title: Effect of tumor necrosis factor-alpha on endothelial and inducible nitric oxide synthase messenger ribonucleic acid expression and nitric oxide synthesis in ischemic and nonischemic isolated rat heart.
abstract: OBJECTIVE
  The present study aimed to investigate the influence of endogenous tumor necrosis factor-alpha (TNF-alpha) that was synthesized during ischemia and exogenous TNF-alpha on endothelial and inducible nitric oxide synthase (eNOS and iNOS) messenger ribonucleic acid (mRNA) expression and nitric oxide (NO) production in the isolated rat heart.
  
  
  BACKGROUND
  Tumor necrosis factor-alpha is recognized as being a proinflammatory cytokine with a significant cardiodepressant effect. One of the proposed mechanisms for TNF-alpha-induced cardiac contractile dysfunction is increased NO production via iNOS mRNA upregulation, but the role of NO in TNF-alpha-induced myocardial dysfunction is highly controversial.
  
  
  METHODS
  Isolated rat hearts studied by a modified Langendorff model were randomly divided into subgroups to investigate the effect of 1-h global cardioplegic ischemia or the effect of 1-h perfusion with exogenous TNF-alpha on the expression of eNOS mRNA and iNOS mRNA and on NO production.
  
  
  RESULTS
  After 1 h of ischemia, there were significant increases in TNF levels in the effluent (from hearts), and eNOS mRNA expression had declined (from 0.91 +/- 0.08 to 0.68 +/- 0.19, p < 0.001); but there were no changes in iNOS mRNA expression, and NO was below detectable levels. Perfusion of isolated hearts with TNF-alpha had a cardiodepressant effect and decreased eNOS mRNA expression to 0.67 +/- 0.04 (p < 0.002). Inducible nitric oxide synthase mRNA was unchanged, and NO was below detectable levels.
  
  
  CONCLUSIONS
  We believe this is the first study to directly show that TNF-alpha does not increase NO synthesis and release but does downregulate eNOS mRNA in the ischemic and nonischemic isolated rat heart.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Paz
authors.forename: Inna
authors.initials: I
authors.lastname: Frolkis
authors.forename: Dimitri
authors.initials: D
authors.lastname: Pevni
authors.forename: Itzhak
authors.initials: I
authors.lastname: Shapira
authors.forename: Yael
authors.initials: Y
authors.lastname: Yuhas
authors.forename: Adrian
authors.initials: A
authors.lastname: Iaina
authors.forename: Yoram
authors.initials: Y
authors.lastname: Wollman
authors.forename: Tamara
authors.initials: T
authors.lastname: Chernichovski
authors.forename: Nahum
authors.initials: N
authors.lastname: Nesher
authors.forename: Chaim
authors.initials: C
authors.lastname: Locker
authors.forename: Rephael
authors.initials: R
authors.lastname: Mohr
authors.forename: Gideon
authors.initials: G
authors.lastname: Uretzky
mesh_terms: D000818:Animals; D017931:DNA Primers; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat