Qi Min-You, Liu Hao-Ran, Dai De-Zai, Li Na, Dai Yin
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
J Pharm Pharmacol. 2008 Dec;60(12):1687-94. doi: 10.1211/jpp/60.12.0016.
Total triterpene acids (TTAs) isolated from Cornus officinalis Sieb., one of the herbs contained in Liuwei Dihuang decoction, were aimed at alleviating diabetic cardiomyopathy. We hypothesized that the benefits of TTAs may result from suppressing the endothelin-reactive oxidative species (ET-ROS) pathway in the myocardium. Diabetes was produced by a single injection of streptozotocin (STZ, 60 mg kg(-1), i.p.) in rats. Assessment of cardiac function, calcium handling proteins, endothelin-1 (ET-1) and redox system was conducted 8 weeks after STZ injection. Medication with TTAs (50 mg kg(-1), i.g.) was installed in the last 4 weeks. The compromised cardiac function was characterized by depressed contractility (LVSP and LV+dp/dt(max)) and relaxation (LVEDP and -LVdp/dt(min)) in association with hyperglycaemia (30.2 +/- 2.6 mmol L(-1)) in STZ-injected rats. Down-regulated expression of FKBP12.6 (calstabin 2), sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) and phospholamban (PLB) were also found. These changes occurred in connection with an increased ET-1, up-regulated mRNA of propreET-1 and endothelin converting enzyme (ECE), and a state of oxidant stress was found by increased malondialdehyde (MDA), decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity, and an enhanced activity and expression of inducible nitric oxide synthase (iNOS) in the diabetic myocardium. After 4 weeks of treatment with TTAs, these changes were alleviated dramatically despite a mild reduction in hyperglycaemia (26.9 +/- 3.4 mmol L(-1)). In conclusion, TTAs, as active ingredients of Liuwei Dihuang decoction, alleviated diabetic cardiomyopathy by normalizing the abnormality of FKBP12.6 and SERCA2a and ET-ROS pathway in the myocardium rather than by hypoglycaemic activity.
从六味地黄丸所含草药之一山茱萸中分离出的总三萜酸（TTAs）旨在缓解糖尿病性心肌病。我们推测TTAs的益处可能源于抑制心肌中的内皮素-活性氧（ET-ROS）途径。通过单次腹腔注射链脲佐菌素（STZ，60 mg kg⁻¹）在大鼠中诱导糖尿病。在注射STZ 8周后评估心脏功能、钙处理蛋白、内皮素-1（ET-1）和氧化还原系统。在最后4周给予TTAs（50 mg kg⁻¹，灌胃）进行药物治疗。注射STZ的大鼠心脏功能受损表现为收缩性（左心室收缩压和左心室压力上升最大速率）和舒张性（左心室舒张末压和左心室压力下降最大速率）降低，同时伴有高血糖（30.2±2.6 mmol L⁻¹）。还发现FKBP12.6（钙调蛋白2）、肌浆网Ca²⁺-ATP酶2a（SERCA2a）和受磷蛋白（PLB）的表达下调。这些变化与ET-1增加、前体ET-1和内皮素转化酶（ECE）的mRNA上调有关，并且通过糖尿病心肌中丙二醛（MDA）增加、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-px）活性降低以及诱导型一氧化氮合酶（iNOS）活性和表达增强发现氧化应激状态。用TTAs治疗4周后，尽管高血糖略有降低（26.9±3.4 mmol L⁻¹），但这些变化显著缓解。总之，TTAs作为六味地黄丸的活性成分，通过使心肌中FKBP12.6和SERCA2a以及ET-ROS途径的异常正常化而非通过降血糖活性来缓解糖尿病性心肌病。
