THE EFFECT OF A NITRIC-OXIDE SYNTHASE INHIBITOR ON THE MODULATION OF AIRWAY RESPONSIVENESS IN RATS

The possible role of nitric oxide (NO) in the regulation of airway ton e remains to be fully explored. In the present study we examined the e ffect of N-G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of N O synthase, on airway responsiveness in rats. The effect of L-NAME on endotoxin (lipopolysaccharide; LPS)-induced changes in airway responsi veness was also evaluated. L-NAME (1 mg/kg given intravenously) caused a 33.3 +/- 6.9% increase in blood pressure, but did not influence bas eline airway tone or the provocative dose of carbachol causing a 50% i ncrease in pulmonary resistance (RL) (PD(50)RL). Exposure of F344 rats to LPS induced a transient increase in airway responsiveness at 90 mi n after exposure, followed by a significant hyporesponsiveness between 9 and 12 h after exposure. L-NAME (1 mg/kg intravenously) did not inf luence the increase in responsiveness but inhibited the LPS-induced hy poresponsiveness; in LPS-exposed, L-NAME-treated animals, the PD(50)RL for carbachol was 3.0 +/- 0.1, versus 4.8 +/- 0.3 mu g/kg in the LPS- exposed, placebo-pretreated group (p < 0.05). The effect of L-NAME was abolished by pretreatment with L-arginine but not with D-arginine. L- NAME did not influence the LPS-induced increase of neutrophils in bron choalveolar lavage fluid (BALF). These results suggest that in rats, c onstitutive NO synthesis does not contribute either to basal airway to ne or to the basal degree of airway responsiveness, but that inducible NO synthesis mediates endotoxin-induced hyporesponsiveness.