Big-endothelin release in baboon bacteremia is partially TNF dependent.
Big-endothelin (big-ET) is one of the endothelium-derived vasoactive substances that plays an important role in regulating the vascular tone. Because the role of this agent in bacteremia remains unknown, we investigated whether bacteremia induces the release of big-ET in a subhuman primate model and whether tumor necrosis factor (TNF) is an important mediator of big-ET release. To study this, we infused 8 male baboons (17 to 19 kg body weight) intravenously for 2 hours with Escherichia coli (5 x 10(8) CFU/kg) and observed them for 72 hours. Plasma was obtained at various intervals and assayed for big-ET by using immunoassay. Four bacteremic animals given vehicle only showed a peak big-ET plasma concentration of 15.1 +/- 4.6 fmol/ml at 10 hours, as compared with a baseline concentration of 0.9 +/- 0.5 fmol/ml. Administration of anti-TNF monoclonal antibodies (CB6, 15 mg/kg) 2 hours before E. coli infusion in additional animals prevented the rise in plasma TNF levels (5.7 +/- 2.5 ng/ml versus nondetectable) and significantly (p < 0.01) attenuated the release of big-ET. Hemodynamic measurements revealed the typical pattern of sepsis, with generally more stable circulatory conditions in the anti-TNF-treated animals. Moreover, the mortality rate decreased from 100% to 0% with anti-TNF treatment. These studies, therefore, lead us to conclude that TNF, directly or indirectly through another mediator, plays an important role in the endothelin production/release during bacteremia and that neutralization of circulating TNF appears to be beneficial for improving the survival after bacteremia.
Redl
H
H
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.
Schlag
G
G
Bahrami
S
S
Kargl
R
R
Hartter
W
W
Woloszczuk
W
W
Davies
J
J
D000818:Animals; D016470:Bacteremia / Q000097:blood* / Q000401:mortality / Q000503:physiopathology; D019332:Endothelin-1; D016232:Endothelins / Q000097:blood*; D004731:Endotoxins / Q000097:blood; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000097:blood* / Q000401:mortality / Q000503:physiopathology; D006439:Hemodynamics; D008297:Male; D010215:Papio; D011498:Protein Precursors / Q000097:blood*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D019332:Endothelin-1; D016232:Endothelins; D004731:Endotoxins; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha