阿托伐他汀对自发性高血压大鼠心室重构的影响

目的 :观察阿托伐他汀对自发性高血压大鼠(SHR)心室重构的影响。方法 :2 4只SHR随机分为4组 ,每组 6只。SHR对照组、阿托伐他汀 5 0mg组(5 0mg·kg-1·d-1)、阿托伐他汀 10mg组(10mg·kg-1·d-1)和缬沙坦组 (2 0mg·kg-1·d-1) ;6只Wistar Kyoto大鼠 (WKY)作为正常对照组。灌胃给药共 6周 ,分别于给药前和给药后每 2周测量大鼠尾动脉收缩压 (SBP)。酶法测定血清总胆固醇(TC)、甘油三酯 (TG)、高密度脂蛋白胆固醇 (HDL C)及低密度脂蛋白胆固醇 (LDL C)含量 ,放免法测定血浆和心肌血管紧张素Ⅱ (AngⅡ )水平 ,并检测心肌羟脯氨酸、胶原蛋白含量和全心重量 (HW )、左室重量 (LVM )及左室重量指数 (LVMI)。透射电镜观察心肌超微结构改变。结果 :用药前SHR各组SBP均显著高于WKY正常对照组 (P <0 .0 1) ,给药后第 4、6周 ,阿托伐他汀 5 0mg组SBP明显下降 (P <0 .0 1) ,阿托伐他汀 10mg组不明显 ;缬沙坦组自给药后第 2周 ,SBP明显下降 (P <0 .0 1)。阿托伐他汀5 0mg组TC、TG及LDL C水平较SHR对照组明显降低 (P <0 .0 5或P <0 .0 1) ,阿托伐他汀 10mg组仅LDL C水平明显下降 (P <0 .0 5 )。SHR对照组血浆AngⅡ浓度与WKY正常对照组比较无显著性差异 ,但心肌AngⅡ浓度明显增高 (P <0 .0 5 ) ;给药 6周后 ,阿托伐他     

血府逐瘀汤联合西药对老年高血压45例患者心室重构状态的影响观察

目的观察血府逐瘀汤联合阿托伐他汀对老年高血压患者心室重构状态的影响。方法将在本院治疗的90例老年高血压患者作为这次的实验对象,现将其进行随机分组,每组45例。对照组用阿托伐他汀治疗,观察组的患者用血府逐瘀汤联合阿托伐他汀治疗。将两组结果进行比较,分别以治疗前及治疗2个月后患者的血管功能情况、心室重构指标进行比对。结果通过比对,治疗2个月后观察组患者的VDDL较对照组低,并且较治疗前降低,而VTId及VTIs均高于对照组,也较治疗前升高,P<0.05,差异具有统计学意义。结论血府逐瘀汤可保护血管内皮细胞,改善心肌纤维化,提高心肌舒缩功能,防治高血压心肌重构,血府逐瘀汤联合阿托伐他汀治疗治疗老年高血压,对比单用阿托伐他汀而言,有着更好的效果,值得在临床推广及使用。     

阿托伐他汀对自发性高血压大鼠血压和细胞色素P450表氧化酶2C11基因表达的影响

目的研究阿托伐他汀降低自发性高血压大鼠(SHR)血压的作用是否与其调节细胞色素P450表氧化酶2C11(CYP2C11)基因表达的作用有关。方法18只SHR随机分为SHR模型组、阿托伐他汀50和10 mg.kg-1组;6只W istar-Kyoto大鼠(WKY)作为正常对照组。阿托伐他汀ig给药,每日1次,共10周。分别于给药前和给药后每2周测量大鼠尾动脉收缩压(SBP);RT-PCR和W estern印迹法分别检测心、肝、肾及主动脉组织中CYP2C11mRNA和蛋白质表达;ELISA方法检测尿液中14,15二-氢二十碳三烯酸(DHET)含量;并测定血脂含量。结果阿托伐他汀50 mg.kg-1组在给药后第6~10周和10 mg.kg-1组在给药后第10周SBP明显低于SHR模型组。在CYP2C11 mRNA和蛋白质表达中,SHR模型组心、肾和主动脉均明显高于WKY组;给药10周后,阿托伐他汀50 m.gkg-1组的4种组织和10 m.gkg-1组的心、肾和主动脉的表达明显高于SHR模型组。治疗前SHR各组尿液中DHET的含量均显著高于WKY组,给药后阿托伐他汀50 m.gkg-1组的含量明显高于SHR模型组;同时,阿托伐他汀50 mg.kg-1组血脂水平明显低于SHR模型组。结论阿托伐他汀可上调CYP2C11基因的表达,并增加其代谢产物表氧化二十碳三烯酸,这可能是其降低血压的作用机制之一。     

