Characterization of prejunctional muscarinic autoreceptors in the guinea‐pig trachea

Abstract

1 The effects of ten muscarinic antagonists on electrically evoked [³H]‐acetylcholine release and muscle contraction were compared in an epithelium‐free preparation of the guinea‐pig trachea that had been preincubated with [³H]‐choline. 2 The M₃‐selective antagonists UH‐AH 37, 4‐diphenyl‐acetoxy‐N‐piperidine methobromide and para‐fluorohexahydrosiladiphenidol were more potent in reducing the contractile response than in facilitating the evoked [³H]‐acetylcholine release. Hexahydrosiladiphenidol did not discriminate between pre‐ and postjunctional effects. The rank order of the postjunctional potencies of the ten antagonists as well as the postjunctional pA₂ values obtained for hexahydrosiladiphenidol (7.95) and AQ‐RA 741 (7.08) identified the muscular receptor as an M₃ subtype. 3 The M₂‐selective antagonists methoctramine, AF‐DX 116 and AQ‐RA 741 were more potent in facilitating the evoked [³H]‐acetylcholine release than in inhibiting the contractile response. The increase in release by low concentrations of methoctramine, AF‐DX 116 and AQ‐RA 741 was paralleled by an enhancement of the stimulation‐evoked contractions. 4 Comparison of the pre‐ and postjunctional potencies of the M₁‐, M₂‐ and M₃‐selective antagonists suggests that autoinhibition of acetylcholine release is mediated via an ‘M₂‐like’ receptor which differs from the cardiac type M₂ receptor in its relatively high affinity for hexahydrosiladiphenidol.