Modulation of non-adrenergic, non-cholinergic neural bronchoconstriction in guinea-pig airways via GABA(B)-receptors

1. Evidence suggests that γ-aminobutyric acid (GABA) and its receptor are present in the peripheral nervous system. We have now investigated the effect of GABA and related substances on non-adrenergic, non-cholinergic (NANC) neurally-evoked bronchoconstriction in the anaesthetised guinea-pig. 2. Bilateral vagal stimulation (5 V, 5 ms, 3 or 5 Hz) for 30 s, after propranolol (1 mg kg^-1 i.v.) and atropine (1 mg kg^-1 i.v.) evoked a NANC bronchoconstrictor response manifest as a mean tracheal pressure rise of 21.9 ± 1.04 cmH₂O (n = 70). The bronchoconstrictor response was reproducible for any given animal. 3. GABA (10 μg-10 mg kg^-1 i.v.) did not alter basal tracheal pressure but reduced the NANC bronchoconstrictor response to vagal stimulation in a dose-dependent manner (ED₅₀ = 186 μg kg^-1 with a maximal inhibition of 74 ± 3.4% at 10 mg kg^-1). Neither the opioid antagonist naloxone (1 mg kg^-1 i.v.) nor the α-adrenoceptor antagonist phentolamine (2.5 mg kg^-1 i.v.) had any significant effect on the inhibitory response produced by GABA (500 μg kg^-1). 4. GABA-induced inhibition was not antagonised by the GABA(A)-antagonist bicuculline (2 mg kg^-1 i.v.). 5. The GABA(B)-agonist baclofen (10 μg-3 mg kg^-1 i.v.) caused a dose-dependent inhibition of the NANC response (ED₅₀ = 100 μg kg^-1 with a maximal inhibition of 35.5 ± 2.8% at 3 mg kg^-1). The GABA(A)-agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-C] pyridin-3-ol (THIP), also inhibited the NANC bronchoconstrictor response. However, the dose of THIP required for this effect was high (3 mg kg^-1) and the effect (<10% inhibition) was small. 6. Substance P (SP; 5 μg kg^-1 or 25 μg kg^-1), produced a bronchoconstrictor response equivalent to that produced by NANC vagal stimulation. This response was significantly increased by injection of GABA. Baclofen had no significant effect on responses evoked by exogenous SP. 7. We conclude that GABA inhibits the release of transmitter from NANC nerves via an action at GABA(B) receptors and that GABA might play a role in the regulation of neurogenic responses in the airways.