Role of ouabain-like factors in hypertension: Effects of ouabain and certain endogenous ouabain-like factors in hypertension

Several reports suggest the presence of sodium-potassium pump inhibitor in plasma and various tissues, particularly during volume-expanded state and low-renin hypertension. It has been hypothesized that by inhibiting the cardiovascular muscle-cell Na⁺-K⁺ pump, this inhibitor can constrict blood vessels, enhance vasoconstriction, and increase cardiac contractility, thereby raising blood pressure. Only two such endogenous inhibitors have been chemically characterized: the bufodienolide derivative, resibufogenin, obtained from toad skin and plasma; and a factor with the same structure (based on mass spectral analysis) as ouabain, from human plasma. However, unlike bufalin (aglycone), which is almost structurally identical to resibufogenin, neither ouabain nor ouabagenin (aglycone of ouabain) caused a sustained increase in blood pressure when infused in equimolar doses during a 30-min period in rats. Because the rat is 10⁴-fold less sensitive to ouabain than the human is, we wondered whether the absence of a response to ouabain was due to the short infusion time. Therefore, in new experiments ouabain was administered chronically during a 6- to 7-week period to two-kidney normal rats and rats with 70, 60, and 25% reduced renal mass. Reduced renal mass rats were used because these rats have decreased sodium excretion capacity, and thus we hoped the action of exogenous ouabain would be potentiated in these volume-expanded rats. Compared with controls (animals receiving vehicle), all animals receiving ouabain developed a dose-dependent, significant increase in blood pressure that was confirmed by direct measurement. The cardiac output and ventricular weight, however, were not different. Plasma ouabain levels in experimental animals were not different relative to controls. However, kidney ouabain levels were elevated in experimental animals. These data show that ouabain given chronically induces hypertension, which is probably due mainly to the elevated peripheral resistance, and thus ouabain or a compound with a similar structure has the attributes of an endogenous sodium-pump inhibitor.