ENDOGENOUS NITRIC-OXIDE MODIFIES ANTIGEN-INDUCED MICROVASCULAR LEAKAGE IN SENSITIZED GUINEA-PIG AIRWAYS

To examine the role of endogenous nitric oxide in allergic airway infl ammation, we investigated the effect of a nitric oxide synthase inhibi tor, N omega-nitro-L-arginine methyl ester (L-NAME), on antigen-induce d airway microvascular leakage in actively senstitized guinea pigs by using Evans blue dye. Three weeks after sensitization with obalbumin ( 10 mu g), the tracheas were cannulated, and lungs were artifically ven tilated. Animals were pretreated with atropine and propranolol (both 1 mg/kg, intravenously) to avoid neural modification. Ovalbumin inhalat ion (3 mg/ml, 1 minute) challenge caused significant microvascular lea kage in all airway portions, which was significantly suppressed in a d ose-dependent manner by pretreatment with intravenous injection of L-N AME (1 and 10 mg/kg) but not with the inactive enantiomer D-NAME (10 m g/kg). This inhibition by L-NAME was significantly reversed by co-admi nistration of L-arginine (100 mg/kg, intravenously). Pretreatment with a vasoconstrictor, phenylephrine (20 mu g/kg, intravenously), had no inhibitory effects on antigen-induced airway microvascular leakage des pite increasing systemic blood pressure. Inhalation of representative mast cell-derived mediators, histamine (2 mg/ml, 1 minute) or leukotri ene D-4 (5 mu g/ml, 1 minute), produced significant microvascular leak age in all airways. L-NAME (10 mg/kg, intravenously) partially but sig nificantly inhibited leukotriene D-4-induced leakage, whereas histamin e-induced leakage was not affected. These results suggest that endogen ous nitric oxide acts to increase airway microvascular leakage after a irway allergic reaction.