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多种药物可引起心电图QT间期延长,增加发生心律失常的可能性。研究支持阻断心脏快激活的延迟整流K电流(I_(Kr))是药物的主要作用靶点,但是磷酸肌醇3激酶(PI3K)/蛋白激酶(A_(kt))信号转导通路在药物致QT间期延长中亦起重要的作用。酪氨酸激酶抑制剂如抗肿瘤药物尼洛替尼等可以抑制下游PI3K/Akt信号转导通路,减小I_(Kr)和缓慢激活的延迟整流K电流I_(Ks)以及L型Ca电流(I_(Ca-L)),但增大晚Na电流(I_(Na-L))。I_(Na-L)增大通过多重作用调节动作电位时程,从而增加尖端扭转型室性心动过速发生危险。研究还发现长时间(数小时)暴露于典型的IKr阻断剂多非利特、E-4031、d-索他洛尔等,亦可通过PI3K/Akt信号通路增加I_(Na-L),而I_(Na-L)的增大又可明显增强I_(Kr)阻断剂的致心律失常作用,提示I_(Kr)阻断剂作用机制的复杂性。
A variety of drugs can cause ECG QT interval prolongation, increase the possibility of arrhythmia. Studies have shown that delayed rectifier K current (I Kr), which blocks rapid cardiac activation, is the primary target of the drug, but the phosphoinositide 3 kinase (Akt) signal transduction pathway, To extend the QT interval also plays an important role. Tyrosine kinase inhibitors such as nilotinib, an antitumor drug, can inhibit downstream PI3K / Akt signaling pathway, reduce I_ (Kr) and slow activation of delayed rectifier K current I_ (Ks) and L-type Ca current I_ (Ca-L)), but increased the late Na current (I_ (Na-L)). Increasing I_ (Na-L) regulates the action potential duration through multiple actions, thereby increasing the risk of torsades de pointes (Torsades de pointes). The study also found that exposure to prolonged (several hours) exposure to the typical IKr blockers such as dofetilide, E-4031, d-sotalol, etc., also increased I_ (Na-L) via the PI3K / Akt signaling pathway, However, the increase of I_ (Na-L) can obviously enhance the arrhythmic effect of I_ (Kr) blockers, suggesting the complexity of the mechanism of action of I_ (Kr) blockers.