Excessive dietary intake of sodium appears to play a significant role in human essential hypertension. The underlying mechanism may involve the excessive secretion of a humoral natriuretic factor in response to the salt load. Deproteinized plasma from patients with essential hypertension contains elevated levels of an ouabain-like inhibitor of dog kidney sodium plus potassium-dependent adenosine triphosphatase. This substance, by inhibiting renal sodium transport, should have a natriuretic effect. Plasma from hypertensive patients also produces an ouabain-like sensitization of vascular smooth muscle (rabbit aorta) to exogenous norepinephrine. These data suggest that a circulating inhibitor of the sodium pump may play a key role in generating increased peripheral vascular resistance. Cellular mechanisms that link sodium pump inhibition to increased vascular resistance involve increased norepinephrine release and reduced re-uptake and directly increased smooth muscle contractility and reactivity, as a result of increased cell sodium.