Vol. 297, Issue 1, 148-154, April 2001

Dexfenfluramine-Associated Changes in 5-Hydroxytryptamine Transporter Expression and Development of Hypoxic Pulmonary Hypertension in Rats

Saadia Eddahibi, Serge Adnot, Eric Frisdal, Micheline Levame, Michel Hamon and Bernadette Raffestin

Institut National de la Santé et de la Recherche Médicale U492 et Département de Physiologie, Hôpital H. Mondor, AP-HP, Créteil, France (S.E., S.A., E.F., M.L.); Institut National de la Santé et de la Recherche Médicale U288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France (M.H.); and Département de Physiologie, Université René Descartes, Hôpital Ambroise Paré, AP-HP, Boulogne, France (B.R.)

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 (10⁶ M) markedly reduced [³H]5-HT uptake and [³H]thymidine incorporation in response to 5-HT (10⁶ 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.