阿托伐他汀对心肌梗死后大鼠转化生长因子-β1和白介素-1β转录水平的影响

目的:探讨心肌梗死后细胞转化生长因子-β_1 (TGF-β_1)和白介素-1β(IL-1β)的转录水平以及阿托伐他汀对其的影响。方法:结扎冠脉左前降支造成急性心梗模型,随机分为心肌梗死组和阿托伐他汀治疗组,每组21只,另设13只为假手术组。阿托伐他汀治疗组于手术后2 d起灌胃给药,心肌梗死组和假手术组只给予等量清水灌胃。第1周后各组取3只大鼠检测TGF-β_1和IL-1βmRNA的转录水平变化;第6周后行超声心动图、心室重塑、TGF-β_1和IL- 1βmRNA的测定。结果:与心肌梗死组相比,阿托伐他汀治疗组左室舒张末期内径(LVEDD)及左、右心室肥厚指数降低;短轴缩短率(FS)和左室射血分数(EF)均增加(P<0.05);心肌梗死后第1周心肌梗死组和阿托伐他汀治疗组梗死区周边TGF-β_1和IL- 1βmRNA的转录较假手术组有不同程度增高(P<0.05)。梗死后第6周心肌梗死组IL-1βmRNA的转录与第1周相比有明显降低,而TGF-β_1 mRNA仍呈高转录水平(P<0.05);与假手术组相比两细胞因子仍增高(P<0.05)。梗死后第6周阿托伐他汀治疗组IL-1β和TGF-β_1 mRNA的表达较第1周相比皆降低(P<0.05);与心肌梗死组相比也降低(P<0.05)。结论:阿托伐他汀能降低急性心梗大鼠心肌TGF-β_1和IL-1β转录水平,减轻心室重塑,改善心功能。     

阿托伐他汀联合氯沙坦逆转改善原发性高血压左室肥厚的临床研究

目的:观察阿托伐他汀联合氯沙坦治疗原发性高血压患者左室肥厚的效果.方法:选取原发性高血压左室肥厚患者84例,随机分为两组,阿托伐他汀和氯沙坦联合组43例,在基础治疗上加用阿托伐他汀20 mg,每日1次和氯沙坦50 ng,每日1次;氯沙坦组41例,在基础治疗上加用氯沙坦50 mg,每日1次,两组均治疗6个月,分析疗效.结果:联合治疗组舒张期室间隔厚度、舒张期左室后壁厚度、左室心肌重量指数治疗前后比较差异有统计学意义(P＜0.01),氯沙坦组舒张期室间隔厚度、舒张期左室后壁厚度、左室心肌重量指数治疗前后比较差异有统计学意义(P＜0.05),两组治疗后舒张期室间隔厚度、舒张期左室后壁厚度、左室心肌重量指数比较差异有统计学意义(P＜0.05).结论:阿托伐他丁联合氯沙坦治疗高血压,既可使血压、血脂迅速达标,又可有效逆转左室肥厚.     

