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Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling.
Int J Mol Sci
June 2020
Laboratory of Cardiology, GIGA Cardiovascular Sciences, University of Liège, 4000 Liège, Belgium.
Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling.
View Article and Find Full Text PDFSerotonin transporter and serotonin receptors.
Handb Exp Pharmacol
July 2014
INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, 94010, Créteil, France,
The nature of the primary defect responsible for triggering and maintaining pulmonary artery smooth muscle (PA-SMC) proliferation in pulmonary artery hypertension (PAH) is poorly understood but may be either an inherent characteristic of PA-SMCs or a secondary response to an external abnormality, such as upregulation of growth factors. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex. The anorexiant dexfenfluramine which inhibits 5-HT neuronal uptake, causes 5-HT platelet depletion, and increases plasma levels of 5-HT, was then shown to increase the relative risk of developing PAH in the adults.
View Article and Find Full Text PDFDexfenfluramine discontinuous treatment does not worsen hypoxia-induced pulmonary vascular remodeling but activates RhoA/ROCK pathway: consequences on pulmonary hypertension.
Eur J Pharmacol
January 2009
Laboratoire de Physiopathologie de la Paroi Artérielle, LABPART EA3852, IFR 135, Université François Rabelais, Tours Cedex 1, France.
The anorectic drug, dexfenfluramine has been associated with an increase in the relative risk of developing pulmonary hypertension. 5-hydroxytryptamine (5-HT) is a mitogen for smooth muscle cell, an effect that relies on 5-HT transporter expression and which has been proposed to explain pulmonary side effect of dexfenfluramine, and more particularly its effect on vascular remodeling. However recent data supported a major role of pulmonary artery vasoconstriction through the RhoA/Rho-kinase pathway.
View Article and Find Full Text PDFConverging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice.
Circulation
June 2008
Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Background: The incidence of pulmonary arterial hypertension secondary to the use of indirect serotinergic agonists such as aminorex and dexfenfluramine led to the "serotonin hypothesis" of pulmonary arterial hypertension; however, the role of serotonin in dexfenfluramine-induced pulmonary arterial hypertension remains controversial. Here, we used novel transgenic mice lacking peripheral serotonin (deficient in tryptophan hydroxylase-1; Tph1(-/-) mice) or overexpressing the gene for the human serotonin transporter (SERT; SERT(+) mice) to investigate this further.
Methods And Results: Dexfenfluramine administration (5 mg x kg(-1) x d(-1) PO for 28 days) increased systolic right ventricular pressure and pulmonary vascular remodeling in wild-type mice but not in Tph1(-/-) mice, which suggests that dexfenfluramine-induced pulmonary arterial hypertension is dependent on serotonin synthesis.
The natural mutation encoding a C terminus-truncated 5-hydroxytryptamine 2B receptor is a gain of proliferative functions.
Mol Pharmacol
April 2005
INSERM U616 Hospital Pitié-Salpetrière, Batiment Pédiatrie, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
Although potentially implicated in several physiological functions, few functional mutations have been identified in the human 5-hydroxytryptamine (HT)(2B) receptor gene. A heterozygous mutation R393X in the 5-HT(2B) receptor was recently identified in a patient diagnosed with pulmonary hypertension after intake of the anorexigenic dexfenfluramine. Although reported to generate a lack of function, this C terminus-truncated 5-HT(2B) receptor should somehow affect transduction pathways relevant to pulmonary hypertension.
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