EVIDENCE THAT EPITHELIUM-DERIVED RELAXING FACTOR RELEASED BY BRADYKININ IN THE GUINEA-PIG TRACHEA IS NITRIC-OXIDE

Bradykinin, applied locally to the airways, is a weak bronchoconstrict or agent in guinea pigs in vivo and it may cause constriction or dilat ation of guinea pig airways smooth muscle in vitro. We examined the mo tor effect of bradykinin perfused through the lumen of isolated guinea pig tracheal tubes with or without nitric oxide (NO) synthase inhibit ors. In the presence of N-G-nitro-D-arginine methyl ester (D-NAME) or N-G-monomethyl-D-arginine (D-NMMA) intraluminal bradykinin caused a mo derate concentration-dependent relaxation. In contrast, in the presenc e of N-G-nitro-L-arginine methyl ester (L-NAME) or N-G-monomethyl-L-ar ginine (L-NMMA) tracheas developed a sustained increase in tone, and b radykinin caused a marked, concentration-dependent contraction, both e ffects being reversible by pretreatment with L-arginine, but not with D-arginine. The ability of bradykinin to relax (in the presence of D-N AME) or contract (in the presence of L-NAME) guinea pig tracheal tubes was not affected by indomethacin. Bradykinin contracted epithelium-de nuded tracheas in the presence of either L-NAME or D-NAME. Both contra ction and relaxation by bradykinin were blocked by the kinin B-2 recep tor antagonist, HOE 140. Baseline production of guanosine 3',5'-cyclic monophosphate (cyclic CMP) in strips of guinea pig trachealis in vitr o was markedly reduced by L-NAME, but not by D-NAME. Bradykinin increa sed baseline cyclic GMP concentration. These results indicate that bra dykinin releases NO or a NO-related molecule, which, possibly by incre asing cyclic CMP concentrations, mediates relaxation and opposes contr action induced by bradykinin itself, and further, that bradykinin rele ases NO from the tracheal epithelium.