阿托伐他汀对大鼠心肌梗死后肿瘤坏死因子、丙二醛表达的影响

目的观察阿托伐他汀对心肌梗死后心肌重塑的影响。方法按照随机方法分为两组:假手术组和手术组,手术组心肌梗死模型建立成功后再随机分为心肌梗死组和阿托伐他汀组。在标准饲养方法的基础上,每天对每只大鼠灌胃1.0ml双蒸水,其中阿托伐他汀组大鼠灌胃液中含阿托伐他汀(立普妥)5mg/(kg.d),其余组灌胃液中无任何药物。给药时间持续4周。测定非梗死区心肌组织TNF-α浓度、MDA的浓度,测定心室肥厚指数及心肌细胞凋亡指数。结果AMI对照组和阿托伐他汀干预组心室肥厚指数及心肌细胞凋亡指数明显高于假手术组,阿托伐他汀干预组显著低于AMI对照组。非梗死区心肌组织TNF-α浓度、MDA的浓度与心肌细胞凋亡指数呈正相关。结论阿托伐他汀可以减少心肌梗死后心肌细胞凋亡,改善心肌重塑和心功能。     

阿托伐他汀对高血压大鼠肾脏血管紧张素转换酶2表达的影响

目的:观察阿托伐他汀对两肾一夹(2K1C)高血压大鼠肾脏血管紧张素转换酶2(ACE2)表达的影响,探讨阿托伐他汀降血压作用可能的新的作用机制。方法:40只雄性Wistar大鼠随机分为5组(每组8只):假手术组、高血压组、缬沙坦组(20 mg·kg-1·d-1)、阿托伐他汀组(10 mg·kg-1·d-1)和阿托伐他汀组(30 mg·kg-1·d-1)。鼠尾容积法测定术前、术后1周及药物干预后4、8周的SBP变化。8周后,免疫组化法检测肾脏ACE2蛋白表达,放射免疫分析法测定心肌组织血管紧张素Ⅱ(AngⅡ)水平,RT-PCR法检测肾脏组织ACE2 mRNA表达。结果:高剂量阿托伐他汀组SBP较高血压组降低显著(P<0.01);高剂量阿托伐他汀组较高血压组降低心肌组织AngⅡ浓度显著(P<0.01);RT-PCR显示缬沙坦组和低、高剂量阿托伐他汀组肾脏组织ACE2 mRNA的表达较高血压组不同程度增高(P<0.05)。结论:2K1C高血压大鼠肾脏组织ACE2蛋白、ACE2 mRNA表达降低。阿托伐他汀在降低高血压大鼠SBP的同时,降低心肌组织AngⅡ浓度,增加肾脏组织ACE2蛋白、ACE2 mRNA表达。     

伊贝沙坦对结缔组织生长因子在自发性高血压大鼠心室肌表达的影响

目的:研究结缔组织生长因子(CTGF)在自发性高血压大鼠(SHR)心脏中的表达及其与高血压心室重构和心肌纤维化的关系,并探讨血管紧张素II受体拮抗剂对其表达的影响以及改善高血压心室重构和心肌纤维可能的作用机制。方法:20只12周龄雄性自发性高血压大鼠随机分为SHR组(n=10)和伊贝沙坦组(n=10),伊贝沙坦组每只大鼠予以伊贝沙坦50mg·kg-1·d-1灌胃,给药12周,同时取10只12周龄雄性京都种Wistar(WKY)大鼠作为对照组,用免疫组化的方法对TGF-β1、CTGF在三组大鼠的左室心肌的分布及表达进行半定量分析;用RT-PCR的方法检测TGF-β1、CTGFmRNA在心肌表达水平;用MASSON染色法观察左室心肌胶原形态,图象分析测量胶原容积分数(CVF)和血管周围胶原面积(PVCA)。结果:(1)左室重量指数(LVI)、CVF、PVCA在SHR组大鼠明显高于WKY组大鼠(P<0.01);相比SHR组,伊贝沙坦组则显著降低(P<0.05)。(2)CTGF主要在血管平滑肌和心肌间质中表达,WKY组在心肌间质中呈弱表达。(3)相关分析表明,CTGF与TGF-β1(r=0.562,P<0.05)的表达呈正相关。(4)CTGF及其mRNA在SHR组左室心肌中的表达较WKY组明显增强(P<0.05),相比SHR组,伊贝沙坦组则明显减少。结论:高血压大鼠心室肌CTGF表达增加,伊贝沙坦对高血压大鼠心室肌CGTF表达具有抑制作用,且能够明显改善高血压心室重构和心肌纤维化,此种作用可能是血管紧张素II受体拮抗剂抑制左室重构改善心肌纤维化新的机制。     

