The effect of fenfluramine on the pulmonary disposition of 5-hydroxytryptamine in the isolated perfused rat lung: a comparison with chlorphentermine.
A possible mechanism for fenfluramine-induced pulmonary hypertension has been investigated. Fenfluramine, like chlorphentermine, may inhibit the pulmonary uptake and/or metabolism of 5-hydroxytryptamine (5-HT). This allows more 5-HT to remain in the pulmonary circulation, where it may exert a greater vasoconstrictor action resulting in pulmonary hypertension. Chlorphentermine has been shown to inhibit the uptake and metabolism of 5-HT. The effect of fenfluramine on the pulmonary disposition of [14C]5-HT has been investigated, in comparison with chlorphentermine, using a recirculating isolated perfused rat lung system. The pulmonary disposition of [14C]5-HT was assessed by measuring the change in [14C]5-HT concentration in the perfusion medium during the experiment and at the end, and the concentration in the lung at the end of the experiment. The concentration of 5-hydroxyindoleacetic acid, a metabolite of 5-HT, was measured in perfusate and lung samples. Mean pulmonary clearance of 5-HT for the control lung and lungs challenged with either fenfluramine (2.5 microM) or chlorphentermine (25 microM) was 4.514, 1.316 and 1.007 mL min(-1), respectively (n = 5). The concentration of 5-HT found in the lungs at the end of the experiment for the control and the lungs preloaded with fenfluramine or chlorphentermine was 695.05+/-9.69, 638.65+/-10.27 and 617.3+/-14.38 ng g(-1), respectively. Fenfluramine, like chlorphentermine, inhibited the pulmonary disposition of 5-HT resulting in an elevated perfusate level of 5-HT. This is a possible contributing mechanism for fenfluramine-induced pulmonary hypertension. The effect of fenfluramine was less pronounced than chlorphentermine.
Valodia
P
P
Department of Pharmacology, University of the Western Cape, Bellville, South Africa.
Syce
J A
JA
D000818:Animals; D002745:Chlorphentermine / Q000494:pharmacology*; D002853:Chromatography, Liquid; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000032:analysis / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000032:analysis / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013566:Sympathomimetics / Q000494:pharmacology*
D002745:Chlorphentermine; D005277:Fenfluramine; D016166:Free Radical Scavengers; D006897:Hydroxyindoleacetic Acid; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013566:Sympathomimetics