Neuropharmacology of the muscarinic antagonist telenzepine in myenteric ganglia of the guinea-pig small intestine

Abstract

Intracellular recording methods were used to investigate the actions of the putative M i muscarinic receptor antagonist telenzepine on the electrical and synaptic behavior of myenteric neurons. Telenzepine had no effect on resting membrane potential. input resistance, excitability and antidromic potentials in both AH/type 2 and S/type l neurons, when applied in concentrations of 0.1–2000 nM, although higher concentrations (10–100 μM) did have a significant non-specific effect on the postsynaptic membrane. Micromolar concentrations of telenzepine (1–2 M) had no effect on excitatory responses to substance P. vasoactive intestinal peptide, the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium or the nicotinic action of acetylcholine. Nicotinic fast excitatory postsynaptic potentials were also unaffected by 2 μiM telenzepine. In contrast, at submicromolar concentrations (100 nM). telenzepine abolished responses to either muscarine or the muscarinic component of the acetylcholin0e response. The excitatory effect of muscarine at postsynaptic M 1 receptors was dese dependently inhibited by telenzepine (0.1–1000 nM) at concentrations which had no effect on the electrical properties of the cells. This effect was slowly reversible, usually requiring more than 60 min for significant recovery. The threshold dose of telenzepine as an antagonist of the muscarinic depolarization in AH/type 2 neurons was in the range of 0.1–1 nM. The IC 50 concentration of telenzepine needed to abolish the response was 8.5 nM. A small proportion of stimulus-evoked slow excitatory postsynaptic potentials in both AH/type 2 and S/type 1 cells were abolished by 1 μM telenzepine, while the majority of them remained unaffected, indicating that some slow excitatory postsynaptic potentials are mediated by the muscarinic action of released acetylcholine. The antagonist profile displayed by telenzepine at postsynaptic M 1 receptors confirms that this compound has specificity and high affinity for the postsynaptic m 1 receptors located on myenteric neurons of the small intestine.