阿托伐他汀对哮喘大鼠气道炎症及气道重构的影响

目的：探讨阿托伐他汀对卵清白蛋白致敏哮喘模型大鼠气道炎症和重构的影响。方法清洁级 SD 雄性大鼠24只按随机数字表法分为对照组、哮喘组和阿托伐他汀组,每组8只。对照组大鼠采用0．9％氯化钠溶液（生理盐水）进行致敏和激发,哮喘组大鼠采用卵清白蛋白致敏和激发,阿托伐他汀组在致敏和激发前以阿托伐他汀口服。采用肺功能检测3组大鼠气道呼气阻力;采用图像分析软件测定肺组织切片中的支气管壁内周长、支气管管壁面积、支气管平滑肌面积;胶原表达通过气道壁 Masson 染色进行观察;实验动物血清中白介素－13（IL－13）及转化生长因子－β1（TGF－β1）的水平以 ELISA 法测定。结果肺功能检测显示哮喘组平均呼气阻力显著升高,阿托伐他汀组低于哮喘模型组（ P ＜0．05）;病理检查显示哮喘组气道炎症明显,对照组和阿托伐他汀组与之相比炎症轻微;阿托伐他汀组大鼠气道管壁面积、平滑肌面积图像分析和哮喘组比较差异有统计学意义（ P ＜0．05）;阿托伐他汀组肺组织中胶原沉积表达较哮喘组减少（ P ＜0．05）;阿托伐他汀组大鼠血清中 IL－13和 TGF－β1较哮喘组降低（ P ＜0．05）。结论阿托伐他汀能够明显减轻哮喘大鼠气道炎症,降低哮喘大鼠的气道基本阻力;减少肺组织中胶原沉积,降低气道管壁面积、平滑肌层面积,减轻哮喘气道重构。阿托伐他汀治疗能够降低血清中 TGF －β1和 IL－13水平,或为其减轻炎症和气道重构的机制。     

阿托伐他汀对急性心肌梗死后慢性心力衰竭大鼠心肌 IL-6 表达的影响简

目的 探讨阿托伐他汀对急性心肌梗死后慢性心力衰竭的抑制作用及机制.方法 45只雄性急性心肌梗死模型大鼠随机均分为阿托伐他汀高、低剂量组及模型组(n＝15).另取10只大鼠作为假手术组.阿托伐他汀高、低剂量组分别给予阿托伐他汀20,10 mg.kg^-1.d^-1,灌胃6周,假手术组和模型组不予治疗.第6周末以超声心动图检测各组大鼠左心室形态功能变化,测定左室心肌肥厚指数(LVHI).假手术组取位于左心室游离壁心肌组织,心肌梗死各组取位于左心室梗死区、交界区心肌组织分别以免疫荧光激光共聚焦显微镜及Western blot检测白细胞介素(IL)-6表达. 结果模型组、阿托伐他汀高、低剂量组大鼠左室舒张期内径(LVEDD)、左室收缩内径(LVESD)、舒张末期容积(EDV)、收缩末期容积(ESV)、LVHI、心肌IL-6水平较假手术组均显著升高(P<0.05或P<0.01);左室射血分数(LVEF)较假手术组降低(P<0.05或P<0.01).与模型组比较,高、低剂量阿托伐他汀组大鼠LVEDD、LVESD、EDV、ESV、LVHI、心肌IL-6水平均显著降低(P<0.05或P<0.01),LVEF显著升高(P<0.05或P<0.01).与阿托伐他汀低剂量组比较,高剂量组大鼠LVEDD、LVESD、EDV、ESV、LVHI、心肌IL-6水平均显著降低(P<0.05),LVEF显著升高(P<0.05).结论 阿托伐他汀可能通过抑制IL-6过度表达而发挥抑制心室重塑作用,其作用呈剂量依赖性.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.