| 11457791 |
Belohlavkova S, Simak J, Kokesova A, Hnilickova O, Hampl V: Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and potassium channels. J Appl Physiol. 2001 Aug;91(2):755-61.
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 (K (V)) 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-HT (2) 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 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 approximately 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 K (V) channels by 4-aminopyridine (3 x 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 K (V)-channel activity is low. This finding suggests that preexisting K (V)-channel insufficiency may predispose some patients to the development of pulmonary hypertension during fenfluramine treatment. |
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