Beneficial effects of concomitant neuronal and inducible nitric oxide synthase inhibition in ovine burn and inhalation injury.
Different isoforms of nitric oxide (NO) synthase are critically involved in the development of pulmonary failure secondary to acute lung injury. Here we tested the hypothesis that simultaneous blockade of inducible and neuronal NO synthase effectively prevents the pulmonary lesions in an ovine model of acute respiratory distress syndrome induced by combined burn and smoke inhalation injury. Chronically instrumented sheep were allocated to a sham-injured group (n = 6), an injured and untreated group (n = 6), or an injured group treated with simultaneous infusion of selective inducible and neuronal NO synthase inhibitors (n = 5). The injury was induced by 48 breaths of cotton smoke and a third-degree burn of 40% total body surface area. All sheep were mechanically ventilated and fluid resuscitated. The injury induced severe pulmonary dysfunction as indicated by decreases in PaO2/FiO2 ratio and increases in pulmonary shunt fraction, ventilatory pressures, lung lymph flow, and lung wet/dry weight ratio. The treatment fully prevented the elevations in lymph and plasma nitrate/nitrite levels, pulmonary shunting, ventilatory pressures, lung lymph flow, and wet/dry weight ratio and significantly attenuated the decline in PaO2/FiO2 ratio. In conclusion, simultaneous blockade of inducible and neuronal NO synthase exerts beneficial pulmonary effects in an ovine model of acute respiratory distress syndrome secondary to combined burn and smoke inhalation injury. This novel treatment strategy may represent a useful therapeutic adjunct for patients with these injuries.
Department of Anesthesiology, Investigational Intensive Care Unit, The University of Texas Medical Branch, and Shriners Hospitals for Children, Galveston, Texas 77550, USA. lanm@gmx.de
Matthias
M
Lange
Atsumori
A
Hamahata
Perenlei
P
Enkhbaatar
Robert A
RA
Cox
Yoshimitsu
Y
Nakano
Martin
M
Westphal
Lillian D
LD
Traber
David N
DN
Herndon
Daniel L
DL
Traber
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000517:prevention & control; D000818:Animals; D002056:Burns / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects; D005260:Female; D006339:Heart Rate; D007093:Imidazoles / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009589:Nitrogen Oxides / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011743:Pyrimidines / Q000627:therapeutic use*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D034561:Sheep, Domestic; D015208:Smoke Inhalation Injury / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology
D007093:Imidazoles; D007191:Indazoles; C487929:N-((1,3-benzodioxol-5-yl)methyl)-1-(2-(1H-imidazol-1-yl)pyrimidin-4-yl)-4-(methoxycarbonyl)piperazine-2-acetamide; D009589:Nitrogen Oxides; D010879:Piperazines; D011743:Pyrimidines; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C080122:7-nitroindazole
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