Comparison of metoprolol and carvedilol pharmacology and cardioprotection in rabbit ischemia and reperfusion model.
Carvedilol, a selective alpha1 and non-selective beta-adrenoceptor antagonist and antioxidant, has been shown to provide significant cardiac protection in animal models of myocardial ischemia. To further explore the mechanisms contributing to carvedilol cardioprotection efficacy, the effects of carvedilol on hemodynamic variables, infarct size and myeloperoxidase activity (an index of neutrophil accumulation) were compared with a beta1-selective adrenoceptor antagonist, metoprolol. Carvedilol (1 mg/kg) or metoprolol (1 mg/kg or 1 mg/kg + 0.5 mg/kg 90 min later) was given intravenously 5 min before reperfusion. In vehicle-treated rabbits, ischemia (60 min) and reperfusion (180 min) resulted in significant increments in left ventricular end diastolic pressure, large infarcts (59+/-2.6% of area-at-risk) and marked increase in myeloperoxidase activity (0.59+/-0.09 U/100 mg tissue). Carvedilol treatment resulted in sustained reduction of pressure-rate-index and significantly smaller infarcts (22.0+/-2.5%, P < 0.01 vs. vehicle) as well as decreased myeloperoxidase activity (0.186+/-0.056 U/100 mg tissue, P < 0.01 vs. vehicle). The highest dose of metoprolol, 1 mg/kg + 0.5 mg/kg, that resulted in pressure-rate-index comparable to that of 1.0 mg/kg carvedilol, failed to reduce myeloperoxidase activity in the ischemic myocardial tissue, and the infarct size (35+/-3.1%) was significantly larger than in carvedilol-treated animals. Taken together, this study suggests that the superior cardioprotection of carvedilol over metoprolol is not a consequence of hemodynamic variances but possibly the result of the additional pharmacological properties of carvedilol such as the antioxidant and anti-neutrophil effects.
SmithKline Beecham Pharmaceuticals, Department of Cardiovascular Pharmacology, King of Prussia, PA 19406-0939, USA.
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Feuerstein
G L
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Liu
T L
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Yue
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Cheng
J P
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Hieble
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Arch
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Ruffolo
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D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000077261:Carvedilol; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008790:Metoprolol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D011412:Propanolamines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011433:Propranolol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D011994:Recombinant Proteins; D000077261:Carvedilol; D011433:Propranolol; D009195:Peroxidase; D008790:Metoprolol