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

The anorexic agent fenfluramine considerably increases the risk of primary pulmonary hypertension. The mechanism of this effect is unknown. The appeti te-reducing action of fenfluramine is mediated by its interaction with the metabolism of serotonin [5-hydroxytryptamine (5-HT)] in the brain. We teste d 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 pota ssium (KV) channel activity would potentiate the pulmonary vascular reactiv ity to fenfluramine. Using isolated rat lungs perfused with Krebs-albumin s olution, 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 x 10(-4) mol/l) caused significant i ncreases in perfusion pressure. Ritanserin at a dose (10(-7) mol/l) suffici ent to inhibit >80% of the response to 5-HT reduced the response to fenflur amine by similar to 50%. A higher ritanserin dose (10(-5) mol/l) completely abolished the responses to 5-HT but had no more inhibitory effect on the r esponses to fenfluramine. A pharmacological blockade of KV channels by 4-am inopyridine (3 x 10(-3) mol/l) markedly potentiated the pulmonary vasoconst rictor response to fenfluramine but was without effect on the reactivity to 5-HT. These data indicate that the pulmonary vasoconstrictor response to f enfluramine is partly mediated by 5-HT receptors. Furthermore, the pulmonar y vasoconstrictor potency of fenfluramine is elevated when the K-V-channel activity is low. This finding suggests that preexisting K-V-channel insuffi ciency may predispose some patients to the development of pulmonary hyperte nsion during fenfluramine treatment.