去甲肾上腺素的急性作用加重糖尿病大鼠心室电重构而易于诱发室性心律失常的作用及其机制

Effects and mechanism of acute norepinephrine aggravating ventricular electrical remodeling and facilitating susceptibility of ventricular arrhythmia in diabetes rats

目的:探讨去甲肾上腺素(NE)的急性作用对糖尿病大鼠室性心律失常的影响及其机制。方法:将健康雄性大鼠分为对照组(C组,n=10)、糖尿病组(D组,n=10)和NE组(N组,n=10),D组大鼠经腹腔注射链脲佐菌素诱导,成功制备糖尿病模型,N组是在完成D组数据采集后加入NE作用。通过电生理记录技术,观察心电图记录的心率、PR、RR和QT间期以及QT间期离散度变化;在体心室肌单相动作电位的幅度(APA)、最大上升速率(Maxdv/dt)、复极化恢复到10%、50%、90%时间(APD_(10)、APD_(50)、APD_(90)),以及复极化时程三角测量值(Triangulation)变化,基础刺激周长(BCL)为200 ms时心室有效不应期(ERP200),以及短阵快速刺激诱发室性心律失常的BCL和诱发率。酶解法分离单个心室肌细胞,全细胞膜片钳技术观察每组心室肌细胞瞬时外向钾电流(Ito)及其电流-电压(I-V)曲线改变。结果:与D组比较,N组心率减慢,PR、RR和QT间期延长以及QT离散度增加均非常显著(均P<0.05);且N组APA降低,Maxdv/dt减慢,APD_(10)、APD_(50)、APD_(90)和Triangulation的延长亦非常明显(均P<0.05);另外,N组ERP200和诱发室性心律失常BCL均明显延长,诱发率显著增加(均P<0.05);最后,N组Ito的幅度减小,当钳制电位为+50 m V时,N组大鼠心室肌细胞Ito的电流密度由D组的(12.09±2.29)pA/pF明显减小到(7.94±1.93)pA/pF(P<0.01),其Ito的I-V曲线处于D组的下面。结论:NE的急性作用在糖尿病引起心室电重构和交感神经调节功能损伤的基础上,使得糖尿病心室的电重构加重,易感性加强而更利于诱发室性心律失常,其机制可能与NE急性作用引起糖尿病心室肌细胞Ito减小有关。

Objective:To investigate effects and mechanism of acute norepinephrine(NE)aggravating ventricular electrical remodeling and facilitating susceptibility of ventricular arrhythmia in diabetes rats.Methods:The healthy and male rats were divided into control goup(C group,n=10),diabetes mellitus group(D group,n=10),and diabetes mellitus with NE group(N group,n=10).The diabetic models were induced with intraperitoneal injection of streptozotocin(65 mg/kg),and justified success by observing severity changes of clinic sign and fasting blood glucose values.The some main electrical parameters in 3 groups were recorded such as heart rate,PR,RR,and QT interval as well as QT dispersion from normalⅡelectrocardiogram,and APA,Max_(dv/dt),APD_(10),APD_(20),APD_(90),and Triangulation with monophasic action potential(MAP)recording,as well as ERP_(200),BCL,and inducibility of ventrucular arrhythmias by recording of programmed electrical stimulation and Burst-pacing in left ventricualar tissue of rats in vivo.The transient outward potassium current(I_(to))was recorded via whole-cell patch clamp technique in enzymatically dissociated single rats ventricular myocytes.Results:Compared with D group,the heart rate was significantly slowed,PR,RR,and QT interval were obviously shortened,QT dispersion was significantly increased in N group(all P<0.05).Moreover,APA was significantly reduced,Max_(dv/dt)was slowly accelerated,APD_(10),APD_(50),APD_(90)and Triangulation were all significantly prolongated in administrating N group with diabetic rats(all P<0.05).Otherwise,the ERP_(200)and BCL value of induced ventricular arrhythmias were markedly lengthened,and the induced rate of ventricular arrhythmias was obviously increased in diabetic rats administrated NE(all P<0.05).At last,with voltage clamp model,NE could significantly decrease the current amplitude of I_(to)in different command potential in diabetic ventricular myocytes.When holding potential was-50 m V and command potential was+50 m V,the current densities of I_(to)were significantly decreased from(12.09±2.29)pA/pF in D group to(7.94±1.93)pA/pF in N group(P<0.01)with NE administration.Otherwise,NE could completely change the I-V curve downward without changing the I-V relationship curve direction in diabetic ventricular myocytes of rats.Conclusion:NE was aggravated the ventricular electrical remodeling to facilitate susceptibility of ventricular arrhythmias in diabetic rats throughα_1-adrenoceptors at acute administation,which might completedly have developed the ventricular electrical remodeling and damage of sympathetic nerve regulation.It could be suggested that the mechanisms might attribute to that NE with abnormal sympathetic regulation could significantly decreased the amplitude of I_(to)in diabetic ventricular myocytes of rats.