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目的探讨氯沙坦对自发性高血压大鼠(SHR)心室肌细胞编码瞬间外向钾电流(Ito)、延迟整流性钾电流(Ik)、内向整流钾电流(Ik1)关键钾通道α和β亚基[Ito(Kv4.2、KChIP2)、IK(ERG、KvLQT1)、IK1(Kir2.1)]mRNA和蛋白水平的变化,研究氯沙坦抗室性心律失常效应的分子基础。方法SHR随机分成2组:对照组(n=12)和氯沙坦组[10mg/(kg.d),n=12,灌胃]。年龄、体质量匹配的WKY(n=12)作为对照。用药8周后采用膜片钳技术记录离体心脏、酶分解所得左室心肌细胞动作电位、Ito、Ik1、Ik,并采用逆转录聚合酶链反应(RT-PCR)及免疫印迹(Westernblot)方法测定Kv4.2、KChIP2、ERG、KvLQT1、Kir2.1的mRNA及蛋白水平。结果氯沙坦组心肌动作电位50%及90%复极化时程[(16.8±3.8)、(68.5±13.2)ms]短于对照组[(24.6±4.6)、(73.3±15.5)ms,均P<0.01]。氯沙坦组的Ito电流密度(从+40到+70mV)高于对照组(P<0.01)。氯沙坦组Kv4.2、Kir2.1mRNA及蛋白水平高于对照组(均P<0.01)。3组大鼠心肌细胞IK电流密度和ERG、KChIP2mRNA及蛋白水平均无差异(均P>0.05)。结论氯沙坦能够逆转SHR左室的电重构,缩短单个心肌细胞动作电位时程,这与I、I电流密度增加和Kv4.2、Kir2.1mRNA及蛋白水平增加密切相关。
Objective To investigate the effects of losartan on the expressions of Ito, Ik, Ik1 and K + I in spontaneously hypertensive rats (SHR) To investigate the molecular basis of the anti-ventricular arrhythmia effect of losartan on the changes of mRNA and protein levels of Ito (Kv4.2, KChIP2), IK (ERG, KvLQT1) and IK1 (Kir2.1) Methods SHR were randomly divided into 2 groups: control group (n = 12) and losartan group [10mg / (kg.d), n = 12, intragastric administration]. Age, body mass matched WKY (n = 12) served as control. Patch clamp technique was used to record the action potentials of isolated cardiomyocytes, Ito, Ik1 and Ik in isolated hearts after 8 weeks of treatment. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting The mRNA and protein levels of Kv4.2, KChIP2, ERG, KvLQT1 and Kir2.1 were determined. Results The duration of 50% and 90% repolarization of losartan group [(16.8 ± 3.8), (68.5 ± 13.2) ms] were shorter than that of the control group [(24.6 ± 4.6) and (73.3 ± 15.5) ms, All P <0.01]. Losartan group Ito current density (from +40 to +70 mV) higher than the control group (P <0.01). Losartan group Kv4.2, Kir2.1 mRNA and protein levels were higher than the control group (P <0.01). There were no differences in IK current density, ERG, KChIP2 mRNA and protein levels between the three groups (all P> 0.05). Conclusion Losartan can reverse the electrical remodeling of left ventricular in SHR and shorten the action potential duration of single cardiomyocytes, which is closely related to the increase of I and I current density and the increase of mRNA and protein levels of Kv4.2 and Kir2.1.