坎地沙坦抑制盐负荷高血压大鼠肾脏氧化应激

目的 探讨血管紧张素Ⅱ(AngⅡ)受体拮抗剂坎地沙坦对盐负荷易卒中自发性高血压大鼠(SHR-SP)肾脏氧化应激和氧化型低密度脂蛋白受体1(LOX-1)表达的影响.方法 12周龄Wistar-Kyoto(WKY)大鼠和SHRSP予8%高盐饮食.高盐WKY大鼠(n=6)作为对照组,高盐SHRSP随机分为3组:1)坎地沙坦组(Can,n=6),Can 1.0 mg/(kg·d)灌胃;2)三氯噻嗪组(TCM,n=6),TCM 1.6 mg/(kg·d);3)SHRSP组(n=6),给予等量溶媒.用尾部袖套测量法每周检测1次血压.大鼠给药2周后摘取肾脏,留取24 h尿量.采用实时定量PCR检测肾脏NAD(P)H氧化酶亚单位p22phox、p47phox和gp91phox mRNA表达,RT-PCR方法检测LOX-1、转化生长因子β1(TGF-β1)和Ⅳ型胶原mRNA的表达.免疫组化检测肾组织gp91phox和LOX-1蛋白表达,ELISA方法检测尿白蛋白排泄,放免法检测肾脏AngⅡ水平,天狼猩红染色观察肾组织胶原表达.结果 实验2周后,SHRSP组收缩压显著高于对照组(P＜0.01),Can和TCM均降低高盐SHRSP组的收缩压(P＜0.01),二者间的降压幅度无差别(P＞0.05).与对照组比较,肾皮质NAD(P)H氧化酶亚单位、LOX-1、TGF-β1和Ⅳ型胶原mRNA的表达、肾组织AngⅡ水平和尿白蛋白排泄,SHRSP组显著增高;Can降低高盐SHRSP肾组织AngⅡ水平(P＜0.01),下调肾皮质NAD(P)H氧化酶亚单位、LOX-1、TGF-β1和Ⅳ型胶原mRNA的表达(P＜0.01),减少尿白蛋白的排泄(P＜0.01),减轻肾组织胶原的沉积.等效降压剂量的TCM对高盐SHRSP肾组织NAD(P)H氧化酶亚单位、LOX-1的表达和尿白蛋白水平无明显影响.结论 Can对盐负荷SHRSP的肾脏保护作用,与抑制氧化应激和LOX-1表达有关,可能不一定依赖其降压作用.     

4羟基2.2.6.6四甲基哌啶对肾性高血压大鼠主动脉重构的影响

背景线粒体是活性氧产生的主要来源之一，4羟基2．2．6．6四甲基哌啶（Temp01）可作用于线粒体，清除活性氧。目的探讨Tempol对肾性高血压大鼠主动脉功能和结构的影响以及作用机理。方法两肾-夹的方法建立肾性高血压大鼠模型，术后4周随机分为假手术组（n=8）、高血压组（n=6）及治疗组（n=6），治疗组给予含Tempol 1 mmol／L饮用水。干预8周后观察血压、血管紧张素Ⅱ（AngⅡ）、一氧化氮（NO）、8异前列腺素F2a、胸主动脉NADPH氧化酶亚单位p22 phox mRNA表达的变化；对胸主动脉进行离体血管环实验和HE染色观察其舒张功能和结构的变化。结果1）模型高血压组与假手术组比较，血压、主动脉中膜厚度、中膜厚度／内径显著增加（P均〈0．01）；AngⅡ、8异前列腺素F2a、NO显著降低（P均〈0．01）；离体主动脉环对乙酰胆碱（Ach）引起的最大舒张百分数显著下降（P〈0．01）；主动脉NADPHp22phoxmRNA表达上调。2）治疗组用Tempol治疗8周后与高血压组比较，血压、主动脉中膜厚度、中膜厚度／内径下降；AngⅡ、8异前列腺素F2a显著下降（P均〈0．01）；NO水平上升（P〈0．05）；离体主动脉环对Ach引起的最大舒张百分比显著上升（P〈0．01）；主动脉p22 phox mRNA表达下调；AngⅡ比较没有差异。3）各组间离体主动脉环对硝普钠引起的最大舒张百分比无差异；用L硝基精氨酸甲酯（L-NAME）抑制NO后，各组间离体主动脉环对Ach最大舒张反应无差异。结论Tempol可以明显降低肾性高血压大鼠中氧化应激水平，改善NO代谢，降低血压，其降压机制与其改善NO代谢有关，Tempol还可下调主动脉p22phoxmRNA表达改善主动脉内皮依赖性的舒张功能。     

