【摘要】 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。更多还原

【Abstract】 Objective To investigate the molecular basis for anti-ventricular arrhythmic effects by losartan through measuring alteration in mRNA and protein levels of key K+ channel α and β subunits that encode Ito (Kv4.2 and KChIP2), IKr (ERG), IKs (KvLQT1), and IK1 (Kir2.1) in ventricular cardiomyocytes in spontaneously hypertensive rats (SHR).MethodsSHR were randomly assigned to losartan [10 mg/(kg·d), n=12, by gavage] or placebo(n=12), with age and weight matched WKY rats (n=12) as control.After 8 weeks of treatment, cardiomyocytes were isolated enzymatically.Action potential of cardiomyocytes Ito, IK1 and IK were recorded and mRNA and protein levels of Kv4.2, KChIP2, ERG, KvLQT1 and Kir2.1 were assessed by RT-PCR and Western blot.ResultsThe action petential(APD) measured at 50% and 90% repolarization[(16.8±3.8) and(68.5±13.2)ms] was significantly shortened by losartan treatment than that in SHR placeto [(24.6±4.6),(73.3±15.5) ms, all P<0.01].Losartan treartment increased Ito current density, associated with a markedly increases in the mean levels of mRNA and protein of Kv4.2 and Kir2.1 compared with those in placebo SHR (all P<0.01). Little change were found in the current density of IK and mRNA and protein expression levels of ERG and KChIP2 in placebo group, WKY rats group and losartan group (all P>0.05).ConclusionChronic blockade of AT1 receptors with losartan reverses electrical remodeling of cardiomyocytes in SHR, resulting in shortening of APD, which is associated with increasing IK1 and Ito density by increased mRNA and protein expression of Kv4.2 and Kir2.1 and by decreased mRNA and protein expression of KChIP2.更多还原