HYPORESPONSIVENESS TO INHALED NITRIC-OXIDE IN ISOLATED, PERFUSED LUNGS FROM ENDOTOXIN-CHALLENGED RATS

Inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in patients with the adult respiratory distress syndrome (ARDS). Approximately 30% of ARDS patients fail to respond to iNO. Because sepsis syndrome often accompanies a decreased response t o iNO, we investigated NO responsiveness in isolated, perfused lungs f rom rats exposed to lipopolysaccharide (LPS). Eighteen hours after int raperitoneal injection of 0.5 mg/kg LPS, rat lungs were isolated, perf used, and preconstricted with U-46619. Ventilation with 0.4, 4, and 40 parts per million by volume NO vasodilated LPS-pretreated lungs 75, 4 7, and 42% less than control lungs (P < 0.01 value differs at each con centration). The diminished vasodilatory response to iNO was associate d with decreased NO-stimulated guanosine 3',5'-cyclic monophosphate (c GMP) release into the perfusate. Soluble guanylate cyclase activity di d not differ in lung extracts from LPS-pretreated and control rats. LP S increased pulmonary cGMP-phosphodiesterase (PDE) activity by 40%. Th e PDE-sensitive cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosph ate vasodilated lungs from LPS-pretreated rats less than lungs from co ntrol rats. In contrast, the PDE-insensitive 8-para-chlorophenylthiogu anosine 3',5'-cyclic monophosphate vasodilated lungs equally from both groups. After LPS challenge, the rat pulmonary vasculature becomes hy poresponsive to iNO. Hyporesponsiveness to iNO appears partly attribut able to increased pulmonary cGMP-PDE activity.