Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2001

Open Access 01-12-2001 | Commentary

Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: lessons for the future in pathogenesis

Authors: Saadia Eddahibi, Serge Adnot

Published in: Respiratory Research | Issue 1/2001

Login to get access

Abstract

Epidemiological studies have established that fenfluramine, D-fenfluramine, and aminorex, but not other appetite suppressants, increase the risk of primary pulmonary hypertension (PH). One current hypothesis suggests that fenfluramine-like medications may act through interactions with the serotonin (5-hydroxytryptamine [5-HT]) transporter (5-HTT) located on pulmonary artery smooth muscle cells and responsible for the mitogenic action of 5-HT. Anorexigens may contribute to PH by boosting 5-HT levels in the bloodstream, directly stimulating smooth muscle cell growth, or altering 5-HTT expression. We suggest that individuals with a high basal level of 5-HTT expression related to the presence of the long 5-HTT gene promoter variant may be particularly susceptible to one or more of these potential mechanisms of appetite-suppressant-related PH.
Literature
1.
2.
Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B: Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med. 1996, 335: 609-616. 10.1056/NEJM199608293350901.PubMedCrossRef
3.
4.
Eddahibi S, Fabre V, Boni C, Martres MP, Raffestin B, Hamon M, Adnot S: Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin. Circ Res. 1999, 84: 329-336.PubMedCrossRef
5.
Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Blakely RD: Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning expression, and chormosomal localization. Proc Natl Acad Sci USA. 1993, 90: 2542-2546.PubMedPubMedCentralCrossRef
6.
Rothman RB, Ayestas MA, Dersch CM, Baumann MH: Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation. 1999, 100: 869-875.PubMedCrossRef
7.
Rubin LJ: Primary pulmonary hypertension. N Engl J Med. 1997, 336: 111-117. 10.1056/NEJM199701093360207.PubMedCrossRef
8.
Lee SL, Wang WW, Moore BJ, Fanburg BL: Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cell in culture. Circ Res. 1991, 68: 1362-1368.PubMedCrossRef
9.
Lee S, Wang W, Fanburg BL: Dexfenfluramine as a mitogen signal via the formation of superoxide anion. FASEB J. 2001, 15: 1324-1325.PubMed
10.
Eddahibi S, Hanoun N, Lanfumey L, Lesch K, Raffestin B, Hamon M, Adnot S: Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest. 2000, 105: 1555-1562.PubMedPubMedCentralCrossRef
11.
Eddahibi S, Adnot S, Frisdal E, Levame M, Hamon M, Raffestin B: Dexfenfluramine-associated changes in 5-hydroxytryptamine transporter expression and development of hypoxic pulmonary hypertension in rats. J Pharmacol Exp Ther. 2001, 297: 148-154.PubMed
12.
Eddahibi S, Chouaid C, Sediame S, Housset B, Hamon M, Adnots S: Serotonin uptake and citalopram binding in platelets from patients with chronic pulmonary hypertension [abstract]. Am J Respir Crit Care Med. 1999, 159: A165-CrossRef
13.
Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S: Hyperplasia of pulmonary artery smooth muscle cells causally related to overexpression of the serotonin transporter in primary pulmonary hypertension. J Clin Invest. 2001, 108: 1141-1150. 10.1172/JCI200112805.PubMedPubMedCentralCrossRef
14.
Lesch K-P, Gross UB, Strauss K, Wolozin BL, Murphy DL, Riederer P: Organization of the human serotonin transporter gene. J Neural Transm. 1994, 95: 157-162.CrossRef
15.
Celada P, Martin F, Artigas F: Effects of chronic treatment with dexfenfluramine on serotonin in rat blood, brain and lung tissue. Life Sci. 1994, 55: 1237-1243. 10.1016/0024-3205(94)00663-6.PubMedCrossRef
16.
Raleigh MJ, Brammer GL, Ritvo ER, Geller E, McGuire MT, Yuwiler A: Effects of chronic fenfluramine on blood serotonin, cerebrospinal fluid metabolites and behaviour in monkeys. Psychpharmacology. 1986, 90: 503-508.CrossRef
17.
MacLean M, Herve P, Eddahibi S, Adnot S: 5-hydroxytryptamine and the pulmonary circulation: receptors, transporters and relevance to pulmonary arterial hypertension. Br J Pharmacol. 2000, 131: 161-168.PubMedPubMedCentralCrossRef
18.
Sato K, Webb S, Tucker A, Rabinovitch M, O'Brien RF, McMurtry IF, Stelzner TJ: Factors influencing the idiopathic development of pulmonary hypertension in the Fawn Hooded rat. Am Rev Respir Dis. 1992, 145: 793-797.PubMedCrossRef
19.
Rothman RB, Redmon B, Raatz SK, Kwong CA, Swanson JE, Bantle JP: Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin. Am J Cardiol. 2000, 85: 913-916. 10.1016/S0002-9149(99)00896-6.PubMedCrossRef
20.
Louis WJ: Primary pulmonary hypertension and anorectic drugs. N Engl J Med. 1999, 340: 482-483. 10.1056/NEJM199902113400614.
21.
Raiteri M, Bonanno G, Vallebuona F: In vitro and in vivo effects of D-fenfluramine: no apparent relation between 5-hydroxytryptamine release and hypophagia. J Pharmacol Exp Ther. 1995, 273: 643-649.PubMed
22.
Miyata M, Ito M, Sasajima T, Ohira H, Kasukawa R: Effect of a serotonin receptor antagonist on interleukin-6-induced pulmonary hypertension in rats. Chest. 2001, 119: 554-561. 10.1378/chest.119.2.554.PubMedCrossRef
23.
Blakely RD, Ramamoorthy S, Qian Y, Schroeter S, Bradley CC: Regulation of antidepressant-sensitive serotonin transporters. In Neurotransmitters Transporters: Structure, Function and Regulation. Edited by Reith MEA. NJ: Humana Press Inc;. 1996, 29-72.
24.
Semple-Rowland SL, Mahatme A, Rowland NE: Effects of dexfenfluramine or 5,7-dihydroxytryptamine on tryptophan hydroxylase and serotonin transporter mRNAS in rat dorsal raphe. Mol Brain Res. 1996, 41: 121-127. 10.1016/0169-328X(96)00076-9.PubMedCrossRef
25.
Lesch K-P, Bengel D, Heils A, Sabol SZ, Greeberg BD, Müller CR, Hamer DH, Murphy DL: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996, 274: 1527-1531. 10.1126/science.274.5292.1527.PubMedCrossRef
26.
Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA: Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000, 67: 737-744. 10.1086/303059.PubMedPubMedCentralCrossRef
27.
Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE, Nichols WC, Trembath RC: Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000, 26: 81-84. 10.1038/79226.PubMedCrossRef
Metadata
Title
Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: lessons for the future in pathogenesis
Authors
Saadia Eddahibi
Serge Adnot
Publication date
01-12-2001
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2001
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/rr181

Other articles of this Issue 1/2001

Respiratory Research 1/2001 Go to the issue

Commentary

Growth factors in lung development and disease: friends or foe?

Research

Activation of adherent vascular neutrophils in the lung during acute endotoxemia

Research

Mechanism of cigarette smoke condensate-induced acute inflammatory response in human bronchial epithelial cells

Review

The importance of balanced pro-inflammatory and anti-inflammatory mechanisms in diffuse lung disease

Review

Genetic polymorphisms in lung disease: bandwagon or breakthrough?

Review

Surfactant gene polymorphisms and interstitial lung diseases
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits