Characterization of prejunctional muscarinic autoreceptors in the guinea‐pig trachea

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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.