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. 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 mechanism. 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. It has been suggested that ouabain interaction with these high-affinity sites could be responsible for the additional inotropic mechanism. The existence of two classes of ouabain-binding sites has been documented not only in guinea pig heart, but also in dog, rat and human heart. 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 doses. Its inotropic effect can be entirely accounted for by the inhibition of the pump. 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.

The inotropic effect of ouabain and its antagonism by dihydroouabain in rat isolated atria and ventricles in relation to specific binding sites

“…In this preparation, Na+, K+-pump inhibition seems to be the only mechanism responsible for the positive inotropic effect of dihydroouabain, the derivative of ouabain with a saturated lactone ring (Godfraind & Ghysel-Burton, 1980). Furthermore, dihydroouabain has been shown to act as an antagonist to the positive inotropic effect of ouabain that is independent of Na+, K+-pump inhibition (Godfraind, Ghysel-Burton & De Pover, 1982). Therefore, we have studied the inotropic action of dihydroouabain on rat ventricular strips and examined how this drug interfered with the action of ouabain.…”

Cardiac glycoside receptors in cultured heart cells—II

“…Does the existence of two dasses of cardiac glycoside receptors represent the exception, being restricted to the rat , or does it represent a more common phenomenon? At least for some species (guinea pig , dog, man) , experimental evidence is present for different receplor types [36][37][38][39][40].…”

Selective inhibition by ethylisopropylamiloride of the positive inotropic effect evoked by low concentrations of ouabain in rat isolated ventricles

“…In the guinea-pig isolated atria, it has been observed that amiloride inhibits the positive inotropic effect of both ouabain and dihydroouabain, whereas EIPA inhibits the effect of ouabain but not that of dihydroouabain (Ghysel-Burton & Godfraind, 1986). In guinea-pig atria, the inotropic effect of dihydroouabain has been attributed to an interaction with low affinity binding sites, whereas the inotropic effect of ouabain has been ascribed to an interaction with both low and high affinity binding sites (Godfraind et al, 1982). In the present experiments, we have studied the action ofEIPA on the inotropic effect ofouabain in rat ventricular strips where two different Na/K-ATPase activities with different affinities for ouabain have 'Author for correspondence.…”

“…In guinea-pig atria, the inotropic effect of dihydroouabain has been attributed to an interaction with low affinity binding sites, whereas the inotropic effect of ouabain has been ascribed to an interaction with both low and high affinity binding sites (Godfraind et al, 1982).…”