Wellsmith N V, Lindenmayer G E
Circ Res. 1980 Nov;47(5):710-20. doi: 10.1161/01.res.47.5.710.
Some evidence indicates that the inotropic effect of cardiac glycosides occurs at concentrations too low to affect Na+,K+-ATPase activity. This suggests that some receptor other than Na+,K+-ATPase mediates the inotropic effect. We studied ouabain binding to sarcolemma-enriched preparations from canine ventricle under conditions known to promote binding to Na+,K+-ATPase. Profiles for binding and dissociation were characterized by two kinetic components: (1) fast association and slow dissociation; (2) slow association and fast dissociation. Profiles in the absence of supporting ligands were consistent with a single species of receptors with slow association, fast dissociation and minimal effect on Na+,K+-ATPase activity. Binding supported by magnesium plus inorganic phosphate inhibited Na+,K+-ATPase activity by 86%. The two binding components were affected differentially by heating at 55 degrees C. It was concluded that the preparation possesses two receptors for ouabain: the Na+,K+-ATPase and a "new" receptor. The latter may be different chemically from the Na+,K+-ATPase. The more likely possibility is that the "new" receptor is the Na+,K+-ATPase in a state characterized by low catalytic activity, low affinity for ouabain, and no requirement of specific ligands for ouabain binding. Further, the data suggest an interdependence between the two forms. This leads to a mechanism which allows an inotropic effect to precede loss of Na+,K+-ATPase activity even though both result from glycoside binding to Na+,K+-ATPase. The mechanism involves an equilibrium between inactive and active forms of the Na+,K+-ATPase such that the inactive form buffers loss of the active form upon exposure to a cardiac glycoside.
一些证据表明，强心苷的正性肌力作用发生在浓度过低而无法影响Na⁺,K⁺-ATP酶活性的情况下。这表明除Na⁺,K⁺-ATP酶之外的某些受体介导了正性肌力作用。我们在已知能促进与Na⁺,K⁺-ATP酶结合的条件下，研究了哇巴因与犬心室富含肌膜的制剂的结合情况。结合和解离曲线的特征是有两个动力学成分：（1）快速结合和缓慢解离；（2）缓慢结合和快速解离。在没有支持性配体的情况下，曲线与单一类型的受体一致，该受体结合缓慢、解离迅速且对Na⁺,K⁺-ATP酶活性影响最小。镁加无机磷酸盐支持的结合使Na⁺,K⁺-ATP酶活性抑制了86%。这两个结合成分在55℃加热时受到不同的影响。得出的结论是，该制剂具有两种哇巴因受体：Na⁺,K⁺-ATP酶和一种“新”受体。后者在化学性质上可能与Na⁺,K⁺-ATP酶不同。更有可能的情况是，“新”受体是处于低催化活性、对哇巴因低亲和力且结合哇巴因不需要特定配体状态的Na⁺,K⁺-ATP酶。此外，数据表明这两种形式之间存在相互依存关系。这导致了一种机制，即使强心苷与Na⁺,K⁺-ATP酶结合会导致正性肌力作用和Na⁺,K⁺-ATP酶活性丧失，但正性肌力作用会先于Na⁺,K⁺-ATP酶活性丧失出现。该机制涉及Na⁺,K⁺-ATP酶的无活性形式和活性形式之间的平衡，使得无活性形式在暴露于强心苷时缓冲活性形式的丧失。
