Effect of β-blockers on free radical-induced cardiac contractile dysfunction

Background-We examined the effects of hydroxyl radicals (OH .) on human myocardial contractility and on sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity and the effects of the beta-receptor antagonists metoprolol, carvedilol, and its metabolite BM-910228. Methods and Results-Isometric force of contraction was determined in isolated human myocardium. H2O2 1 mmol/L and Fe3+-nitrilotriacetic acid (Fe3+-NTA) 0.1 mmol/L used for generation of OH . induced a decrease in basal force of contraction and an increase in diastolic tension in atrial and left ventricular myocardial preparations. After challenge with OH ., the maximum positive inotropic response to Ca2+ 1.8 to 15 mmol/L was decreased by 60% and by 39%, respectively. The effects of OH . could be blocked by catalase. Carvedilol and its metabolite BM-910228 attenuated the OH .-induced impairment of the inotropic response to Ca2+ in atrial myocardial preparations. Metoprolol had no significant effect. The stimulation frequency (0.5 to 3.0 Hz)-dependent increase in force of contraction and decrease in diastolic tension were abolished after exposure of atrial trabeculae to OH .. Ln parallel, SERCA activity was decreased by OH . concentration-dependently, as determined in myocardial membrane preparations. BM-910228 partially restored the force-frequency relationship and preserved SERCA activity. Conclusions-OH . radicals induce an impairment of contraction and relaxation and an attenuation of the force-frequency relationship in human myocardium accompanied by an inhibition of SERCA. Carvedilol and BM-910228 partly prevented OH .-induced contractile dysfunction. These observations could explain the improvement of ejection fraction in heart failure trials with carvedilol without a restoration of beta-adrenergic receptor density.