Modulation of non‐adrenergic, non‐cholinergic neural bronchoconstriction in guinea‐pig airways via GABAB‐receptors

Abstract

1 Evidence suggests that γ-aminobutyric acid (GABA) and its receptors 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.