The 5-HT4 receptor mediates 5-hydroxytryptamine-induced rise in short circuit current in the human jejunum in vitro.
BACKGROUND
5-Hydroxytryptamine (5-HT) is a potent intestinal secretagogue for chloride and a mediator of diarrhea in the carcinoid syndrome. 5-HT-induced chloride secretion is seen as a change in short circuit current (Isc) in muscle-stripped, chambered human jejunum. The aim of this study was to determine which 5-HT receptors mediate a 5-HT-induced change in Isc in the human jejunum.


METHODS
Segments of jejunum obtained from patients (n = 23) having obesity surgery were stripped of muscularis, and the mucosal sheets were mounted in flux chambers and short-circuited. By a cumulative method, a 5-HT-induced change in Isc was measured in the presence or absence of 0.2 mumol/L of neural conduction inhibitor tetrodotoxin or 5-HT receptor antagonists (n = 4 to 5): 10 mumol/L 5-HTP-DP, a 5-HT1p antagonist; 0.1 mumol/L ketanserin, a 5-HT2 antagonist; 0.3 mumol/L ondansetron, a 5-HT3 antagonist; 0.05 and 1 mumol/L ICS 205-930, a selective 5-HT3 antagonist at 0.05 mumol/L and also a 5-HT4 antagonist at 1 mumol/L or more; and 0.01 mumol/L GR 113808, a new selective 5-HT4 antagonist. A chloride-free solution or furosemide (100 mumol/L) was used to show the relationship of a 5-HT-induced change in Isc to chloride secretion.


RESULTS
Data were analyzed by ANOVA; p < 0.05 was significant. The chloride-free solution and furosemide significantly (p < 0.05) depressed the maximum change in Isc. Significant shifts occurred in the median effective concentration (1.5 +/- 0.2 mumol/L) for 5-HT in the presence of 1 mumol/L ICS 205-930 (3 +/- 0.2) and 0.03 mumol/L GR 113808 (2.4 +/- 0.2), but not in the presence of 5-HTP-DP (1.2 +/- 0.4), methysergide (1.8 +/- 0.3), ketanserin (2.4 +/- 0.6), ondansetron (1.6 +/- 0.1), 0.05 micron ICS 205-930 (1.3 +/- 0.1), or tetrodotoxin (1.4 +/- 0.4).


CONCLUSIONS
In the human jejunum in vitro, a 5-HT-induced change in Isc is mediated through a tetrodotoxin-insensitive pathway by the 5-HT4 receptor. Antagonists to this receptor may be useful in the treatment of diarrhea in carcinoid syndrome.
Budhoo
M R
MR
Department of Surgery, Medical College Virginia, Richmond 23298.
Kellum
J M
JM
D018118:Chloride Channels / Q000187:drug effects*; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D000077526:Tropisetron
D018118:Chloride Channels; D002712:Chlorides; D007211:Indoles; D011985:Receptors, Serotonin; D013449:Sulfonamides; D012701:Serotonin; D013779:Tetrodotoxin; D000077526:Tropisetron; C082871:GR 113808