Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and potassium channels
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- 4-Aminopyridine pharmacology MeSH
- Angiotensin II pharmacology MeSH
- Time Factors MeSH
- Potassium Channels drug effects physiology MeSH
- Fenfluramine pharmacology MeSH
- Kinetics MeSH
- Rats MeSH
- Perfusion MeSH
- Lung blood supply physiology MeSH
- Pulmonary Circulation drug effects physiology MeSH
- Rats, Wistar MeSH
- Receptors, Serotonin drug effects physiology MeSH
- Ritanserin pharmacology MeSH
- Serotonin pharmacology MeSH
- In Vitro Techniques MeSH
- Vasoconstriction drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 4-Aminopyridine MeSH
- Angiotensin II MeSH
- Potassium Channels MeSH
- Fenfluramine MeSH
- Receptors, Serotonin MeSH
- Ritanserin MeSH
- Serotonin MeSH
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.
References provided by Crossref.org
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