GABA-mediated inhibition of the anaphylactic response in the guinea-pig trachea

摘要

1. In sensitized guinea-pigs, the effects of γ-aminobutyric acid (GABA) and GABAmimetic drugs have been investigated on tracheal segments contracted by cumulative application of an allergen (ovoalbumin, OA) and on serosal mast cells. The same drugs have also been tested on activation of alveolar macrophages isolated from unsensitized guinea-pigs. 2. Superfusion with GABA (1-1000 μM) reduced the contraction intensity of tracheal strips. The effect of GABA (100 μM) was not affected by the carrier blockers, nipecotic acid and β-alanine (300 μM each). It was mimicked by the GABA_B agonist (-)-baclofen (100 μM) but not 3-aminopropanephosphinic acid (100 μM, 3-APA). The GABA_A agonist, isoguvacine (100 μM) did not exert any effect. GABA (10 μM)-induced inhibition of tracheal contractions was reduced by the GABA_B antagonist, 2-hydroxysaclofen (100 μM, 2-HS), but not by the GABA_A antagonist, bicuculline (30 μM). 3. The reduction in contraction intensity induced by GABA (100 μM) was prevented by a 40 min preincubation of tracheal strips with capsaicin (10 μM), but not tetrodotoxin (TTX, 0.3 μM). The effect of GABA (1000 μM) was absent after preincubation with indomethacin (2.8 μM) but unmodified when nordihydroguaiaretic acid (NDGA, 3.3 μM) was used. Finally, removal of the epithelium prevented the GABA effect. 4. Anaphylactic histamine release from serosal mast cells isolated from sensitized animals was not affected either by GABA (10-1000 μM) or the selective receptor agonists (-)-baclofen (0.1-1000 μM) and isoguvacine (10-1000 μM). The release of platelet-activating factor (PAF) from alveolar macrophages stimulated by formyl-Met-Leu-Phe (FMLP; 1 μM) was modified neither by GABA (100 μM) nor by (-)-baclofen (100 μM). 5. In conclusion, these data show that GABA can inhibit allergic phenomena in the guinea-pig airways through activation of GABA_B receptors. An involvement of neuropeptidergic sensory structures is suggested but a role for epithelial cells and arachidonate metabolites is not definitely proved.