Synergy between 5-HT4 receptor activation and acetylcholinesterase inhibition in human colon and rat forestomach.
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.
Cellek
S
S
Neurology and Gastroenterology Centre of Excellence in Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK. selim.2.cellek@gsk.com
Thangiah
R
R
Jarvie
E M
EM
Vivekanandan
S
S
Lalude
O
O
Sanger
G J
GJ
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004357:Drug Synergism; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013270:Stomach / Q000187:drug effects / Q000201:enzymology
D002800:Cholinesterase Inhibitors; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D000110:Acetylcholinesterase