Flesch M, Schwinger R H, Schiffer F, Frank K, Südkamp M, Kuhn-Regnier F, Arnold G, Böhm M
Klinik III für Innere Medizin Universität zu Köln, FRG.
Circulation. 1996 Sep 1;94(5):992-1002. doi: 10.1161/01.cir.94.5.992.
The present study aimed at investigating the expression of the Na(+)-Ca2+ exchanger and its functional role in human failing myocardium.
Na(+)-Ca2+ exchanger mRNA and protein levels were examined in nonfailing (NF, n = 8) and failing human myocardium (New York Heart Association functional class IV) with idiopathic dilated cardiomyopathy (DCM, n = 8) or ischemic heart disease (ICM, n = 6). The inotropic effect of the Na+ channel activator BDF 9148 was determined in electrically driven left ventricular papillary muscle strip preparations (1 Hz, 37 degrees C) from nonfailing (n = 8) and failing (n = 8) human hearts. Na(+)-Ca2+ exchanger mRNA levels were significantly increased, by 79% (P < .001) in DCM and by 58% (P < .01) in ICM compared with NF; protein levels increased by 36% (P < .001) and by 20% (P < .05), respectively. BDF 9148 increased the force of contraction concentration dependently, with a similar maximal effect in NYHA class IV and NF, but was more potent in NYHA class IV as demonstrated by a significantly smaller (P < .01) EC50 value (NYHA class IV, 0.18 [0.16 to 0.22] mumol/L; NF, 1.65 [1.3 to 3.0] mumol/L). In NYHA class IV, BDF 9148 (0.1 mumol/L) restored the positive force-frequency relationship and reduced the frequency-dependent increase in diastolic tension in relation to force of contraction.
The increased expression of the Na(+)-Ca2+ exchanger is a possible explanation for the increased inotropic potency of the Na+ channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na+ concentration. Enhancement of Na(+)-Ca2+ exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.
本研究旨在调查钠钙交换体在人类衰竭心肌中的表达及其功能作用。
检测了非衰竭（NF，n = 8）及患有特发性扩张型心肌病（DCM，n = 8）或缺血性心脏病（ICM，n = 6）的纽约心脏协会心功能IV级的衰竭人类心肌中钠钙交换体的mRNA和蛋白水平。在来自非衰竭（n = 8）和衰竭（n = 8）人类心脏的电驱动左心室乳头肌条标本（1 Hz，37℃）中测定钠通道激活剂BDF 9148的正性肌力作用。与NF相比，DCM中钠钙交换体mRNA水平显著升高79%（P < 0.001），ICM中升高58%（P < 0.01）；蛋白水平分别升高36%（P < 0.001）和20%（P < 0.05）。BDF 9148浓度依赖性地增加收缩力，在纽约心脏协会心功能IV级和NF中具有相似的最大效应，但在纽约心脏协会心功能IV级中更有效，表现为EC50值显著更小（P < 0.01）（纽约心脏协会心功能IV级，0.18 [0.16至0.22] μmol/L；NF，1.65 [1.3至3.0] μmol/L）。在纽约心脏协会心功能IV级中，BDF 9148（0.1 μmol/L）恢复了正性力-频率关系，并降低了与收缩力相关的频率依赖性舒张张力增加。
钠钙交换体表达增加可能解释了钠通道激活剂BDF 9148在人类衰竭心肌中正性肌力作用增强的原因。交换体分子的增加可能与通过增加细胞内钠浓度的药物调节心脏收缩性具有功能相关性。增强钠钙交换体活性可能是慢性心力衰竭中增加心脏收缩性的一个重要机制。
