肝旺痰阻型高血压大鼠模型的建立和评价研究

目的:建立和评价肝旺痰阻型高血压大鼠模型。方法:采用自发性高血压大鼠,以长期激怒联合高质饮食法建立肝旺痰阻的复合证候。通过观察大鼠性情动态的变化及体重、血压及血脂和血管紧张素Ⅱ的变化,对高血压大鼠肝旺痰阻证型进行综合评价。结果:模型组大鼠在性情动态及体重、血压、血脂和血管紧张素Ⅱ等方面均与对照组有较大差异(P<0.05),符合了中医肝旺痰阻证型的表现。结论:采用自发性高血压大鼠,以长期激怒联合高质饮食法,可建立肝旺痰阻型高血压大鼠动物模型。     

肝旺痰阻型高血压大鼠模型的建立和评价研究

目的：建立和评价肝旺痰阻型高血压大鼠模型。方法：采用自发性高血压大鼠,以长期激怒联合高质饮食法建立肝旺痰阻的复合证候。通过观察大鼠性情动态的变化及体重、血压及血脂和血管紧张素II的变化,对高血压大鼠肝旺痰阻证型进行综合评价。结果：模型组大鼠在性情动态及体重、血压、血脂和血管紧张素II等方面均与对照组有较大差异（P〈0．05）,符合了中医肝旺痰阻证型的表现。结论：采用自发性高血压大鼠,以长期激怒联合高质饮食法,可建立肝旺痰阻型高血压大鼠动物模型。     

多因素复合制作气虚血瘀证脑缺血动物模型的实验研究

目的通过复制气虚血瘀证型大鼠脑缺血动物模型,探索病证结合动物模型制作方法.方法选用老年Wistar大鼠,采用饥饿、疲劳、寒湿、惊恐、高脂饮食等多因素复合方法复制气虚血瘀证动物模型,采用双侧颈总动脉结扎复制脑缺血动物模型.结果通过对一般体征和微观指标的观测,发现模型大鼠基本符合中医气虚血瘀证候特点和现代医学脑缺血病理变化规律.[HTH〗结论多因素复合作用可成功复制病证结合动物模型,本动物模型有可能成为将来中医药防治脑缺血科研工作的实验基础.     

肝郁脾虚型肠易激综合征便秘大鼠模型的建立和评价

目的筛选便秘型肠易激综合征动物模型的最佳建立方法,并探讨所建立模型的中医证候属性。方法分别采用母婴分离法、冰水灌胃法、限水法、母婴分离结合冰水灌胃法、母婴分离结合限水法制作便秘大鼠模型,观察大鼠一般行为学变化、体重和24 h进食量,测定4 h内排便颗粒数,并对大鼠粪便进行Bristol分型积分和含水量测定,采用直肠扩张实验评价内脏敏感性,观察各组大鼠肠组织形学变化,筛选出符合IBS-C临床特征的动物模型建立方法。并采用复方中药逍遥散进行反证,判定模型的中医证候范畴。结果采用母婴分离结合冰水灌胃法建立的模型具有排便颗粒数减少,粪便含水量降低,Bristol分型积分显示为便秘型的特征,且其肠道敏感性显著升高,结肠组织无形态学改变,符合IBS-C的临床特征。经逍遥散验证,该IBS-C模型属于中医"肝郁脾虚证"范畴。结论母婴分离结合冰水灌胃法能够建立中医肝郁脾虚证IBS-C大鼠模型,能高度拟合IBS-C的临床特征,造模成功率高。     

心气虚血瘀证动物模型的构建与评价

中医证候模型起步较晚,为推动中医现代化的发展,要求深入研究和探讨中医证候动物模型。气虚血瘀证作为心血管疾病常见的证型,其动物模型的建立是中医证候实验研究的热点问题,通过对各种心气虚血瘀证动物模型造模方法进行研究,观察实验动物的宏观体征、超声心动图、血流动力学等指标,客观评价其造模方法,同时提出当前中医证候动物模型研究中存在的问题,并对其进行了展望,为今后探究心气虚血瘀证的临床治疗提供模型支持。     

