TNF-ALPHA AND MYOCARDIAL DEPRESSION IN ENDOTOXEMIC RATS - TEMPORAL DISCORDANCE OF AN OBLIGATORY RELATIONSHIP

Exogenous tumor necrosis factor-alpha (TNF-alpha) induces delayed myoc ardial depression in vivo but promotes rapid myocardial depression in vitro. The temporal relationship between endogenous TNF-alpha and endo toxemic 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 te mporal relationship of changes in circulating and myocardial TNF-alpha with myocardial depression, 2) the influences of protein synthesis in hibition or immunosuppression on TNF-alpha production and myocardial d epression, and 3) the influence of neutralization of TNF-alpha on myoc ardial 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. Pretre atment with cycloheximide or dexamethasone abolished the increase in c irculating and myocardial TNF-alpha and preserved myocardial contracti le function. Similarly, treatment with TNF binding protein immediately after LPS prevented myocardial depression. We conclude that endogenou s 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.