Inhibition of delayed rectifier potassium channels and induction of arrhythmia
Inhibition of delayed rectifier potassium channels and induction of arrhythmia
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DOI：
10.1074/jbc.m708100200
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发表时间：
2008-01-18
影响因子：
4.8
通讯作者：
Singh, Satpal
中科院分区：
文献类型：
--
作者：
Frolov, Roman V.;Berim, Ilya G.;Singh, Satpal
环氧合酶-2(COX-2)的选择性抑制剂，如罗非昔布(Vioxx)、塞来昔布(Celebrex)和伐地昔布(BExtra)，已被开发用于治疗关节炎和其他肌肉骨骼疾病。选择性地抑制COX-2比抑制COX-1导致前列环素的产生优先于血栓素A2的产生，从而导致比非选择性COX抑制剂(如乙酰水杨酸(阿司匹林))对胃的影响更小。在这里，我们展示了塞来昔布通过一个独立于COX-2抑制的机制产生的新作用。该药抑制果蝇、大鼠和人的延迟整流(Kv2)钾通道，并导致果蝇明显的心律失常和培养的大鼠心脏细胞心律失常。尽管果蝇基因组中没有环氧合酶，并且环氧合酶-1和环氧合酶-2的有效抑制剂乙酰水杨酸未能抑制大鼠Kv2.1通道，但这些效应仍然发生。果蝇Shab(Kv2)通道的一个基因零突变复制了塞来昔布的心脏效应，该药物无法进一步增强突变的效果。这些观察揭示了塞来昔布对果蝇心脏和大鼠心脏细胞的意想不到的作用，暗示Kv2通道的抑制是这种作用的机制。
Selective inhibitors of cyclooxygenase-2 (COX-2), such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), have been developed for treating arthritis and other musculoskeletal complaints. Selective inhibition of COX-2 over COX-1 results in preferential decrease in prostacyclin production over thromboxane A2 production, thus leading to less gastric effects than those seen with nonselective COX inhibitors such as acetylsalicylic acid (aspirin). Here we show a novel effect of celecoxib via a mechanism that is independent of COX-2 inhibition. The drug inhibited the delayed rectifier (Kv2) potassium channels from Drosophila, rats, and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture. These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid, a potent inhibitor of both COX-1 and COX-2, to inhibit rat Kv2.1 channels. A genetically null mutant of Drosophila Shab (Kv2) channels reproduced the cardiac effect of celecoxib, and the drug was unable to further enhance the effect of the mutation. These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats, implicating the inhibition of Kv2 channels as the mechanism underlying this effect.