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 microM) reduced the contraction intensity of tracheal strips. The effect of GABA (100 microM) was not affected by the carrier blockers, nipecotic acid and beta-alanine (300 microM each). It was mimicked by the GABAB agonist (-)-baclofen (100 microM) but not 3-aminopropanephosphinic acid (100 microM, 3-APA). The GABAA agonist, isoguvacine (100 microM) did not exert any effect. GABA (10 microM)-induced inhibition of tracheal contractions was reduced by the GABAB antagonist, 2-hydroxysaclofen (100 microM, 2-HS), but not by the GABAA antagonist, bicuculline (30 microM). 3. The reduction in contraction intensity induced by GABA (100 microM) was prevented by a 40 min preincubation of tracheal strips with capsaicin (10 microM), but not tetrodotoxin (TTX, 0.3 microM). The effect of GABA (1000 microM) was absent after preincubation with indomethacin (2.8 microM) but unmodified when nordihydroguaiaretic acid (NDGA, 3.3 microM) 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 microM) or the selective receptor agonists (-)-baclofen (0.1-1000 microM) and isoguvacine (10-1000 microM). The release of platelet-activating factor (PAF) from alveolar macrophages stimulated by formyl-Met-Leu-Phe (FMLP; 1 microM) was modified neither by GABA (100 microM)nor by (-)-baclofen (100microM).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.
Gentilini
G
G
Department of Preclinical and Clinical Pharmacology Mario Aiazzi Mancini, University of Florence, Italy.
Franchi-Micheli
S
S
Mugnai
S
S
Bindi
D
D
Zilletti
L
L
D000707:Anaphylaxis / Q000139:chemically induced*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D002211:Capsaicin / Q000494:pharmacology; D004347:Drug Interactions; D004847:Epithelial Cells; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D010047:Ovalbumin / Q000633:toxicity; D010972:Platelet Activating Factor / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives*; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*; D015091:beta-Alanine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
D018755:GABA Agonists; D018756:GABA Antagonists; D009557:Nipecotic Acids; D010972:Platelet Activating Factor; D018079:Receptors, GABA; D015091:beta-Alanine; C030278:nipecotic acid; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010047:Ovalbumin; D011392:Proline; C010983:homoproline; D002211:Capsaicin