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

Evidence is given that β-blocker treatment differentially influences gene expression and up-regulation of β 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 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. Ca 2+ -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 Ca 2+ sensitivity of DT and MYO as well as tension cost being increased in DCM_NBB compared with NF. Metoprolol treatment restored TNI phosphorylation, decreased Ca 2+ 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 Ca 2+ 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.