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Synergy between 5‐HT 4 receptor activation and acetylcholinesterase inhibition in human colon and rat forestomach
Author(s) -
Cellek S.,
Thangiah R.,
Jarvie E. M.,
Vivekanandan S.,
Lalude O.,
Sanger G. J.
Publication year - 2008
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/j.1365-2982.2007.01062.x
Subject(s) - neostigmine , cholinergic , agonist , acetylcholine , endocrinology , acetylcholinesterase , receptor antagonist , medicine , chemistry , acetylcholinesterase inhibitor , receptor , pharmacology , antagonist , biology , biochemistry , enzyme
5‐Hydroxytryptamine (5‐HT 4 ) 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‐HT 4 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‐HT 4 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‐HT 4 receptor agonist, prucalopride (10 nmol L −1 –30 μmol L −1 ) and an AChE inhibitor, neostigmine (1 nmol L −1 –10 μmol 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 ω ‐nitro‐ l ‐arginine methyl ester, 300 μmol 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‐HT 4 receptor antagonist. In the presence of a minimum effective concentration of neostigmine (30 nmol L −1 ) and a submaximum concentration of prucalopride (3 μmol 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‐HT 4 receptor agonism and AChE inhibition could be established pharmacologically which could be utilized as a novel prokinetic approach to functional GI disorders.