Akera T, Bennett R T, Olgaard M K, Brody T M
J Pharmacol Exp Ther. 1976 Nov;199(2):287-97.
The major evidence against the hypothesis that Na+, K+-adenosine triphosphatase (Na+, K+-ATPase) inhibition is the mechanism of the positive inotropic action of digitalis is that the myocardial sodium content does not increase at the time of the inotropic response. In order to understand the relationship between sodium pump inhibition and myocardial sodium content, a computer simulation of the intracellular sodium concentration ([Na+]i) during a cycle of myocardial function was performed. The model for the computer simulation is a small compartment adjacent to the inner surface of the sarcolemma. The change in [Na+]i in this compartment is determined by the rate of sodium influx (published data utilized) and the rate of active sodium transport was estimated from the activities of partially purified dog heart Na+, K+-ATPase preparations assayed with various concentrations of sodium and ouabain. The initial rapid sodium influx results in maximal sodium pump activation, but the pump activity decreases with time as the [Na+]i decreases. Thus, the sodium pump functions at a rate close to its maximal velocity during the initial phase of each cycle but at reduced rates during the later phase. Inhibition of Na+, K+-ATPase by ouabain decreases the maximal velocity during the intiial phase of each cycle but at reduced rates during the later phase. Inhibition of Na+, K+-ATPase by ouabain decreases the maximal velocity of the sodium pump but increases the time in each cycle at which the sodium pump operates at its highest possible rate under these conditions, i.e., a rate close to the inhibited maximal velocity. A 40% inhibition of Na+, K+-ATPase activity, caused by inotropic concentrations of ouabain, increases the peak [Na+]i but fails to cause intracellular sodium accumulation since [Na+]i approaches control levels before the beginning of the next cardiac cycle. With greater enzyme inhibition, caused by arrhythmic concentrations of ouabain, [Na+]i fails to return to the precycle level and thus each subsequent cycle causes a progressive accumulation of myocardial sodium. Computer simulation predicts that a positive inotropic concentration of ouabain causes a myocardial sodium accumulation at a high heart rate but not at a lower heart rate. This was confirmed by experiments with Langendorff preparations of guinea-pig hearts. It is concluded that a moderate sodium pump inhibition by inotropic concentrations of ouabain enhances the intracellular sodium transient (a transient increase in intracellular sodium concentration associated with each membrane excitation) but does not cause a significant myocardial sodium accumulation at normal heart rates. A progressive myocardial sodium accumulation occurs only when the degree of Na+, K+-ATPase inhibition exceeds a critical magnitude.
反对“钠钾 - 腺苷三磷酸酶（Na⁺，K⁺ - ATP酶）抑制是洋地黄正性肌力作用机制”这一假说的主要证据是，在出现正性肌力反应时心肌钠含量并未增加。为了理解钠泵抑制与心肌钠含量之间的关系，对心肌功能周期中的细胞内钠浓度（[Na⁺]i）进行了计算机模拟。计算机模拟的模型是肌膜内表面附近的一个小室。该小室内[Na⁺]i的变化由钠内流速率（利用已发表的数据）决定，而主动钠转运速率则根据用不同浓度的钠和哇巴因测定的部分纯化犬心脏Na⁺，K⁺ - ATP酶制剂的活性来估算。最初快速的钠内流导致钠泵最大程度激活，但随着[Na⁺]i降低，泵活性随时间下降。因此，钠泵在每个周期的初始阶段以接近其最大速度的速率运转，但在后期阶段速率降低。哇巴因对Na⁺，K⁺ - ATP酶的抑制作用会降低每个周期初始阶段的最大速度，但在后期阶段速率降低幅度较小。哇巴因对Na⁺，K⁺ - ATP酶的抑制作用降低了钠泵的最大速度，但增加了每个周期中钠泵在这些条件下以其最高可能速率（即接近受抑制的最大速度的速率）运转的时间。由产生正性肌力作用浓度的哇巴因引起的40%的Na⁺，K⁺ - ATP酶活性抑制会增加[Na⁺]i峰值，但不会导致细胞内钠蓄积，因为在下次心动周期开始前[Na⁺]i接近对照水平。当由产生心律失常浓度的哇巴因引起更大程度的酶抑制时，[Na⁺]i无法恢复到周期前水平，因此随后的每个周期都会导致心肌钠的逐渐蓄积。计算机模拟预测，产生正性肌力作用浓度的哇巴因在高心率时会导致心肌钠蓄积，而在低心率时则不会。豚鼠心脏Langendorff标本实验证实了这一点。结论是，产生正性肌力作用浓度的哇巴因对钠泵的适度抑制会增强细胞内钠瞬变（与每次膜兴奋相关的细胞内钠浓度的短暂增加），但在正常心率下不会导致明显的心肌钠蓄积。只有当Na⁺，K⁺ - ATP酶抑制程度超过临界值时，才会发生心肌钠的逐渐蓄积。