四逆汤对肾性高血压大鼠主要靶器官血管活性物质表达的影响

目的研究四逆汤对肾性高血压大鼠主要靶器官血管活性物质表达的影响。方法健康雌性Wistar大鼠24只，随机分为正常对照组、肾性高血压组和四逆汤治疗组，每组8只。根据双肾动脉夹闭法建立肾性高血压动物模型，免疫组化法测定心、脑、肾组织内皮素受体A（ETRA）、一氧化氮合酶（NOS）、血管紧张素Ⅱ（Ang—Ⅱ）、降钙素基因相关肽（CGRP）的表达。结果①各靶器官ETRA表达水平，肾性高血雎组均显著高于正常对照组（P〈O．05）；四逆汤治疗组在肾和心均显著低于肾性高血压组（P〈0．05），但在脑无显著性差异（P〉0．05）。②肾和脑iNOS表达水平，肾性高血压组显著高于正常对照组（P〈0．05）；四逆汤治疗组明显低于肾性高血压组（P〈0．01）。心脏eNOS表达水平，肾性高血压组显著低于正常对照组（P〈0．01），治疗组显著高于高血压组（P〈0．01）。③各器官CGRP表达水平，肾性商血压组较正常对照组均显著升高（P〈0．05）；四逆汤治疗组较肾性高血压组均明显降低（P〈0．01）；④Ang—Ⅱ在肾和心的表达水平，四逆汤治疗纰较肾性高血压组均明显降低（P〈0．05），但在脑无显著性差异（P〉0.05）。结论四逆汤可能通过调节肾性高血压大鼠肾、心、脑组织中ETRA、NOS、Ang—Ⅱ和CGRP的表达水平，发挥其血压调节作用。     

肾上腺髓质素对血管紧张素Ⅱ促血管外膜成纤维细胞胶原生成作用的影响

目的探讨肾上腺髓质素（ADM）对血管紧张素Ⅱ（AngⅡ）诱导的血管外膜成纤维细胞胶原生成的影响及机制。方法体外培养大鼠主动脉外膜成纤维细胞,通过放射免疫法测定培养上清中ADM含量,采用酶联免疫吸附法（ELISA）测定培养上清中Ⅰ、Ⅲ型胶原蛋白含量,用逆转录一聚合酶链反应（RT—PCR）及Western印迹法检测转化生长因子β1（TGFβ1）和基质金属蛋白酶-2（MMP-2）mRNA及蛋白的表达。结果AngII呈剂量依赖性地刺激血管外膜成纤维细胞分泌ADM,在AngⅡ（10^-6mol／L）刺激前30min加入氯沙坦或（和）PD123319,氯沙坦（10^-5mol／L）可明显降低AngⅡ刺激的ADM分泌,其抑制率为45％（P〈0．01）,而PD123319（10mmol／L）作用后抑制率仅为3％（P〉0．05）,氯沙坦＋PD123319组与单独氯沙坦组相比差异无统计学意义（P〉0．05）;AngⅡ显著增加培养上清中Ⅰ、Ⅲ型胶原蛋白含量,ADM呈剂量依赖地抑制AngⅡ上述作用,其中ADM（10“mol／L）组中I、Ⅲ型胶原合成分别抑制了30％和31％（P〈0．01）,ADM（10^-7mol／L）组则分别抑制了43％和42％（P〈0．01）。ADM受体拈抗剂ADM22-52可增强AngII上述作用,Ⅰ、Ⅲ型胶原合成分别增加了38％和43％（P〈0．01）;ADM呈剂量依赖性抑制AngⅡ刺激的TGFβ1mRNA及蛋白表达,其中ADM（10^-8mol／L）组中TGFβ1mRNA及蛋白表达分别抑制了55％和45％（P〈0．01）,ADM（10^-7mol／L）组则分别抑制了70％和59％（P〈0．01）;AngⅡ明显下调细胞内MMP-2mRNA及蛋白表达,ADM呈剂量依赖性抑制上述作用,其中10^-8mol／LADM组细胞内MMP-2mRNA及蛋白表达分别增加了1．0和0．9倍。结论AngⅡ可刺激血管外膜成纤维细胞释放ADM,而自分泌旁分泌的ADM可能通过下调细胞内TGFN表达和上调MMP-2表达,抑制AngⅡ刺激的Ⅰ、Ⅲ型胶原蛋白生成,从而发挥有效的抗血管重构作用。     

