ABSTRACT
OBJECTIVE: Acute respiratory distress syndrome/acute lung injury is a serious complication of burn patients with concomitant smoke inhalation injury. Nitric oxide has been shown to play a major role in pulmonary dysfunction from thermal damage. In this study, we have tested the hypothesis that inhibition of neuronal nitric oxide synthase could ameliorate the severity of acute lung injury using our well-established ovine model of cutaneous burn and smoke inhalation. DESIGN: Prospective, randomized, controlled, experimental animals study. SETTING: Investigational intensive care unit at university hospital. SUBJECTS: Adult female sheep. INTERVENTIONS: Female sheep (n = 16) were surgically prepared for the study. Seven days after surgery, all sheep were randomly allocated into three study groups: sham (noninjured, nontreated, n = 6); control (injured, treated with saline, n = 6); and neuronal nitric oxide synthase (injured, treated with specific neuronal nitric oxide synthase inhibitor, ZK 234238 (n = 4). Control and neuronal nitric oxide synthase groups were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. Animals in sham group received fake injury also under halothane anesthesia. After injury or fake injury procedure, all sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Neuronal nitric oxide synthase group was administered with continuous infusion of ZK 234238 started 1 hr postinjury with a dose of 100 microg/kg/hr. Sham and control groups received same amount of saline. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary hemodynamics monitored during the 24-hr experimental time period was stable in the sham group. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and inflammatory indices, such as interleukin-8. Treatment of injured sheep with neuronal nitric oxide synthase inhibitor attenuated all the observed pulmonary pathophysiology. CONCLUSIONS: The results provide definitive evidence that inhibition of neuronal nitric oxide synthase-derived excessive nitric oxide may be a novel and beneficial treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.
Subject(s)
Acute Lung Injury/prevention & control , Nitric Oxide Synthase Type I/antagonists & inhibitors , Oxazines/therapeutic use , Acute Lung Injury/enzymology , Acute Lung Injury/etiology , Animals , Burns/complications , Disease Models, Animal , Female , Sheep , Smoke Inhalation Injury/complicationsABSTRACT
Fluorinated dihydroquinolines showed reduced basicity of the amidine function. Their syntheses and potencies as neuronal nitric oxide synthase (n-NOS) inhibitors are reported.
Subject(s)
Amidines/metabolism , Enzyme Inhibitors/pharmacology , Fluorine/chemistry , Nitric Oxide Synthase/antagonists & inhibitors , Quinolines/pharmacology , Enzyme Inhibitors/chemistry , Nitric Oxide Synthase Type I , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Dihydroquinolines with aminoalkyl side chains have been synthesized and have been shown to be potent n-NOS inhibitors. A marked selectivity versus e-NOS of up to approximately 300-fold was observed, whereas i-NOS was moderately inhibited.
Subject(s)
Amines/chemistry , Nitric Oxide Synthase/antagonists & inhibitors , Quinolines/chemistry , Quinolines/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Quinolines/chemical synthesis , Recombinant Proteins/antagonists & inhibitors , Reference Values , Structure-Activity RelationshipABSTRACT
Dihydroquinolines have been synthesized and have been shown to be potent n-NOS inhibitors. Selectivity versus e-NOS was increased to approximately 100-fold through appropriate substitution at the benzene ring.