Brixius K, Lu R, Boelck B, Grafweg S, Hoyer F, Pott C, Mehlhorn U, Bloch W, Schwinger R H G
Department of Molecular and Cellular Sport Medicine, German Sport University, Cologne, Germany.
J Pharmacol Exp Ther. 2007 Jul;322(1):222-7. doi: 10.1124/jpet.106.116798. Epub 2007 Apr 4.
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.
有证据表明，β受体阻滞剂治疗对人类心肌中β(1)肾上腺素能受体的基因表达和上调有不同影响。在此，我们研究长期使用卡维地洛或美托洛尔治疗是否会在终末期人类心力衰竭中功能性地改变肌原纤维功能。研究在因特发性扩张型心肌病接受心脏移植患者的离体心脏经Triton X（1%，4℃，20小时）处理的肌纤维标本中进行。5例患者未接受β肾上腺素能受体阻滞剂治疗（DCM_NBB），5例患者接受卡维地洛（DCM_CAR）或美托洛尔（DCM_MET）治疗。因技术原因无法移植的非衰竭（NF）供体心脏（n = 5）作为对照进行研究。测量了Ca(2+)依赖性张力（DT）的产生和肌动球蛋白-ATP酶活性（MYO），并通过DT与MYO的比值（“张力消耗”）计算张力依赖性ATP消耗。此外，我们通过反向磷酸化测量了肌钙蛋白I（TNI）的磷酸化。与NF相比，DCM_NBB中最大DT和TNI磷酸化降低，DT和MYO的肌原纤维Ca(2+)敏感性以及张力消耗增加。美托洛尔治疗恢复了TNI磷酸化，降低了张力产生和肌球蛋白-ATP酶活性的Ca(2+)敏感性，但未改变张力依赖性ATP消耗。卡维地洛治疗改善了最大DT并显著降低了张力依赖性ATP消耗，而未改变肌原纤维Ca(2+)敏感性。卡维地洛治疗的患者中TNI去磷酸化增加。总之，慢性β肾上腺素能受体阻滞在功能上改变了肌原纤维功能。卡维地洛治疗患者中更经济的横桥循环可能为卡维地洛治疗慢性心力衰竭患者的疗效提供了解释。