高血压患者中医分型治疗观察

目的:评价中医分型治疗高血压临床疗效,并就不同疗效评价标准与西医治疗相对比,探讨中医分型治疗起效特点与应用价值。方法:取原发高血压患者200例,100例以西药治疗纳入西医组,100例在中医分型基础上以中药组方制剂治疗,分别评价动态血压、瞬时血压、中医证候疗效。结果:中医组动态血压有效率85.00%、中医证候显效率56.00%高于西医组45.00%、46.00%,中医组证候显效率56.00%高于瞬时血压显效率47.00%,西医组动态血压有效率45.00%低于瞬时血压总有效率93.00%、中医证候疗效总有效率83.00%,差异具有统计学意义(P0.05);两组瞬时血压疗效、中医证候无效率差异无统计学意义(P0.05)。结论:中西医在降低瞬时血压效果上疗效无显著性差异,多数患者血压不同程度下降,但仍有部分患者难获有效疗效,可能与治病危险因素仍存在有关;动态血压疗效与证候疗效评价更具科学性,两者具有一定联系,能较突出的反应中医优势;中医分型治疗原发高血压,有助于缓解高血压相关症状,避免血压剧烈波动,降低靶器官损害。     

大鼠、小鼠辨证的思路与方法

辨证论治是中医学的特色和优势,为开展辨证论治的研究与发展,我国业已发展出百余种证侯动物模型,起到了积极的作用。本文在扼要回顾存在的问题和研究进展后,以气虚证为例,介绍了大鼠和小鼠辨证的思路与方法：（1）人类与大鼠、小鼠气虚证候的比较。研究表明,大鼠、小鼠的气虚表现与人类十分近似,是可以模拟人类气虚辨证的方法和思路,给大鼠、小鼠辨证的。（2）大鼠、小鼠气虚的计量化辨证。标准化和计量化辨证涉及4个基本问题,即如何计量化采集四诊指标、如何计量化辨证、如何确定辨证的标准和阈值,以及如何判断证候及其改善的程度。为此,我们借鉴药理行为学检测技术,比较了悬尾不动、抖笼、旷场、抓力等方法,最终确定旷场和抓力作为气虚证的计量化四诊指标,建立气虚程度/指数计算公式：气虚程度/指数=各动物抓力实测值/正常组均数×0.5＋各动物水平移动实测值/正常组均数×0.3＋各动物直立次数/正常组均数×0.2,以及气虚辨证的入选标准和阈值。通过大量、重复的实验检测与应用,证明以上方法和辨证标准是可行的,而且初步证明气虚证在神经-内分泌-免疫网络有其广泛的基因表达与剪接改变的基础。目前已初步实现大鼠、小鼠常见虚证标准化、计量化的四诊检测和辨证,该方法和技术可以动态跟踪疾病动物证候的演变,评价辨证论治疗效,还可以广泛用于病-证结合的动物实验研究,辨证论治治疗方案的实验优化和评价,中药、中药有效成分和方剂药性的判断等,适用于中医基础、药理、诊断、临床等各中医药学科的研发工作。     

肾性高血压大鼠延髓尾端神经元型一氧化氮合酶表达的改变

实验采用免疫组织化学方法观察两肾一夹肾性高血压大鼠延髓尾端两个区域（延髓腹面降压区和尾端加压区）内神经元型一氧化氮合酶（neuronal oxide synthase,nNOS）表达的变化。肾性高血压大鼠延髓尾端这两个区域的nNOS的表达均增加,说明高血压对L-Arg-NO通路活性增强。NO的前体L-Arg能增强nNOS的表达,nNOS抑制剂L-NAME则降低nNOS的表达。以上两个区域nNOS表达变化的特点在肾性高血压4周和7周的动物相同,肾性高血压7周的nNOS表达和4周比较,未见明显差异。     

