Blockade of nuclear factor-κB activation prevents hypodynamic shock and gastric hypoperfusion induced by endotoxin in anesthetized dogs

Abstract

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. Prospective, randomized, animal study in a laboratory at a university hospital. Twenty-three anesthetized male beagle dogs (10-14 kg). 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). 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. 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.