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Cardioprotective potential of carvedilol
R R Ruffolo1, A Bril, G Z Feuerstein
1Department of Pharmacology, SmithKline Beecham Pharmaceuticals p.l.c., King of Prussia, Pa. 19406.
Insights
Carvedilol significantly reduced infarct size in animal models of myocardial infarction, outperforming propranolol. This cardiovascular drug
Area of Science:
- Cardiovascular pharmacology
- Myocardial infarction research
- Experimental therapeutics
Background:
- Carvedilol is a cardiovascular drug with nonselective beta-adrenoceptor antagonist and vasodilator properties.
- Beta-adrenoceptor antagonists decrease myocardial workload by reducing heart rate and contractility.
- Vasodilation by carvedilol further reduces myocardial workload by decreasing afterload and ventricular wall tension.
Purpose of the Study:
- To compare the efficacy of carvedilol and propranolol in reducing infarct size in experimental models of acute myocardial infarction.
- To evaluate the additional myocardial salvage provided by carvedilol's vasodilating activity compared to beta-blockade alone.
Main Methods:
- Studies were conducted in rat, pig, and dog models of acute myocardial infarction.
- Carvedilol and propranolol were administered at various doses.
- Infarct size was quantified using image analysis of stained myocardial tissue sections.
- Diltiazem was used as a comparator in pig studies.
Main Results:
- Carvedilol significantly reduced infarct size in rats (47%), pigs (46-89%), and dogs (46-78%) across different models.
- The extent of myocardial survival with carvedilol consistently exceeded that observed with propranolol in all studies.
- Dose-dependent reductions in infarct size were noted with carvedilol in pigs and dogs.
Conclusions:
- Carvedilol demonstrates significant infarct-limiting potential in experimental myocardial infarction.
- Carvedilol's combined beta-blockade and vasodilating actions offer superior myocardial protection compared to propranolol.
- These findings support carvedilol's therapeutic role in managing acute myocardial infarction.
Abstract:
Carvedilol is a multiple-action cardiovascular agent that is a nonselective beta-adrenoceptor antagonist and a vasodilator. beta-Adrenoceptor antagonists reduce myocardial work, secondary to reductions in heart rate and contractility, both in animals and in humans. For these reasons, carvedilol may improve survival of acutely ischemic myocardium. The additional vasodilating activity of carvedilol, further reducing myocardial work by decreasing afterload and ventricular wall tension, may provide additional salvage over that afforded by beta-adrenoceptor blockade alone. The comparative ability of carvedilol and propranolol to reduce infarct size in experimental models of acute myocardial infarction in the rat, pig and dog has been investigated utilizing a variety of experimental techniques. In the pig, the calcium channel antagonist, diltiazem, was also included as a second comparator agent. Infarct size was examined on stained tissue sections using quantitative image analysis. In the rat, carvedilol (1 mg/kg) reduced infarct size by 47% (p < 0.01, n = 11), and in the pig, carvedilol, at doses of 0.3 and 1 mg/kg, reduced infarct size by 46% (p < 0.05, n = 6) and 89% (p < 0.001, n = 6), respectively. In dogs subjected to ischemia and reperfusion, carvedilol (1 mg/kg) reduced infarct size by 78% (p < 0.02, n = 6), and in dogs subjected to permanent left anterior descending coronary artery occlusion, carvedilol, at doses of 0.3 and 1 mg/kg, reduced infarct size by 46 and 63%, respectively (p < 0.02, n = 12-16). In all studies, the extent of myocardial survival on carvedilol exceeded that on propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)