Invited Review CALL FOR PAPERS Molecular Mechanisms Linking Salt to Hypertension Vascular Na /Ca exchanger: implications for the pathogenesis and therapy of salt-dependent hypertension

Iwamoto, Takahiro. Vascular Na /Ca exchanger: implications for the pathogenesis and therapy of salt-dependent hypertension. Am J Physiol Regul Integr Comp Physiol 290: R536–R545, 2006; doi:10.1152/ajpregu.00592.2005.—The Na /Ca exchanger is an ion transporter that exchanges Na and Ca in either Ca efflux or Ca influx mode, depending on membrane potential and transmembrane ion gradients. In arterial smooth muscle cells, the Na /Ca exchanger is thought to participate in the maintenance of vascular tone by regulating cytosolic Ca concentration. Recent pharmacological and genetic engineering studies have revealed that the Ca influx mode of vascular Na /Ca exchanger type-1 (NCX1) is involved in the pathogenesis of salt-dependent hypertension. SEA0400, a specific Na /Ca exchange inhibitor that preferentially blocks the Ca 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 saltdependent hypertension, whereas transgenic mice with vascular smooth musclespecific overexpression of NCX1 readily develop hypertension after high-salt loading. SEA0400 reverses the cytosolic Ca 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.