Iwamoto Takahiro
Department of Pharmacology, School of Medicine, Fukuoka University, 7-45-1 Nanakuma Jonan-ku, Fukuoka 814-0180, Japan.
Am J Physiol Regul Integr Comp Physiol. 2006 Mar;290(3):R536-45. doi: 10.1152/ajpregu.00592.2005.
The Na+/Ca2+ exchanger is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on membrane potential and transmembrane ion gradients. In arterial smooth muscle cells, the Na+/Ca2+ exchanger is thought to participate in the maintenance of vascular tone by regulating cytosolic Ca2+ concentration. Recent pharmacological and genetic engineering studies have revealed that the Ca2+ influx mode of vascular Na+/Ca2+ exchanger type-1 (NCX1) is involved in the pathogenesis of salt-dependent hypertension. SEA0400, a specific Na+/Ca2+ exchange inhibitor that preferentially blocks the Ca2+ influx mode, lowers arterial blood pressure in salt-dependent hypertensive models, but not in normotensive rats or other types of hypertensive rats. Furthermore, heterozygous mice with reduced expression of NCX1 are resistant to development of salt-dependent hypertension, whereas transgenic mice with vascular smooth muscle-specific overexpression of NCX1 readily develop hypertension after high-salt loading. SEA0400 reverses the cytosolic Ca2+ elevation and vasoconstriction induced by nanomolar ouabain, as well as humoral factors in salt-loaded animals. One possibility is that circulating endogenous cardiotonic steroids may be necessary for NCX1-mediated hypertension. These findings help to explain how arterial smooth muscle cells in blood vessels contribute to salt-elicited blood pressure elevation and suggest that NCX1 inhibitors might be therapeutically useful for salt-dependent hypertension.
钠钙交换体是一种离子转运蛋白，可根据膜电位和跨膜离子梯度，以钙外流或钙内流模式交换钠离子和钙离子。在动脉平滑肌细胞中，钠钙交换体被认为通过调节胞质钙离子浓度参与血管张力的维持。最近的药理学和基因工程研究表明，血管1型钠钙交换体（NCX1）的钙内流模式参与盐依赖性高血压的发病机制。SEA0400是一种特异性钠钙交换抑制剂，优先阻断钙内流模式，可降低盐依赖性高血压模型中的动脉血压，但对正常血压大鼠或其他类型的高血压大鼠无效。此外，NCX1表达降低的杂合小鼠对盐依赖性高血压的发展具有抗性，而血管平滑肌特异性过表达NCX1的转基因小鼠在高盐负荷后很容易发生高血压。SEA0400可逆转纳摩尔哇巴因以及盐负荷动物中的体液因子诱导的胞质钙离子升高和血管收缩。一种可能性是循环内源性强心甾体可能是NCX1介导的高血压所必需的。这些发现有助于解释血管中的动脉平滑肌细胞如何导致盐诱导的血压升高，并表明NCX1抑制剂可能对盐依赖性高血压具有治疗作用。
