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  • Title: N-acetylcysteine treatment normalizes serum tumor necrosis factor-alpha level and hinders the progression of cardiac injury in hypertensive rats.
    Author: Bourraindeloup M, Adamy C, Candiani G, Cailleret M, Bourin MC, Badoual T, Su JB, Adubeiro S, Roudot-Thoraval F, Dubois-Rande JL, Hittinger L, Pecker F.
    Journal: Circulation; 2004 Oct 05; 110(14):2003-9. PubMed ID: 15451797.
    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-alpha (TNF-alpha). 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/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. CONCLUSIONS: 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.
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