We evaluated the inhibitory effects of the atypical antipsychotic drug risperidone on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Risperidone suppressed Kv currents in reversible and concentration-dependent manners with an apparent half-maximal effective concentration (IC50 value) of 5.54 ± 0.66 μM and a slope factor of 1.22 ± 0.07. The inactivation of Kv currents was significantly accelerated by risperidone. The rate constants of association and dissociation for risperidone were 0.25 ± 0.01 μM-1s-1 and 1.36 ± 0.14 s-1, respectively. Application of risperidone shifted the steady-state activation curve in the positive direction and the inactivation curve in the negative direction, suggesting that the risperidone-induced inhibition of Kv channels was mediated by effects on the voltage sensors of the channels. Application of train pulses at 1 and 2 Hz led to a progressive increase in the blockage of Kv currents by risperidone. In addition, the recovery time constants from inactivation were extended in the presence of risperidone, indicating that risperidone inhibited Kv channels in a use (state)-dependent manner. Pretreatment with the Kv1.5 subtype inhibitor reduced the inhibitory effects of risperidone on Kv channels. However, pretreatment with a Kv2.1 or Kv7.X subtype inhibitor did not affect the inhibitory effects of risperidone. Risperidone induced vasoconstriction and membrane depolarization. Based on these results, we conclude that risperidone inhibits Kv channels in a concentration-, time-, and state-dependent manners. Our results should be taken into consideration when using risperidone to study the kinetics of K+ channels in vascular smooth muscle.

译文

:我们评估了非典型抗精神病药利培酮对兔冠状动脉平滑肌细胞电压依赖性钾离子(Kv)通道的抑制作用。利培酮以可逆和浓度依赖性方式抑制Kv电流,表观最大有效浓度(IC50值)为5.54±0.66μM,斜率系数为1.22±0.07。利培酮显着加速了Kv电流的失活。利培酮的缔合和解离速率常数分别为0.25±0.01μM-1s-1和1.36±0.14s-1。利培酮的应用使稳态激活曲线向正方向移动,而灭活曲线向负方向移动,这表明利培酮诱导的Kv通道抑制作用是通过对通道电压传感器的影响来介导的。施加1和2 Hz的脉冲脉冲会导致利培酮对Kv电流的阻滞作用逐渐增加。另外,在存在利培酮的情况下延长了失活的恢复时间常数,这表明利培酮以使用(状态)依赖的方式抑制了Kv通道。用Kv1.5亚型抑制剂预处理可降低利培酮对Kv通道的抑制作用。但是,用Kv2.1或Kv7.X亚型抑制剂预处理不会影响利培酮的抑制作用。利培酮引起的血管收缩和膜去极化。基于这些结果,我们得出结论,利培酮以浓度,时间和状态依赖性方式抑制Kv通道。当使用利培酮研究血管平滑肌中K通道的动力学时,应考虑我们的结果。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录