Bradykinin, applied locally to the airways, is a weak bronchoconstrictor agent in guinea pigs in vivo and it may cause constriction or dilatation of guinea pig airways smooth muscle in vitro. We examined the motor effect of bradykinin perfused through the lumen of isolated guinea pig tracheal tubes with or without nitric oxide (NO) synthase inhibitors. In the presence of NG-nitro-D-arginine methyl ester (D-NAME) or NG-monomethyl-D-arginine (D-NMMA) intraluminal bradykinin caused a moderate concentration-dependent relaxation. In contrast, in the presence of NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) tracheas developed a sustained increase in tone, and bradykinin caused a marked, concentration-dependent contraction, both effects being reversible by pretreatment with L-arginine, but not with D-arginine. The ability of bradykinin to relax (in the presence of D-NAME) or contract (in the presence of L-NAME) guinea pig tracheal tubes was not affected by indomethacin. Bradykinin contracted epithelium-denuded tracheas in the presence of either L-NAME or D-NAME. Both contraction and relaxation by bradykinin were blocked by the kinin B2 receptor antagonist, HOE 140. Baseline production of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in strips of guinea pig trachealis in vitro was markedly reduced by L-NAME, but not by D-NAME. Bradykinin increased baseline cyclic GMP concentration. These results indicate that bradykinin releases NO or a NO-related molecule, which, possibly by increasing cyclic GMP concentrations, mediates relaxation and opposes contraction induced by bradykinin itself, and further, that bradykinin releases NO from the tracheal epithelium.

1 This study investigated the possibility that tachykinins relax the guinea-pig isolated trachea by releasing nitric oxide (NO) from the epithelium. The types of tachykinin receptor mediating both relaxation and contraction of the trachea were also studied. Isometric tension was recorded in isolated tracheal tube preparations precontracted with acetylcholine (10 gM) in which compounds were administered intraluminally in the presence of phosphoramidon and indomethacin (both gUM) and 5 These results demonstrate that tachykinins relax guinea-pig tracheal tube preparations by releasing NO via the stimulation of epithelial NK, receptors by a mechanism independent of histamine release.The NK, receptor type involved is sensitive to SP, NKA, NKB and [Sar9, Met(O2)"]-SP but not to septide, and is pharmacologically distinct from the NKI receptor that mediates contraction, which is stimulated by all the agonists, including septide.

1 The effect of bradykinin, capsaicin, substance P and low pH medium on plasma extravasation in the guinea-pig conjunctiva has been studied. Evans blue dye was measured in the conjunctiva after local instillation of the agents into the conjunctival sac.2 Bradykinin (2-50nmol), capsaicin (20-50nmol) and substance P (0.5-5mnmol) caused a dosedependent increase in plasma extravasation with the following order of potency: substance P> bradykinin = capsaicin. The effect of capsaicin (50 nmol) and substance P (5 nmol) was abolished by the tachykinin NKI receptor antagonist, CP-99,994 (8 pmol kg-', i.v.) (P<0.01), whereas CP-100,263 (8 pmol kg-', i.v.) the inactive enantiomer of CP-99, 994 was without effect. CP-99,994 inhibited by 70% (P<0.01) the effect of bradykinin. 3 The kinin B2 receptor antagonist, Hoe 140 (icatibant, 10 nmol kg-', i.v.) abolished the response to bradykinin (50 nmol) (P <0.01), but did not affect the responses to capsaicin (50 nmol) or substance P (5 nmol). Plasma extravasation induced by low pH medium (pH 1) was abolished by CP-99,994 (P<0.01) and by Hoe 140 (P<0.01). 4 The present findings suggest that: endogenous or exogenous tachykinins increase plasma extravasation in the guinea-pig conjunctiva by activation of NKI receptors; bradykinin-induced plasma extravasation is mediated by tachykinin release from sensory nerve endings; low pH media cause plasma extravasation via release of kinins that by activation of B2 receptors release tachykinins from sensory nerve endings.

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Nedocromil sodium (NS) and sodium cromoglycate (CS) (both applied locally into the conjunctival sac) reduced in a dose dependent manner plasma extravasation induced by topical bradykinin and by topical substance P (SP), NS being approximately ten times more potent than CS. Plasma extravasation induced by SP was unaffected by the histamine H(1) receptor antagonist, pyrilamine, which completely blocked the plasma extravasation induced by histamine. NS and CS reduced the plasma extravasation caused by the mechanical stimulation of the conjunctiva, a response that was not affected by the tachykinin NK(1) antagonist CP-(99.994). NS or CS did not affect the contraction of strips of the guinea-pig trachea in vitro caused by SP in the presence of the tachykinin NK(2) receptor antagonist SR-(48968). NS, more potently than CS, reduces the plasma extravasation caused by various inflammatory stimuli in the guinea-pig conjunctiva, without inhibiting tachykinin NK(1) receptors, but probably by acting at the level of the venular endothelium. However, an inhibitory action of NS and CS on neural transmission of sensory nerves cannot be excluded.