作者：Gang Li等 日期：2019-07-23 浏览量：50
1 Department of Cardiology， First Affiliated Hospital of Zhengzhou University
2 Department of Cardiology， Peking University First Hospital
Gang Li1， Chengyu Wang2， Manxin Lin2， Jiangying Luo2， Peixin He2， Qing Zhang2， and Lin Wu2
Objective: Late sodium current (INaL) inhibitors are expected to be a channel- specific treatment of patients with LQT3. However， the efficacy varies in different mutations. To determine the mechanisms underlying the difference of therapeutic effects of INaL inhibitors in HEK 293 cells expressing drug sensitive (N1325S and R1623Q) and resistant (M1652R) mutations， respectively
Methods: Whole cell patch-clamp was used to determine the gating poperties and drug responses of the mutant channels expressed in HEK293 cells. Lidocaine and oral mexiletine were used in LQT3 patients with causative mutation of N1325S and R1623Q.
Results: N1325S， R1623Q and M1652R mutations resulted in defects of rapid inactivation with increased window current and INaL in rate-dependence manners (n=?， p<0.05). N1325S， but not R1623Q and M1652R， caused a leftward shift of the steady-state activation curves by 7.9 mV. N1325S and M1652R caused rightward shifts of the inactivation curves by 6.7 and 5.6 mV， respectively (n=?， p<0.05). R1623Q caused hyperpolarized shift of the inactivation curve by 15.2 mV and increased inactivation of the channel. The amplitude of late INaL in M1652R mutation was about two fold greater than that of N1325S and R1623Q mutations. Mexiletine (10 μM) improved the impaired rapid inactivation channels， slowed the recovery process and caused a leftward shift of steady-state inactivation curve of the mutant channels (n=5-13， p<0.05) without affacting their activation. Mexiletine reduced the window currents in N1325S and R1623Q， but not in M1652R mutations， and inhibited INaL with IC50s of 3.77±0.33 and 3.27±0.30 μM in N1325S and R1623Q which was lower than that of M1652 (11.14±1.18， n=3-6， p<0.05). The IC50 of eleclazine was 10 to 20 fold lower than that of mexiletine， lidocaine， ranolazine and propranolol . The IC50s of the INaL inhibitors in N1325S and R1623Q mutations were also lower than that in M1652R mutation. The results in the in vitro study were consistent with the effects of lidocaine and mexiletine treatment in patients with relative mutations.
Conclusion: Gating properties of mutant sodium channel predict the response to INaL inhibitors in LQT3.