Chronic Treatment with Carvedilol Improves Ca2+-Dependent ATP Consumption in Triton X-Skinned Fiber Preparations of Human Myocardium
- K. Brixius,
- R. Lu,
- B. Boelck,
- S. Grafweg,
- F. Hoyer,
- C. Pott,
- U. Mehlhorn,
- W. Bloch and
- R. H. G. Schwinger
- 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.)
- 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
Abstract
Evidence is given that β-blocker treatment differentially influences gene expression and up-regulation of β1-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 β-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 β-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.
Footnotes
-
This work was supported by the Köln Fortune program of the faculty of medicine from the University of Cologne (to K.B.), the Graduiertenkolleg der Universität Köln (to R.L.), and the Deutsche Forschungsgesellschaft (PO 1004-1/2) (to C.P.). This work contains part of the doctoral thesis of R.L.
-
K.B. and R.L. contributed equally to this work.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.106.116798.
-
ABBREVIATIONS: DCM, dilative cardiomyopathy; NF, nonfailing; MET, metoprolol; CAR, carvedilol; NBB, non-β-adrenoceptor blocker treatment; pCa, –log [Ca].
-
- Received November 6, 2006.
- Accepted April 2, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
