title: N-acetylcysteine abolishes the protective effect of losartan against left ventricular remodeling in cardiomyopathy hamster.
abstract: Oxidative stress mediated by activation of angiotensin II type-1 receptor (AT(1)R) plays a crucial role in the progression of heart failure. We investigated the effect of N-acetylcysteine (NAC) and an AT(1)R blocker on oxidative stress and left ventricular (LV) remodeling in BIO14.6 cardiomyopathy hamsters. The cardiomyopathy hamsters were treated with NAC or the AT(1)R blocker losartan for 20 weeks. Although NAC and losartan inhibited oxidative stress and upregulation of iNOS in the cardiomyopathy hamster heart, only losartan inhibited LV chamber dilation, myocardial fibrosis, and LV dysfunction in the cardiomyopathy hamster. Co-treatment with NAC abolished the protective effect of losartan against LV remodeling associated with inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt and eNOS activation. An iNOS inhibitor 1400W or a nonselective NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) exacerbated LV remodeling in the cardiomyopathy hamster. However, L-NAME but not 1400W abrogated losartan-mediated inhibition of LV remodeling. These results suggest that redox-sensitive upregulation of iNOS plays a crucial role in preventing LV remodeling in the BIO14.6 cardiomyopathy hamster. Losartan inhibits LV remodeling by switching the cardioprotective mechanism from iNOS- to eNOS-dependence, but NAC abolishes the protective effect of losartan by inhibiting redox-sensitive activation of PI3K/Akt and eNOS in the cardiomyopathy hamster.
authors.affiliation: The Second Department of Internal Medicine, Division of Cardiology, Kansai Medical University, Moriguchi City, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Matsuhisa
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Toru
authors.initials: T
authors.lastname: Okazaki
authors.forename: Koji
authors.initials: K
authors.lastname: Yamashita
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Akita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sato
authors.forename: Akira
authors.initials: A
authors.lastname: Moriguchi
authors.forename: Toshiji
authors.initials: T
authors.lastname: Iwasaka
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000578:Amidines / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006224:Cricetinae; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D016166:Free Radical Scavengers / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D000578:Amidines; D047228:Angiotensin II Type 1 Receptor Blockers; D001596:Benzylamines; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester; D000111:Acetylcysteine