1. To study the mechanisms involved in the action of
Z-338, a newly synthesized gastroprokinetic agent, experiments were performed with the paratracheal
ganglion cells acutely dissociated from 2-week-old Wistar rats. The effects of
Z-338 on both nicotinic and
muscarinic responses of the
ganglion cells were studied by
nystatin perforated patch recording configuration under the current- and voltage-clamp conditions. 2.
Acetylcholine (ACh) or
nicotine, and
muscarine or
oxotremorine-M (OX-M) induced membrane depolarization with rapid and slow time courses respectively, followed by repetitive generation of action potentials in the
ganglion cell. Corresponding to the membrane depolarization induced by
cholinergic agents, ACh induced biphasic inward currents with rapid and slow time courses under the voltage-clamp condition.
Nicotine and
muscarine or OX-M evoked inward currents with rapid and slow time courses, respectively. The rapid and slow inward currents were accompanied by increase and decrease in the membrane conductance, respectively. In addition, OX-M dose-dependently suppressed the M-type K(+) current evoked in response to hyperpolarizing voltage-steps from V(H) of -25 mV to -50 mV, indicating that the activation of
muscarinic acetylcholine receptors inhibits M-type K(+) current, thus inducing inward current in the
ganglion cell. 3.
Z-338 competitively suppressed the inward currents induced by OX-M through M(1)
ACh receptor, and uncompetitively suppressed the currents induced by
nicotine. 4. The inhibitory actions of
Z-338 on the membrane depolarization and corresponding inward currents mediated by M(1)-muscarinic and neuronal nicotinic
ACh receptors in the isolated
ganglion cells were discussed in relation to the inhibitory actions on
autoreceptors in the parasympathetic nerve terminals, which would explain the gastroprokinetic actions of
Z-338.