Blockade of nuclear factor-kappaB activation prevents hypodynamic shock and gastric hypoperfusion induced by endotoxin in anesthetized dogs.
OBJECTIVE
To investigate whether pyrrolidinone derivative (N2733), an inhibitor of nuclear factor (NF)-kappaB activation, improves altered metabolic and hemodynamic changes and organ dysfunctions caused by endotoxic shock.


METHODS
Prospective, randomized, animal study in a laboratory at a university hospital.


METHODS
Twenty-three anesthetized male beagle dogs (10-14 kg).


METHODS
Dogs were mechanically ventilated and monitored with a pulmonary arterial catheter and a gastric tonometer. A central venous catheter was inserted into the femoral vein, and lactated Ringer's solution (10 ml/kg per hour) was administered throughout the study period. Three groups of animals were studied: (a) the lipopolysaccharide (LPS) group (n=8), which received LPS (250 ng/kg per minute for 2 h); (b) the LPS plus N2733 group (n=8), which received N2733 (30 mg/kg intravenously and 10 mg/kg hour for 6 h) after the start of LPS; and (c) the N2733 group (n=7), which received N2733 (30 mg/kg intravenously and 10 mg/kg per hour for 6 h).


RESULTS
Changes in hemodynamics, blood gas, gastric intramural pH, and renal and hepatic function were measured for 6 h. Coadministration of N2733 increased oxygen delivery index and prevented the LPS-induced hypotension, metabolic acidosis, and gastric mucosal acidosis but did not affect renal or hepatic function.


CONCLUSIONS
Administration of N2733 increased oxygen delivery index and prevented the LPS-induced hypotension and metabolic and gastric mucosal acidosis in an anesthetized canine endotoxic shock model, suggesting its beneficial effect on local blood flow against tissue hypoxia. These findings suggest that blockade of NF-kappaB activation prevents hypodynamic shock and gastric hypoperfusin in endotoxic shock.
Mitaka
Chieko
C
Department of Critical Care Medicine, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Bunkyo-ku, 113-8519 Tokyo, Japan. c.mitaka.icu@tmd.ac.jp
Hirata
Yukio
Y
Narumi
Yutaka
Y
Yokoyama
Kuninori
K
Makita
Koshi
K
Katsuyama
Koichi
K
Imai
Takasuke
T
D000818:Animals; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D007677:Kidney Function Tests; D008111:Liver Function Tests; D008297:Male; D009102:Multiple Organ Failure / Q000517:prevention & control*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011897:Random Allocation; D012772:Shock, Septic / Q000188:drug therapy*
D016328:NF-kappa B; D011760:Pyrrolidinones