Comparative evaluation of torasemide and spironolactone on adverse cardiac remodeling in a rat model of dilated cardiomyopathy

BACKGROUND Chronic heart failure (CHF) involves fluid retention and volume overload, leading to impaired cardiac function. In these conditions, diuretic agents are most commonly used to treat edema and thereby reducing the volume load on the failing heart. There are several other beneficial effects of diuretics apart from their action on urinary excretion. METHODS To identify the effects of diuretic agents on adverse cardiac remodeling in CHF, this study was carried out, where we have compared the effects of torasemide and spironolactone in a rat model of dilated cardiomyopathy induced by porcine cardiac myosin-mediated experimental autoimmune myocarditis. RESULTS Cardiac protein expression levels of inflammation, endoplasmic reticulum stress, and fibrosis markers were upregulated in the hearts of CHF rats, while treatment with either torasemide or spironolactone has downregulated their expression. The effect produced by spironolactone on cardiac fibrosis markers was comparably lesser than torasemide. Further, immunohistochemical analysis and histopathological studies have provided evidence to confirm the beneficial effects of these drugs on adverse cardiac remodeling in rats with CHF. CONCLUSION Torasemide treatment has benefits against adverse cardiac remodeling in CHF rats, which was better than the protection offered by spironolactone.

[1]  Kenji Suzuki,et al.  Comparative effects of torasemide and furosemide on gap junction proteins and cardiac fibrosis in a rat model of dilated cardiomyopathy , 2017, BioFactors.

[2]  Kenji Suzuki,et al.  Curcumin alleviates renal dysfunction and suppresses inflammation by shifting from M1 to M2 macrophage polarization in daunorubicin induced nephrotoxicity in rats. , 2016, Cytokine.

[3]  R. D. de Boer,et al.  The fibrosis-cell death axis in heart failure , 2016, Heart Failure Reviews.

[4]  J. Sowers,et al.  Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females , 2015, Hypertension.

[5]  Kenji Suzuki,et al.  Naringenin ameliorates daunorubicin induced nephrotoxicity by mitigating AT1R, ERK1/2-NFκB p65 mediated inflammation. , 2015, International immunopharmacology.

[6]  R. Hartmann,et al.  Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice. , 2015, Journal of molecular and cellular cardiology.

[7]  K. Anstrom,et al.  A reappraisal of loop diuretic choice in heart failure patients. , 2015, American heart journal.

[8]  L. Rashed,et al.  Effect of aliskiren, telmisartan and torsemide on cardiac dysfunction in l-nitro arginine methyl ester (l-NAME) induced hypertension in rats , 2014, Journal of advanced research.

[9]  Kenji Suzuki,et al.  Comparative evaluation of torasemide and furosemide on rats with streptozotocin-induced diabetic nephropathy. , 2014, Experimental and molecular pathology.

[10]  M. Nagata,et al.  Involvement of AMPK and MAPK signaling during the progression of experimental autoimmune myocarditis in rats and its blockade using a novel antioxidant. , 2012, Experimental and molecular pathology.

[11]  M. Nagata,et al.  Beneficial effects of edaravone, a novel antioxidant, in rats with dilated cardiomyopathy , 2012, Journal of cellular and molecular medicine.

[12]  Kenji Suzuki,et al.  Candesartan cilexetil protects from cardiac myosin induced cardiotoxicity via reduction of endoplasmic reticulum stress and apoptosis in rats: involvement of ACE2-Ang (1-7)-mas axis. , 2012, Toxicology.

[13]  M. Nagata,et al.  Quercetin offers cardioprotection against progression of experimental autoimmune myocarditis by suppression of oxidative and endoplasmic reticulum stress via endothelin-1/MAPK signalling , 2012, Free radical research.

[14]  Kenji Suzuki,et al.  Regulation of inflammation and myocardial fibrosis in experimental autoimmune myocarditis. , 2011, Inflammation & allergy drug targets.

[15]  I. Komuro,et al.  Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum–Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload , 2010, Circulation.

[16]  C. Acuña.  [Update: prolonged-release torasemide]. , 2010, Drugs of today.

[17]  K. Yamaguchi,et al.  [Effects of various diuretics on cardiac function in rats with heart failure]. , 2009, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[18]  G. Fishman,et al.  Gap Junction Remodeling and Spironolactone-Dependent Reverse Remodeling in the Hypertrophied Heart , 2009, Circulation research.

[19]  Arantxa González,et al.  Impact of Treatment on Myocardial Lysyl Oxidase Expression and Collagen Cross-Linking in Patients With Heart Failure , 2009, Hypertension.

[20]  M. Hori,et al.  Overexpression of endoplasmic reticulum-resident chaperone attenuates cardiomyocyte death induced by proteasome inhibition. , 2008, Cardiovascular research.

[21]  Kenji Suzuki,et al.  Torasemide, a long-acting loop diuretic, reduces the progression of myocarditis to dilated cardiomyopathy. , 2008, European journal of pharmacology.

[22]  Kenji Suzuki,et al.  Comparative effects of torasemide and furosemide in rats with heart failure. , 2008, Biochemical pharmacology.

[23]  Arantxa González,et al.  Identification of a potential cardiac antifibrotic mechanism of torasemide in patients with chronic heart failure. , 2007, Journal of the American College of Cardiology.

[24]  N. Mochizuki,et al.  Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome , 2007, Circulation.

[25]  T. Kato,et al.  Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Failure in Low-Aldosterone Hypertensive Rats , 2006, Hypertension.

[26]  M. Čolić,et al.  Suppression of experimental autoimmune myocarditis by sodium fusidate (fusidin). , 2005, Pharmacological research.

[27]  M. Hori,et al.  Prolonged Endoplasmic Reticulum Stress in Hypertrophic and Failing Heart After Aortic Constriction: Possible Contribution of Endoplasmic Reticulum Stress to Cardiac Myocyte Apoptosis , 2004, Circulation.

[28]  Arantxa González,et al.  Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure. , 2004, Journal of the American College of Cardiology.

[29]  R. Weiss,et al.  Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[30]  B. Maisch,et al.  Pathophysiology of Cardiac Inflammation: Molecular Mechanisms , 2002, Herz.

[31]  J. Funder.  MINERALOCORTICOIDS AND CARDIAC FIBROSIS: THE DECADE IN REVIEW , 2001, Clinical and experimental pharmacology & physiology.

[32]  C. Brilla,et al.  [Spironolactone: renaissance of anti-aldosterone therapy in heart failure?]. , 1997, Praxis.

[33]  Brater Dc.  Benefits and risks of torasemide in congestive heart failure and essential hypertension. , 1996 .

[34]  Kenichi Watanabe,et al.  A novel phenylpyridazinone, T-3999, reduces the progression of autoimmune myocarditis to dilated cardiomyopathy , 2010, Heart and Vessels.

[35]  D. Brater.  Benefits and Risks of Torasemide in Congestive Heart Failure and Essential Hypertension , 1996, Drug safety.