【作者】 杨华伟；

【导师】 赵立诚；

【作者基本信息】 广州中医药大学 ， 中医内科学， 2005， 博士

【摘要】 背景 慢性充血性心力衰竭是各种心脏疾病发展到严重阶段的一种临床症状群。我国心力衰竭住院率占同期心血管病的20%,死亡率却占40%,提示预后严重,五年存活率与恶性肿瘤相仿。因此心力衰竭的治疗的是临床重要课题。 洋地黄是目前治疗心衰的基础药物,但是目前困扰洋地黄类药物应用的问题主要是洋地黄中毒问题,洋地黄中毒机制是洋地黄明显抑制心肌Na⁺—K⁺—ATP酶。黄芪亦是治疗心衰的常用中药,同时研究表明具有抗心衰患者心律失常的作用,并认为作用的机制可能与黄芪恢复心肌细胞Na⁺—K-ATP酶功能有关。我们在以往的实验研究中观察黄芪注射液对哇巴因致豚鼠心脏毒性的保护作用,说明黄芪注射液有减少洋地黄中毒发生的作用。 研究目的 研究黄芪注射液改善慢性心力衰竭大鼠的血流动力学指标、改善心衰病人症状、减少洋地黄中毒的作用,同时初步探讨减少洋地黄中毒的机理,为临床应用黄芪注射液治疗心衰、预防洋地黄中毒的发生提供一定的理论、和临床基础。 研究内容与方法 一、实验研究 清洁级SD大鼠60只,造模成功大鼠随机分成6组,每组各10只大鼠。A组,B组,C组,分别为生理盐水组、低剂量黄芪组、大剂量黄芪组,进行急性洋地黄中毒实验;E、F、G组分别为生理盐水组、低剂量黄芪组、大剂量黄芪组,进行慢性洋地黄中毒实验。A、B、C组动物麻醉,3号硬外麻导管进行右颈总动脉插管,逆行插至左心室,导管通过血压换能器连接BM6000型八道生理记录仪,然后分离左侧颈外静脉,插入塑料套管,以电动恒速注射器,各组注入A、B、C各组药物（5ml）,然后持续以12.5mg/min注入0.005%哇巴因。用示波器监视心电图,记录出现室性心动过速、室颤及心跳停止时所注入的哇巴因剂量。同时分别记录注射药物前（Ⅰ点）、注射生理盐水或黄芪注射液1min后（Ⅱ点）、开始滴注哇巴因1min后（Ⅲ点）、及出现室速时（Ⅳ点）的血流动力学指标,包括心率（HR）、左室收缩压（LVSP）、左室舒张末压力（LVEDP）和左室压力最大变化速率(±dp/dt_max)。最后取心脏,测定更多还原

