High sodium intake in the presence of an intrinsic or acquired defect in renal sodium excretion will result in extracellular fluid volume (ECFV) expansion which is accompanied by decreased baroreceptor reflex sensitivity. We have shown that ECFV-expansion also stimulates the secretion of an endogenous inhibitor of the Na-K-ATPase enzyme and high activity of this sodium transport inhibitor was detected in plasma of patients with primary aldosteronism, the most classical type of volume-dependent hypertension. Thus, vasoconstriction due to inhibition of sodium pump activity of the vascular smooth muscle cell may contribute to the pathogenesis of human arterial hypertension. In analogy, ouabain (8.5 micrograms/kg) when administered i.v. to healthy volunteers inhibited RBC - Na-K-ATPase by 49% and significantly increased peripheral vascular resistance by 24 - 36%. The calcium entry blocker nifedipine (10 mg orally) completely prevented ouabain-induced vasoconstriction suggesting that the action of ouabain was mediated by a rise in intracellular calcium. High potassium intake partially abolished the vasoconstrictor effect of ouabain and also significantly increased baroreceptor reflex sensitivity. The results of these studies support the concept that inhibition of the sodium and potassium pump of vascular smooth muscle cells by a yet putative endogenous inhibitor of Na-K-ATPase (natriuretic hormone) may represent a crucial mechanism in the pathogenesis of at least certain forms of essential and secondary hypertension in man.