GABA-MEDIATED INHIBITION OF THE ANAPHYLACTIC RESPONSE IN THE GUINEA-PIG TRACHEA

1 In sensitized guinea-pigs, the effects of gamma-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 mu M) reduced the contraction intensity of tracheal strips. The effect of GABA (100 mu M) was not affected by the carrier blockers, nipecotic acid and beta-alanine (300 mu M each). It was mimicked by the GABA, agonist (-)-baclofen (100 mu M) but not 3-aminopropanephosphinic acid (100 mu M, 3-APA). The GABAA agonist, isoguvacine (100 mu M) did not exert any effect. GABA (10 mu M)induced inhibition of tracheal contractions was reduced by the GABA(B) antagonist, 2-hydroxysaclofen (100 mu M, 2-HS), but not by the GABA(A) antagonist, bicuculline (30 mu M). 3 The reduction in contraction intensity induced by GABA (100 mu M) was prevented by a 40 min preincubation of tracheal strips with capsaicin (10 mu M), but not tetrodotoxin (TTX, 0.3 mu M). The effect of GABA (1000 mu M) was absent after preincubation with indomethacin (2.8 mu M) but unmodified when nordihydroguaiaretic acid (NDGA, 3.3 mu M) 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 mu M) or the selective receptor agonists (-)-badofen (0.1-1000 mu M) and isoguvacine (10-1000 mu M). The release of platelet-activating factor (PAF) from alveolar macrophages stimulated by formyl-Met-Leu-Phe (FMLP; 1 mu M) was modified neither by GABA (100 CIM) nor by (-)-baclofen (100 mu M). 5 In conclusion, these data show that GABA can inhibit allergic phenomena in the guinea-pig airways through activation of GABAB receptors. An involvement of neuropeptidergic sensory structures is suggested but a role for epithelial cells and arachidonate metabolites is not definitely proved.