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目的研究内向整流钾通道激动剂扎考必利(zacopride,Zac)对异丙肾上腺素(isoproterenol,ISO)诱发的心肌肥厚大鼠心律失常的抑制作用及其电生理机制。方法1 51只SD大鼠(200~230 g),随机分为对照组、ISO组和ISO+Zac组(n=17)。连续7 d经腹腔注射5 mg·kg~(-1)ISO,建立大鼠心肌肥厚模型;2利用体表心电图观察Zac对ISO诱发的心肌肥厚大鼠心律失常的效应;3应用全细胞膜片钳技术观测Zac对模型组大鼠心肌细胞内向整流钾电流(I_(K1))、静息电位(RMP)、延迟后除极(DADs)及触发活动(TA)的影响。结果 1 M型超声心动图显示,与对照组相比,ISO组大鼠左室舒张末期内径(LVEDD)和左室收缩末期内径(LVESD)均明显降低,左室后壁舒张末期厚度(LVPWd)和室间隔舒张末期厚度(IVSd)均增高(P<0.05),提示ISO诱发建立大鼠心肌肥厚模型成功;2体表心电图显示,ISO组肥厚大鼠88.89%发生室性心律失常(频发室性期前收缩),生理盐水对照组大鼠未观察到心律失常的发生。在连续7 d给予15μg·kg~(-1) Zac干预后,肥厚大鼠心律失常发生率降至11.11%(P<0.05);3与对照组相比,ISO组大鼠RMP由(-71.05±1.27)m V降低至(-69.38±1.21)m V(P<0.05);连续7 d给予15μg·kg~(-1) Zac后,RMP增加至(-73.86±1.33)m V,较对照组和ISO组均明显增大(P<0.05);4 ISO+Zac组大鼠单个心肌细胞DADs和TA发生率较ISO致心肌肥厚组明显降低,由88.24%降低至11.76%(P<0.05);5与对照组相比,ISO组大鼠内向整流钾通道电流(I_(K1))明显降低,在给予Zac(15μg·kg~(-1))后I_(K1)明显增加(P<0.05)。结论选择性I_(K1)通道激动剂Zac可明显抑制ISO诱发的心肌肥厚大鼠心律失常的发生,其机制与它通过增强I_(K1)使膜电位负值增大和抑制延迟后除极的效应有关。
Objective To study the inhibitory effect of zacopride (Zac), an inward rectifier potassium channel agonist, on cardiac arrhythmia induced by isoproterenol (ISO) in rats and its electrophysiological mechanism. Methods Fifty-one SD rats (200-230 g) were randomly divided into control group, ISO group and ISO + Zac group (n = 17). The model of cardiac hypertrophy was established by intraperitoneal injection of 5 mg · kg -1 ISO for 7 consecutive days. 2 The effect of Zac on cardiac arrhythmia induced by ISO-induced myocardial hypertrophy was observed by surface electrocardiogram. 3 Whole-cell patch-clamp To observe the effects of Zac on inward rectifier potassium current (I_ (K1)), resting potential (RMP), post-depolarization depolarization (DADs) and triggering activity (TA) in model rats. Results 1 M-mode echocardiography showed that left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) were significantly decreased in the ISO group compared with those in the control group. Left ventricular posterior wall thickness (LVPWd) (P <0.05), suggesting that ISO-induced myocardial hypertrophy model was established successfully.2 Body surface electrocardiogram showed that 88.89% of hypertrophic rats in ISO group had ventricular arrhythmia Period before contraction), normal saline control group, no arrhythmia was observed. The incidence of arrhythmia in hypertrophied rats decreased to 11.11% (P <0.05) after 15 μg · kg -1 Zac administration for 7 consecutive days. 3 Compared with the control group, the RMP in the ISO group increased from -71.05 ± 1.27) m V decreased to (-69.38 ± 1.21) m V (P <0.05). The RMP increased to (-73.86 ± 1.33) m V after 15 μg · kg -1 Zac administration for 7 days, (P <0.05). The incidence of DADs and TA in single cardiomyocytes of ISO + Zac group was significantly lower than that of ISO-induced hypertrophy group (88.24% vs 11.76%, P <0.05) ; Compared with the control group, the inward rectifier potassium channel current (I_ (K1)) in ISO group was significantly decreased, while the I_ (K1) increased significantly after Zac administration (P <0.05) ). Conclusions Zac, a selective I_ (K1) channel agonist, can significantly inhibit the arrhythmia induced by ISO in rats with hypertrophic cardiomyopathy, and its mechanism is related to its effect by increasing I_ (K1) negative value of membrane potential and delaying delayed depolarization related.