title: Selective inhibition of the inducible isoform of nitric oxide synthase prevents pulmonary transvascular flux during acute endotoxemia.
abstract: The inducible isoform of nitric oxide synthase (iNOS) is expressed in various organs, including the lung, during systemic endotoxemia. Overproduction of nitric oxide (NO) by iNOS contributes significantly to the vascular failure and end-organ damage in endotoxemia. Using selective pharmacological inhibitors of iNOS, the purpose of this study was to define the role of iNOS in a rat model of endotoxin-induced pulmonary transvascular flux (TVF). Lung TVF was assessed by a method of Evans Blue permeability index (PI). Bacterial lipopolysaccharide (LPS) (15 mg/kg intraperitoneally [IP]) significantly increased pulmonary iNOS activity and serum levels of nitrite/nitrate (NO2/NO3). This was accompanied by a significant elevation of the PI 5 hours after injection. Selective iNOS inhibition with either S-methyl isothiourea (SMT; 5 mg/kg IP) or aminoguanidine (AG; 20 mg/kg IP), administered 2 hours after LPS injection, significantly prevented the increase in PI associated with LPS injection. Similarly, inhibition of the induction of iNOS with dexamethasone (10 mg/kg IP), given 3 hours before LPS, also inhibited the increase in PI. All three treatments significantly prevented the increase in both lung iNOS activity and serum NO2/NO3 associated with endotoxemia. In conclusion, the overproduction of NO generated by iNOS during systemic endotoxemia causes a vascular leak in the lung. Thus, it is speculated that selective inhibition of iNOS may be beneficial in preventing the development of acute respiratory failure in sepsis.
authors.affiliation: Division of Surgery, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Arkovitz
authors.forename: J R
authors.initials: JR
authors.lastname: Wispé
authors.forename: V F
authors.initials: VF
authors.lastname: Garcia
authors.forename: C
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019446:Endotoxemia / Q000150:complications*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015633:Extravascular Lung Water / Q000201:enzymology*; D006146:Guanidines / Q000494:pharmacology; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000382:microbiology* / Q000517:prevention & control*
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D007550:Isothiuronium; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium; C004479:pimagedine