Systemic Hypertension: The Roles of Salt, Vascular Na+/K+ ATPase and the Endogenous Glycosides, Ouabain and Marinobufagenin

Essential hypertension has been shown to be significantly associated with an increased risk for cardiovascular disease and is not well controlled in many patients. In a large portion of people with essential hypertension, sodium intake has been shown to play a significant role in the production of their hypertension. The mechanism through which increased sodium intake manifests hypertension is unresolved and likely multifactorial. Endogenous cardiac glycosides such as endogenous ouabain (EO) and marinobufagenin have been proposed to play a role in salt-sensitive essential hypertension through their inhibition of Na+/K+ ATPase (NKA). The normal function of the NKA pump is to extrude Na+ from the intracellular environment and import K+. Blocking the NKA disrupts its normal maintenance function. EO is proposed to produce alteration in smooth muscle cell contractility by inhibiting the alpha(2)-isoform of NKA, altering Na+ in a microdomain of the cell. In this region of the plasma membrane the alpha(2)-isoform of the NKA colocalizes with another transmembrane protein, the Na+/Ca2+ exchanger (NCX). The normal function of NCX is to extrude Ca2+ and import Na+. Inhibition of NKA produces an increase in Na+ within the microdomain, which in turn alters the function of the NCX so that less Ca2+ is extruded, leading to increased intracellular Ca2+ and increased vascular contraction. EO has been shown to be synthesized and secreted by the adrenal cortex in response to chronically elevated sodium intake. The levels of EO have been shown to be significantly elevated in 40% of all untreated hypertensive patients. Marinobufagenin, another cardiac glycoside, has also been implicated as a possible cause of essential hypertension through its preferential inhibition of the alpha(1)-isoform of NKA. Antagonism of the endogenous inhibitors of NKA is currently a target of clinical research for the development of innovative antihypertensive treatments.