Iwamoto Takahiro, Watanabe Yasuhide, Kita Satomi, Blaustein Mordecai P
Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
Cardiovasc Hematol Disord Drug Targets. 2007 Sep;7(3):188-98. doi: 10.2174/187152907781745288.
The Na(+)/Ca(2+) exchanger (NCX) is a bidirectional transporter that normally extrudes Ca(2+) from the cell (forward mode), but also brings Ca(2+) into the cell (reverse mode) under special conditions such as intracellular Na(+) (Na(+)(i)) accumulation or membrane depolarization. There are three mammalian NCX isoforms: NCX1 is widely expressed in the heart, kidney, brain, blood vessels, and so on; whereas the expression of NCX2 and NCX3 is limited mainly to the brain and skeletal muscle. The pharmacology of NCX inhibitors has been studied extensively since the development of KB-R7943, a prototype benzyloxyphenyl NCX inhibitor, in 1996. Currently, experiments are actively progressing with more selective inhibitors: SEA0400, SN-6, and YM-244769. Intriguingly, the inhibitory potency of benzyloxyphenyl NCX inhibitors is directly coupled to the rate of Na(+)(i)-dependent inactivation. Therefore, the benzyloxyphenyl inhibitors are apparently dormant during the forward mode under normal conditions (low Na(+)(i)), but become effective during the reverse mode under pathological conditions (high Na(+)(i)). This should be an ideal profile for calcium regulators against Na(+)(i)-related diseases, such as ischemia/reperfusion injuries, salt-dependent hypertension, and digitalis arrhythmia. Existing ion channel blockers, such as amiodarone, dronedarone, bepridil, aprindine, and cibenzoline, have been found to have an NCX inhibitory action. It is possible that this property is partly responsible for their antiarrhythmic and cardioprotective effects. This article presents the characteristics of selective and non-selective NCX inhibitors and their therapeutic potential as a new calcium regulator.
钠钙交换体（NCX）是一种双向转运体，正常情况下它将钙离子从细胞内排出（正向模式），但在特殊条件下，如细胞内钠离子（Na⁺(i)）积累或细胞膜去极化时，也会将钙离子带入细胞内（反向模式）。哺乳动物有三种NCX亚型：NCX1在心脏、肾脏、大脑、血管等组织中广泛表达；而NCX2和NCX3的表达主要局限于大脑和骨骼肌。自1996年原型苄氧基苯基NCX抑制剂KB-R7943开发以来，对NCX抑制剂的药理学进行了广泛研究。目前，使用更具选择性的抑制剂（SEA0400、SN-6和YM-244769）的实验正在积极推进。有趣的是，苄氧基苯基NCX抑制剂的抑制效力与Na⁺(i)依赖性失活速率直接相关。因此，苄氧基苯基抑制剂在正常条件下（低Na⁺(i)）的正向模式中显然处于休眠状态，但在病理条件下（高Na⁺(i)）的反向模式中变得有效。这对于针对与Na⁺(i)相关疾病（如缺血/再灌注损伤、盐依赖性高血压和洋地黄引起的心律失常）的钙调节剂来说应该是一个理想的特性。现有的离子通道阻滞剂，如胺碘酮、决奈达隆、苄普地尔、阿普林定和西苯唑啉，已被发现具有NCX抑制作用。这种特性可能部分解释了它们的抗心律失常和心脏保护作用。本文介绍了选择性和非选择性NCX抑制剂的特点及其作为新型钙调节剂的治疗潜力。
