Differential actions of eplerenone and spironolactone on the protective effect of testosterone against cardiomyocyte apoptosis in vitro.
OBJECTIVE
Testosterone deficiency is associated with a poor prognosis in patients with heart failure. It is not clear whether testosterone reduces cardiomyocyte apoptosis or whether the effect of spironolactone, an aldosterone receptor blocker with progestogenic and anti-androgen activity, differs from that of the selective aldosterone blocker eplerenone.


METHODS
Apoptosis induced by hyperosmotic stress in the embryonic rat heart cell line H9c2 was monitored by measuring cell viability, DNA fragmentation and caspase-3, -8 and -9 activation. The effect of testosterone was investigated in the presence or absence of spironolactone and eplerenone.


RESULTS
Exposure to sorbitol (0.6 M, 3 h) decreased cell viability and increased DNA fragmentation and caspase-3, -8 and -9 activation. These effects were all significantly reduced by testosterone, 100 nM (P< .01). Pretreatment with spironolactone, 10 .M, blocked the effects of testosterone, decreased cell viability (P< .01) and increased caspase activation (P< .01). In contrast, eplerenone, 10 .M, increased cell viability (P< .001) without altering the effect on caspase activation. These actions were not modified by the androgen receptor blocker flutamide. They were mediated by SAPK/JNK and ERK1/2 signaling pathways (P< .01).


CONCLUSIONS
Testosterone appears to have a protective effect against cardiomyocyte apoptosis which is antagonized by spironolactone but not by eplerenone. These effects await confirmation in in vivo models, but their presence could have clinical and therapeutic implications.
Sánchez-Más
Jesús
J
Unidad de Insuficiencia Cardiaca, Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca, Facultad de Medicina, Universidad de Murcia, El Palmar, Murcia, Spain.
Turpín
María C
MC
Lax
Antonio
A
Ruipérez
Juan A
JA
Valdés Chávarri
Mariano
M
Pascual-Figal
Domingo A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D000077545:Eplerenone; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D051381:Rats; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013739:Testosterone / Q000494:pharmacology*
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D013739:Testosterone; D000077545:Eplerenone