Proteinases present in myocytes and leukocytes have been thought to contribute to ischemic myocellular death. To test this concept, the effects of three potent proteinase inhibitors (leupeptin, antipain and pepstatin) on myocardial infarct size were investigated. In the first experiment, rats received leupeptin intravenously (in either a "low" [10 mg/kg] or a "high" [40 mg/kg] dose) 10 minutes before coronary artery occlusion; additional doses were given 2, 4, 6 and 24 hours after occlusion. Low and high doses were previously shown to reduce proteolysis in ischemic myocardium by 49 and 72%, respectively. Infarct size, measured histologically at 72 hours, did not differ significantly among control (40 ± 2% of left ventricular surface, n = 30), low dose (37 ± 5%, n = 21) and high dose (41 ± 3%, n = 23) groups. In the second experiment, rats received a combination of leupeptin (40 mg/kg), antipain (20 mg/kg) and pepstatin (5 mg/kg) intravenously before and 2 and 4 hours after coronary occlusion. This treatment was previously shown to decrease proteolysis in ischemic regions by 88% at 15 minutes and by 72% at 6 hours of occlusion. Infarct size, determined at 6 hours by incubating heart slices in triphenyl-tetrazolium-chloride, was not significantly different between control (44 ± 3% of left ventricular weight, n = 23) and treated (48 ± 2%, n = 30) animals. Thus, despite almost complete suppression of proteolysis throughout the development of irreversible injury, the ultimate extent of ischemic damage was not reduced. These results indicate that proteolysis occurring during the early phase of acute myocardial infarction does not in itself cause ischemic myocellular death. Accordingly, proteinase inhibition soon after coronary occlusion does not appear to be an infarct-sparing mechanism.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine