NITRIC-OXIDE SYNTHASE INHIBITOR AND LIPOPOLYSACCHARIDE EFFECTS ON REACTIVITY OF GUINEA-PIG AIRWAYS

The in vivo and in vitro effects of nitric oxide (NO) synthase inhibit ors and lipopolysaccharide (LPS) on reactivity of guinea pig airways w ere examined. In isolated, perfused tracheas from untreated animals, t he NO synthase inhibitors, N omega-nitro-L-arginine methyl ester (L-NA ME; 10(-4) M), N-G-methyl-L-arginine (L-NMMA; 10(-4) M) and aminoguani dine (10(-4) M) had no effect or inhibited reactivity to extraluminall y (EL) or intraluminally (IL) applied methacholine and histamine. L-NM MA (10(-4) M) did not appreciably contract resting or methacholine-con tracted preparations (+/-3 x 10(-4) M L-arginine) and L-arginine only weakly relaxed contracted tracheas (+/-L-NMMA). Sodium nitroprusside a nd S-nitroso-N-penicillamine elicited relaxant responses and were more potent extraluminally than intraluminally. Methylene blue (10(-5) M) antagonized relaxation to sodium nitroprusside. Incubation with Escher ichia coli LPS (10 mu g/ml; 30 min incubation) alone in the EL and IL baths depressed methacholine and histamine concentration-response curv es. In the presence of LPS, L-NAME potentiated responses to intralumin ally applied methacholine but did not affect responses to extraluminal ly added methacholine. Four days after i.p. injection of animals with LPS (4 mg/kg), L-NAME potentiated responses to IL methacholine, and L- arginine acquired greater relaxant activity. LPS injection increased s ensitivity to intraluminally added but not extraluminally added isopro terenol. LPS given by i.p. injection or by inhalation did not affect b asal specific airway resistance of conscious animals or reactivity to methacholine aerosol during a postexposure period of 6 to 72 h. NO see ms to have little role in regulating reactivity of guinea pig airways to bronchoconstrictor agonists, except after in vitro or in vivo expos ure to LPS. After LPS injection the in vitro changes suggestive of NO synthase induction are not associated with altered airway reactivity t o inhaled methacholine.