Fenfluramine-induced pulmonary vasoconstriction:: role of serotonin receptors and potassium channels
Fenfluramine-induced pulmonary vasoconstriction:: role of serotonin receptors and potassium channels
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DOI：
10.1152/jappl.2001.91.2.755
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发表时间：
2001-08-01
影响因子：
3.3
通讯作者：
Hampl, V
中科院分区：
文献类型：
--
作者：
Belohlávková, S;Simák, J;Hampl, V
抗氧化剂芬氟拉明会显著增加原发性肺动脉高压的风险。这种效应的机制尚不清楚。芬氟拉明的食欲降低作用是通过其与脑中5-羟色胺（5-HT）代谢的相互作用介导的。我们检验了芬氟拉明的肺血管收缩作用至少部分是由5-HT受体激活介导的假设。此外，我们试图确定是否药理学降低电压门控钾（KV）通道活性将增强肺血管反应芬氟拉明。使用离体大鼠肺灌注Krebs白蛋白溶液，我们比较了利坦色林，5-HT 2受体拮抗剂，芬氟拉明和5-HT引起的血管收缩的抑制作用。5-HT（10（-5）mol/l）和芬氟拉明（5 × 10（-4）mol/l）均引起灌注压显著升高。剂量（10（-7）mol/l）足以抑制对5-HT反应的80%以上的利坦色林可使对芬氟拉明的反应降低50%。较高剂量的利坦色林（10（-5）mol/l）可完全抑制对5-HT的反应，但对芬氟拉明的反应无明显抑制作用。用4-氨基吡啶（3 × 10（-3）mol/l）阻断KV通道可显著增强对芬氟拉明的肺血管收缩反应，但对5-HT的反应性无影响。这些数据表明，芬氟拉明的肺血管收缩反应部分是由5-HT受体介导的。此外，当K-V通道活性低时，芬氟拉明的肺血管收缩效力升高。这一发现表明，预先存在的K-V通道功能不全可能使一些患者在芬氟拉明治疗期间容易发生肺动脉高压。
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 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 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 responses to fenfluramine. A pharmacological blockade of KV 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.