Topics on the Na+/Ca2+ exchanger: role of vascular NCX1 in salt-dependent hypertension.

Excess salt intake is a major risk factor for hypertension. However, the molecular mechanisms underlying salt-dependent hypertension remain obscure. Our recent studies using selective Na(+)/Ca(2+) exchange inhibitors and genetically engineered mice provide compelling evidence that salt-dependent hypertension is triggered by Ca(2+) entry through Na(+)/Ca(2+) exchanger type 1 (NCX1) in arterial smooth muscle. Endogenous cardiac glycosides, which may contribute to salt-dependent hypertension, seem to be necessary for NCX1-mediated hypertension. Intriguingly, recent studies by Dostanic-Larson et al. using knock-in mice with modified cardiac glycoside binding affinity of Na(+),K(+)-ATPases demonstrate that this binding site plays an important physiological role in blood pressure control. Thus, when cardiac glycosides inhibit Na(+),K(+)-ATPase in arterial smooth muscle cells, the elevation of local Na(+) on the submembrane area is believed to facilitate Ca(2+) entry through NCX1, resulting in vasoconstriction. This proposed pathway may have enabled us to explain how to link dietary salt to hypertension.