Diedrichs Holger, Frank Konrad, Schneider Christian A, Burst Volker, Hagemeister Jens, Zobel Carsten, Müller-Ehmsen Jochen
Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Int Heart J. 2007 Nov;48(6):755-66. doi: 10.1536/ihj.48.755.
The present study aimed to investigate the hypothesis that the function of the Na,Ca-exchanger (NCX) is of higher importance for contractility and Ca(2+)-homeostasis in left ventricle from terminally failing than from nonfailing human hearts. The effect of decreasing extracellular Na (140 to 25 mmol/L) on force of contraction in isolated left ventricular papillary muscle strips was studied as a reflection of NCX function in multicellular preparations (terminally failing, DCM, dilated cardiomyopathy, NYHA IV, n = 13; nonfailing, NF, donor hearts, n = 10). Decreasing Na has previously been shown to increase contractility in vitro secondary to a decreased Ca(2+)-extrusion by the NCX. In addition, the NCX activity was measured as Na(+)-dependent (45)Ca(2+)-uptake into isolated myocardial vesicles as a function of time and Ca(2+)-concentration (DCM n = 8, NF n = 8). Decreasing Na enhanced the contractility of papillary muscle strips in both DCM and NF, but the contractility of DCM was increased at smaller reductions of Na than NF. The NCX activity in isolated myocardial vesicles was unchanged as a function of time (T(1/2): DCM 2.4 +/- 0.3 s versus NF 2.5 +/- 0.3 s) and as a function of Ca(2+) (DCM 0.99 +/- 0.08 versus NF 0.96 +/- 0.07 nmol/mg protein x 3 s, K(1/2): DCM 39.2 microM versus NF 38.3 microM). These results demonstrate a higher sensitivity of the failing human myocardium towards Na,Ca-exchanger mediated positive inotropic effects, suggesting a higher significance of the Na,Ca-exchanger for the extrusion of Ca(2+)-ions in intact failing versus nonfailing human myocardium. Since the activity and the Ca (2+)-affinity of the Na,Ca-exchanger in isolated vesicles was unchanged, we propose that alterations in Ca(2+)-and Na(+)-homeostasis (due to impaired function of the sarcoplasmic reticulum and the Na(+), K(+)-ATPase) or the prolonged action potential are the reason for this observation.
与非终末期衰竭的人类心脏相比，钠钙交换体（NCX）的功能在终末期衰竭的左心室收缩性和钙稳态中更为重要。研究了降低细胞外[Na⁺]（e）（从140 mmol/L降至25 mmol/L）对离体左心室乳头肌条收缩力的影响，以此反映多细胞制剂中NCX的功能（终末期衰竭、扩张型心肌病（DCM）、纽约心脏协会心功能IV级，n = 13；非衰竭，NF，供体心脏，n = 10）。先前已表明，降低[Na⁺]（e）会因NCX介导的钙外流减少而在体外增加收缩性。此外，通过测量钠依赖性（⁴⁵）Ca²⁺摄取到离体心肌囊泡中的量来测定NCX活性，该摄取量是时间和钙浓度的函数（DCM，n = 8；NF，n = 8）。降低[Na⁺]（e）增强了DCM和NF中乳头肌条的收缩性，但DCM的收缩性在[Na⁺]（e）降低幅度较NF小时就增加了。离体心肌囊泡中的NCX活性在时间函数上（半衰期：DCM为2.4±0.3秒，NF为2.5±0.3秒）以及钙函数上（DCM为0.99±0.08，NF为0.96±0.07 nmol/mg蛋白×3秒，半数最大结合浓度：DCM为39.2 μM，NF为38.3 μM）均未改变。这些结果表明，衰竭的人类心肌对钠钙交换体介导的正性肌力作用具有更高的敏感性，这表明在完整的衰竭与非衰竭人类心肌中，钠钙交换体对钙离子外流具有更高的重要性。由于离体囊泡中钠钙交换体的活性和钙亲和力未改变，我们推测钙和钠稳态的改变（由于肌浆网和钠钾ATP酶功能受损）或延长的动作电位是这一观察结果的原因。
