Inhibitory effect of YM060 on 5-HT 3 receptor-mediated depolarization in colonic myenteric neurons of the guinea pig

Abstract

We used conventional intracellular recording methods to examine the effects of YM060 {(−)-( R)-5-[(1-methyl-1 H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole monohydrochloride}, a novel 5-HT 3 receptor antagonist, on 5-hydroxytryptamine (5-HT, serotonin)-evoked fast membrane depolarization in myenteric neurons of the guinea pig distal colon, and compared its potency to that of other 5-HT 3 receptor antagonists. Microapplication of 5-HT from fine-tipped pipettes evoked both fast and slowly activating depolarizing responses in 78% and 40% of colonic myenteric neurons, respectively. The selective 5-HT 3 receptor agonist 2-methyl-5-HT applied with short pressure pulses (100–300 ms) mimicked the fast but not the slow response. The 5-HT 3 receptor antagonists YM060, granisetron and ondansetron suppressed the 5-HT-evoked fast response in 98% of colonic myenteric neurons in a concentration-dependent manner with pIC 50 values of 8.62, 7.77 and 6.90, respectively. Methysergide and GR113808 did not affect the fast responses at concentrations sufficient to block 5-HT 1, 5-HT 2 and 5-HT 4 receptors, respectively. YM060 did not affect the slowly activating response to 5-HT or any other electrophysiological parameter of the neurons including resting membrane potential, input resistance and the amplitude of action potentials evoked by injection of depolarizing current. Stimulus-evoked fast excitatory postsynaptic potentials were unchanged by YM060 at concentrations up to 10 −8 M, excluding any possible local anesthetic or anticholinergic effects of YM060. The results confirm that the fast component of the two depolarizing responses to 5-HT in colonic myenteric neurons is mediated by 5-HT 3 receptors. They also demonstrate that YM060 is a potent and selective 5-HT 3 receptor antagonist.