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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 361, Issue 1, pp 85–91 | Cite as

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

  • L.X. Cubeddu
  • H. Bönisch
  • M. Göthert
  • G. Molderings
  • K. Racké
  • G. Ramadori
  • K.J. Miller
  • H. Schwörer
Original Article

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 µM) 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 µM) 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 µM), somatostatin (1 µM) 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 µM) 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.

Metformin 5-HT receptors 5-HT release 5-HT3 receptors Enterochromaffin cells 

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Copyright information

© Springer-Verlag 0000

Authors and Affiliations

  • L.X. Cubeddu
    • 1
  • H. Bönisch
    • 3
  • M. Göthert
    • 3
  • G. Molderings
    • 3
  • K. Racké
    • 3
  • G. Ramadori
    • 4
  • K.J. Miller
    • 2
  • H. Schwörer
    • 4
  1. 1.Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Venezuela
  2. 2.NOVA Southeastern University, 3200 S University Dr., HPD, College of Pharmacy, Ft. Lauderdale, FL 33328, USA
  3. 3.Institute of Pharmacology and Toxicology, University of Bonn, 53113 Bonn, Germany
  4. 4.Department of Internal Medicine, Division of Gastroenterology and Endocrinology, University of Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany

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