两肾两夹高血压与自发性高血压大鼠左心室肥厚的比较

目的 比较两肾两夹和自发性高血压大鼠左心室肥厚的异同.方法 采用不同周龄两肾两夹高血压和自发性高血压大鼠模型,测定动脉血压和心肌肥大指数, 超声心动图观察左心室结构和功能,左心室插管检测血流动力学指标.结果 不同周龄两肾两夹高血压和自发性高血压大鼠的血压及心肌肥大指数均显著高于周龄匹配的对照大鼠.与对照组相比,手术后4周的两肾两夹大鼠及8、12、16周龄的自发性高血压大鼠,其室间隔及左室后壁厚度均明显增加,左室内径显著减小,呈现出明显的向心性肥厚.而手术后8周及12周的两肾两夹大鼠,其室间隔及左室后壁厚度均明显减小,左室内径显著增大,呈明显的离心性肥厚.同时,手术后8周、12周的两肾两夹大鼠以及16周龄的自发性高血压大鼠,其射血分数、缩短分数、室内压最大上升和下降速率均较对照组显著降低,左室舒张末压及等容舒张期压力下降的时间常数明显升高.表明随时间延长,二者心功能都有不同程度的下降.结论 两肾两夹高血压和自发性高血压大鼠均发生了不同程度的左心室肥厚,但其肥厚表型不同.     

胃溃疡中医证候动物模型研究进展

胃溃疡是一种常见的消化系统疾病,中医药治疗该病效果显著,但其治疗机制至今尚未明确。建立一套科学客观的胃溃疡中医证候动物模型及模型评价体系,对促进中医药在此领域的发展以及进一步的研究具有重大意义。笔者对近10年中医药治疗胃溃疡相关文献进行整理,总结和分析了胃溃疡中医证候动物模型的制作与评价方法,对肝胃不和证、脾胃湿热证、胃络瘀阻证、脾胃虚寒证、胃阴不足证、肝郁脾虚证等动物模型的制作方法进行总结,发现目前的胃溃疡动物模型存在中医辨证分型不够统一、造模思路与证型局限、造模方法标准不一、模型病证结合不紧密、模型评价体系不规范等问题,并提出模型改进意见,以期为此领域的研究提供参考。     

The combination of atenolol and amlodipine is better than their monotherapy for preventing end‐organ damage in different types of hypertension in rats

Combinations therapy is often used in hypertensive patients whether combination therapy is necessary for preventing end‐organ damage is not known. The objective of this study was to determine in four different hypertensive animal models the necessity of adding the calcium channel blocker amlodipine to therapy with the ß‐blocker atenolol to modulate end‐organ damage. Spontaneously hypertensive rats, DOCA‐salt hypertensive rats, two‐kidney, one‐clip renovascular hypertensive rats and Lyon genetically hypertensive rats were used to study this objective. These animal models have different sensitivities to atenolol and amlodipine. The dosages of therapy employed were 10 mg/kg atenolol alone, 1 mg/kg amlodipine, 10 mg atenolol + 1 mg/kg amlodipine and 5 mg/kg atenolol+0.5 mg/kg amlodipine. BP was continuously recorded in all animals. After determination of baroreflex sensitivity, rats were sacrificed for end‐organ damage evaluation. The combination of amlodipine and atenolol had a synergistic inhibitory effect on blood pressure and blood pressure variability, and end‐organ damage as compared with monotherapy with atenolol or amlodipine in all animal models. Baroreflex sensitivity also improved with the combination therapy more than with monotherapy. In conclusion, atenolol and amlodipine combination exerts a superior effect on blood pressure, blood pressure variability, baroreflex sensitivity and end‐organ damage. The superior effect of the combination was observed in all four models of hypertension.     

