MYOCARDIAL PROTECTION WITH CARVEDILOL

Carvedilol is a multiple-action cardiovascular agent that is both a beta-adrenoceptor antagonist and a vasodilator and has recently been made available for the treatment of mild-to-moderate hypertension. Clinical trials are ongoing to establish the efficacy of carvedilol in angina and congestive heart failure. Beta-adrenoceptor antagonists are known to reduce myocardial work secondary to reductions in heart rate and contractility; accordingly, they have been shown to be cardioprotective in animals and in humans. Because carvedilol has beta-adrenoceptor antagonist activity, it also should provide significant cardioprotection. The additional vasodilating activity of carvedilol, which will further reduce myocardial work by decreasing afterload and myocardial wall tension, should provide more salvage of ischemic myocardium than that afforded by a pure beta-adrenoceptor antagonist, such as propranolol. We investigated the ability of carvedilol and propranolol to reduce infarct size in experimental models of acute myocardial infarction in the rat, pig, and dog. The left anterior descending coronary artery was occluded for 30 (rat) or 45 min (pig) and then reperfused for 24 h (rat) or 4 h (pig). In the dog, the left circumflex coronary artery was occluded for 60 min and reperfused for 24 h. Vehicle, carvedilol, or propranolol was administered intravenously 15 min before ischemia (and, in the rat only, repeated 4 h after ischemia). An additional group of dogs was subjected to permanent left anterior descending coronary artery occlusion for 6 h, and carvedilol or propranolol was given 15 min after occlusion. Infarct size was examined on stained tissue sections using quantitative image analysis. In the rat, carvedilol (1 mg/kg) reduced infarct size by 47% (n = 11, p < 0.01). In the pig, carvedilol reduced infarct size by 46% (n = 6, p < 0.05) and 89% (n = 6, p < 0.001) at doses of 0.3 and 1 mg/kg, respectively. In dogs subjected to ischemia and reperfusion, carvedilol (1 mg/kg) reduced infarct size by 78% (p < 0.02, n = 6). In dogs subjected to permanent left anterior descending coronary artery occlusion, carvedilol reduced infarct size by 46% (n = 12, p < 0.02) and 63% (n = 16, p < 0.02) at doses of 0.3 and 1 mg/kg, respectively. In all studies, the highly significant myocardial protective effects of carvedilol exceeded those of the pure beta-adrenoceptor antagonist propranolol. Taken together. these studies clearly demonstrate the efficacy of carvedilol in protecting ischemic myocardial tissue from necrosis. This cardioprotective effect of carvedilol may ultimately be of benefit when the drug is used in the treatment of hypertension and may also underlie the use of carvediiol in the treatment of angina and congestive heart failure.