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(Circulation. 2004;110:2003-2009.)
© 2004 American Heart Association, Inc.

Hypertension

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

Marie Bourraindeloup, MD; Christophe Adamy, PhD; Gabriele Candiani, MSci; Michel Cailleret, MSci; Marie-Claude Bourin, PhD; Thierry Badoual, MD; Jin Bo Su, PhD; Sylviane Adubeiro; Françoise Roudot-Thoraval, MD; Jean-Luc Dubois-Rande, MD, PhD; Luc Hittinger, MD, PhD; Françoise Pecker, PhD

From the Fédération de Cardiologie, Hôpital Henri Mondor (M.B., J.-L.D.-R., L.H.); INSERM Unité 581, Hôpital Henri Mondor (C.A., G.C., M.C., M.-C.B., S.A., F.P.); INSERM Unité 400, Faculté de Médecine (T.B., J.B.S., J.-L.D.-R., L.H.); and Service de Santé Publique, Hôpital Henri Mondor (F.R.-T.), Créteil, France.

Correspondence to Françoise Pecker, INSERM Unité 581, Hôpital Henri Mondor, 94010 Créteil, France. E-mail francoise.pecker{at}im3.inserm.fr

Received May 10, 2004; revision received July 13, 2004; accepted July 15, 2004.

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- (TNF-).

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- 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- 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- in cardiac failure and that TNF- antagonism may be achieved by glutathione supplementation.

Key Words: tumor necrosis factor • acetylcysteine • glutathione • heart failure • N^G-nitroarginine methyl ester

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