A selective inhibitor for inducible nitric oxide synthase improves hypotension and lactic acidosis in canine endotoxic shock.
OBJECTIVE
To investigate whether ONO-1714, a putative selective inhibitor for inducible nitric oxide synthase, modulates systemic hemodynamics, arterial blood gases, lactate concentrations, gastric mucosal perfusion, and renal and hepatic functions in endotoxic shock.


METHODS
Prospective, randomized, controlled animal study.


METHODS
Laboratory at a university hospital.


METHODS
Eighteen male beagle dogs (12-19 kg) under pentobarbital anesthesia.


METHODS
Dogs were mechanically ventilated and monitored with a pulmonary arterial catheter and a gastric tonometer. They were divided in three groups: a) lipopolysaccharide (LPS) plus vehicle group (n = 6), which received LPS (250 ng/kg/min for 2 hrs) and saline 1 hr later; b) LPS plus ONO (0.05) group (n = 6), which received ONO-1714 (0.05 mg/kg) 1 hr after the start of LPS; c) LPS plus ONO (0.1) group (n = 6), which received ONO-1714 (0.1 mg/kg) 1 hr after the start of LPS.


RESULTS
Hemodynamics, blood gas parameters, gastric intramural pH, urine output, and serum levels of lactate, transaminases, bilirubin, and creatinine were measured during a 6-hr observation period. LPS induced hypotension, lactic acidosis, gastric mucosal acidosis, and renal and hepatic dysfunction. ONO-1714 reversed the LPS-induced hypotension and lactic acidosis without deteriorating cardiac output, oxygen delivery, or gastric mucosal acidosis.


CONCLUSIONS
These findings suggest that ONO-1714 is a useful agent to reverse hypotension and lactic acidosis in a canine endotoxic shock model.
Mitaka
C
C
Department of Critical Care Medicine, Tokyo Medical and Dental University Graduate School, Tokyo, Japan. c.mitaka.icu@med.tmd.ac.jp
Hirata
Y
Y
Yokoyama
K
K
Makita
K
K
Imai
T
T
D000140:Acidosis, Lactic / Q000188:drug therapy* / Q000209:etiology; D000578:Amidines / Q000627:therapeutic use*; D000818:Animals; D001784:Blood Gas Analysis; D003404:Creatinine / Q000652:urine; D004285:Dogs; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects*; D006574:Heterocyclic Compounds, 2-Ring / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D007022:Hypotension / Q000188:drug therapy* / Q000209:etiology; D008070:Lipopolysaccharides; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D008070:Lipopolysaccharides; D003404:Creatinine; D019001:Nitric Oxide Synthase