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Vol. 285, Issue 1, 83-94, April 1998
Prassis Research Institute Sigma-Tau, The inhibition of the long-term pressor effect of ouabain may be useful
for the therapy of essential hypertension. Here, for the first time, a
selective inhibitor of the ouabain pressor effect is described.
In vitro, 17
-(3-furyl)-5-androstane-3, 14,
17
-triol (PST 2238) displaced ouabain from its binding sites on
purified sodium, potassium ATPase enzyme (Na-K ATPase)
(IC50 1.7 × 10
6 M) without interacting
with other receptors involved in blood pressure regulation or hormonal
control. In cultured renal cells, incubation with ouabain
(1010 to 108 M) for 5 days stimulated the
Na-K pump at Vmax, whereas PST 2238 showed the
same effect at micromolar concentration. The ouabain-dependent increase
in the Na-K pump rate was abolished by PST 2238 at concentrations from
1014 to 109 M. In rats made hypertensive by
chronic infusion of 50 µg/kg/day of ouabain, PST 2238 given p.o at
very low doses (0.1-1 µg/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 very potent compound
that normalizes both blood pressure and alterations 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 forms of hypertension
sustained by the concomitant increase of endogenous ouabain levels and
alterations in the Na-K pump.
0022-3565/98/2851-0083$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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