Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and potassium channels

Author:

Bělohlávková Simona1,Šimák Jan1,Kokešová Alena1,Hniličková Olga1,Hampl Václav2

Affiliation:

1. 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

Abstract

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 × 10−4 mol/l) caused significant increases in perfusion pressure. Ritanserin at a dose (10−7 mol/l) sufficient to inhibit >80% of the response to 5-HT reduced the response to fenfluramine by ∼50%. A higher ritanserin dose (10−5 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 × 10−3 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.

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology

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