Effect of ONO1714, a specific inducible nitric oxide synthase inhibitor, on lung lymph filtration and gas exchange during endotoxemia in unanesthetized sheep.
BACKGROUND
The effect of nitric oxide synthase inhibitor on acute lung injury remains controversial. The current study was designed to examine effects of a newly synthesized and selective inducible nitric oxide synthase inhibitor, ONO1714, on endotoxin-induced lung injury in unanesthetized sheep.


METHODS
Thirteen unanesthetized sheep chronically instrumented with a lung lymph fistula and vascular catheters for monitoring were prepared. Animals were randomly allocated into two experimental groups. In experiment 1, sheep (n = 6) were infused only with endotoxin (1 microg/kg) for 30 min. In experiment 2, sheep (n = 7) were pretreated with ONO1714 (0.1 mg/kg) before 30 min of endotoxin administration, and the endotoxin was infused in the same manner as in experiment 1. Mean pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, and lung lymph flow were measured. Observation was continued over 5 h after endotoxin administration.


RESULTS
ONO1714 did not cause any pulmonary hemodynamic changes at baseline or exert any influences on transient pulmonary hypertension and increased pulmonary vascular resistance during endotoxemia. However, inducible nitric oxide synthase inhibition with ONO1714 significantly reduced lung lymph filtration and improved abnormal oxygenation during endotoxemia. In addition, increased nitrate-nitrite in plasma and lung lymph in response to endotoxin was prevented by treatment with ONO1714.


CONCLUSIONS
These findings suggest that nitric oxide release by the inducible nitric oxide synthase pathway partially contributes to the increased permeability of pulmonary edema and decreased oxygenation during endotoxemia in sheep.
Koizumi
Tomonobu
T
First Department of Medicine, Shinshu University School of Medicine, Asahi Matsumoto, Japan. tomonobu@hsp.md.shinshu-u.ac.jp
Ogasawara
Hitoshi
H
Yamamato
Hiroshi
H
Tsushima
Kenji
K
Ruan
Zonghai
Z
Jian
Mingyuan
M
Fujimoto
Keisaku
K
Kubo
Keishi
K
D000208:Acute Disease; D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000502:physiology; D019446:Endotoxemia / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D008168:Lung / Q000502:physiology*; D008196:Lymph / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011652:Pulmonary Circulation / Q000502:physiology; D011659:Pulmonary Gas Exchange / Q000187:drug effects*; D012131:Respiratory Insufficiency / Q000503:physiopathology; D018805:Sepsis / Q000503:physiopathology; D012756:Sheep
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II