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

Abstract

1 The inotropic effect of ouabain has been studied in rat ventricles and atria. 2 The concentration-effect curve of ouabain may be fitted by a model assuming the existence of two saturable components. The component with the higher sensitivity to ouabain accounted for 30% of the maximal increase in systolic tension in ventricles and for only 5 % in atria. Increase in diastolic tension was only apparent at ouabain concentrations required to observe the low sensitivity component. [3H]-ouabain binding has been examined in microsomes prepared from atria and ventricles. High and low affinity binding sites have been observed. The ratio of high and low affinity ouabain binding sites was 4 fold lower in microsomes from rat atria than from rat ventricles. This could account for the difference in the response of these two tissues to the inotropic action of ouabain. 4 In ventricular strips the high sensitivity component was much less apparent in the presence of dihydroouabain than with ouabain. 5 When ventricular strips were preincubated in the presence of dihydroouabain 3 AM, the increase in systolic tension evoked by ouabain 1 AM was significantly reduced. Cumulative concentrationeffect curve studies showed dihydroouabain antagonism to the high sensitivity component.

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

“…They show that the biphasic model (equation 2) has a lower variance than the monophasic model (equation 1) (P < 0.01 and P < 0.05). This is consistent with previous findings (Finet et al, 1983) Figure lc shows that the experimental data for the positive inotropic effect of ouabain in presence of EIPA 20 IuM are fitted by a monophasic curve that has the same characteristics as the low affinity inotropic component computed in the absence of EIPA (ED50 equal respectively to 0.07 ± 0.02 mM and 0.06 ± 0.01 mM; P>0.1). This confirms that EIPA affected only the high affinity component.…”

“…been demonstrated (Noel & Godfraind, 1984). In this tissue, the dose-effect curve of ouabain shows two components related to those high and low affinity binding sites (Finet et al, 1983). The present results show that the inotropic effect resulting from the interaction of ouabain with high affinity sites is selectively inhibited by EIPA.…”

“…It has been demonstrated that under normal conditions, the interaction of ouabain with high affinity binding sites does not induce an increase in the resting tension (diastolic). Only the interaction of ouabain with low affinity receptors produces such toxic effects (Finet et al, 1983). The present results show that the positive inotropic effect evoked by low and high concentrations of ouabain are not equally affected after pretreatment with EIPA; EIPA 10 and 20 lM depressed the positive inotropic effect of ouabain that is related to an interaction with high affinity binding sites whereas it did not significantly modify the positive inotropic effect of ouabain related to the low affinity binding sites.…”

Erythrosin B inhibits high affinity ouabain binding in guinea‐pig heart Na+‐K+‐ATPase without influence on cardiac glyoside induced contractility

“…In contrast Lazdunski et al (1983), who in cultured chick heart cells could also demonstrate two ouabain binding sites, suggested that the low affinity ouabain binding, which was related to the inhibition ofthe cardiac Na' -K+ -ATPase, was probably responsible for both the cardiotonic and cardiotoxic effects of this drug. Finally, an intermediate interpretation is given by Adams et al (1982) and Finet et al (1983), who postulated from experiments on rat isolated heart muscle preparations, that the high affinity and the low affinity ouabain binding sites were involved in the inotropic action of this drug: low cardiac glycoside concentrations could cause an increased mobilization of intracellular calcium and higher ouabain concentrations result in an inhibition of the Na'-K+-pump and consequent activation of the Na'-Ca2+-exchange mechanism.…”

Portal veins of mice infected with Schistosoma mansoni exhibit an increased reactivity to 5-hydroxytryptamine

“…Statistics -EC 50 and E max were estimated independently for each experiment by non-linear regression using the simplest model of drug-receptor interaction (Finet et al 1983). Student's t test for determining the significance of the differences between control and infected groups was performed considering the arithmetic (E max ) or geometric (EC 50 ) means.…”