【Abstract】 BackgroundCongestive Heart Failure(CHF) is a complex clinic syndrome that can resultfrom all kinds of heart diseases in their last serious stage. The hospitalization rate of CHF in patients with cardiovascular disease is approximately 20%, and the mortality is 40%. Patients with CHF is poor prognosis, the five years survival rate is like tumor. So the management of CHF is the importantObjectiveTo study the improvement effect of Huangqi Injection on the haemodynamic parameters in CHF rats, symptom of patients with CHF, and the prevention of the occurrence of digitalis toxicity. We also to primary study the mechanism of its decrease the prevalence of digitalis toxicity. We can provide some theories and clinic groundwork for using the Huangqi Injection to treat CHF and to prevent the occurrence of digitalis toxicity.Content and MethodsThe Digitalis is the basal drug to treat CHF. The major problem of the use of digitalis is the toxicity. The mechanism of the digitalis toxicity is that can restrain the activity of Na~+-K~+-ATP ase in myocardium. HuangqiInjection which can anti-arrhythmias in patients with CHF is also the commonly use drug to treat CHF. The mechanism of anti- arrhythmias is considered that Huangqi Injection can resume the activity of Na+-K+-ATP ase. We have observed that Huangqi Injection can protect the guinea pig myocardium from the Ouabain(a kind of digitalis) toxicity in former experiment. It indicates that Huangqi Injection can decrease the prevalence of digitalis toxicity.1. Experimental research60 SD rats those were successfully established CHF animal models with abdominal aortic banding for 8 weeks were randomly divided into six groups. The A, B, and C group, which is respectively normal saline group, lower dosage Huangqi Injection group and high dosage Huangqi Injection group, will do the acute toxicity experiment. The E, F and G group, which is respectively normal saline group, lower dosage Huangqi Injection group and high dosage Huangqi Injection group, add 10 normal rats as D group, will do the chronic toxicity experiment. The rats in A, B and C group were anaesthetized and then 3# extradural anaesthesia tube which wes insert the left venticle through the right common carotid was connect the 8 lead physiologyical recorder with the pressure transducer. We insert the venous cannulate through the left jugular vein and respectively inject the drug(5ml) which used in A, B and C group, and then inject 0. 005% Ouabain Injection with 12. 5mg/min by electronic constant injector. Monitoring the ECG in oscillograph and recording the dosage of Ouabain when ECG shows Ventricular Tachycardia(VT), Ventricular Flutter(VF). We also record the haemodynamic parameters, such as Heart Rates(HR), Left Ventricular Systolic Pressure(LVSP), Left Ventricular End Diastolic Pressure(LVEDP) and Left Ventricular Pressure change rate(± dp/dtmax) in such four time point, before injection (point I), 1 min after injection of normal saline or Huangqi Injection (point II), lmin after injection of Ouabain Injection (point III) and the ECG show VT (point IV).At last killed rats and tested the activity of Na+-K+-ATP ase in myocardium cell membrane.As for the chronic toxicity groups, rats in D group were feed normal saline as well as rats in E, F and G group were feed with digoxin solution 0. 125mg/kg ? d. At the same time, the rats in four groups were injected in abdominal cavity respectively for normal saline 2ml/d, normal saline 2ml/d, Huangqi Injection 2ml/d and Huangqi Injection 4ml/d. A week later, we monitored and record haemodynamic parameters of rats , killed them and tested the activity of Na+ —K+—ATPase in myocardium cell membrane.2. Clinic researchWe made a retrospective investigation of medical history of the in-patients with CHF who hospitalized in Cardiovasology yard of First Affiliated Hospital of Guangzhou University of Traditional Chinese and First Affiliated Hospital of Sun Yat-sen university and were treated with digitalis. The patients were divided into two groups according whether they were used or not used Huangqi Injection. To study the effect of cardiac function treat by Huangqi Injection combine with digoxin, and prevention of the occurrence of digitalis toxicity.Results1. Experimental researchThe LVSP and +dp/dtmai were principal haemodynamic parameters those can reflect the systolic function of heart. We observed in our experiment that LVSP and +dp/dtBM of rats in A, B and C group have non-significant difference in statistics (P>0. 05) after the rats were successfully established CHF animal models. The parameters also have non-significant difference in point II, and rise significantly in point III. When it was in point IV, the parameters became lower significantly(P<0. 01) than those were in early three points. There were extremely significant difference(P<0.01) between A and B group, andsignificant difference between B and C group(P<0.05).The LVEDP and —dp/dt?, were principal haemodynamic parameters those can reflect the diastolic function of heart. Those parameters in those three group have non-significant difference in statistics (P>0.05) in point I. LVEDP in point II became higher obviously than those in point, But there were non-significant difference among three groups(P<0. 01). -dp/dt?, in point II also has no significant difference with this in point I(P>0. 05). In point III, the parameters have non-significantly difference. When it was in point IV, LVEDP became higher significantly(P<0.01), -dp/dtMI became lower significantly(P<0.01) than those were in early three points. There was extremely significant difference(P<0.01) between A and B group, and significant difference between B and C group(P<0. 05).The tolerance doses of Ouabain in B group rats is bigger than those in A group lower than those in C group(P<0.05).The activity of Na+—K+ATP ase in myocardium membrane in rats of the three groups decreased extremely, there were extremely significant difference between there three groups and D groups (P<0.01). It suggested that Ouabain seriously restrain the activity of Na+—K+ATP ase. And it was the reason that leads to Ventricle Premature Contraction(VPC), VT, even VF of rats.In chronic digitalis toxicity experiment, we have observed that the Heart Rate of rats in E, F and G group decreased significant than D group. The parameters of rats in E, F, G group, not only those reflect the systolic function, but also the diastolic function, were significant different from those of D group rats (P<0.05). The ECG shows that, rats in E group have more VPC than D group. LVEDP is more higher than that of A, B and C group(P<0. 01), while LVSP^ ±dp/dtmaxdecreased obviously (P<0. 05). That demonstrated that the rats were posined by digoxin. The cardiac systolic and diastolic functions were worse than those of rats with CHF. Compared with those of E group, LVSP and idp/dtw, of F group increased, LVEDP decreased, VPC decreased obviously.更多还原