Published Online
on January 19, 2004

A more recent version of this article appeared on January 27, 2004

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Submitted on December 16, 2002
Revised on August 12, 2003
Accepted on September 19, 2003

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, and 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.

^* To whom correspondence should be addressed. E-mail: francoise.pecker{at}im3.inserm.fr.

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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