Dexfenfluramine-associated changes in 5-hydroxytryptamine transporter expression and development of hypoxic pulmonary hypertension in rats

The appetite suppressant dexfenfluramine, which inhibits neuronal 5-HT upta ke 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 r elationship between dexfenfluramine and pulmonary hypertension, we examined 1) the effect of dexfenfluramine on 5-HT uptake by PA-SMCs and the mitogen ic response of these cells to 5-HT, and 2) 5-HTT mRNA in lung tissue from n ormoxic and chronically hypoxic rats during and at discontinuation of a 4-w eek dexfenfluramine treatment (2 mg/kg/day). In cultured PA-SMCs, dexfenflu ramine (10(-6) M) markedly reduced [H-3]5-HT uptake and [H-3] thymidine inc orporation in response to 5-HT (10(-6) M). In lungs from rats exposed to 4- week hypoxia (10% O-2), 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 n ot affected by concomitant treatment with dexfenfluramine. One week after d iscontinuation of dexfenfluramine, 5-HTT mRNA levels increased substantiall y, this effect being additive with that of hypoxia (364.0 +/- 13.1 in hypox ic 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 ven tricular hypertrophy was more severe and muscularization of distal pulmonar y 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 pulmon ary hypertension.