SMALL DOSES OF CANRENONE BLOCK THE EFFECTS OF OUABAIN ON THE MECHANICAL-ACTIVITY OF THE HEART AND VESSELS OF THE RAT

Canrenone has been described as an antihypertensive drug that blocks e ndogenous ouabain effects in volume-dependent hypertensive models. Con sidering that some canrenone metabolites may be putative mutagenic fac tors, therapeutic dose reduction might be advantageous if the blockade of ouabain effects is maintained. In this study, the effects of low d oses 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, an d 5 mg/ml) produced a dose-dependent negative inotropic effect in papi llary muscles contracting isometrically and blocked the positive inotr opic effect produced by 660 mu M ouabain. In Langendorff-perfused hear ts beating spontaneously, a low concentration of canrenone (10 mu g/ml ) increased the isovolumic systolic pressure obtained at several diast olic pressures. Higher concentrations of canrenone (20, 30 mu g/ml) br oght the isovolumic pressure toward control values, and 100 mu g/ml ca nrenone produced an isovolumic pressure reduction. In these preparatio ns, 20 mu g/ml canrenone reduced significantly the positive inotropic effects of 100 mu M ouabain. Investigating the vascular smooth muscle reactivity to phenylephrine (PE; 0.5, 1, and 2 mu g bolus injections) in the perfused rat-tail vascular bed, it was observed that canrenone blocked completely the enhancement,lf PE presser effect produced by 1- h treatment with 100 mu M 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 1 8 mu g/kg ouabain on PE reactivity. In conclusion, results presented h ere suggest that canrenone may block ouabain effects at very low conce ntrations. It blocked myocardial positive inotropic effects of ouabain on both papillary muscle and perfused hearts, and the sensitization o f PE presser effects. The results also suggest that canrenone at very small doses might be used to reduce arterial blood pressure in hyperte nsive conditions accompanied by increased ouabain plasma levels as the main therapeutic procedure or as an adjunct treatment to prevent ouab ain sensitizing effects on presser responses.