Congenital NOS2 deficiency protects mice from LPS-induced hyporesponsiveness to inhaled nitric oxide

Background: In animal models, endotoxin (lipopolysaccharide) challenge impa irs the pulmonary vasodilator response to inhaled nitric oxide (NO). This i mpairment is prevented by treatment with inhibitors of NO synthase 2 (NOS2) , including glucocorticoids and L-arginine analogs. However, because these inhibitors are not specific for NOS2, the role of this enzyme in the impair ment of NO responsiveness by lipopolysaccharide remains incompletely define d. Methods: To investigate the role of NOS2 in the development of lipopolysacc haride-induced impairment of NO responsiveness, the authors measured the va sodilator response to inhalation of 0.4, 4, and 40 ppm NO in isolated, perf used, and ventilated lungs obtained from lipopolysaccharide-pretreated (50 mg/kg intraperitoneally 16 h before lung perfusion) and untreated wild-type and NOS2-deficient mice. The authors also evaluated the effects of breathi ng NO for 16 h on pulmonary vascular responsiveness during subsequent venti lation with NO. Results: In wild-type mice, lipopolysaccharide challenge impaired the pulmo nary vasodilator response to 0.4 and 4 ppm NO (reduced 79% and 45%, respect ively, P < 0.001), but not to 40 ppm. In contrast, lipopolysaccharide admin istration did not impair the vasodilator response to inhaled NO in NOS2-def icient mice. Breathing 20 ppm NO for 16 h decreased the vasodilator respons e to subsequent ventilation with NO in Lipopolysaccharide-pretreated NOS2-d eficient mice, but not in lipopolysaccharide-pretreated wild-type, untreate d NOS2-deficient or untreated wild-type mice. Conclusions: In response to endotoxin challenge, NO, either endogenously pr oduced by NOS2 in wild-type mice or added to the air inhaled by NOS2-defici ent mice, is necessary to impair vascular responsiveness to inhaled NO. Pro longed NO breathing, without endotoxin, does not impair vasodilation in res ponse to subsequent NO inhalation. These results suggest that NO, plus othe r lipopolysaccharide-induced products, are necessary to impair responsivene ss to inhaled NO in a murine sepsis model.