Antihypertensive effect of a compound (PST 2238) that displaces ouabain from sodium pump in experimental hypertension

Abstract

A major biologically active Na,K-ATPase inhibitor in the mammalian body may be ouabain-like compound (OLC). We investigated the contribution of OLC to high blood pressure (BP) in reduced renal mass-saline hypertension as a classical model of sodium-dependent hypertension. We used PST 2238 (PST), an orally active antiouabain agent, to block the action of OLC. First, the antihypertensive effect was examined in ouabain-induced hypertensive rats to confirm the antagonistic action of PST (10 mg/kg/day) against ouabain in vivo. Second, we tested the effect of PST in comparison with potassium canrenoate (100 mg/kg/day) on BP in established reduced renal mass (5/6)-saline hypertension in rats. Potassium canrenoate has been supposed to act partially as an ouabain antagonist and was used as a reference drug. Third, we compared the antihypertensive effect of PST on established reduced renal mass (4/6)-saline hypertension with those of potassium canrenoate and doxazosin mesylate (2 mg/kg/day). The continuous ouabain (100 μg/kg/day) infusion with osmotic minipump elevated BP after 4 weeks and a concomitant treatment with PST for 4 weeks abolished this rise in BP (P < 0.01). In rats with severe reduced renal mass-saline hypertension, PST administration for 2 weeks lowered BP (P < 0.01) to the same degree as potassium canrenoate. Also in rats with less severe reduced renal mass-saline hypertension, PST administration for 4 weeks reduced BP (P < 0.01) to the same degree as potassium canrenoate and doxazosin mesylate. These findings suggest that OLC may contribute to the elevated BP in reduced renal mass-saline hypertension and that PST may be an effective antihypertensive agent in several forms of hypertension characterized by increased OLC levels.

Ouabain, ouabain-like compound, sodium dependent hypertension, potassium canrenoate