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Molecular Mechanisms Linking Salt to Hypertension

Vascular Na⁺/Ca²⁺ exchanger: implications for the pathogenesis and therapy of salt-dependent hypertension

Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka, Japan

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.

hypertension; salt intake; Na⁺-K⁺-ATPase; vascular smooth muscle

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