title: Inducible nitric oxide synthase dimerization inhibitor prevents cardiovascular and renal morbidity in sheep with combined burn and smoke inhalation injury.
abstract: Inducible nitric oxide synthase (iNOS) is implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). ARDS treatment is frequently complicated by significant extrapulmonary comorbidity. This study was designed to clarify the role of iNOS in mediating extrapulmonary comorbidity in sheep after combined burn and smoke inhalation injuries using a potent and highly selective iNOS dimerization inhibitor, BBS-2. Twenty-two female sheep were operatively prepared. After 5 days of recovery, tracheostomy was performed under ketamine-halothane anesthesia. Sheep were given a 40% total body surface third-degree burns and insufflated with cotton smoke (48 breaths, <40 degrees C). Sheep were divided into four groups: noninjured and nontreated (sham group; n = 6), noninjured but treated with BBS-2 (sham/BBS-2 group; n = 4), injured but nontreated (control group, n = 6), and injured but treated with 100 microg.kg-1.h-1 BBS-2 (BBS-2 group; n = 6). Evaluation was in a laboratory intensive care unit setting for 48 h. The sham group had stable cardiopulmonary and systemic hemodynamics. Control animals showed multiple signs of morbidity. Decreased left ventricular stroke work index and stroke volume index with elevated left atrial pressure indicated myocardial depression. Systemic vascular leak was evidenced by robust hemoconcentration, decreased plasma oncotic pressure, and increased transvascular fluid flux into the lymphatic system. Finally, severely impaired renal function (urinary output) was associated with adverse net fluid balance. Treatment with BBS-2 prevented all these morbidities without adversely effecting cardiovascular hemodynamics such as cardiac index and mean arterial pressure. The results identify a major role for iNOS in mediating extrapulmonary comorbidity in a clinically relevant and severe trauma model and support the use of highly selective iNOS inhibitors as novel treatments in critical care medicine.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, 610 Texas Ave., Galveston, TX 77555, USA.
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: Kazunori
authors.initials: K
authors.lastname: Murakami
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shimoda
authors.forename: Akio
authors.initials: A
authors.lastname: Mizutani
authors.forename: Lillian
authors.initials: L
authors.lastname: Traber
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
authors.forename: John
authors.initials: J
authors.lastname: Parkinson
authors.forename: John R
authors.initials: JR
authors.lastname: Salsbury
authors.forename: Nettie
authors.initials: N
authors.lastname: Biondo
authors.forename: Frank
authors.initials: F
authors.lastname: Schmalstieg
authors.forename: Ann
authors.initials: A
authors.lastname: Burke
authors.forename: Robert
authors.initials: R
authors.lastname: Cox
authors.forename: Hal
authors.initials: H
authors.lastname: Hawkins
authors.forename: David
authors.initials: D
authors.lastname: Herndon
authors.forename: Daniel
authors.initials: D
authors.lastname: Traber
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002056:Burns / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins; D009200:Myocardial Contraction; D019001:Nitric Oxide Synthase / Q000737:chemistry / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D013318:Stroke Volume
chemical_list: D004791:Enzyme Inhibitors; D006454:Hemoglobins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II