Increased defaecation caused by 5-HT4 receptor activation in the mouse.
The precursor to 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan, (5-HTP, 5-50 mg.kg-1) administered subcutaneously (s.c.) to conscious, fed mice caused a dose dependent increase in faecal pellet and fluid output. To avoid provoking watery diarrhoea, all experiments were performed using 5-HTP at 10 mg.kg-1. This dose caused maximal increases in the fluid content (471 +/- 41%) and number of formed faecal pellets defaecated (328 +/- 13% n = 25), 10 and 20 min respectively after administration, when compared to saline-treated mice. In both saline- and 5-HTP-treated mice methiothepin, ketanserin, mianserin and granisetron reduced defaecation at high s.c. doses (100 micrograms.kg-1 or 1000 micrograms.kg-1). The 5-HT4 receptor antagonists, DAU 6285 (endo-6-methoxy-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H-benzimidazole-1-carboxylate hydrochloride), SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) and SB 204070 ([1-butyl-4-piperidinylmethyl]-8-amino-7-chloro-1,4-benzodioxan -5- carboxylate), had no effects when administered s.c. to saline-treated mice, but dose-dependently inhibited the 5-HTP-evoked responses. Only SB 204070 at 1000 micrograms.kg-1 completely inhibited the responses to 5-HTP returning them to normal levels. We conclude that SB 204070 is a potent antagonist for the investigation of 5-HT4 receptor function in both normal and disturbed gastrointestinal activity.
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SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Smith
M I
MI
Bywater
D
D
Gaster
L M
LM
Sanger
G J
GJ
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000818:Animals; D003672:Defecation / Q000187:drug effects*; D004146:Dioxanes / Q000494:pharmacology*; D005243:Feces / Q000737:chemistry; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014867:Water / Q000032:analysis; D062366:para-Aminobenzoates
D004146:Dioxanes; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D062366:para-Aminobenzoates; D014867:Water; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; C084858:SB 204070A; D044422:Receptors, Serotonin, 5-HT4; D006916:5-Hydroxytryptophan; D010129:4-Aminobenzoic Acid