Chronic treatment with carvedilol improves Ca(2+)-dependent ATP consumption in triton X-skinned fiber preparations of human myocardium.
Evidence is given that beta-blocker treatment differentially influences gene expression and up-regulation of beta(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 degrees C, 20 h)-skinned fiber preparations of explanted hearts from patients undergoing heart transplantation due to idiopathic dilative cardiomyopathy. Five patients were not on beta-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 beta-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.
Brixius
K
K
Department of Molecular and Cellular Sport Medicine, German Sport University, Cologne, Germany.
Lu
R
R
Boelck
B
B
Grafweg
S
S
Hoyer
F
F
Pott
C
C
Mehlhorn
U
U
Bloch
W
W
Schwinger
R H G
RH
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D008790:Metoprolol / Q000494:pharmacology; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009210:Myofibrils / Q000187:drug effects* / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D017830:Octoxynol / Q000494:pharmacology; D010766:Phosphorylation; D011412:Propanolamines / Q000494:pharmacology*; D019210:Troponin I / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D019210:Troponin I; D000077261:Carvedilol; D017830:Octoxynol; D009218:Myosins; D008790:Metoprolol; D002118:Calcium