Autoregulation of acetylcholine release from vagus nerve terminals through activation of muscarinic receptors in the dog trachea

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Abstract
1 The effects of pirenzepine and gallamine on the membrane and contractile properties of smooth muscle cells and on excitatory neuro-effector transmission in the dog trachea were investigated by means of microelectrode, double sucrose gap and tension recording methods. 2 Pirenzepine (10−7 m) and gallamine (10−5 m) had no effect on the resting membrane potential or the input resistance of the smooth muscle cells. 3 Pirenzepine (10−10-10−9 m) and gallamine (10−7 m) enhanced the amplitude of twitch contractions evoked by field stimulation in the combined presence of indomethacin (10−5 m) and propranolol (10−6 m). At higher concentrations pirenzepine (10−8 m) inhibited the twitch contractions in a dose-dependent manner. Both pirenzepine and gallamine in doses over 10−7 and 10−5 m, respectively, reduced muscle tone. 4 Pirenzepine (10−10-10−9 m) and gallamine (10−7 m) enhanced the amplitude of excitatory junction potentials (e.j.ps) evoked by field stimulation (single or repetitive stimulation). However, a high concentration of pirenzepine (10−8 m) reduced the amplitude of e.j.ps. In parallel with its action on e.j.ps, pirenzepine (over 10−9 m) reduced the response of smooth muscle cells to acetylcholine (ACh), in a dose-dependent manner. Gallamine (5 × 10−5 m) markedly enhanced the amplitude of e.j.ps but also reduced the response of muscle cells to ACh. 5 ACh (10−10-10−9 m) inhibited twitch contractions evoked by field stimulation, with a slight increase of resting tension. 6 Gallamine enhanced the summation of e.j.ps during repetitive field stimulation at a high frequency (20 Hz), but was without effect on the depression phenomena of e.j.ps observed during double stimulus experiments at different time intervals (5–60 s). 7 These results indicate that both pirenzepine and gallamine have dual actions on pre- and postjunctional muscarinic receptors in dog tracheal tissue. At low concentrations both agents potentiate excitatory neuro-effector transmission, presumably due to enhancement of release of ACh from vagal nerve terminals through blockade of a negative auto-regulatory process activated by endogenous ACh. At higher concentrations, these agents inhibit the response of smooth muscle cells to ACh through post-junctional muscarinic receptors and relaxation of the muscle tissue occurs.