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Objective To assess possible relationships between endogenous ouabain, sodium balance and blood pressure.Content This review concerns the structure of endogenous ouabain, circulating levels of this steroid in various disorders of fluid and electrolyte balance, recent evidence for the association of endogenous ouabain with human hypertension, the influence of sodium and volume factors on ouabain-induced hypertension, and possible mechanisms for the hypertensinogenic activity of ouabain.Conclusions The human circulation contains a closely related isomer of ouabain of putative adrenocortical origin. Elevated circulating levels of this 'endogenous ouabain' are common but not universal in physiologic and pathologic states associated with positive sodium balance or high blood pressure, or both. In the absence of adrenal hyperfunction, elevating circulating levels of endogenous ouabain appear to be secondary to impaired renal clearance. Prolonged elevation of circulating ouabain in the rat induces sustained hypertension. This model exhibits normal plasma renin activity, increased levels of ouabain in the hypothalamus, pituitary, and kidney, and responds to angiotensin converting enzyme inhibitors. !n rats with normal kidney function, ouabain-induced hypertension is primarily sodium-insensitive although maneuvers that hinder renal sodium excretion augment the pressor effect of this steroid. Prolonged administration of ouabain into the brain ventricles augments sympathetic nervous system activity and induces sustained hypertension. These observations lead us to propose the following hypothesis. Among Caucasian patients with essential hypertension, a large fraction have elevated circulating levels of endogenous ouabain, possibly caused by an inherited or acquired renal defect in clearance of this steroid. In these patients, and in rats with ouabain-induced hypertension, increased local generation of, or increased target organ sensitivity to, angiotensin II, or both, may contribute critically to heightened vasoconstriction and a sustained increase in blood pressure. Investigations of the efferent pressor mechanisms and the renal handling of endogenous ouabain are novel approaches to the etiology and therapy of several common cardiovascular disorders.