N-acetylcysteine treatment normalizes serum tumor necrosis factor-α level and hinders the progression of cardiac injury in hypertensive rats

• Published in: Circulation (New York, N.Y.) Vol. 110; no. 14; pp. 2003 - 2009
• Main Authors: BOURRAINDELOUP, Marie, ADAMY, Christophe, HITTINGER, Luc, PECKER, Francoise, CANDIANI, Gabriele, CAILLERET, Michel, BOURIN, Marie-Claude, BADOUAL, Thierry, JIN BO SU, ADUBEIRO, Sylviane, ROUDOT-THORAVAL, Francoise, DUBOIS-RANDE, Jean-Luc
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 05.10.2004
• Subjects: Acetylcysteine - pharmacology; Acetylcysteine - therapeutic use; Animals; Antihypertensive agents; Antioxidants - pharmacology; Antioxidants - therapeutic use; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Collagen - analysis; Coronary heart disease; Disease Progression; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Evaluation, Preclinical; Glutathione - deficiency; Glutathione - physiology; Heart; Heart Ventricles - chemistry; Hypertension - blood; Hypertension - chemically induced; Hypertension - complications; Hypertension - drug therapy; Male; Matrix Metalloproteinase 2 - analysis; Matrix Metalloproteinase 9 - analysis; Medical sciences; Myocardial Contraction; Myocardium - metabolism; NG-Nitroarginine Methyl Ester - toxicity; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Oxidative Stress - drug effects; Pharmacology. Drug treatments; Rats; Rats, Wistar; Sodium Chloride, Dietary - toxicity; Sphingomyelin Phosphodiesterase - metabolism; Tumor Necrosis Factor-alpha - analysis; Ultrasonography; Ventricular Dysfunction, Left - blood; Ventricular Dysfunction, Left - diagnostic imaging; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - prevention & control; Ventricular Remodeling - drug effects; Hypertension; heart failure; Thiol; Rat; NG-nitroarginine methyl ester; glutathione; Cytokine; Rodentia; Acetylcysteine; Cardiovascular disease; Mucolytic; Vertebrata; Mammalia; Treatment; tumor necrosis factor; Animal; Tumor necrosis factor α
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000143630.14515.7C

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-alpha (TNF-alpha). 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/L-NAME administration. Importantly, increase in serum TNF-alpha 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-alpha level, and limited activation of matrix metalloproteinases -2 and -9 and collagen deposition in LV tissues. These findings suggest that glutathione status determines the adverse effects of TNF-alpha in cardiac failure and that TNF-alpha antagonism may be achieved by glutathione supplementation.