Further evidence for prejunctional GABA-B inhibition of cholinergic and peptidergic bronchoconstriction in guinea pigs: studies with new agonists and antagonists.

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 inhibited by baclofen (EC50 = 5 mumol/l), 3-APPi (EC50 = 0.3 mumol/l) and SKF 97541 (EC50 = 0.4 mumol/l). The inhibition by baclofen (30 mumol/l) was reduced by CGP 35348 (IC50 = 65 mumol/l), 2-hydroxysaclofen (IC50 = 273 mumol/l) and 3-APPA (IC50 = 355 mumol/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 microA, 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.(ABSTRACT TRUNCATED AT 250 WORDS)