Comparative effects of carvedilol and metoprolol on cardiac ischemia-reperfusion injury.
The effects of carvedilol, a multiple-action neurohormonal antagonist, and metoprolol, a highly selective beta1 antagonist, were compared on postischemic contractile recovery and contracture. Isolated rabbit hearts were aerobically perfused for 45 min and subjected to zero-flow normothermic ischemia for 30 or 60 min followed by reperfusion for 30 min. Carvedilol and metoprolol were added to the perfusion solution 10 min before inducing ischemia and were maintained in the perfusate throughout reperfusion. Left ventricular developed pressure (LVDP) and left ventricular end-diastolic pressure (LVEDP) were assessed with an intraventricular balloon. Because the volume of the balloon was held constant, an increase in LVEDP reflected an increase in diastolic chamber stiffness or "contracture." After 30 min of ischemia, the carvedilol-treated hearts exhibited a significantly better cardiac function than did control or metoprolol-treated hearts. At the end of reperfusion, the control group LVDP recovered to 21.4+/-9.9% of the preischemic value. With 0.03, 0.1, and 0.3 microM metoprolol, LVDP recovered to 33.2+/-13.6%, 41.7+/-13.0%, and 48.8+/-13.3% of initial developed pressure, respectively. In the carvedilol group, a greater recovery of LVDP was obtained at 0.03, 0.1, and 0.3 microM: 64.0+/-2.5%, 60.4+/-6.3%, and 68.0+/-2.0% of preischemic values, respectively (p < 0.05 vs. controls). Within the first 5 min of reperfusion, LVEDP increased to 70.3+/-2.7 mm Hg in control hearts, indicating a pronounced contracture, whereas metoprolol reduced LVEDP when given at high concentration, 0.3 microM (41.9+/-10.7 mm Hg). Carvedilol, even at the lowest concentration, 0.03 microM, almost completely inhibited the postischemic contracture (16.5+/-4.0 mm Hg; p < 0.05 vs. control and metoprolol). The cardioprotection provided by carvedilol also is observed in hearts subjected to more severe ischemic periods. After 60 min of ischemia, control hearts failed to restore LVDP function; in the metoprolol group, ventricular function recovered to only 4.6+/-3.1%, whereas carvedilol-treated hearts exhibited 23.6+/-1.9% of preischemic values at the end of reperfusion. In addition, carvedilol induced a reduction in ischemic contracture: control, 36.7+/-3 mm Hg; metoprolol, 38.7+/-3.7 mm Hg; and carvedilol, 15.7+/-8.4 mm Hg at 50 min of ischemia. Similarly, carvedilol reduced contracture during the reperfusion compared with metoprolol and control groups (83.2+/-3.4 mm Hg, 106.9+/-3.3 mm Hg, and 107.6+/-4.1 mm Hg, respectively). These data clearly demonstrate that carvedilol was markedly more effective than metoprolol to protect systolic function after ischemia and to reduce postischemic contracture.
Khandoudi
N
N
SmithKline Beecham Laboratoires Pharmaceutiques, Saint-Grégoire, France.
Percevault-Albadine
J
J
Bril
A
A
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008790:Metoprolol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits; D016277:Ventricular Function, Left / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D007770:L-Lactate Dehydrogenase; D008790:Metoprolol