Characterization of prejunctional muscarinic autoreceptors in the guinea-pig trachea.
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 (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.
Pharmakologisches Institut, Universität Mainz, F.R.G.
H
H
Kilbinger
R
R
Schneider
H
H
Siefken
D
D
Wolf
G
G
D'Agostino
D000109:Acetylcholine / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D002794:Choline / Q000302:isolation & purification / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D010276:Parasympatholytics / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D002794:Choline; D000109:Acetylcholine