title: Non-genomic effects of spironolactone and eplerenone in cardiomyocytes of neonatal Wistar rats: do they evoke cardioprotective pathways?
abstract: Mineralocorticoid receptor (MR) antagonists of aldosterone (spironolactone and eplerenone) display beneficial effects in the treatment of cardiopathies; however, many of these responses are independent of this antagonism. The mechanisms of action of these drugs are not well known; few studies have comparatively evaluated whether eplerenone as well as spironolactone display cardioprotective effects independent of the blockade of aldosterone. To study these mechanisms, which lead to cardioprotective responses, and to evaluate comparatively their effects in vitro, we have evaluated the proliferative effect of spironolactone and eplerenone in primary culture of cardiomyocytes and fibroblasts of neonatal Wistar rats in the presence and absence of aldosterone. Spironolactone and eplerenone promoted proliferation of cardiomyocyte even in the absence of aldosterone, suggesting a signaling pathway independent of the antagonism over aldosterone. Spironolactone was able to reduce the proliferation of fibroblasts and to reverse the proliferation promoted by aldosterone, which was also displayed by eplerenone. To elucidate the biochemical pathways evoked by these drugs, we sought to analyze Ca(2+), cAMP, and cGMP, and the activity of PKC and ERK1/2. Spironolactone and eplerenone increased the levels of Ca(2+), cGMP and activity of ERK 1/2, and reversed the action of aldosterone on the activity of PKC and ERK1/2. Interestingly, only spironolactone increased the levels of cAMP. Our data support the fact that in addition to aldosterone, both spironolactone and eplerenone display rapid responses (non-genomic) such as an increase on cAMP, Ca(2+), and cGMP by spironolactone, and Ca(2+) and cGMP by eplerenone. We have observed a more consistent cardioprotection promoted by spironolactone; however, these effects have yet to be tested clinically. Therefore, our data show that these drugs do not only act as an antagonist of MR, but could lead to a new pharmacological classification of these drugs.
authors.affiliation: a Laboratory of Hypertesion, Research Center in Biological Science (NUPEB), Institute of Exact and Biological Sciences (ICEB), Federal University of Ouro Preto (UFOP), Campus Morro do Cruzeiro, 35400-000 Ouro Preto, Minas Gerais, Brazil.
authors.forename: Milla Marques
authors.initials: MM
authors.lastname: Hermidorff
authors.forename: Gabriela de Oliveira
authors.initials: Gde O
authors.lastname: Faria
authors.forename: Gabriela de Cassia Sousa
authors.initials: Gde C
authors.lastname: Amâncio
authors.forename: Leonardo Vinícius Monteiro
authors.initials: LV
authors.lastname: de Assis
authors.forename: Mauro César
authors.initials: MC
authors.lastname: Isoldi
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D000077545:Eplerenone; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D000242:Cyclic AMP; D011493:Protein Kinase C; D006152:Cyclic GMP; D002118:Calcium
keywords: cardio-protection; cardiomyocytes; cardioprotection; eplerenone; fibroblastes; fibroblasts; sentiers de signalisation; signaling pathways; spironolactone; spironolactone et éplérénone