氯沙坦调节瞬间外向钾电流的分子学研究  

Molecular basis for losartan regulating transient outward potassium current

作　　者：邬松林[1] 黄从新[1] 

机构地区：[1]武汉大学人民医院老年病科,430060

出　　处：《中华老年医学杂志》2010年第5期424-428,共5页Chinese Journal of Geriatrics

摘　　要：目的观察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）关键钾通道a亚基（Kv4．2、Kv4．3）、B亚基（KChIP2）mRNA和蛋白水平变化的影响，探讨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：氯沙坦组（10mg·d-1·kg-1灌胃）和SHR对照组各12只大鼠。鼠龄、体质量匹配的WKY大鼠12只为WKY对照组。用药8周后采用膜片钳技术记录左心室心肌细胞动作电位、Ito，并采用反转录聚合酶链反应及免疫印迹反应（Westernblot）方法测定Kv4．2、Kv4．3、KChIP2mRNA及蛋白水平。结果氯沙坦组左心室细胞的动作电位复极至50％及90％时程分别为（16．82±3．79）ms和（68．49±13．25）ms，短于SHR对照组的（24．56±4．59）ms和（73．26±15．47）ms，二者差异有统计学意义（均P〈0．01）。氯沙坦组的ho电流密度高于SHR对照组（从＋40mV到＋70mV，均P〈0．01）。氯沙坦组Kv4．2、Kv4．3mRNA及蛋白水平高于sHR对照组（均P〈0．01）。氯沙坦组KChIP2mRNA及蛋白水平低于sHR对照组（均P〈0．01）。结论氯沙坦慢性阻滞血管紧张素受体，逆转SHR左心室的电重构，缩短单个心肌细胞动作电位时程，增加Ito电流密度，这与Kv4．2、Kv4．3表达增加及KChIP2表达降低相关。Objective To investigate the molecular basis for anti-ventricular arrhythmic effects by losartan through measuring alteration in mRNA and protein levels of key K＋a cbannel-and-βsubunits （Kv4.2, Kv4.3 and KChIP2） in ventricular myocytes in spontaneously hypertensive rats （SHRs）. Methods SHRs were randomly assigned to losartan [10 mg · kg-1 · d-1 , n= 12] or placebo （n= 12） with age-and weight-matched WKY rats （n= 12） as control. After 8 weeks of treatment, cardiomyocytes were isolated by enzymolysis. Action potential of cardiomyocytes Ito was recorded, mRNA and protein levels of Kv4.2, Kv4.3 and KChIP2 were assessed by reverse transcriptase polymerase chain reaction and Western blot. Results The action potential duration （APD） measured at 50% and 90% repolarization was shorter in losartan group [（16.82＋-3.79） ms and （68. 49±13.25） ms]than in SHR control group [（24. 56±4. 59） ms and （73.26±15.47） ms, all P〈0.01]. Losartan increased ho current density associated with significant increases in the mean levels of mRNA and protein of Kv4.2 and Kv4.3, and with significant decreases in the mean levels of mRNA and protein of KChIP2 compared with those in placebo SHR （all P〈0. 01）. Conclusions Chronic blockade of AT1 receptors with losartan reverses cardiomyocytes electrical remodeling in SHR, resulting in the shortening of APD, which is associated with increasing ho density by increasing mRNA and protein expression of Kv4.2, Kv4.3 and by decreasing mRNA and protein expression of KChIP2.

关 键 词：受体 血管紧张素 大鼠 近交SHR 钾通道 

分 类 号：R544.1[医药卫生—心血管疾病]