缬沙坦与胰激肽原酶合用逆转自发性高血压大鼠左室重构的机制

目的探讨缬沙坦（Val）和胰激肽原酶（PK）联合应用对自发性高血压大鼠（SHR）左心室重构的作用及对血管紧张素Ⅱ（AngⅡ）水平、血清一氧化氮（NO）含量的影响。方法选用雄性15周龄的SHR24只、WKY大鼠8只，分为4组：SHR组、PK组、Val＋PK组、WKY组，实验期4w。放免法测定AngⅡ、化学法检测血浆NO水平、常规测量各组血收缩压（SBP）、左心室重量指数（LVMI）、心肌胶原体积比例（CVF）和心肌血管周围胶原与管腔面积的比例（PVCA）。结果SHR组的SBP、LVMI、CVF、PVCA、AngⅡ水平明显增高而血清NO含量明显下降，较WKY组有显著差异（P〈0．01）；治疗组（PK组、Val＋PK组）SBP、LVMI、CVF及PVCA均显著下降（P〈0．01），血清NO水平明显升高（P〈0．01），Val＋PK组血浆AngⅡ水平显著上升（P〈0．01），而心肌AngⅡ水平明显下降P〈0．01），PK组心肌局部和血浆AngⅡ变化不明显。结论PK能有效的改善高血压左室重构，与Val合用效果更佳。     

氯沙坦对心力衰竭患者血浆内皮素-1和降钙素基因相关肽的影响

目的了解心力衰竭患者血浆内皮素-1（ET1）、血管紧张素Ⅱ（AngⅡ）和降钙素基因相关肽（CGRP）的变化，并观察氯沙坦对其的影响。方法测定40例健康者（正常对照组）和90例心力衰竭患者血浆ET-l、AngⅡ和CGRP浓度，随后90例心力衰竭患者被随机分成常规治疗组和氯沙坦组（常规治疗＋氯沙坦50mg每日1次），每组45例。治疗14天后复测血浆ET-1、AngⅡ和CGRP浓度，同时应用彩色多普勒超声显像仪测量正常对照组和心力衰蝎患者治疔前后的左心室射血分数（LVEF）。结果与正常对照组相比较，心力衰竭患者血浆ET-1、AngⅡ明显升高（P〈0．01），ET-1和AngⅡ与LVEF呈负相关（r=-0．7l，r=-0．62，P〈0．01），ET-1和AngⅡ呈正相关（r=0．69，P〈0．01）。治疗14天后，氯沙坦组血浆ET-1明显下降（P〈0．01），CGRP显著升高（P〈0．01），LVEF得到改善（P〈0．05）。而常规治疗组无明显变化（P〉0．05）。结论心力衰竭患者血浆ET-1、AngⅡ浓度明显升高，且与LVEF呈负相关，血浆CGRP显著下降。氯沙坦具有降低ET-1，升高CGRP并改善LVEF的作用。     

血管紧张素Ⅱ及其受体1在食管鳞癌血管生成中的作用

目的 探讨血管紧张素Ⅱ（AngⅡ）及其受体1（AT1R）在食管鳞癌组织中的表达及其在血管生成中的作用。方法 应用免疫组化SP法检测30例食管鳞癌患者癌组织及其食管断端正常鳞状上皮中AngⅡ、AT1R和血管内皮生长因子（VEGF）蛋白的表达。结果 AngⅡ、AT1R和VEGF蛋白表达主要定位于鳞癌细胞iAngⅡ、AT1R在鳞癌组织中的表达均显著高于正常鳞状上皮（P均〈0．01）；癌组织中AngⅡ的表达程度与VEGF的表达程度呈正相关（ra′=0．4249，P〈0．05），AT1R的表达程度与VEGF无相关性（ra′=0．1298，P〉0．05）。结论 食管鳞癌癌组织中高水平表达AngⅡ及AT1R，二者可能通过诱导VEGF的产生促进肿瘤新生血管的形成。     

