PST2238 - A NEW ANTIHYPERTENSIVE COMPOUND THAT ANTAGONIZES THE LONG-TERM PRESSOR EFFECT OF OUABAIN

The inhibition of the long-term presser effect of ouabain may be usefu l for the therapy of essential hypertension. Here, for the first time, a selective inhibitor of the ouabain presser effect is described. In vitro, 17 beta-(3-furyl)-5 beta-androstane-3 beta, 14 beta, 17 alpha-t riol (PST 2238) displaced ouabain from its binding sites on purified s odium, potassium ATPase enzyme (Na-K ATPase) (IC50 1.7 x 10(-6) M) wit hout interacting with other receptors involved in blood pressure regul ation or hormonal control. In cultured renal cells, incubation with ou abain (10(-10) to 10(-8) M) for 5 days stimulated the Na-K pump at V-m ax, whereas PST 2238 showed the same effect at micromolar concentratio n. The ouabain-dependent increase in the Na-K pump rate was abolished by PST 2238 at concentrations from 10(-14) to 10(-9) M. In rats made h ypertensive by chronic infusion of 50 mu g/kg/day of ouabain, PST 2238 given p.o at very low doses (0.1-1 mu g/kg/day for 4 weeks) abolished the increase in blood pressure and renal Na-K ATPase activity caused by ouabain. PST 2238 did not affect either blood pressure or renal Na- K ATPase activity in normotensive rats. In conclusion, PST 2238 is a v ery potent compound that normalizes both blood pressure and alteration s in the Na-K pump caused by ouabain. Thus it represents the prototype of a new class of antihypertensive drugs that could be effective in f orms of hypertension sustained by the concomitant increase of endogeno us ouabain levels and alterations in the Na-K pump.