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(Circulation. 2004;109:406-411.)
© 2004 American Heart Association, Inc.

Basic Science Reports

N-Acetylcysteine Prevents the Deleterious Effect of Tumor Necrosis Factor- on Calcium Transients and Contraction in Adult Rat Cardiomyocytes

Michel Cailleret, MSci^*; Aïssata Amadou, MSci^*; Nathalie Andrieu-Abadie, PhD; Artur Nawrocki, PhD; Christophe Adamy, PhD; Bouziane Ait-Mamar, MD; François Rocaries, PhD; Martin Best-Belpomme, MD, PhD; Thierry Levade, MD, PhD; Catherine Pavoine, PhD; Françoise Pecker, PhD

From INSERM Unité 581, Hôpital Henri Mondor, Créteil (M.C., A.A., A.N., C.A., B.A.-M., M.B.-B., C.P., F.P.), INSERM Unité 466, CHU Rangueil, Toulouse (N.A.-A., T.L.), and Ecole Superieure d’Ingenieurs en Electrotechnique et Electronique, Noisy-Le-Grand (F.R.), France. Dr Nawrocki is now at the Medical Academy of Bialystok, Department of Physiology, Bialystok, Poland.

Correspondence to Françoise Pecker, INSERM Unité 99, Hôpital Henri Mondor, 94010 Créteil, France. E-mail francoise.pecker{at}im3.inserm.fr

Received December 16, 2002; de novo received August 12, 2003; accepted September 19, 2003.

Background— The negative effect of tumor necrosis factor- (TNF-) on heart contraction, which is mediated by sphingosine, is a major component in heart failure. Because the cellular level of glutathione may limit sphingosine production via the inhibition of the Mg-dependent neutral sphingomyelinase (N-SMase), we hypothesized that cardiac glutathione status might determine the negative contractile response to TNF-.

Methods and Results— We examined the effects of TNF- in isolated cardiomyocytes obtained from control rats or rats that were given the glutathione precursor N-acetylcysteine (NAC, 100 mg IP per animal). In cardiomyocytes obtained from control rats, 25 ng/mL TNF- increased reactive oxygen species generation and N-SMase activity (500% and 34% over basal, respectively) and decreased the amplitude of [Ca²⁺]_i in response to electrical stimulation (22% below basal). NAC treatment increased cardiac glutathione content by 42%. In cardiomyocytes obtained from NAC-treated rats, 25 ng/mL TNF- had no effect on reactive oxygen species production or N-SMase activity but increased the amplitude of [Ca²⁺]_i transients and contraction in response to electrical stimulation by 40% to 50% over basal after 20 minutes. This was associated with a hastened relaxation (20% reduction in t_1/2 compared with basal) and an increased phosphorylation of both Ser¹⁶- and Thr¹⁷-phospholamban residues (260% and 115% of maximal isoproterenol effect, respectively).

Conclusions— It is concluded that cardiac glutathione status, by controlling N-SMase activation, determines the severity of the adverse effects of TNF- on heart contraction. Glutathione supplementation may therefore provide therapeutic benefits for vulnerable hearts.

Key Words: tumor necrosis factor- • phospholamban • N-acetylcysteine • glutathione • sphingomyelinase

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