BACKGROUND: We examined the effects of hydroxyl radicals (OH.) on human myocardial contractility and on sarcoplasmic reticulum Ca(2+)-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. H(2)O(2) 1 mmol/L and Fe(3+)-nitrilotriacetic acid (Fe(3+)-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 Ca(2+) 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 Ca(2+) 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 beta-adrenergic receptor density.
BACKGROUND: We examined the effects of hydroxyl radicals (OH.) on human myocardial contractility and on sarcoplasmic reticulum Ca(2+)-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. H(2)O(2) 1 mmol/L and Fe(3+)-nitrilotriacetic acid (Fe(3+)-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 Ca(2+) 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 Ca(2+) 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 beta-adrenergic receptor density.
Authors: Dominik Linz; Arne van Hunnik; Christian Ukena; Sebastian Ewen; Felix Mahfoud; Stephan H Schirmer; Matthias Lenski; Hans-Ruprecht Neuberger; Ulrich Schotten; Michael Böhm Journal: Clin Res Cardiol Date: 2014-03-29 Impact factor: 5.460
Authors: Stefanie A Fahlbusch; Dimitrios Tsikas; Christina Mehls; Frank-Mathias Gutzki; Rainer H Böger; Jürgen C Frölich; Dirk O Stichtenoth Journal: Eur J Clin Pharmacol Date: 2004-03-05 Impact factor: 2.953