TNF-alpha and myocardial depression in endotoxemic rats: temporal discordance of an obligatory relationship.
Exogenous tumor necrosis factor-alpha (TNF-alpha) induces delayed myocardial depression in vivo but promotes rapid myocardial depression in vitro. The temporal relationship between endogenous TNF-alpha and endotoxemic myocardial depression is unclear, and the role of TNF-alpha in this myocardial disorder remains controversial. Using a rat model of endotoxemia not complicated by shock, we sought to determine 1) the temporal relationship of changes in circulating and myocardial TNF-alpha with myocardial depression, 2) the influences of protein synthesis inhibition or immunosuppression on TNF-alpha production and myocardial depression, and 3) the influence of neutralization of TNF-alpha on myocardial depression. Rats were treated with lipopolysaccharide (LPS, 0.5 mg/kg ip). Circulating and myocardial TNF-alpha increased at 1 and 2 h, whereas myocardial contractility was depressed at 4 and 6 h. Pretreatment with cycloheximide or dexamethasone abolished the increase in circulating and myocardial TNF-alpha and preserved myocardial contractile function. Similarly, treatment with TNF binding protein immediately after LPS prevented myocardial depression. We conclude that endogenous TNF-alpha mediates delayed myocardial depression in endotoxemic rats and that inhibition of TNF-alpha production or neutralization of TNF-alpha preserves myocardial contractile function in endotoxemia.
Meng
X
X
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Ao
L
L
Meldrum
D R
DR
Cain
B S
BS
Shames
B D
BD
Selzman
C H
CH
Banerjee
A
A
Harken
A H
AH
D000704:Analysis of Variance; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D019446:Endotoxemia / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide