Saint D A
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia.
Br J Pharmacol. 2008 Mar;153(6):1133-42. doi: 10.1038/sj.bjp.0707492. Epub 2007 Dec 10.
The sodium current in the heart is not a single current with a mono-exponential decay but rather a mixture of currents with different kinetics. It is not clear whether these arise from distinct populations of channels, or from modulation of a single population. A very slowly inactivating component, [(INa(P))] I(Na(P)) is usually about 1% of the size of the peak transient current [I(Na(T))], but is enhanced by hypoxia. It contributes to Na(+) loading and cellular damage in ischaemia and re-perfusion, and perhaps to ischaemic arrhythmias. Class I antiarrhythmic agents such as flecainide, lidocaine and mexiletine generally block I(NA(P)) more potently than block of I(Na(T)) and have been used clinically to treat LQT3 syndrome, which arises because mutations in SCN5A produce defective inactivation of the cardiac sodium channel. The same approach may be useful in some pathological situations, such as ischaemic arrhythmias or diastolic dysfunction, and newer agents are being developed with this goal. For example, ranolazine blocks I(Na(P)) about 10 times more potently than I(Na(T)) and has shown promise in the treatment of angina. Alternatively, the combination of I(Na(P)) block with K(+) channel block may provide protection from the induction of Torsades de Pointe when these agents are used to treat atrial arrhythmias (eg Vernakalant). In all of these scenarios, an understanding of the role of I(Na(P)) in cardiac pathophysiology, the mechanisms by which it may affect cardiac electrophysiology and the potential side effects of blocking I(Na(P)) in the heart and elsewhere will become increasingly important.
心脏中的钠电流并非具有单指数衰减的单一电流，而是具有不同动力学的电流混合物。目前尚不清楚这些电流是源自不同的通道群体，还是来自单一群体的调制。一种非常缓慢失活的成分，即[I(Na(P))]，通常约为峰值瞬时电流[I(Na(T))]大小的1%，但在缺氧时会增强。它在缺血和再灌注过程中导致钠负荷增加和细胞损伤，可能还与缺血性心律失常有关。I类抗心律失常药物，如氟卡尼、利多卡因和美西律，通常对I(NA(P))的阻断作用比对I(Na(T))的阻断作用更强，并且已在临床上用于治疗LQT3综合征，该综合征是由于SCN5A基因突变导致心脏钠通道失活缺陷而引起的。同样的方法在某些病理情况下可能有用，如缺血性心律失常或舒张功能障碍，并且正在开发以该目标为导向的新型药物。例如，雷诺嗪对I(Na(P))的阻断作用比对I(Na(T))的阻断作用强约10倍，并且在心绞痛治疗中已显示出前景。或者，当这些药物用于治疗房性心律失常（如维纳卡兰）时，I(Na(P))阻断与钾通道阻断的联合应用可能提供预防尖端扭转型室速的作用。在所有这些情况下，了解I(Na(P))在心脏病理生理学中的作用、其可能影响心脏电生理学的机制以及阻断心脏和其他部位的I(Na(P))的潜在副作用将变得越来越重要。
