N -Acetylcysteine Treatment Normalizes Serum Tumor Necrosis Factor-α Level and Hinders the Progression of Cardiac Injury in Hypertensive Rats

Abstract

Background— Studies in isolated cardiomyocytes showed that replenishment in cellular glutathione, achieved with the glutathione precursor N -acetylcysteine (NAC), abrogated deleterious effects of tumor necrosis factor-α (TNF-α). Methods and Results— We examined the ability of NAC to limit the progression of cardiac injury in the rat model of hypertension, induced by the nitric oxide synthase inhibitor N G -nitro- l -arginine methyl ester (L-NAME) (50 mg/kg per day SC) and high-salt diet (HS) (8% NaCl). Four-week HS/L-NAME administration induced hypertension (193±8 versus 122±4 mm Hg for low-salt diet [LS] group) and left ventricular (LV) dysfunction, revealed by echocardiography and characterized by decreased LV shortening fraction (38±2% versus 49±4% for LS group; P <0.05) and decreased LV posterior wall thickening (49±3% versus 70±4% for LS group; P <0.05). LV dysfunction worsened further after 6-week HS/LNAME administration. Importantly, increase in serum TNF-α level was strongly correlated with shortening fraction decrease and cardiac glutathione depletion. NAC (75 mg/d) was given as a therapeutic treatment in a subgroup of HS/L-NAME animals during weeks 5 and 6 of HS/L-NAME administration. NAC treatment, which replenished cardiac glutathione, had no effect on hypertension but reduced LV remodeling and dysfunction, normalized serum TNF-α level, and limited activation of matrix metalloproteinases -2 and -9 and collagen deposition in LV tissues. Conclusions— These findings suggest that glutathione status determines the adverse effects of TNF-α in cardiac failure and that TNF-α antagonism may be achieved by glutathione supplementation.