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 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.
Belohlávková
S
S
Department of Pathophysiology, Charles University First Medical School, Prague 128 53, Czech Republic.
Simák
J
J
Kokesová
A
A
Hnilicková
O
O
Hampl
V
V
D015761:4-Aminopyridine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000098:blood supply / Q000502:physiology*; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D016713:Ritanserin / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
D015221:Potassium Channels; D011985:Receptors, Serotonin; D000804:Angiotensin II; D016713:Ritanserin; D005277:Fenfluramine; D012701:Serotonin; D015761:4-Aminopyridine