Dihydroouabain is an antagonist of ouabain inotropic action

Abstract

The Na⁺, K⁺-pump controls a wide variety of cellular systems and its inhibition by cardiac glycosides modifies important physiological functions and evokes several pharmacological effects (refs 1, 2 and refs therein). However, not all the actions of cardiac glycosides can be attributed to Na⁺, K⁺-pump inhibition and several observations show that, at low doses, cardiac glycosides stimulate the pump^3–5. It has been proposed that their positive inotropic effect could be the sum of two processes: the inhibition of the pump and a still unknown additional inotropic mechanism⁶. In guinea pig heart, low doses of ouabain interact with high-affinity binding sites, which differ from the lower-affinity sites responsible for Na⁺, K⁺-pump inhibition^3,7–9. It has been suggested that ouabain interaction with these high-affinity sites could be responsible for the additional inotropic mechanism⁶. The existence of two classes of ouabain-binding sites has been documented not only in guinea pig heart, but also in dog¹⁰, rat^11,12 and human heart¹³. Dihydroouabain, a derivative of ouabain in which the lactone ring is saturated, is about 50-fold less potent than ouabain as an inhibitor of Na⁺, K⁺-pump and does not stimulate the pump at low doses⁷. Its inotropic effect can be entirely accounted for by the inhibition of the pump^6,14. We have examined the pharmacological action of ouabain in the presence of dihydroouabain and report here that dihydroouabain reduces ouabain inotropic action but not Na⁺, K⁺-pump inhibition.