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 beta(1) 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 1 0 min before inducing ischemia and were maintained in the perfusate th roughout reperfusion. Left ventricular developed pressure (LVDP) and l eft ventricular end-diastolic pressure (LVEDP) were assessed with an i ntraventricular balloon. Because the volume of the balloon was held co nstant, an increase in LVEDP reflected an increase in diastolic chambe r stiffness or ''contracture.'' After 30 min of ischemia, the carvedil ol-treated hearts exhibited a significantly better cardiac function th an 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 mu M metoprolol, LVDP recovered to 33. 2 +/- 13.6%, 41.7 +/- 13.0%, and 48.8 +/- 13.3% of initial developed p ressure, respectively. In the carvedilol group, a greater recovery of LVDP was obtained at 0.03, 0.1, and 0.3 mu M: 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 HE in control hearts, indicating a pronounced contr acture, whereas metoprolol reduced LVEDP when given at high concentrat ion, 0.3 mu M (41.9 +/- 10.7 mm Hg). Carvedilol, even at the lowest co ncentration, 0.03 mu M, almost completely inhibited the postischemic c ontracture (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 grou p, ventricular function recovered to only 4.6 +/- 3.1%, whereas carved ilol-treated hearts exhibited 23.6 +/- 1.9% of preischemic values at t he 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 HE at 50 min of ischemia. S imilarly, carvedilol reduced contracture during the reperfusion compar ed with metoprolol and control groups (83.2 +/- 3.4 mm Hg, 106.9 +/-:3 .3 mm Hg, and 107.6 +/- 4.1 Mn Hg, respectively). These data clearly d emonstrate that carvedilol was markedly more effective than metoprolol to protect systolic function after ischemia and to reduce postischemi c contracture.