TY - JOUR T1 - Dexfenfluramine-Associated Changes in 5-Hydroxytryptamine Transporter Expression and Development of Hypoxic Pulmonary Hypertension in Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 148 LP - 154 VL - 297 IS - 1 AU - Saadia Eddahibi AU - Serge Adnot AU - Eric Frisdal AU - Micheline Levame AU - Michel Hamon AU - Bernadette Raffestin Y1 - 2001/04/01 UR - http://jpet.aspetjournals.org/content/297/1/148.abstract N2 - The appetite suppressant dexfenfluramine, which inhibits neuronal 5-HT uptake and elevates plasma 5-HT levels, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. 5-HT is a mitogen for pulmonary artery smooth muscle cells (PA-SMCs), an effect that depends upon activity of the 5-HT transporter (5-HTT). To investigate the relationship between dexfenfluramine and pulmonary hypertension, we examined 1) the effect of dexfenfluramine on 5-HT uptake by PA-SMCs and the mitogenic response of these cells to 5-HT, and 2) 5-HTT mRNA in lung tissue from normoxic and chronically hypoxic rats during and at discontinuation of a 4-week dexfenfluramine treatment (2 mg/kg/day). In cultured PA-SMCs, dexfenfluramine (10−6 M) markedly reduced [3H]5-HT uptake and [3H]thymidine incorporation in response to 5-HT (10−6 M). In lungs from rats exposed to 4-week hypoxia (10% O2), 5-HTT mRNA levels were higher than in normoxic rats (233.5 ± 22.5 versus 121.8 ± 4.8 amol/mg of RNA, P < 0.05), but were not affected by concomitant treatment with dexfenfluramine. One week after discontinuation of dexfenfluramine, 5-HTT mRNA levels increased substantially, this effect being additive with that of hypoxia (364.0 ± 13.1 in hypoxic versus 164.2 ± 10 amol/mg of RNA in normoxic rats). When exposure to 2 weeks of hypoxia followed discontinuation of a 4-week treatment, right ventricular hypertrophy was more severe and muscularization of distal pulmonary arteries more marked (P < 0.01) than in rats pretreated with the vehicle. These data show that, in rats, the increased 5-HTT expression that follows dexfenfluramine discontinuation promotes the development of hypoxic pulmonary hypertension. The American Society for Pharmacology and Experimental Therapeutics ER -