Antihypertensive effects of vanadium compounds in hyperinsulinemic,hypertensive rats

Although considerable evidence lends credence to the association between insulin resistance, hyperinsulinemia and essential hypertension, the precise nature of this relationship remains unexplained. In the present investigation, we examined the proposition that these metabolic defects contribute causally to the development of high blood pressure. If these metabolic abnormalities were responsible for the development of hypertension, then drug interventions that improve these defects should also decrease high blood pressure. Since previous studies have demonstrated that vanadium compounds enhance insulin action and lower plasma insulin levels in nondiabetic rats, we examined the effects of these compounds on insulin sensitivity, plasma insulin concentration and blood pressure in two hyperinsulinemic models of experimental hypertension. The animal models studied were the genetically predisposed spontaneously hypertensive rat and the fructose-hypertensive rat, where hypertension is induced in normotensive rats by feeding them a high fructose diet. Vanadium compounds caused marked and sustained decreases in plasma insulin concentration and blood pressure in both the animal models studied. Furthermore, the effect of the drugs on blood pressure was reversed by restoring plasma insulin levels in the drug-treated rats to those observed in their untreated counterparts. These data suggest that either hyperinsulinemia contributes to the development of hypertension in both the spontaneously hypertensive and the fructose-hypertensive rats or that the underlying mechanism is closely related to the expression of both these disorders.     

Effect of exercise training on liver antioxidant status of deoxycorticosterone acetate salt induced hypertensive rats

Several animal models have been developed to study the pathogenesis of hypertension. Deoxycorticosterone acetate (DOCA) salt induced hypertensive rats are adrenal models used to mimic human Conn's syndrome. Because previous studies showed a beneficial effect of chronic exercise (swimming) on the development of arterial hypertension in spontaneously hypertensive rats (which appears similar to human essential hypertension), we decided to evaluate the effects of swimming on DOCA-salt induced hypertension and liver antioxidant status. Therefore, the aim of this experiment was to study whether the swim training would improve hypertension and liver antioxidant status in DOCA-salt rats. DOCA-salt rats and control Sprague-Dawley rats were trained to swim 1 h/day, 5 days/week for 6 weeks and were sacrificed 48 h after the last exercise period. Systolic blood pressure was recorded before the sacrifice, and liver antioxidant status was evaluated in hepatic homogenates after the sacrifice. Swim exercise did not decrease systolic blood pressure in control and DOCA-salt rats but induced changes in liver activities of antioxidant enzymes, showing that exercise provoked liver oxidative stress in control and DOCA-salt rats. In comparison with our previous studies using spontaneously hypertensive rats, we conclude that the beneficial effects of chronic exercise on systolic blood pressure in rats are dependent on strain and the type of experimental hypertension.     

四种不同高血压大鼠模型形成过程中血清抗AT1A受体自身抗体的检测

本实验采用不同的方法复制两肾-夹（two-kidney one-cliprenal hypertensive,2K1C）、神经性、DOCA-盐高血压和自发性高血压大鼠模型,观察AT1A受体自身抗体（AT1A-receptorautoantibodies,AT1A-AAs）在不同高血压发病的变化规律,同时对自身抗体生物活性进行分析。实验结果表明,在高血压发病过程中AT1A-AAs的阳性率和滴度均明显增加,在四种模型中,自发性高血压组最明显,2K1C和神经性组次之。AT1A-AAs的生物活性显示,可增加培养的新生鼠心肌细胞跳动频率和血管收缩张力。结果提示,自身免疫机制参与了高血压的形成,AT1A-AAs可能与心肌肥厚有关。     

Decreased ANF atrial content and vascular reactivity to ANF in spontaneous and renal hypertensive rats

The relationship between ANF activity and hypertension was determined by measuring ANF atrial content and vascular reactivity in two different models: spontaneous hypertensive rats (SHR) and renal hypertensive rats (RHR). Atrial extracts and aortic strips were prepared from hypertensive and normotensive animals. Relaxant activities of extracts, synthetic ANF and nitroglycerin were assayed on superfused aortic strips previously contracted by norepinephrine. ANF atrial content was statistically significantly lower in both models of hypertension, presumably by increased ANF release into the circulation which results in depletion of tissue storage sites. Vascular subsensitivity to ANF and nitroglycerin was found in both models of hypertension. Diminished ANF vascular reactivity in hypertension could be due to receptor down-regulation and/or to a decrease in the ability of cGMP to induce relaxation.     

