小檗碱抗心肌肥厚的作用及机制研究
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摘要
心肌肥厚(cardiac hypertrophy)与重塑(remodeling)是心脏在多种神经体液因素刺激下发生的一种适应性反应，以此来补偿心功能的需求。但心肌肥厚发生时，心脏结构与形态的改变将导致心功能障碍，增加心血管危险事件的发生率，因此心肌肥厚又被称为心血管系统疾病的独立危险因素。深入研究心肌肥厚与重塑的病理演变过程及机制，积极发现并使用药物干预心功能不全和损伤后的重建与修复，对于降低心血管疾病的发病率、死亡率，改善患者生存质量具有重要意义。
心肌肥厚的发生与发展的过程中有多种因素参与，如交感神经系统、肾素-血管紧张素系统以及其他多种神经内分泌的激活、细胞因子的活化、血管活性肽、细胞内信息分子及传导通路的改变、基因表达异常以及多种基因之间的相互作用等。而抑制交感神经活性对于改善心衰患者症状，逆转心衰患者的心肌肥厚和心室重构具有积极作用。
小檗碱(berberine)是中药清热药黄连所含的主要生物碱。黄连味苦，性寒，归心、脾、胃等经。中药药性理论的现代药理研究结果认为：寒凉药物多具有抗交感-肾上腺系统的作用。有报道显示，小檗碱具有抗心律失常、降压、强心等作用，并对难治性心衰及病毒性心肌炎后出现的心律失常有积极治疗作用。但小檗碱是否对心肌肥厚与重塑有抑制作用尚缺乏研究资料报道。
本研究以目前公认的具有抑制心肌肥厚作用的药物——血管紧张素转化酶抑制剂(卡托普利)、β-肾上腺素受体阻滞剂(美托洛尔)、血管紧张素受体阻滞剂(氯沙坦)为阳性对照药，探讨小檗碱对心肌肥厚的抑制作用及相关机制，对药物作用靶标的形态、结构、功能进行了组织病理学、细胞和分子生物学的研究，结果如下：
1．小檗碱对压力超负荷致心肌肥厚模型大鼠心脏结构的影响
1．1 小檗碱对腹主动脉结扎模型大鼠心肌肥厚的影响
目的：研究小檗碱对压力超负荷型大鼠心肌肥厚的抑制作用。
方法：结扎大鼠腹主动脉使之外径缩窄至0.6mm，导致心脏后负荷增高，形成心肌肥厚。造模后2周给予治疗药物：小檗碱5、10、20mg/kg，卡托普利45mg/kg，美托洛尔10mg/kg，氯沙坦10mg/kg。连续给药10周。分别于造模后2周、给药后4周、10周测定心脏重量，并计算心重指数。
结果：①结扎大鼠腹主动脉使之缩窄致心脏后负荷增高可诱发心肌肥厚，2周后心脏重量及心重指数即明显高于假手术组，但造模时间延长心重指数有所下降。②小檗碱连续给药对结扎腹主动脉诱发的大鼠心肌肥厚有一定抑制作用，使心重指数有所下降，作用与各阳性对照药相似。
结论：小檗碱对腹主动脉结扎所敛的大鼠心肌肥厚有一定抑制作用，作用强度与阳性对照药卡托普利、美托洛尔及氯沙坦无显著差异。其抗肥厚作用还需从改善心脏形态、
Background
Cardiac hypertrophy is an important and fundamental adaptive response to a requirement for increased contractile power. It is not only a factor intimately associated with chronic heart failure(CHF), but also an important cause of increased morbidity and mortality of cardiac diseases. Hence, cardiac hypertrophy is regarded as a major risk factor of heart disease.
Berberine is an alkaloid from Hydrastis canadensis L.,Berberidaceae. It is also the basic chemical component of Coptis chinensis Franch(coptis). In China, some Chinese physicians succeeded by using coptis or berberine in the treatment of cardiac diseases, like hypertension and CHF. In the present project, the effects of berberine on attenuating the development of cardiac hypertrophy in both pressure-overload induced cardiac hypertrophy rat model and cell culture were studied, and the underline mechanism of its action was revealed to a certain extent.
Methods and Results
1. Pretective effects of berberine on myocardial hypertrophy and remodelling in established cardiac pressure-overload hypertrophy in rats with aortic banding
1.1 Effect of berberine on inhibiting the development of cardiac hypertrophy in rat with aortic banding
Objective: To learn the inhibitory effect of berberine on the development of cardiac hypertrophy in pressure overload induced cardiac hypertrophy in rats.
