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

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Background and purpose:Adding spironolactone to standard therapy in heart failure reduces morbidity and mortality, but the underlying mechanisms are not fully understood. We analysed the effect of canrenone, the major active metabolite of spironolactone, on myocardial contractility and intracellular calcium homeostasis.Experimental approach:Left ventricular papillary muscles and cardiomyocytes were isolated from male Wistar rats. Contractility of papillary muscles was assessed with force transducers, Ca2+ transients by fluorescence and Ca2+ fluxes by electrophysiological techniques.Key results:Canrenone (300–600 μmol·L−1) reduced developed tension, maximum rate of tension increase and maximum rate of tension decay of papillary muscles. In cardiomyocytes, canrenone (50 μmol·L−1) reduced cell shortening and L-type Ca2+ channel current, whereas steady-state activation and inactivation, and reactivation curves were unchanged. Canrenone also decreased the Ca2+ content of the sarcoplasmic reticulum, intracellular Ca2+ transient amplitude and intracellular diastolic Ca2+ concentration. However, the time course of [Ca2+]i decline during transients evoked by caffeine was not affected by canrenone.Conclusion and implications:Canrenone reduced L-type Ca2+ channel current, amplitude of intracellular Ca2+ transients and Ca2+ content of sarcoplasmic reticulum in cardiomyocytes. These changes are likely to underlie the negative inotropic effect of canrenone.

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