The role of the renin-angiotensin system in malignant vascular injury affecting the systemic and cerebral circulations

Malignant hypertension is a rare but serious syndrome complicating 1% of essential hypertension and causing neurological, renal and cardiac complications. Despite improved anti-hypertensive medication, the incidence of this condition fails to decline. In the first part of this review, we discuss transgenic rat models of malignant hypertension, generated by over-expressing renin, to illustrate the role of the renin–angiotensin system in the development of systemic hypertensive vascular remodelling and hypertension. In the second part, we focus on the cerebrovascular response to hypertension and discuss new data using a conditional, transgenic model of malignant hypertension, the inducible hypertensive rat (IHR). Cerebral infarction associates strongly with hypertension in man and the mechanisms by which hypertension predisposes to different types of stroke remains poorly understood. Rats have similar cerebrovascular anatomy and structure to humans and as such provide a good experimental tool. To date, such models lack controllability and blood-pressure matched controls. Using the IHR, we have manipulated dietary salt and water intake to generate a novel, controllable stroke phenotype. Hypertensive small-vessel stroke develops over a predictable time period, permitting the study of developing cerebrovascular lesions. Systemic end-organ injury and hypertension are not affected. Dissociation of the systemic and central vascular responses in this way, will allow for comparative study of animals with equivalent hypertension, genetic background and systemic features of hypertension with or without stroke.     

心钠素表达细胞移植降低高血压大鼠的血压和增加其尿量

为探讨心钠素基因转移治疗高血压和慢性心肾功能衰竭等慢性疾病的潜力,首先利用逆转录病毒载体获得可表达和分泌人心钠素的遗传工程细胞,然后将这种细胞植于自发性高血压大鼠SHR的皮下。结果发现,人心钠素遗传工程细胞的移植可使动物血浆中的心钠素浓度在移植后第7天时明显升高。在整个实验期间,虽然实验组动物的血压会随个体发育而逐渐升高,但在实验开始后的42 d内却始终明显低于空载体组,其中第14天血压的差异高达33 mm Hg。在实验开始后的第14天和第21天,实验组动物的尿量也明显增加。以上结果说明,人心钠素遗传工程细胞的皮下移植可明显抑制SHR大鼠血压的上升趋势和改善其泌尿功能,提示该方法具有治疗高血压和慢性心肾功能衰竭等慢性疾病的潜力。     

Chronic effect of prazosin and yohimbine on the renal epinephrine content of DOCA-sodium and SHR-hypertensive rats

The chronic effect of two alpha-adrenergic receptor blockers, prazosin and yohimbine, on the renal noradrenaline (NA) content was investigated in two models of hypertensive rats, the DOCA-salt and the spontaneously hypertensive rats (SHR). In DOCA-salt rats an inversal relation exists between the level of blood pressure and renal NA content in all groups studied, except those treated with yohimbine and prazosin plus yohimbine. In SHR rats a decreased renal NA content has been detected with respect to their normotensive Wistar-Kyoto (WKY) rat controls. The administration of prazosin and/or yohimbine did not alter the renal NA content of the SHR rats, while on the contrary these agents produced an elevation of these levels in kidneys from normotensive WKY rats. These results suggest that the alpha-selective blocker agents used, demonstrate a different effect on the renal NA content in the two models of hypertension studied.     

Phenotypic selection: a successful strategy to fix major genes of hypertension.

Hypertension is dominantly inherited in cross hybrids between hypertensive SHR/Mol and normotensive BB/OK rats. We used these cross hybrids for repeated backcrossing of selected hypertensive animals onto normotensive BB/OK rats to fix high blood pressure and to generate a hypertensive and diabetic BB/OK rat subline. After 8 backcrosses, the backcross parents were genetically analysed with the aid of 259 microsatellite markers to identify SHR genes causing blood pressure of 177 +/- 10 mmHg in this BB/OK rat subline. Loci on chromosomes 1, 14 and 18 showed longest heterozygosity. These loci might contain major genes of the SHR rat causing hypertension in this BB/OK rat subline. This classical strategy seems to be most suitable to fix major genes of hypertension in particular and complex traits in general and therefore to generate new animal models.