Methods: Pressure overload cardiac hypertrophy was induced by abdominal aorta constriction(banding) in rats. The drugs were orally administered for 10 wks starting from 2 weeks after surgery at dosage of berberine 5, 10, 20mg/kg, captopril 45 mg/kg, metoprolol 10mg/kg and losartan 10mg/kg. The heart weight and cardiac index were measured for three times at 2 wks after surgery, and 4 or 10 wks after treatment with drugs.
Results: (1)2 weeks after aorta constriction surgery, the heart weight and cardiac index of
心肌肥厚的发生与发展的过程中有多种因素参与，如交感神经系统、肾素-血管紧张素系统以及其他多种神经内分泌的激活、细胞因子的活化、血管活性肽、细胞内信息分子及传导通路的改变、基因表达异常以及多种基因之间的相互作用等。而抑制交感神经活性对于改善心衰患者症状，逆转心衰患者的心肌肥厚和心室重构具有积极作用。
小檗碱(berberine)是中药清热药黄连所含的主要生物碱。黄连味苦，性寒，归心、脾、胃等经。中药药性理论的现代药理研究结果认为：寒凉药物多具有抗交感-肾上腺系统的作用。有报道显示，小檗碱具有抗心律失常、降压、强心等作用，并对难治性心衰及病毒性心肌炎后出现的心律失常有积极治疗作用。但小檗碱是否对心肌肥厚与重塑有抑制作用尚缺乏研究资料报道。
本研究以目前公认的具有抑制心肌肥厚作用的药物——血管紧张素转化酶抑制剂(卡托普利)、β-肾上腺素受体阻滞剂(美托洛尔)、血管紧张素受体阻滞剂(氯沙坦)为阳性对照药，探讨小檗碱对心肌肥厚的抑制作用及相关机制，对药物作用靶标的形态、结构、功能进行了组织病理学、细胞和分子生物学的研究，结果如下：
1．小檗碱对压力超负荷致心肌肥厚模型大鼠心脏结构的影响
1．1 小檗碱对腹主动脉结扎模型大鼠心肌肥厚的影响
目的：研究小檗碱对压力超负荷型大鼠心肌肥厚的抑制作用。
方法：结扎大鼠腹主动脉使之外径缩窄至0.6mm，导致心脏后负荷增高，形成心肌肥厚。造模后2周给予治疗药物：小檗碱5、10、20mg/kg，卡托普利45mg/kg，美托洛尔10mg/kg，氯沙坦10mg/kg。连续给药10周。分别于造模后2周、给药后4周、10周测定心脏重量，并计算心重指数。
结果：①结扎大鼠腹主动脉使之缩窄致心脏后负荷增高可诱发心肌肥厚，2周后心脏重量及心重指数即明显高于假手术组，但造模时间延长心重指数有所下降。②小檗碱连续给药对结扎腹主动脉诱发的大鼠心肌肥厚有一定抑制作用，使心重指数有所下降，作用与各阳性对照药相似。
结论：小檗碱对腹主动脉结扎所敛的大鼠心肌肥厚有一定抑制作用，作用强度与阳性对照药卡托普利、美托洛尔及氯沙坦无显著差异。其抗肥厚作用还需从改善心脏形态、
Background
Cardiac hypertrophy is an important and fundamental adaptive response to a requirement for increased contractile power. It is not only a factor intimately associated with chronic heart failure(CHF), but also an important cause of increased morbidity and mortality of cardiac diseases. Hence, cardiac hypertrophy is regarded as a major risk factor of heart disease.
Berberine is an alkaloid from Hydrastis canadensis L.,Berberidaceae. It is also the basic chemical component of Coptis chinensis Franch(coptis). In China, some Chinese physicians succeeded by using coptis or berberine in the treatment of cardiac diseases, like hypertension and CHF. In the present project, the effects of berberine on attenuating the development of cardiac hypertrophy in both pressure-overload induced cardiac hypertrophy rat model and cell culture were studied, and the underline mechanism of its action was revealed to a certain extent.
Methods and Results
1. Pretective effects of berberine on myocardial hypertrophy and remodelling in established cardiac pressure-overload hypertrophy in rats with aortic banding
1.1 Effect of berberine on inhibiting the development of cardiac hypertrophy in rat with aortic banding
Objective: To learn the inhibitory effect of berberine on the development of cardiac hypertrophy in pressure overload induced cardiac hypertrophy in rats.
Methods: Pressure overload cardiac hypertrophy was induced by abdominal aorta constriction(banding) in rats. The drugs were orally administered for 10 wks starting from 2 weeks after surgery at dosage of berberine 5, 10, 20mg/kg, captopril 45 mg/kg, metoprolol 10mg/kg and losartan 10mg/kg. The heart weight and cardiac index were measured for three times at 2 wks after surgery, and 4 or 10 wks after treatment with drugs.
Results: (1)2 weeks after aorta constriction surgery, the heart weight and cardiac index of
引文
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