Synergy between 5‐HT₄ receptor activation and acetylcholinesterase inhibition in human colon and rat forestomach

Abstract

5-Hydroxytryptamine (5-HT4) receptor agonists increase gastrointestinal (GI) motility by enhancing enteric acetylcholine release which is then metabolized by acetylcholinesterase (AChE) to inactive metabolites. As both AChE inhibitors and, more usually, 5-HT4 receptor agonists are used to increase GI motility, an understanding of how these two different types of drugs might interact becomes of great importance. Our aim was to investigate the hypothesis that the effect of AChE inhibition will synergise with the ability of 5-HT4 receptor agonism to increase cholinergic activity, leading to an effect greater than that evoked by each action alone. We tested the activity of the 5-HT4 receptor agonist, prucalopride (10 nmol L(-1)-30 micromol L(-1)) and an AChE inhibitor, neostigmine (1 nmol L(-1)-10 micromol L(-1)) on cholinergically mediated contractions elicited by electrical field stimulation of human isolated colon circular muscle and rat isolated forestomach longitudinal strips. The experiments with human colon were performed in the presence of an inhibitor of nitric oxide synthase (N(omega)-nitro-l-arginine methyl ester, 300 micromol L(-1)). Prucalopride and neostigmine both enhanced cholinergic contractions in both tissues. The effect of prucalopride was inhibited in both tissues by SB-204070, a 5-HT4 receptor antagonist. In the presence of a minimum effective concentration of neostigmine (30 nmol L(-1)) and a submaximum concentration of prucalopride (3 micromol L(-1)) the enhancement of contractions was greater than either compound alone in both tissues. These data demonstrate that the combination of prucalopride and neostigmine potentiate cholinergic contractions more than their arithmetic sum of their individual values. The results suggest that a synergy between 5-HT4 receptor agonism and AChE inhibition could be established pharmacologically which could be utilized as a novel prokinetic approach to functional GI disorders.

Increased colonic transit in rats produced by a combination of a cholinesterase inhibitor with a 5‐HT4 receptor agonist

“…Importantly, these findings suggest that a combination of subeffective doses of each compound is capable of producing a statistically significant synergistic promotility effects in this model. Our in vivo finding in the rat is in agreement with a recent study in which synergy between another 5‐HT 4 receptor agonist, prucalopride and neostigmine was observed in vitro in isolated segments of human colon and rat fore‐stomach 16 . In these experiments at a submaximal concentration of prucalopride and a minimally effective concentration of neostigmine were investigated and the magnitude of the contractile responses was greater than that observed with either compound alone in muscle strips from the human colon and from rat fore‐stomach.…”

“…This is an expected response to a partial 5‐HT 4 receptor agonist such as tegaserod compared to a cholinesterase inhibitor in this in vivo system. A similar observation was made using an in vitro muscle strip preparation where a lesser effect was observed with the 5‐HT 4 agonist, prucalopride compared to neostigmine in response to electrical stimulation 16 …”

“…As AChE inhibitors and 5‐HT 4 receptor agonists work independently at cholinergic synapses to elevate synaptic levels of ACh and thus amplify cholinergic neurotransmission, we aimed to investigate the potential synergy that might occur with a combination of a 5‐HT 4 agonist and a cholinesterase inhibitor on intestinal transit. A recently published study utilized isolated nerve muscle strips prepared from human colon and from rat fore‐stomach exposed to the 5‐HT 4 agonist, prucalopride, and also neostigmine demonstrated a synergistic effect of the drug combination on the contractile responses to electrical field stimulation 16 . With the exception of one study in dogs which showed that addition of neostigmine increased smooth muscle contractions in the upper GI tract following treatment with cisapride, which has some 5‐HT 4 agonist activity, there are no reports which demonstrate such synergy in vivo , particularly for enhancing colonic motility.…”

Drug discovery approaches to irritable bowel syndrome

“…The effects on colonic propulsive motility can be measured by transit time of artificial fecal pellets [93]. The latter has been used to characterize prokinetic actions of 5-HT 4 receptor agonists such as prucalopride and mosapride [94][95][96].…”

Distribution of 5-HT3, 5-HT4, and 5-HT7Receptors Along the Human Colon

“…[1][2][3][4][5] Inflammation contributes to these disorders due to underlying inflammatory states in coeliac disease and inflammatory bowel disease and in part because it modulates serotonin levels. 1,4,6 The serotonin (5-HT) 4 receptor is expressed in several different cell types in the human colon [7][8][9][10][11][12][13][14][15][16] where it stimulates intestinal activity (ie, prokinetic action) and is a target for treating constipation predominant IBS (IBS-C) and chronic constipation. The 5-HT 4 receptor partial agonist, tegaserod was used for treatment of IBS-C until withdrawn in 2007 as it was associated with rare adverse cardiovascular effects.…”