TY - JOUR T1 - Possible Role of Valvular Serotonin 5-HT<sub>2B</sub> Receptors in the Cardiopathy Associated with Fenfluramine JF - Molecular Pharmacology JO - Mol Pharmacol SP - 75 LP - 81 VL - 57 IS - 1 AU - Lawrence W. Fitzgerald AU - Timothy C. Burn AU - Barry S. Brown AU - John P. Patterson AU - Martha H. Corjay AU - Patricia A. Valentine AU - Jung-Hui Sun AU - John R. Link AU - Ilgar Abbaszade AU - Jeannine M. Hollis AU - Brian L. Largent AU - Paul R. Hartig AU - Gregory F. Hollis AU - Paul C. Meunier AU - Albert J. Robichaud AU - David W. Robertson Y1 - 2000/01/01 UR - http://molpharm.aspetjournals.org/content/57/1/75.abstract N2 - 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-HT2 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-HT2 receptor subtypes and examined the expression of these receptors in human and porcine heart valves. Fenfluramine binds weakly to 5-HT2A, 5-HT2B, and 5-HT2C receptors. In contrast, norfenfluramine exhibited high affinity for 5-HT2B and 5-HT2C receptors and more moderate affinity for 5-HT2A receptors. In cells expressing recombinant 5-HT2B receptors, norfenfluramine potently stimulated the hydrolysis of inositol phosphates, increased intracellular Ca2+, and activated the mitogen-activated protein kinase cascade, the latter of which has been linked to mitogenic actions of the 5-HT2B receptor. The level of 5-HT2B and 5-HT2A receptor transcripts in heart valves was at least 300-fold higher than the levels of 5-HT2C receptor transcript, which were barely detectable. We propose that preferential stimulation of valvular 5-HT2B receptors by norfenfluramine, ergot drugs, or 5-HT released from carcinoid tumors (with or without accompanying 5-HT2A receptor activation) may contribute to valvular fibroplasia in humans. The American Society for Pharmacology and Experimental Therapeutics ER -