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CARDIOVASCULAR

Chronic Treatment with Carvedilol Improves Ca²⁺-Dependent ATP Consumption in Triton X-Skinned Fiber Preparations of Human Myocardium

Department of Molecular and Cellular Sport Medicine, German Sport University, Cologne, Germany (K.B., W.B.); Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Cologne, Germany (K.B., R.L., B.B., S.G., F.H., R.H.G.S.); Clinic of Cardiothoracic Surgery, University of Cologne, Cologne, Germany (U.M.); Clinic of Internal Medicine II, Hospital of Weiden, Weiden, Germany (R.H.G.S.); Department of Pathophysiology, Shanghai University of Traditional Chinese Medicine, Shanghai, China (R.L.); Clinic C–Department of Cardiology and Angiology, Hospital of the University of Münster, Münster, Germany (C.P.)

Evidence is given that -blocker treatment differentially influences gene expression and up-regulation of ₁-adrenoceptors in human myocardium. Here, we investigate whether long-term treatment with carvedilol or metoprolol may functionally alter myofibrillar function in end-stage human heart failure. Investigations were performed in Triton X (1%, 4°C, 20 h)-skinned fiber preparations of explanted hearts from patients undergoing heart transplantation due to idiopathic dilative cardiomyopathy. Five patients were not on -adrenoceptor blocker treatment (DCM_NBB), and 5 patients received either carvedilol (DCM_CAR) or metoprolol (DCM_MET). Nonfailing (NF) donor hearts (n = 5), which could not be transplanted due to technical reasons, were investigated for comparison. Ca²⁺-dependent tension (DT) development and actomyosin-ATPase activity (MYO) were measured and tension-dependent ATP consumption was calculated by the ratio of DT and MYO ("tension cost"). In addition, we measured the phosphorylation of troponin I (TNI) by back phosphorylation. Maximal DT and TNI phosphorylation were reduced, with myofibrillar Ca²⁺ sensitivity of DT and MYO as well as tension cost being increased in DCM_NBB compared with NF. Metoprolol treatment restored TNI phosphorylation, decreased Ca²⁺ sensitivity of tension development and of myosin-ATPase activity, but did not alter the tension-dependent ATP consumption. Carvedilol treatment improved maximal DT and significantly decreased tension-dependent ATP consumption without altering myofibrillar Ca²⁺ sensitivity. TNI dephosphorylation was increased in patients treated with carvedilol. In conclusion, chronic -adrenoceptor blockade functionally alters myofibrillar function. The more economic cross-bridge cycling in patients under carvedilol treatment may provide an explanation for the efficacy of carvedilol in the treatment of chronic heart failure patients.

Address correspondence to: Prof. Dr. med. Robert H.G. Schwinger, Laboratory of Muscle Research and Molecular Cardiology, Clinic III for Internal Medicine, University of Cologne, Joseph-Stelzmann-Str. 9, D-50924 Cologne, Germany. E-mail: robert.schwinger{at}medizin.uni-koeln.de

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