Pre- and postjumntional muscarinic receptor subtypes in dog airways

To examine muscarinic receptor subtypes involved in cholinergically mediated contractions of the airway, we studied the effects of the M₁-selective antagonist, pirenzepine, the M₂-selective antagonist, AF-DX 116, the M₃-selective antagonist, 4-diphenyl-acetoxy-N-methylpiperidine (4-DAMP) methiodide, and the non-selective antagonist, atropine, on acetylcholine (ACh)- and electrically induced contractions in dog bronchi and bronchioles. The relative potencies of the antagonists based on IC₅₀ values of each antagonist for contractions induced by the two concentrations of ACh that produced 50% of the maximum (ed₅₀) and the maximum (ED_max) contractions and the pA₂ values were atropine ≥ 4-DAMP methiodide > pirenzepine = AF-DX 116 in both the bronchi and bronchioles. The IC₅₀ and pA₂ values of each antagonist did not differ significantly between the bronchi and bronchioles. 4-DAMP methiodide significantly inhibited the contractile response to electrical field stimulation (EFS) at 5 Hz at concentrations that did not alter the contractile responses to exogenous ACh in both the bronchi and bronchioles, whereas pirenzepine, AF-DX 116 and atropine inhibited the EFS-induced contraction only at the concentrations that reduced the contraction induced by exogenous ACh. The present results suggest that the cholinergic contraction is mediated via the postsynaptic receptor M ₃, based on functional potencies of muscarinic antagonists and presynaptic receptor auto-facilitatory M₃, based on the suppression of the contractile response to EFS by 4-DAMP methiodide in central and peripheral airways.