5-HT4 receptors located on cholinergic nerves in human colon circular muscle.
5-Hydroxytryptamine 4 (5-HT4) receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5-HT4 receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5-HT4 receptor-mediated stimulation of human colon CM contractile activity. 5-HT4 receptor ligands were tested on electrical field stimulation (EFS)-induced contractions of human colonic muscle strips cut in the circular direction (called 'whole tissue' strips). Additionally, after incubation of tissues with [3H]-choline these compounds were tested on EFS-induced release of tritium in whole tissue strips and in 'isolated' CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS-induced contractions of whole tissue CM strips. Prucalopride (0.3 micromol L-1) evoked a heterogenous response on EFS-induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS-induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS-induced tritium and [3H]-acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5-HT4 receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5-HT4 receptors on cholinergic nerves within the CM of human colon.
Leclere
P G
PG
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
Prins
N H
NH
Schuurkes
J A J
JA
Lefebvre
R A
RA
D000109:Acetylcholine / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000294:innervation* / Q000378:metabolism / Q000502:physiology*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000294:innervation* / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D001572:Benzofurans; D004791:Enzyme Inhibitors; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; D019335:Nitroarginine; D013779:Tetrodotoxin; D019001:Nitric Oxide Synthase; D000109:Acetylcholine