PST2238: a new antihypertensive compound that antagonizes the long-term pressor effect of ouabain.
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, 17beta-(3-furyl)-5beta-androstane-3beta, 14beta, 17alpha-triol (PST 2238) displaced ouabain from its binding sites on purified sodium, potassium ATPase enzyme (Na-K ATPase) (IC50 1.7 x 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 microg/kg/day of ouabain, PST 2238 given p.o at very low doses (0.1-1 microg/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.
Ferrari
P
P
Prassis Research Institute Sigma-Tau, Milan, Italy.
Torielli
L
L
Ferrandi
M
M
Padoani
G
G
Duzzi
L
L
Florio
M
M
Conti
F
F
Melloni
P
P
Vesci
L
L
Corsico
N
N
Bianchi
G
G
D000732:Androstanols / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D008297:Male; D010042:Ouabain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects* / Q000378:metabolism
D000732:Androstanols; D000959:Antihypertensive Agents; D002316:Cardiotonic Agents; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; C106263:rostafuroxin