Negative inotropic effects of aldosterone antagonists in isolated human and guinea-pig ventricular heart muscle.
The effects of K+-canrenoate (Aldactone pro inj.) and its metabolite canrenone on isometric force of contraction were measured in isolated guinea-pig and human papillary muscle preparations driven electrically at a frequency of 1 Hz. In guinea-pig hearts both substances exerted a concentration-dependent negative inotropic effect; the IC50 of K+-canrenoate and canrenone were 129 +/- 22 mumol l-1 (n = 5) and 85 +/- 11 mumol l-1 (n = 12), respectively. At the maximally tested concentration canrenone (250 mumol l-1) and K+-canrenoate (1,000 mumol l-1) reduced force of contraction by 68 +/- 4% (n = 12) and 83 +/- 3% (n = 5), respectively. The negative inotropic effects of canrenone and K+-canrenoate were not affected by 10 mumol l-1 atropine. The negative inotropic effect of canrenone was also not affected by 14 mumol l-1 aldosterone, but canrenone (10 mumol l-1 diminished the maximal positive inotropic effect of dihydro-ouabain from 554 +/- 75% (n = 4) to 269 +/- 39% (n = 4) of the predrug value. In human heart muscles K+-canrenoate and canrenone also exerted a concentration-dependent negative inotropic effect. K+-canrenoate (1,000 mumol l-1) and canrenone (250 mumol l-1) reduced force of contraction by 57 +/- 7% (n = 8) and 67 +/- 2% (n = 6), respectively. A positive inotropic effect of both substances was never observed. It is concluded that the improvement of cardiac performance after application of aldosterone antagonists observed in patients cannot be explained by a direct effect on the heart. K+-canrenoate and canrenone are devoid of any direct cardiotonic action. Instead, K+-canrenoate and canrenone have direct negative inotropic effects at high concentrations.
D000818:Animals; D002191:Canrenoic Acid / Q000494:pharmacology; D002192:Canrenone / Q000494:pharmacology; D004347:Drug Interactions; D006168:Guinea Pigs; D006352:Heart Ventricles; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000031:analogs & derivatives / Q000378:metabolism
D000451:Mineralocorticoid Receptor Antagonists; C000977:dihydroouabain; D010042:Ouabain; D002192:Canrenone; D002191:Canrenoic Acid