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 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.

Effect Of Experimental Diabetes On Gaba‐Mediated Inhibition Of Neurally Induced Contractions In Rat Isolated Trachea

“…In contrast with the findings of Tamaoki et al, 8 but in agreement with the findings of others in tissues such as trachea, 12,41 lung, 9 ileum, 42,43 distal colon 44 muscle 45 from rats, 43,45 guinea-pigs 8,9,12,41,42,45,46 and rabbits, 44 the effect of GABA appeared to be mediated by the GABAB receptor because it was mimicked by baclofen and antagonized by phaclofen. The GABAA receptor does not appear to be involved in this effect, because it was neither mimicked by 3-APS nor modified by bicuculline.…”

GABAAreceptors are expressed and facilitate relaxation in airway smooth muscle

“…Conversely, GABA receptors have never been described in airway smooth muscle itself. It has been known for some time that GABA B -specific agents decrease electrically fieldstimulated airway constriction by modulating acetylcholine release from parasympathetic nerves (13,14,33,53,55). This is mediated by a presynaptic inhibition of acetylcholine release by GABA B receptors.…”

Rat Submandibular Gland Perfusion Method for Clarifying Inhibitory Regulation of GABAA Receptor

“…Their studies led cumulative investigations on the response to GABA and GABA agonists in a series of peripheral organs and a number of suggestive studies on the modulator role for GABA in the heart (5), the lung (6), and in the regulation of the peristaltic reflex (7) and adrenal catecholamine secretion (8). Since 1995, we have shown that inhibitory mechanisms in rat salivary gland were regulated by a GABA A receptor (GABA A -R)-chloride ion channel complex: it was demonstrated that GABA and its biosynthetic and metabolic enzyme existed in rat salivary gland (9,10); and GABA and benzodiazepines accelerated 36 Cl − influx (11) and inhibited amylase release (12) in rat parotid gland acinar cells in vitro.…”