The antimalarial agent mefloquine inhibits ATP-sensitive K-channels
The antimalarial agent mefloquine inhibits ATP-sensitive K-channels
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DOI：
10.1038/sj.bjp.0703638
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发表时间：
2000-10-01
影响因子：
7.3
通讯作者：
Ashcroft, FM
中科院分区：
文献类型：
--
作者：
Gribble, FM;Davis, TME;Ashcroft, FM
本研究的目的是确定抗疟药是否抑制atp敏感钾（K-ATP）通道，从而导致这些药物的副作用甲氟喹（10-100 muM）能刺激胰岛胰岛素释放，而青蒿素（100 muM）不能从表达克隆K-ATP通道的爪蟾卵母细胞中切下的内向外斑块，研究了宏观K-ATP电流甲氟喹（IC50与3mum相似）、奎宁（IC50与3mum相似）和氯喹抑制胰腺β细胞类型的KATP通道Kir6.2/SUR1。Artenusate （100mum）无效甲氟喹和奎宁在没有SUR1的情况下也能阻断Kir6.2的截断形式（Kir6.2 Delta C36）。阻滞程度与Kir6.2/SUR1电流相似我们的研究结果表明，抑制β -细胞K-ATP通道是喹啉类抗疟药刺激胰岛素分泌从而产生低血糖的原因结果还表明，喹啉类抗疟药通过与Kir6.2亚基相互作用抑制K-ATP通道。该亚基普遍存在于β细胞、神经元、心脏、骨骼肌和一些平滑肌K-ATP通道中，表明K-ATP通道抑制可能导致这些药物的其他副作用，包括心脏传导异常和神经精神障碍。
1 The aim of this study was to determine whether antimalarial agents inhibit ATP-sensitive potassium (K-ATP) channels and thereby contribute to the observed side-effects of these drugs.2 Mefloquine (10-100 muM), but not artenusate (100 muM), stimulated insulin release from pancreatic islets in vitvo.3 Macroscopic K-ATP currents were studied in inside-out patches excised from Xenopus oocytes expressing cloned K-ATP channels.4 Mefloquine (IC50 similar to3 muM), quinine (IC50 similar to3 muM), and chloroquine inhibited the pancreatic beta -cell type of KATP channel Kir6.2/SUR1. Artenusate (100 muM) was without effect.5 Mefloquine and quinine also blocked a truncated form of Kir6.2 (Kir6.2 Delta C36) when expressed in the absence of SUR1. The extent of block was similar to that observed for Kir6.2/SUR1 currents.6 Our results suggest that inhibition of the beta -cell K-ATP channel accounts for the ability of quinoline-based antimalarial drugs to stimulate insulin secretion, and thereby produce hypoglycaemia.7 The results also indicate that quinoline-based antimalarial agents inhibit K-ATP channels by interaction with the Kir6.2 subunit. This subunit is common to beta -cell, neuronal, cardiac, skeletal muscle, and some smooth muscle K-ATP channels suggesting that K-ATP channel inhibition may contribute to the other side effects of these drugs, which include cardiac conduction abnormalities and neuropsychiatric disturbances.