title: N-acetylcysteine prevents the deleterious effect of tumor necrosis factor-(alpha) on calcium transients and contraction in adult rat cardiomyocytes.
abstract: BACKGROUND
  The negative effect of tumor necrosis factor-alpha (TNF-alpha) 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-alpha.
  
  
  RESULTS
  We examined the effects of TNF-alpha 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-alpha increased reactive oxygen species generation and N-SMase activity (500% and 34% over basal, respectively) and decreased the amplitude of [Ca(2+)](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-alpha had no effect on reactive oxygen species production or N-SMase activity but increased the amplitude of [Ca(2+)](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 Ser(16)- and Thr(17)-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-alpha on heart contraction. Glutathione supplementation may therefore provide therapeutic benefits for vulnerable hearts.
authors.affiliation: INSERM Unité 99, Hôpital Henri Mondor, 94010 Créteil, France. francoise.pecker@im3.inserm.fr
authors.forename: Michel
authors.initials: M
authors.lastname: Cailleret
authors.forename: Aïssata
authors.initials: A
authors.lastname: Amadou
authors.forename: Nathalie
authors.initials: N
authors.lastname: Andrieu-Abadie
authors.forename: Artur
authors.initials: A
authors.lastname: Nawrocki
authors.forename: Christophe
authors.initials: C
authors.lastname: Adamy
authors.forename: Bouziane
authors.initials: B
authors.lastname: Ait-Mamar
authors.forename: François
authors.initials: F
authors.lastname: Rocaries
authors.forename: Martin
authors.initials: M
authors.lastname: Best-Belpomme
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: Catherine
authors.initials: C
authors.lastname: Pavoine
authors.forename: Françoise
authors.initials: F
authors.lastname: Pecker
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000099211:Phospholamban
chemical_list: D000111:Acetylcysteine; D002118:Calcium; D002135:Calcium-Binding Proteins; D005978:Glutathione; D017382:Reactive Oxygen Species; D013108:Sphingomyelin Phosphodiesterase; D014409:Tumor Necrosis Factor-alpha; D000099211:Phospholamban; C017514:S-methyl glutathione