川芎嗪对心肌梗死大鼠交感神经重构的抑制作用及其机制

Suppression Effect and Underlying Mechanisms of Tetramethylpyrazine on Sympathetic Neural Remodeling in Rats Following Myocardial Infarction

目的探讨川芎嗪是否拮抗氧化应激并减轻心肌梗死(MI)后交感神经重构。方法将40只成年雄性Sprague-Dawley大鼠随机分为对照组(n=10)、模型组(n=15)和治疗组(n=15),后两组采用结扎左前降支的方法制作MI模型,对照组行假手术。治疗组术后24 h腹腔注射川芎嗪注射液120 mg/kg,每天1次,连续6周;另两组腹腔内注射等量生理盐水。术后6周行多普勒心脏彩超检查测定心脏指标,检测血浆超氧化物歧化酶(SOD)和丙二醛(MDA)含量;检测大鼠MI边缘区酪氨酸羟化酶(TH)阳性神经纤维密度,并对氧化应激与交感神经重构程度进行相关分析。结果模型组左心室舒张期末内径(LVEDD)和左心室收缩期末内径(LVESD)均高于对照组,射血分数(EF)、短轴缩短率(FS)均低于对照组(P<0.05);治疗组LVEDD、LVESD均低于模型组,EF、FS均高于模型组(P<0.05)。治疗组血浆SOD含量高于模型组(P<0.05),MDA含量低于模型组(P<0.01)。模型组TH阳性神经纤维密度明显高于对照组,治疗组TH阳性神经纤维密度明显低于模型组(P<0.01)。MDA/SOD与TH阳性神经纤维密度存在直线相关(r=0.909,P<0.01)。结论川芎嗪抑制MI后交感神经重构,与其拮抗氧化应激作用密切相关。川芎嗪抑制MI后交感神经重构为减少MI后室性心律失常提供新的治疗思路。

Aim To investigate whether tetramethylpyrazine can suppress oxidative stress and improve sympa- thetic neural remodeling in rats following myocardial infarction （MI）. Methods A total of 40 male Sprague-Dawley rats were involved in this study. The animals were randomly divided into three groups： control group （n = 10）, MI group （n = 15） and treated group （n = 15）. MI model was established by ligating left anterior descending artery of rats. Rats in treated group were intraperitoneally injected with tetramethylpyrazine at 120 mg/kg per day for 6 weeks post MI. The control group experienced the same procedure but ligation. Six weeks after operation, echocardiography and serological examination were performed to determine cardiac function, superoxide dismutase （SOD） and malondialdehyde （MDA） in each group. Myocardial nerve density was determined in infarct marginal zone by immunohistochemistry staining with anti- tyrosine hydroxylase （TH） antibodies. Liner regression analyses were also performed to examine whether level of oxidative stress were associated with sympathetic neural remodeling. Results The left ventricular end diastolic diameter in diastole （LVEDD） and left ventricular end systolic diameter （LVESD） of MI group were higher than those of control group, while ejection fraction （EF）and fractional shortening （FS） were lower than those of control group （all P 〈 0. 05 ）. LVEDD and LVESD were significantly reduced in treated group, as compared with the MI group, while EF and FS were significantly increased in treated group, as compared with the MI group （ all P 〈 0. 05 ）. SOD content was significantly increased and MDA significantly reduced in treated group, as compared with MI group （P 〈0.05 and P 〈0. 01, respectively）. TH-positive nerves were more abundant in the infarct marginal zone in MI group compared to control group, while TH-positive nerve density were reduced in treated group compared to MI group （ all P 〈 0. 01 ）. Linear correlation between value of MDA/SOD and density of TH-positive nerve has been determined （ r = 0. 909, P 〈 0. 01 ）. Conclusion Tetramethylpyrazine can suppress sympathetic neural remodeling process after MI via attenuated oxidative stress, which may in turn leads to a promising treatment for the malignant ventricular arrhythmias post MI.