Small Doses of Canrenone Block the Effects of Ouabain on the Mechanical Activity of the Heart and Vessels of the Rat

Abstract

Canrenone has been described as an antihypertensive drug that blocks endogenous ouabain effects in volume-dependent hypertensive models. Considering that some canrenone metabolites may be putative mutagenic factors, therapeutic dose reduction might be advantageous if the blockade of ouabain effects is maintained. In this study, the effects of low doses or concentrations of canrenone were investigated in rats by using isolated papillary muscles, Langendorff-perfused hearts, perfused rat-tail vascular bed, and anesthetized animals. Canrenone (0.5, 1, 2, and 5 mg/ml) produced a dose-dependent negative inotropic effect in papillary muscles contracting isometrically and blocked the positive inotropic effect produced by 660 microM ouabain. In Langendorff-perfused hearts beating spontaneously, a low concentration of canrenone (10 microg/ml) increased the isovolumic systolic pressure obtained at several diastolic pressures. Higher concentrations of canrenone (20, 30 microg/ml) brought the isovolumic pressure toward control values, and 100 microg/ml canrenone produced an isovolumic pressure reduction. In these preparations, 20 microg/ml canrenone reduced significantly the positive inotropic effects of 100 microM ouabain. Investigating the vascular smooth muscle reactivity to phenylephrine (PE; 0.5, 1, and 2 microg bolus injections) in the perfused rat-tail vascular bed, it was observed that canrenone blocked completely the enhancement of PE pressor effect produced by 1-h treatment with 100 microM ouabain. Similar results were obtained with the arterial blood pressure reactivity to PE in anesthetized rats. In these animals, canrenone (1 mg/kg) blocked the sensitizing effect of 18 microg/kg ouabain on PE reactivity. In conclusion, results presented here suggest that canrenone may block ouabain effects at very low concentrations. It blocked myocardial positive inotropic effects of ouabain on both papillary muscle and perfused hearts, and the sensitization of PE pressor effects. The results also suggest that canrenone at very small doses might be used to reduce arterial blood pressure in hypertensive conditions accompanied by increased ouabain plasma levels as the main therapeutic procedure or as an adjunct treatment to prevent ouabain sensitizing effects on pressor responses.

Endogenous Cardiotonic Steroids in Kidney Failure: A Review and an Hypothesis

“…One of the first clues that canrenone was a CTS receptor antagonist was the ability of therapeutic doses to reduce the effect of digitalis and ouabain on the heart 157–162 . Subsequent work showed canrenone suppressed ouabain binding to the Na + pump 163,164 and was antihypertensive in some experimental models of hypertension where ouabain-like factors were implicated 165–168 .…”

The negative inotropic action of canrenone is mediated by L‐type calcium current blockade and reduced intracellular calcium transients

“…The beneficial effect was initially attributed to the blockade of aldosterone receptor, but some studies have shown a direct effect of spironolactone and its derivative metabolites on cardiac excitation–contraction coupling (Coraboeuf and Deroubaix, 1974; Mugge et al. , 1984; Vassallo et al. , 1998; Cargnelli et al.…”

A low concentration of ouabain (0.18 µg/kg) enhances hypertension in spontaneously hypertensive rats by inhibiting the Na+ pump and activating the renin-angiotensin system

“…Previous reports have suggested that canrenone interacts with the digitalis receptor site of the Na + pump and antagonizes the binding of ouabain (19,27). Indeed, acute administration of canrenone blocks the positive inotropic effect of ouabain in isolated perfused hearts (18). To clarify this issue, we first tested the effects of canrenone or canrenone plus ouabain on arterial pressure.…”

“…To determine whether the effects of ouabain were caused by inhibition of the Na + pump activity, canrenone (1 mg/ kg) a blocker of ouabain effects, was used because of its antagonistic properties at the digitalis receptor site (18,19). This small concentration of canrenone was used to avoid the changes induced by larger concentrations in myocardial contractility, vascular tone or arterial blood pressure, as previously reported (18).…”

“…This small concentration of canrenone was used to avoid the changes induced by larger concentrations in myocardial contractility, vascular tone or arterial blood pressure, as previously reported (18). Also, two groups were used, one treated with canrenone and the other treated with canrenone plus ouabain.…”