Iptakalim improves cerebral microcirculation in mice after ischemic stroke by inhibiting pericyte contraction  

作　　者：Ruo-bing Guo Yin-feng Dong Zhi Yin Zhen-yu Cai Jin Yang Juan Ji Yu-qin Sun Xin-xin Huang Teng-fei Xue Hong Cheng Xi-qiao Zhou Xiu-lan Sun 

机构地区：[1]Neuroprotective Drug Discovery Key Laboratory,Jiangsu Key Laboratory of Neurodegeneration,Nanjing Medical University,Nanjing 211166,China [2]Nanjing University of Chinese Medicine,The Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210029,China [3]The First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China

出　　处：《Acta Pharmacologica Sinica》2022年第6期1349-1359,共11页中国药理学报（英文版）

基　　金：The National Natural Science Foundation of China(Nos.81973301,81773701,and 82003732);the Medical Research Project of Jiangsu Commission of Health(No.ZDA2020006);the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.18KJA310004);the Major Project of Nanjing Medical University(No.NMUD2018008);the Priority Academic Program Development of Jiangsu Higher Education Institutions.

摘　　要：Pericytes are present tight around the intervals of capillaries,play an essential role in stabilizing the blood-brain barrier,regulating blood flow and immunomodulation,and persistent contraction of pericytes eventually leads to impaired blood flow and poor clinical outcomes in ischemic stroke.We previously show that iptakalim,an ATP-sensitive potassium(K-ATP)channel opener,exerts protective effects in neurons,and glia against ischemia-induced injury.In this study we investigated the impacts of iptakalim on pericytes contraction in stroke.Mice were subjected to cerebral artery occlusion(MCAO),then administered iptakalim(10 mg/kg,ip).We showed that iptakalim administration significantly promoted recovery of cerebral blood flow after cerebral ischemia and reperfusion.Furthermore,we found that iptakalim significantly inhibited pericytes contraction,decreased the number of obstructed capillaries,and improved cerebral microcirculation.Using a collagen gel contraction assay,we demonstrated that cultured pericytes subjected to oxygen-glucose deprivation(OGD)consistently contracted from 3 h till 24 h during reoxygenation,whereas iptakalim treatment(10μM)notably restrained pericyte contraction from 6 h during reoxygenation.We further showed that iptakalim treatment promoted K-ATP channel opening via suppressing SUR2/EPAC1 complex formation.Consequently,it reduced calcium influx and ET-1 release.Taken together,our results demonstrate that iptakalim,targeted K-ATP channels,can improve microvascular disturbance by inhibiting pericyte contraction after ischemic stroke.Our work reveals that iptakalim might be developed as a promising pericyte regulator for treatment of stroke.

关 键 词：stroke cerebral ischemia IPTAKALIM ATP-sensitive potassium channels PERICYTES MICROCIRCULATION 

分 类 号：R965[医药卫生—药理学]