Vascular Na+/Ca2+ exchanger: implications for the pathogenesis and therapy of salt-dependent hypertension.
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.
Department of Pharmacology, School of Medicine, Fukuoka University, 7-45-1 Nanakuma Jonan-ku, Fukuoka 814-0180, Japan. tiwamoto@cis.fukuoka-u.ac.jp
Takahiro
T
Iwamoto
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000959:Antihypertensive Agents; D017673:Sodium Chloride, Dietary; D000254:Sodium-Potassium-Exchanging ATPase