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

Abstract

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 β-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·. In 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 β-adrenergic receptor density.