Topics on the Na⁺/Ca²⁺ Exchanger:
Role of Vascular NCX1 in Salt-Dependent Hypertension

Abstract

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⁺/Ca²⁺ exchange inhibitors and genetically engineered mice provide compelling evidence that salt-dependent hypertension is triggered by Ca²⁺ entry through Na⁺/Ca²⁺ 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 Ca²⁺ entry through NCX1, resulting in vasoconstriction. This proposed pathway may have enabled us to explain how to link dietary salt to hypertension.