Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors.
Nearly 30% of patients treated with metformin experience gastrointestinal side effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether metformin induces 5-HT release from the intestinal mucosa. In 40% of tissue biopsy specimens of human duodenal mucosa, metformin (1, 10, and 30 microM) caused an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak increases in 5-HT outflow were observed after 10-15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin (1 microM) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin-evoked release was not affected by scopolamine + hexamethonium, propranolol, the 5-HT3 receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 microM), somatostatin (1 microM) further reduced metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects of selective 5-HT3 receptor agonists to which metformin (N-N-dimethylbiguanide) is structurally related, we investigated whether metformin directly interacts with 5-HT3 receptors. Receptor binding (inhibition of [3H]-GR65630 binding) and agonist effects (stimulation of [14C]-guanidinium influx) at 5-HT3 receptors were studied in murine neuroblastoma N1E-115 cells, which express functional 5-HT3 receptors. Metformin up to 0.3 mM failed to inhibit [3H]-GR65630 binding and to modify displacement of [3H]-GR65630 binding induced by 5-HT. 5-HT (3 microM) stimulated the influx of [14C]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ substance P-induced influx of [14C]-guanidinium. Our results indicate that metformin induces 5-HT3 receptor-independent release of 5-HT from human duodenal mucosa via neuronal and non-neuronal mechanisms. Part of the gastrointestinal side effects observed during treatment with metformin could, thus, be produced by the release of 5-HT and other neurotransmitter substances within the duodenal mucosa.
Cubeddu
L X
LX
Department of Pharmacology, School of Pharmacy, Central University of Venezuela.
Bönisch
H
H
Göthert
M
M
Molderings
G
G
Racké
K
K
Ramadori
G
G
Miller
K J
KJ
Schwörer
H
H
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004386:Duodenum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004759:Enterochromaffin Cells / Q000187:drug effects / Q000378:metabolism; D019791:Guanidine / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D008687:Metformin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007004:Hypoglycemic Agents; D007093:Imidazoles; D007211:Indoles; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; C059068:GR 65630; D012701:Serotonin; D008687:Metformin; D019791:Guanidine