慢性心力衰竭一氧化氮和血管紧张素Ⅱ浓度的变化及其相互关系

目的：探讨一氧化氮（N0）和血管紧张素Ⅱ（AngⅡ）在慢性心力衰竭（CHF）患者中的变化，及其与心功能的相互关系。方法：选取CHF患者60例及正常人30例，检测NO、AngⅡ水平及左室射血分数（LVEF），进行组问比较及相关分析。结果：（1）CHF组NO、AngⅡ水平明显高于正常对照组，而LVEF水平相反（P〈0．01）；（2）随着心功能减退，NO、AngⅡ水平逐渐升高（P〈0．01或〈0．05）；（3）收缩性与舒张性心力衰竭之间NO、AngⅡ水平差异无统计学意义（P〉0．05）；（4）LVEF与NO、AngⅡ呈负相关（r=-0．415，-0．544，P〈0．01）。结论：NO、AngⅡ参与了CHF形成的病理生理过程，且与CHF的严重程度有关。     

血管紧张素受体与心肌胶原代谢关系的研究

目的 研究血管紧张素Ⅱ受体在心肌胶原代谢中的作用。方法 应用放射免疫结合分析、生化测定、病理检查结合计算机分析等方法检测大鼠腹主动脉缩窄后10周,左室心肌胶原形态、胶原溶积分数（CVF）、血管周围胶原面积（PVCA）、胶原浓度（HC）、Ⅰ、Ⅲ型胶原比值（Ⅰ／Ⅲ）以及血管紧张素Ⅱ含量（AngⅡ）和血管紧张素Ⅱ受体的最大结合量（Bmax)。结果 手术组左室心肌CVF、PVCA、HC、Ⅰ／Ⅲ、AngⅡ和Bmax均显著高于假手术对照组（P＜0．05,P＜0．01）,心肌胶原异常堆积。AngⅡ含量与心肌胶原浓度（HC）呈显著正相关（r1＝0．9045,P＜0．01）。Irbesartan治疗后,上述参数可显著降低（P＜0．05,P＜0．01),异常堆积的的胶原消失。CGP42112A可明显降低血管紧张Ⅱ受体的Bmax（P＜0．01）,而CVF、PVCA、HC、I／Ⅲ、AngⅡ与手术组无显著差异（P＞0．05）。结论 压力超负荷时,大鼠心肌原增生,间质网络发生重建,心脏局部产生的AngⅡ参与了这一病理竽过程,并主要通过血管紧张素Ⅱ的1型受体（ART1）来发挥作用。     

氯沙坦对颈总动脉损伤大鼠血浆Ang Ⅱ与血管TGF-β1表达的影响

目的观察氯沙坦对血管损伤大鼠血浆血管紧张素Ⅱ（AngⅡ）水平与血管转化生长因子β1（TGF—β1）表达的影响。方法采用大鼠颈总动脉挤压术制备血管再狭窄模型，设假手术组、手术组、氯沙坦组，HE染色法观察血管形态学变化，放射免疫法测定血浆AngⅡ含量，免疫组织化学法测定颈总动脉TGF—β1的表达。结果假手术组动脉各层结构正常、清晰，无明显血管平滑机细胞（VSMC）增殖，颈总动脉损伤大鼠VSMC大量增殖，内膜显著增厚，氯沙坦组VSMC增殖程度降低；与假手术组比较，颈总动脉损伤大鼠血浆Ang11含量显著升高（P〈0．01），血管平滑肌TGF-β1。表达显著增强（P〈0．01）；与手术组比较，氯沙坦组血浆AngⅡ含量无显著差异，血管平滑肌TGF—β1表达显著下降（P〈0．01）。结论AngⅡ与TGF-β1，参与血管再狭窄的形成，氯沙坦可通过阻断AngⅡ的作用与降低TGF—β1表达实现抗血管再狭窄的作用。     

Three layer functional model and energy exchange concept of aging process

Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.     

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: Attempts to define mechanisms

Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm²) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Melatonin and photoperiodic time measurement: Seasonal breeding in the sheep

Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Changes in connexin43, the gap junction protein of astrocytes, during development of the rat pineal gland

Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.