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lohlávková1,
imák1,
ová1,
ková1, and1 Department of Pathophysiology, Charles University First Medical School, Prague 128 53; and 2 Department of Physiology, Charles University Second Medical School, Prague 150 00, Czech Republic
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
5 mol/l) and fenfluramine
(5 × 104 mol/l) caused significant increases in
perfusion pressure. Ritanserin at a dose (107 mol/l)
sufficient to inhibit >80% of the response to 5-HT reduced the
response to fenfluramine by ~50%. A higher ritanserin dose (105 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 × 103 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.
pulmonary hypertension; 5-HT receptors; 4-aminopyridine; ritanserin
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