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* From the Section of Respiratory Medicine, Division of Clinical Sciences (Drs. Higenbottam, Laude, and Bee, and Ms. Marriott), Sheffield University, Sheffield, UK; and the S. Maugeri Foundation, Institute for Clinical Care and Research (Dr. Cremona), Veruna, Italy.
Correspondence to: Timothy Higenbottam, MD, FCCP; Section of Respiratory Medicine, Division of Clinical Sciences, Sheffield University Medical School, Beech Hill Rd, Sheffield S10 2RX, UK; e-mail: t.higenbottam{at}sheffield.ac.uk
Study Objectives: Treatment with anorectics has become an important aspect of care for the severely obese. One such anorectic, the phenylethylamine dexfenfluramine (dFen), has been associated with the development of pulmonary hypertension. It works by reducing the neuronal uptake of 5-hydroxytryptamine (5-HT; serotonin) through inhibition of the 5-HT transporter. In this study we investigated whether dFen has a direct vasoconstrictor action on human and porcine pulmonary vasculature.
Design: For the human study, tissue was obtained from patients who had undergone lung and heart-lung transplantation. The effect of dFen was studied in seven isolated colloid perfused human lungs and in rings of human pulmonary artery (PA) dissected from the lungs of a further 19 patients. For the porcine study, regional pulmonary vascular resistances (PVRs) were measured in isolated perfused porcine lungs. Vasoconstriction was assessed following dFen alone and in combination with hypoxia, cyclo-oxygenase blockade (indomethacin, 10-5 mol/L), or nitric oxide synthase (NOS) blockade (NG-nitro-L-arginine, 10-5 mol/L).
Results: In the human study, 5-HT and dFen
caused only limited increases in tension of isolated rings of PA. The
concentration of dFen, 10-4 mol/L, that was needed to
increase tension was higher than that found normally in treated
patients where peak levels are 3.3 x 10-7 mol/L. Other
vasoconstrictors such as prostaglandin F2
,
10-5 mol/L, and the thromboxane analog U46619,
10-6 mol/L, produced far greater increases in tension.
Ketanserin, 10-4 mol/L, attenuated the constrictor
response to 5-HT but had no effect on the constrictor response to dFen.
Removal of the endothelium did not influence the response to dFen. In
the isolated ventilated and perfused lungs, dFen caused an increase in
PVR again only at a comparatively high concentration, 10-4
mol/L. In the porcine study, dFen, 10-4 mol/L, did not
increase any PVR during normoxia or following NOS blockade. Small
insignificant increases in PVR occurred during hypoxia and after
cyclo-oxygenase blockade.
Conclusion: These results do not support the view that dFen would act as a direct vasoconstrictor when given in the usual doses. However, delayed elimination of dFen could raise tissue concentrations to high levels and give rise to vasoconstriction and pulmonary hypertension.
Key Words: dexfenfluramine • human • isolated perfused lung • pulmonary hypertension • porcine • serotonin
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