心力衰竭后交感神经重构的机制及美托洛尔联合神经生长因子干预效果的研究

Mechanism and intervention efficacy of metoprolol combined with nerve growth factor on sympathetic nerve remodeling after heart failure

目的探讨心力衰竭(HF)后交感神经重构的机制及美托洛尔联合神经生长因子(NGF)的干预作用。方法 40只Wistar大鼠分为HF组34只和正常对照组(NC组)6只,HF组采用阿霉素4 mg/kg腹腔注射建立模型。6周后心脏超声评估大鼠心功能,并检测血浆NGF。将HF组存活大鼠分为HF对照组5只(HF-C组)、美托洛尔干预组5只(HF-M组)、NGF注射组5只(HF-N组)、NGF注射+美托洛尔干预组6只(HF-N-M组),其中鼠NGF以60μg/(kg·d)尾静脉注射,美托洛尔以0.25 mg/(kg·d)灌胃,共4周。干预4周后进行心律失常诱发,测定各组大鼠心功能和血浆NGF表达,并检测心脏组织的酪氨酸羟化酶(TH)、生长相关蛋白43(GAP43)、NGF的表达。结果与NC组比较,建模后HF组大鼠左室舒张末期容积(LVEDV)和左室收缩末期容积(LVESV)明显升高,而左室射血分数(LVEF)和血浆NGF表达明显下降(P<0.05)。干预4周后,与HF-C组比较,HF-M组、HF-N组和HF-N-M组LVEF及NGF表达明显升高,LVESV明显降低(P<0.05);HF-N-M组的NGF水平较HF-M组和HF-N组升高,且LVESV明显降低(P<0.05)。HF-C组、HF-M组、HF-N组和HF-N-M组TH、GAP43、NGF mRNA和蛋白表达较NC组明显降低(P<0.05),但HF-M组、HF-N组和HF-N-M组TH、GAP43、NGF mRNA和蛋白表达较HF-C组明显升高(P<0.05),而HF-N-M组与HF-M组、HF-N组比较,差异无统计学意义(P>0.05)。NC组、HF-C组、HF-M组、HF-N组、HF-N-M组心律失常诱发率分别为0、80.00%、20.00%、20.00%、16.67%。结论 Wistar大鼠腹腔注射阿霉素可以成功诱发HF模型,HF后交感神经重构与TH、GAP43、NGF有关,而美托洛尔和NGF可以改善HF后交感神经重构及心功能,降低心律失常的发生率。

Objective To investigate the mechanism of sympathetic nerve remodeling after heart failure（ HF）, and to explore the intervention effect of metoprolol combined with nerve growth factor（NFG） on it. Methods A total of 40 Wistar rats were divided into HF group （n = 34 ） and normal control group （NC group, n = 6 ）, and the modeling was conducted in HF group by intraperitoneal administration with adriamycin（4 mg/kg）. After 6 weeks,the cardiac function was evaluated by echocardiography,and the plasma NGF level was detected. Then the survived rats in HF group were divided into control I-IF group（HF-C group,n =5） ,metoprolol group（HF-M group,n =5） ,NGF group （HF-N group,n =5） ,and NGF and metoprolol group（HF-N-M group,n =6）. And mouse NGF was administered via caudal vein with a dose of 60 μg/（ kg · d）,and metoprolol via stomach with a dose of 0.25 mg/（ kg · d） for 4 weeks. After 4 weeks of treatment, arrhythmia induction and cardiac function measurement were conducted ,and the plasma level of NGF as well as the levels of tyrosine hydroxylase（TH） ,growth associated protein 43（GAP43） and NGF in cardiac tissues were detected. Results Compared to NC group, left ventricular end-diastolic volume （LVEDV） and left ventricular end-systolic volume（LVESV） increased significantly,left ventricular ejection fraction （LVEF） and plasma NGF level decreased significantly in HF group after modeling（P 〈 0. 05 ）. Compared to HF-C group,LVEF and NGF level increased significantly, and LVESV decreased significantly in HF-M group,HF-N group and HF-N-M group after 4 weeks of treatment（P 〈0.05）. Compared to HF-N group or HF-M group ,NGF level increased ,and LVESV decreased in HF-N-M group after 4 weeks of treatment（P 〈 0.05）. The expression levels of TH,GAP43 and NGF mRNA/protein in HF-C group,HF-M group,HF-N group and HF-N-M group were significantly lower than those in NC group（P 〈0.05）. The expression levels of TH, GAP43, NGF mRNA/protein in HF-M group, HF-N group and HF-N-M group were significantly higher than those in HF-C group（P 〈 0.05）, but there was no significant difference between HF-N-M group and HF-M group or HF-N group （P〉0.05）.The induction rates of arrhythmia in NC group,I-IF-C group,HF-M group,HF-N group and I-IF-N-M group were 0,80.00%, 20.00% ,20.00% and 16.67% respectively. Conclusion Adriamycin can successfully induce HF model in Wistar rats. Sympathetic nerve remodeling is associated with TH,GAP43 and NGF. Metoprolol and NGF can improve sympathetic nerve remodehng and cardiac function,and reduce the incidence of arrhythmia after HF.