The diuretic torasemide does not prevent aldosterone-mediated mineralocorticoid receptor activation in cardiomyocytes

• Published in: PloS one 2013-09, Vol.8 (9), p.e73737
• Main Authors: Gravez, Basile, Tarjus, Antoine, Jimenez-Canino, Ruben, El Moghrabi, Soumaya, Messaoudi, Smail, Alvarez de la Rosa, Diego, Jaisser, Frederic
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Aldosterone; Aldosterone - pharmacology; Animal models; Animals; Cardiomyocytes; Cardiovascular diseases; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cercopithecus aethiops; Comparative analysis; Coronary artery disease; COS Cells; Diuretics; Diuretics - pharmacology; Dogs; Fibrosis; Genes; Glucocorticoids; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Health aspects; Heart attacks; Heart cells; Heart diseases; Heart failure; Humans; Hypertension; Immediate-Early Proteins - genetics; Kidneys; Life Sciences; Luciferases - genetics; Luciferases - metabolism; Mice; Microscopy, Confocal; Mineralocorticoid Receptor Antagonists - pharmacology; Morbidity; Mortality; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Nuclear transport; Orosomucoid - genetics; Pharmaceutical sciences; Pharmacology; Physiology; Plasminogen Activator Inhibitor 1 - genetics; Polyamide-imides; Protein-Serine-Threonine Kinases - genetics; Proteins; Rats; Reabsorption; Receptor mechanisms; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - metabolism; Reporter gene; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Serpins - genetics; Signaling; Sodium; Spironolactone; Spironolactone - pharmacology; Steroids (Organic compounds); Sulfonamides - pharmacology; Tenascin; Tenascin - genetics; Transcriptional Activation - drug effects; Translocation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0073737

Aldosterone binds to the mineralocorticoid receptor (MR) and exerts pleiotropic effects beyond enhancing renal sodium reabsorption. Excessive mineralocorticoid signaling is deleterious during the evolution of cardiac failure, as evidenced by the benefits provided by adding MR antagonists (MRA) to standard care in humans. In animal models of cardiovascular diseases, MRA reduce cardiac fibrosis. Interestingly diuretics such as torasemide also appear efficient to improve cardiovascular morbidity and mortality, through several mechanisms. Among them, it has been suggested that torasemide could block aldosterone binding to the MR. To evaluate whether torasemide acts as a MRA in cardiomyocytes, we compared its effects with a classic MRA such as spironolactone. We monitored ligand-induced nuclear translocation of MR-GFP and MR transactivation activity in the cardiac-like cell line H9C2 using a reporter gene assay and known endogenous aldosterone-regulated cardiac genes. Torasemide did not modify MR nuclear translocation. Aldosterone-induced MR transactivation activity was reduced by the MRA spironolactone, not by torasemide. Spironolactone blocked the induction by aldosterone of endogenous MR-responsive genes (Sgk-1, PAI-1, Orosomucoid-1, Rgs-2, Serpina-3, Tenascin-X), while torasemide was ineffective. These results show that torasemide is not an MR antagonist; its association with MRA in heart failure may however be beneficial, through actions on complementary pathways.