Belardinelli L, Shryock J C, Fraser H
Department of Pharmacological Sciences, CV Therapeutics, Inc, 3172 Porter Dr, Palo Alto, CA 94304, USA.
Heart. 2006 Jul;92 Suppl 4(Suppl 4):iv6-iv14. doi: 10.1136/hrt.2005.078790.
Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular sodium (Na(+)) and calcium (Ca(2+)) concentration homeostasis of myocardial cells. A decreased efflux or increased influx of sodium may cause cellular sodium overload. Sodium overload is followed by an increased influx of calcium through sodium-calcium exchange. Failure to maintain the homeostasis of Na(+) and Ca(2+) leads to electrical instability (arrhythmias), mechanical dysfunction (reduced contractility and increased diastolic tension) and mitochondrial dysfunction. These events increase ATP hydrolysis and decrease ATP formation and, if left uncorrected, they cause cell injury and death. The relative contributions of various pathways (sodium channels, exchangers and transporters) to the rise in Na(+) remain a matter of debate. Nevertheless, both the sodium-hydrogen exchanger and abnormal sodium channel conductance (that is, increased late sodium current (I(Na))) are likely to contribute to the rise in Na(+). The focus of this review is on the role of the late (sustained/persistent) I(Na) in the ionic disturbances associated with ischaemia/hypoxia and heart failure, the consequences of these ionic disturbances, and the cardioprotective effects of the antianginal and anti-ischaemic drug ranolazine. Ranolazine selectively inhibits late I(Na), reduces Na(+)-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure. Thus, inhibition of late I(Na) can reduce Na(+)-dependent calcium overload and its detrimental effects on myocardial function.
与氧供需失衡相关的病理状况（例如，缺血、缺氧和心力衰竭）与心肌细胞内细胞内钠（[Na⁺]i）和钙（[Ca²⁺]i）浓度稳态的破坏有关。钠外流减少或内流增加可能导致细胞钠超载。钠超载之后是通过钠钙交换导致钙内流增加。无法维持[Na⁺]i和[Ca²⁺]i的稳态会导致电不稳定（心律失常）、机械功能障碍（收缩力降低和舒张张力增加）和线粒体功能障碍。这些事件会增加ATP水解并减少ATP生成，如果不加以纠正，会导致细胞损伤和死亡。各种途径（钠通道、交换体和转运体）对[Na⁺]i升高的相对贡献仍存在争议。然而，钠氢交换体和异常的钠通道电导（即晚期钠电流（INa）增加）都可能导致[Na⁺]i升高。本综述的重点是晚期（持续/持久）INa在与缺血/缺氧和心力衰竭相关的离子紊乱中的作用、这些离子紊乱的后果以及抗心绞痛和抗缺血药物雷诺嗪的心脏保护作用。雷诺嗪选择性抑制晚期INa，减少[Na⁺]i依赖性钙超载，并减轻与缺血/再灌注和心力衰竭相关的心室复极和收缩力异常。因此，抑制晚期INa可以减少[Na⁺]i依赖性钙超载及其对心肌功能的有害影响。
