Combined blockade of 5-HT3- and 5-HT4-serotonin receptors inhibits colonic functions in conscious rats and mice.
We have already reported that 5-hydroxytryptamine3 (5-HT3) receptor antagonists failed to modify 5-HT-accelerated colonic transit in conscious rats, but the 5-HT3 and 5-HT4 receptor dual antagonist FK1052 prevented the enhancement. In this study, the inhibitory effect on the stimulated colonic transit was not also observed with 5-HT4 receptor antagonists (SDZ205-557 and SB204070) in freely moving rats with chronic cannulas implanted into the proximal colon. In contrast, combined antagonism by simultaneous administration of ondansetron and the 5-HT4 receptor antagonist exerted a drastic inhibitory effect on the propulsive motility. Furthermore, we examined the effect of 5-HT receptor antagonists on 5-HT-induced fluid secretion in mice. Although none of these selective 5-HT receptor antagonists (YM060 and ondansetron as 5-HT3 receptor antagonist, SB204070 as 5-HT4 receptor antagonist) by itself produced a great inhibition of the 5-HT-induced diarrhea, the combination of a 5-HT3 receptor antagonist and a 5-HT4 receptor antagonist markedly reduced the diarrhea. These data suggest that 5-HT-accelerated colonic motility and 5-HT-evoked fluid secretion are mediated by both 5-HT3 and 5-HT4 receptors and that the pathways activated by these receptors may collaborate.
Nagakura
Y
Y
Pharmacological Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Kontoh
A
A
Tokita
K
K
Tomoi
M
M
Shimomura
K
K
Kadowaki
M
M
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D004146:Dioxanes / Q000494:pharmacology; D008297:Male; D051379:Mice; D017294:Ondansetron / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000494:pharmacology*; D062366:para-Aminobenzoates
D004146:Dioxanes; D010880:Piperidines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D062366:para-Aminobenzoates; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; C084858:SB 204070A; D044422:Receptors, Serotonin, 5-HT4; D017294:Ondansetron; D010129:4-Aminobenzoic Acid