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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0190v1 16/1/281    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Guillemot, J. Articles by Lefebvre, H. Search for Related Content PubMed PubMed Citation Articles by Guillemot, J. Articles by Lefebvre, H.

J Guillemot, INSERM U413, EA4310, DC2N, IFRMP 23, University of Rouen, Mont Saint Aignan, France
P Compagnon, Department of Pharmacology, INSERM U644, Institute of Biomedical Research, Rouen University Hospital, Rouen, France
D Cartier, INSERM U413, EA4310, DC2N, IFRMP 23, University of Rouen, Mont Saint Aignan, France
E Thouennon, INSERM U413, EA4310, DC2N, IFRMP 23, University of Rouen, Mont Saint Aignan, France
C Bastard, Laboratory of Oncologic Genetics, Centre Henri Becquerel, Rouen, France
I Lihrmann, INSERM U413, EA4310, DC2N, IFRMP 23, University of Rouen, Mont Saint Aignan, France
P Pichon, Department of Endocrinology, Institute of Biomedical Research, Rouen University Hospital,, Rouen, France
C Thuillez, Department of Pharmacology, INSERM U644, Institute of Biomedical Research, Rouen University Hospital, Rouen, France
P Plouin, Hypertension Unit, Paris Descartes University, AP-HP, Hopital Europeen Georges Pompidou, Paris, France
J Bertherat, Department of Endocrinology, INSERM U567, Cochin Institute, CNRS UMR8104, Paris Descartes University, AP-HP, Cochin Hospital, Paris, France
Y Anouar, INSERM U413, EA4310, DC2N, IFRMP 23, University of Rouen, Mont Saint Aignan, France
J Kuhn, Department of Endocrinology, Institute of Biomedical Research, Rouen University Hospital, Rouen, France
L Yon, INSERM U413, EA4310, DC2N, IFRMP 23, University of Rouen, Mont Saint Aignan, France
H Lefebvre, Department of Endocrinology, University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, Rouen, 76031, France

Correspondence: Herve Lefebvre, Email: herve.lefebvre1{at}free.fr

Abstract

The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas. Our study, an in vitro study performed in an academic research laboratory, investigated the mechanism of action of metoclopramide and expression of serotonin type 4 (5-HT4) receptors in pheochromocytoma tissues. Tissue explants obtained from 18 pheochromocytomas including the tumor removed from a 46 year old female patient who experienced life-threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas (9 benign and 8 malignant). Cultured pheochromocytoma cells derived from this patient who previously received metoclopramide were incubated with metoclopramide and various 5-HT4 receptor ligands. In addition, total mRNAs were extracted from all the 18 tumors. Catecholamine and granin-derived peptide concentrations were measured in pheochromocytoma cell incubation medium by high performance liquid chromatography and radioimmunological assays. In addition, expression of 5-HT4 receptor mRNAs in the 18 pheochromocytomas was investigated by use of reverse transcriptase-polymerase chain reaction. Metoclopramide and the 5-HT4 receptor agonist cisapride were found to activate catecholamine and granin-derived peptide secretions by cultured tumor cells. Metoclopramide- and cisapride-evoked catecholamine and granin-derived peptide productions were inhibited by the 5-HT4 receptor antagonist GR 113808. 5-HT4 receptor mRNAs were detected in the patient's tumor and the series of 17 additional pheochromocytomas. This study shows that pheochromocytomas express functional 5-HT4 receptors that are responsible for the stimulatory action of metoclopramide on catecholamine and granin-derived peptide secretion. All 5-HT4 receptor agonists must therefore be contra-indicated in patients with proven or suspected pheochromocytoma.