Identification of putative 5-HT4 receptors in guinea-pig ascending colon.
Experiments were carried out to characterise pharmacologically a neuronal, non-5-HT3, 5-hydroxytryptamine (5-HT) receptor in guinea-pig isolated ascending colon. In preparations pretreated with methysergide (1 microM) and ondansetron (10 microM), 5-HT (0.003-1 microM) produced repeatable concentration-related contractions of guinea-pig ascending colon with an EC50 value of 29 (20-41) nM. The responses to 5-HT could be antagonised substantially by tetrodotoxin (0.3 microM) and atropine (1 microM) indicating a neuronal cholinergically mediated effect. The 5-HT-induced response was mimicked by 5-methoxytryptamine and alpha-methyl-5-HT with equipotent concentration ratios of 26 and 28, respectively. In contrast, 2-methyl-5-HT, 8-OH-DPAT, sumatriptan, phenylbiguanide and 5-hydroxyindalpine had no agonist activity up to 10 microM. The benzamides, metoclopramide, cisapride, R,S-zacopride and renzapride, mimicked the contractile action of 5-HT, acting like partial agonists. ICS205-930 (3 microM) acted as a competitive antagonist against 5-HT and 5-methoxytryptamine with estimated pKB values of 6.4 and 6.7 respectively. ICS205-930 (1 microM) also antagonised responses to R,S-zacopride and renzapride. Ketanserin (1 microM), phenylbiguanide (10 microM) and sulpiride (1 microM) had no effect on responses to 5-HT. We conclude that the pharmacological characteristics of the receptor, which mediates contraction of guinea-pig ascending colon by activation of cholinergic nerves, are consistent with it being of the putative 5-HT4 receptor type.
Elswood
C J
CJ
Department of Gastrointestinal Pharmacology, Glaxo Group Research Ltd., Ware, Herts, U.K.
Bunce
K T
KT
Humphrey
P P
PP
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008784:Methysergide / Q000494:pharmacology; D008787:Metoclopramide / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D017294:Ondansetron; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D000077526:Tropisetron
D007093:Imidazoles; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013779:Tetrodotoxin; D017294:Ondansetron; D000077526:Tropisetron; D008787:Metoclopramide; D008784:Methysergide