Open AccessJournal Article
Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine.
Lawrence W. Fitzgerald,Timothy Burn,Barry S. Brown,John P. Patterson,Martha H. Corjay,Patricia A. Valentine,Jung-Hui Sun,John Link,Ilgar Abbaszade,Jeannine M. Hollis,Brian L. Largent,Paul R. Hartig,Gregory Hollis,Paul C. Meunier,Albert J. Robichaud,David Robertson +15 more
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TLDR
It is proposed that preferential stimulation of valvular 5-HT(2B) receptors by norfenfluramine, ergot drugs, or5-HT released from carcinoid tumors (with or without accompanying 5- HT(2A) receptor activation) may contribute to valvial fibroplasia in humans.Abstract:
Dexfenfluramine was approved in the United States for long-term use as an appetite suppressant until it was reported to be associated with valvular heart disease. The valvular changes (myofibroblast proliferation) are histopathologically indistinguishable from those observed in carcinoid disease or after long-term exposure to 5-hydroxytryptamine (5-HT)(2)-preferring ergot drugs (ergotamine, methysergide). 5-HT(2) receptor stimulation is known to cause fibroblast mitogenesis, which could contribute to this lesion. To elucidate the mechanism of "fen-phen"-associated valvular lesions, we examined the interaction of fenfluramine and its metabolite norfenfluramine with 5-HT(2) receptor subtypes and examined the expression of these receptors in human and porcine heart valves. Fenfluramine binds weakly to 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. In contrast, norfenfluramine exhibited high affinity for 5-HT(2B) and 5-HT(2C) receptors and more moderate affinity for 5-HT(2A) receptors. In cells expressing recombinant 5-HT(2B) receptors, norfenfluramine potently stimulated the hydrolysis of inositol phosphates, increased intracellular Ca(2+), and activated the mitogen-activated protein kinase cascade, the latter of which has been linked to mitogenic actions of the 5-HT(2B) receptor. The level of 5-HT(2B) and 5-HT(2A) receptor transcripts in heart valves was at least 300-fold higher than the levels of 5-HT(2C) receptor transcript, which were barely detectable. We propose that preferential stimulation of valvular 5-HT(2B) receptors by norfenfluramine, ergot drugs, or 5-HT released from carcinoid tumors (with or without accompanying 5-HT(2A) receptor activation) may contribute to valvular fibroplasia in humans.read more
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Valvular Heart Disease Associated with Fenfluramine–Phentermine
Heidi M. Connolly,Jack L. Crary,Michael D. McGoon,Donald D. Hensrud,Brooks S. Edwards,William D. Edwards,Hartzell V. Schaff +6 more
TL;DR: Concerns are raised that fenfluramine-phentermine therapy may be associated with valvular heart disease, which is arouse concern about serious potential adverse effects, including pulmonary hypertension and valvULAR heart disease.
Journal ArticleDOI
Ectopic expression of the serotonin 1c receptor and the triggering of malignant transformation.
TL;DR: The functional consequences of activating a brain-specific neurotransmitter receptor, the serotonin 5HT1c receptor, in the unnatural environment of a fibroblast were examined and it was found that the generation and maintenance of transformed foci requires continued activation of the serotonin receptor.