. In this study our purpose was to determine whether propranolol could reduce the number of cells which ...

Coronary occlusion in the dog results in irreversible myocardial cell injury which develops first in subendocardial areas of severe ischemica and subsequently spreads into mid and subepicardial areas of moderate ischemia. The effect of propranolol on this progression of ischemic injury was evaluated. Three groups of dogs were studied: 1) untreated, 2) treated with propranolol before and throughout coronary ligation, and 3) treated with propranolol beginning three hours after ligation. Dogs were sacrificed 24 hours after coronary ligation and necrosis was quantitated from histologic sections of transmural slices through the posterior papillary muscle. Propranolol reduced infarct size by preventing necrosis in peripheral (subepicardial) areas of moderately ischemic myocardium. Pretreatment with propranolol reduced necrosis from 85 +/- 3% (untreated) to 52 +/- 4% (P less than 0.05). Delayed propranolol therapy was about half as effective as pre-treatment and reduced necrosis to 71 +/- 3% (P less than 0.05). Propranolol also limited microvascular injury so that perfusion defects, detected with the dye thioflavin S, were smaller in treated dogs.

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