INHALED NITRIC-OXIDE PRETREATMENT BUT NOT POSTTREATMENT ATTENUATES ISCHEMIA-REPERFUSION-INDUCED PULMONARY MICROVASCULAR LEAK

Background: Ischemia-reperfusion (VR) pulmonary edema probably reflect s a leukocyte-dependent, oxidant-mediated mechanism Nitric oxide (NO) attenuates leukocyte-endothelial cell interactions and I/R-induced mic rovascular leak. Cyclic adenosine monophosphate (cAMP) agonists revers e and prevent I/R-induced microvascular leak, but reversal by inhaled NO (INO) has not been tested In addition, the role of soluble guanylyl cyclase (sGC) activation in the NO protection effect is unknown. Meth ods: Rat lungs perfused with salt solution were grouped as either I/R, I/R with INO (10 or 50 ppm) on reperfusion, or time control. Capillar y filtration coefficients (Kfc) mere estimated 25 min before ischemia (baseline) and after 30 and 75 min of reperfusion. Perfusate cell coun ts and lung homoge nate myeloperoxidase activity mere determined in se lected groups. Additional groups were treated with either INO (50 ppm) or isoproterenol (ISO - 10 mu M) after 30 min of reperfusion. Guanyly l cyclase mas inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-o ne (ODQ - 15 mu M), and Kfc was estimated at baseline and after 30 min of reperfusion. Results: (1) Inhaled NO attenuated VR-induced increas es in Kfc. (2) Cell counts were similar at baseline. After 75 min of r eperfusion, lung neutrophil retention (myeloperoxidase activity) and d ecreased perfusate neutrophil counts were similar in all groups. (3) I n contrast to ISO, INO did not reverse microvascular leak. (4) 8-bromo guanosine 3',5'-cyclic monophosphate (8-br-cGMP) prevented I/R-induced microvascular leak in ODQ-treated lungs, but INO was no longer effect ive. Conclusions: Inhaled NO attenuates VR-induced pulmonary microvasc ular leak, which requires sGC activation and may involve a mechanism i ndependent of inhibition of leukocyte-endothelial cell interactions. I n addition, INO is ineffective in reversing VR-induced microvascular l eak.