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

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.