Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and
potassium channels.
Belohlávková, Simona, Jan Šimák, Alena Kokešová, Olga Hnilicková, and Václav
Hampl.
1Department of Pathophysiology, Charles University First Medical School, Prague
128 53, Czech Republic; and 2Department of Physiology, Charles University Second
Medical School, Prague 150 00, Czech Republic
APStracts 8:0248A, 2001.
The anorexic agent fenfluramine considerably increases the risk of primary pulmonary
hypertension. The mechanism of this effect is unknown. The appetite-reducing action of
fenfluramine is mediated by its interaction with the metabolism of serotonin [5-
hydroxytryptamine (5-HT)] in the brain. We tested the hypothesis that the pulmonary
vasoconstrictive action of fenfluramine is at least in part mediated by 5-HT receptor
activation. In addition, we sought to determine whether pharmacological reduction of
voltage-gated potassium (KV) channel activity would potentiate the pulmonary vascular
reactivity to fenfluramine. Using isolated rat lungs perfused with Krebs-albumin solution,
we compared the inhibitory effect of ritanserin, an antagonist of 5-HT2 receptors, on
fenfluramine- and 5-HT-induced vasoconstriction. Both 5-HT (10«minus»5 mol/l) and
fenfluramine (5 × 10«minus»4 mol/l) caused significant increases in perfusion pressure.
Ritanserin at a dose (10«minus»7 mol/l) sufficient to inhibit >80% of the response to
5-HT reduced the response to fenfluramine by ~50%. A higher ritanserin dose
(10«minus»5 mol/l) completely abolished the responses to 5-HT but had no more
inhibitory effect on the responses to fenfluramine. A pharmacological blockade of KV
channels by 4-aminopyridine (3 × 10«minus»3 mol/l) markedly potentiated the
pulmonary vasoconstrictor response to fenfluramine but was without effect on the
reactivity to 5-HT. These data indicate that the pulmonary vasoconstrictor response to
fenfluramine is partly mediated by 5-HT receptors. Furthermore, the pulmonary
vasoconstrictor potency of fenfluramine is elevated when the KV channel activity is low.
This finding suggests that preexisting KV channel insufficiency may predispose some
patients to the development of pulmonary hypertension during fenfluramine treatment.
Received 18 July 2000; accepted in final form 11 April 2001
APS Manuscript Number A0646-0.
Article publication pending J Appl Physiol
ISSN 1080-4757 Copyright 2001 The American Physiological Society.
Published in APStracts on 18 June 2001