Aminoguanidine attenuates endotoxin-induced acute lung injury in rabbits.
OBJECTIVE
To assess the effect of aminoguanidine, a selective inducible nitric oxide synthase inhibitor, on endotoxin-induced acute lung injury in rabbits.


METHODS
Prospective, blinded, controlled laboratory study.


METHODS
University research laboratory.


METHODS
Twenty-eight male rabbits.


METHODS
The animals were randomly assigned to receive one of four treatments (n = 7 for each group): infusion of saline only (S-S group), infusion of saline and aminoguanidine (S-AG group), infusion of Escherichia coli endotoxin (5 mg/kg over 60 mins) (E-S group), and infusion of endotoxin and aminoguanidine (E-AG group). Fifteen minutes before infusion of endotoxin (E-S and E-AG groups) or saline (S-S and S-AG groups), the animals received an intravenous injection of 1 mg/kg of aminoguanidine (S-AG and E-AG groups) or saline (S-S and E-S groups). The same dose of aminoguanidine or saline was given 1 hr after the end of endotoxin or saline infusion. The lungs of the rabbits were ventilated with 40% oxygen.


RESULTS
Hemodynamics, peripheral leukocyte counts, and PaO2 were recorded during the ventilation period (6 hrs). After these observations were made, lung mechanics, cell fraction of bronchoalveolar lavage fluid, and concentrations of thromboxane A2 and prostacyclin metabolites in bronchoalveolar lavage fluid were determined. The wet weight/dry weight ratio of the lung and albumin concentrations in bronchoalveolar lavage fluid were analyzed as indices of pulmonary edema. Endotoxin decreased the lung compliance and PaO2 and increased the wet weight/dry weight ratio, neutrophil counts, and albumin concentrations in bronchoalveolar lavage fluid. The bronchoalveolar lavage fluid concentrations of thromboxane B2 in bronchoalveolar lavage fluid were increased by infusion of endotoxin. Aminoguanidine attenuated these changes. Endotoxin caused extensive morphologic lung damage, which was lessened by aminoguanidine.


CONCLUSIONS
Aminoguanidine given intravenously before and after endotoxin attenuated endotoxin-induced lung injury in rabbits. These findings suggest that inducible nitric oxide synthase inhibition may be useful in the treatment of endotoxin-induced lung injury. However, further studies are required to determine the optimal dosage of aminoguanidine, when the inhibitor is given alone as therapy after lung injury.
Mikawa
K
K
Department of Anaesthesiology, Kobe University School of Medicine, Japan.
Nishina
K
K
Tamada
M
M
Takao
Y
Y
Maekawa
N
N
Obara
H
H
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004926:Escherichia coli; D006146:Guanidines / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
D004731:Endotoxins; D004791:Enzyme Inhibitors; D006146:Guanidines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine