Further Evidence for Prejunctional GABA-B Inhibition of Cholinergic and Peptidergic Bronchoconstriction in Guinea Pigs: Studies with New Agonists and Antagonists

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Abstract
We examined the effect of the potent and selective GABA-B agonists, baclofen, 3-aminopropylphosphinic acid (3-APPi) and 3-aminopropyl (methyl) phosphinic acid (SKF 97541), and the GABA-B antagonists, 3-aminopropyl (diethoxymethyl) phosphinic acid (CGP 35348), 2-hydroxysaclofen and 3-aminopropylphosphonic acid (3-APPA) on cholinergic and peptidergic contractile responses in the airways of guinea pigs. Electrical field stimulation of the isolated guinea pig trachea produced cholinergic contractions that were inibited by baclofen (EC50 = 5 μmol/l), 3-APPi (EC50 = 0.3 μmol/l) and SKF 97541 (EC50= 0.4 μmol/l). The inhibition by baclofen (30 μmol/l) was reduced by CGP 35348 (IC50 = 65 μmol/l), 2-hydroxysaclofen (IC50 = 273 μmol/l) and 3-APPA (IC50 = 355 μmol/l). The in vivo cholinergic bronchoconstrictor response to vagal nerve stimulation (5 V, 20 Hz, 0.5 ms for 5 s) was attenuated by intravenous baclofen (ED50 = 1.7 mg/kg), 3-APPi (ED50 = 0.9 mg/kg) and SKF 97541 (ED50 = 0.2 mg/kg). The inhibition of vagally induced bronchoconstriction by baclofen was blocked by CGP 35348 (1-10 mg/kg, i.v.) and 2-hydroxysaclofen (10 mg/kg, i.v.). A cholinergic bronchoconstriction induced by CNS stimulation (400 μA, 2 ms, 32 Hz for 5 s) was inhibited by baclofen (ED50 = 5.1 mg/kg, i.v.) and 3-APPi (ED50 = 0.6 mg/kg, i.v.). The effect of baclofen was attenuated by 3-APPA (5 mg/kg, i.v.). A peptidergic bronchoconstriction was evoked by intravenous nicotine (1 mg/kg) in animals treated with ipratropium and phosphoramidon. This bronchoconstriction was inhibited by baclofen (ED50 = 1.2 mg/kg, i.v.) and 3-APPi (ED50 = 0.6 mg/kg, i.v.), and the effect of baclofen was attenuated by 3-APPA (5 mg/ kg, i.v.). Therefore, a GABA-B receptor-mediated inhibition of neurally induced cholinergic and peptidergic airway constriction was demonstrated by using baclofen and the newer GABA-B agonists, 3-APPi and SKF 97541. The effects of baclofen were reduced by GABA-B antagonists including CGP 35348, the most potent antagonist available. These results support the hypothesis that a peripheral GABA-B receptor is an inhibitory neuromodulator in the airways.

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