Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors.

Abstract

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.

• Authors: L X Cubeddu, H Bönisch, M Göthert, G Molderings, K Racké, G Ramadori, K J Miller, H Schwörer
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 361 Issue 1 Pg. 85-91 (Jan 2000) ISSN: 0028-1298 [Print] Germany
• PMID: 10651152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoglycemic Agents
• Imidazoles
• Indoles
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT3
• GR 65630
• Serotonin
• Metformin
• Guanidine

Topics

• Animals
• Binding, Competitive (drug effects)
• Cell Membrane (metabolism)
• Chromatography, High Pressure Liquid
• Duodenum (cytology, drug effects, metabolism)
• Enterochromaffin Cells (drug effects, metabolism)
• Guanidine (metabolism)
• Humans
• Hypoglycemic Agents (antagonists & inhibitors, pharmacology)
• Imidazoles (metabolism)
• In Vitro Techniques
• Indoles (metabolism)
• Intestinal Mucosa (cytology, drug effects, metabolism)
• Intestines (cytology, drug effects)
• Metformin (antagonists & inhibitors, pharmacology)
• Mice
• Neuroblastoma (metabolism)
• Radioligand Assay
• Receptors, Serotonin (drug effects)
• Receptors, Serotonin, 5-HT3
• Serotonin (metabolism)
• Tumor Cells, Cultured