Abstract
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, 17β-(3-furyl)-5β-androstane-3β, 14β, 17α-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 (10−10 to 10−8 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 10−14 to 10−9 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.
Footnotes
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Send reprint requests to: Patrizia Ferrari, Prassis Istituto Ricerche Sigma-Tau, via Forlanini 3, 20019 Settimo Milanese (Milano), Italy.
- Abbreviations:
- CS
- control-saline rats
- DBP
- diastolic blood pressure
- DMSO
- dimethylsulfoxide
- MBP
- mean blood pressure
- NRK cells
- normal rat kidney cells
- OLF
- ouabain-like factor
- OS
- ouabain-sensitive rats
- SBP
- systolic blood pressure
- SDS
- sodium dodecylsulfate
- Received May 15, 1997.
- Accepted December 18, 1997.
- The American Society for Pharmacology and Experimental Therapeutics