Abstract
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.
Footnotes
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Send reprint requests to: Dr. Saadia Eddahibi, INSERM U492, Département de Physiologie, Faculté de Médecine de Créteil, 94010 Créteil, France. E-mail:eddahibi{at}im3.inserm.fr
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This research was supported by a grant from the Institut National de la Santé et de la Recherche Médicale and by an Unrestricted Biomedical Research grant from Bristol-Myers Squibb.
- Abbreviations:
- PPH
- primary pulmonary hypertension
- 5-HT
- 5-hydroxytryptamine
- 5-HTT
- 5-hydroxytryptamine transporter
- PA-SMC
- pulmonary artery smooth muscle cell
- DMEM
- Dulbecco's modified Eagle's medium
- FCS
- fetal calf serum
- [3H]5-HT
- 5-hydroxy[G-3H]tryptamine creatinine sulfate
- PCR
- polymerase chain reaction
- Pap
- pulmonary arterial pressure
- Sap
- systemic arterial pressure
- Received September 5, 2000.
- Accepted November 29, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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