The acute effects of dexfenfluramine on human and porcine pulmonary vascular tone and resistance.
OBJECTIVE
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.


METHODS
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 (N(G)-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 F(2)alpha, 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.


CONCLUSIONS
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.
Higenbottam
T
T
Section of Respiratory Medicine, Division of Clinical Sciences , Sheffield University, Sheffield, UK. t.higenbottam@sheffield.ac.uk
Marriott
H
H
Cremona
G
G
Laude
E
E
Bee
D
D
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D046508:Culture Techniques; D020372:Dexfenfluramine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D001067:Appetite Depressants; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D012701:Serotonin; D020372:Dexfenfluramine