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.

N-Acetylcysteine Suppresses the Progression of Ventricular Remodeling in Acute Myocarditis - Studies in an Experimental Autoimmune Myocarditis (EAM) Model -

“…[24][25][26][27] However, at least in the present study, the use of NAC suppressed the progression of myocarditis in a rat EAM model. Theoretically, the primary antioxidant effects of NAC reduce the ROS production and inhibit the activation of nuclear factor-κ B (NFκB) by replenishing glutathione contents.…”

Additive Effect of TAK-491, a New Angiotensin Receptor Blocker, and Pioglitazone, in Reducing Myocardial Infarct Size

“…In the present study, we observed that PIO, and especially TAK, increased Akt phosphorylation after IR injury. Previous studies have shown that ARBs increase Akt phosphorylation in the hearts [28], leading to eNOS phosphorylation.…”

“…Losartan inhibits upregulation of iNOS in the cardiomyopathy hamster heart while it increases eNOS phosphorylation [28]. Therefore, it seems that inhibition of iNOS may be a class effect of ARBs.…”

Aliskiren and Valsartan Reduce Myocardial AT1 Receptor Expression and Limit Myocardial Infarct Size in Diabetic Mice

“…Previously, we showed that azilsartan (TAK-491) reduced IS and increased Akt phosphorylation following ischemiareperfusion in non-diabetic rats [18]. Previous studies have also shown that ARBs increase Akt phosphorylation [27,[54][55][56] and several studies have shown that AL increases Akt phosphorylation in various experimental models [52,[57][58][59][60]. Thus, increased phosphorylation of Akt may mediate the protective effects of VA and AL against ischemia-reperfusion injury.…”