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


METHODS
Left ventricular papillary muscles and cardiomyocytes were isolated from male Wistar rats. Contractility of papillary muscles was assessed with force transducers, Ca(2+) transients by fluorescence and Ca(2+) fluxes by electrophysiological techniques.


RESULTS
Canrenone (300-600 micromol L(-1)) reduced developed tension, maximum rate of tension increase and maximum rate of tension decay of papillary muscles. In cardiomyocytes, canrenone (50 micromol L(-1)) reduced cell shortening and L-type Ca(2+) channel current, whereas steady-state activation and inactivation, and reactivation curves were unchanged. Canrenone also decreased the Ca(2+) content of the sarcoplasmic reticulum, intracellular Ca(2+) transient amplitude and intracellular diastolic Ca(2+) concentration. However, the time course of [Ca(2+)](i) decline during transients evoked by caffeine was not affected by canrenone.


CONCLUSIONS
Canrenone reduced L-type Ca(2+) channel current, amplitude of intracellular Ca(2+) transients and Ca(2+) content of sarcoplasmic reticulum in cardiomyocytes. These changes are likely to underlie the negative inotropic effect of canrenone.
Costa
A R
AR
Cardiology Division, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil. andrea.costa@case.edu
Torres
L B
LB
Medei
E
E
Ricardo
R A
RA
França
J P
JP
Smaili
S
S
Nascimento
J H M
JH
Oshiro
M E M
ME
Bassani
J W M
JW
Ferreira
A T
AT
Tucci
P J F
PJ
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D002192:Canrenone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013148:Spironolactone / Q000378:metabolism
D020746:Calcium Channels, L-Type; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D002110:Caffeine; D002192:Canrenone; D002118:Calcium