血压平逆转肾性高血压大鼠左室重构的作用及机制

目的　探讨复方中药制剂血压平逆转二肾一夹 (2K1C)肾性高血压大鼠左室重构的作用及机制。方法　采用 2K1C法 ,建立肾性高血压大鼠 (RHR)模型 ,术后 8周将造模成功的 40只RHR随机分为 5组 ,每组 8只 ,采用放免法检测血清Ⅲ型前胶原(PCⅢ ) ,测量心肌细胞面积、周长、平均直径、长径和短径。SP免疫组化测量原癌基因C -myc和C -fos表达阳性细胞的平均光密度值。结果　①血压平有降低血压、左室重量 (LVW )、左室重量指数 (LVW /BW )、心肌细胞体积的作用 ;②血压平可降低血清PCⅢ含量 ,抑制原癌基因C -myc和C -fos的表达 ;③血压平的降压和逆转左室重构的药理作用有量效关系。结论　血压平具有逆转RHR左室重构的作用 ,其降低血压、降低血清PCⅢ含量、抑制Ⅲ型胶原合成、防治心肌纤维化及降低原癌基因C -myc和C -fos的表达、抑制心肌细胞肥大、减轻左心室肥厚 ,是其逆转2K1CRHR左室重构的部分机制。     

缬沙坦对肾血管性高血压大鼠心肌肥厚及结缔组织生长因子表达的影响

目的:研究肾血管性高血压(RVH)大鼠心肌肥厚及结缔组织生长因子(CTGF)的表达情况,探讨缬沙坦逆转左室重构的可能机制。方法:用两肾一夹方法构建RVH大鼠模型。以左心室重量(LVW)、LVW与体重比值(LVW/BW)作为心肌肥厚的指标,分别应用RT-PCR法和免疫组织化学染色法检测CTGF的mRNA和蛋白质的表达。结果:①RVH大鼠术后第8周出现心肌肥厚,第12周进一步加重。缬沙坦治疗后,心肌肥厚明显减轻(P<0.01)。②RVH未治疗组CTGF mRNA及蛋白表达与假手术组比较显著增加;缬沙坦治疗4或8周后,其表达较相应未治疗组显著降低(P<0.05)。结论:RVH大鼠CTGF表达增多,缬沙坦能部分抑制其过度表达。这可能是AT受体阻滞剂预防或逆转心肌肥厚重构的机制之一。     

贝那普利和氯沙坦联合阻断肾素—血管紧张素系统对自发性高血压大鼠左心室重构的影响

目的探讨贝那普利和氯沙坦单独与联合治疗对改善及逆转老龄自发性高血压大鼠左心室重构的影响。方法选55周龄Wistar京都大鼠18只,同龄自发性高血压大鼠54只,随机抽取Wistar京都大鼠和自发性高血压大鼠各6只检测,以确定左心室肥厚,其余分为Wistar京都大鼠对照组、自发性高血压大鼠对照组、贝那普利组10 mg/(kg.d)、氯沙坦组30 mg/(kg.d)及贝那普利10 mg/(kg.d) 氯沙坦15 mg/(kg.d)联合用药组。监测动脉收缩压及左心室质量指数,光镜观察心肌组织结构改变,免疫组织化学法测心肌胶原纤维表达,TUNEL末端标记法进行细胞凋亡检测。结果各药物干预组均可降低左心室质量指数(P<0.01),改善心肌组织结构的改变,降低总胶原及Ⅰ型胶原表达(P<0.01),并轻度降低Ⅲ型胶原表达,均以联合用药组更显著(P<0.01);贝那普利组心肌细胞凋亡率显著高于自发性高血压对照组(P<0.01),氯沙坦组及联合用药组心肌细胞凋亡率显著降低(P<0.01)。结论贝那普利和氯沙坦联合治疗自发性高血压大鼠对改善和逆转左心室重构优于单剂。     

血管紧张素Ⅱ-醛固酮诱导肾性高血压大鼠心肌肥厚发生:钙调神经磷酸酶抑制因子的作用

目的:探讨一肾一夹肾性高血压大鼠模型中,心肌组织中钙调神经磷酸酶(CaN)抑制因子(calcineurin-inhibi-tor,Cain)表达的变化,以及血浆中相关活性因子的变化。方法:将21只健康雄性Wistar大鼠,随机分为3组(n=7),即假手术组、手术组(通过一肾一夹法复制肾性高血压大鼠)及螺内酯组:以螺内酯20 mg/(kg.d)灌胃;实验14 d后,大鼠称质量后抽血处死,分别计算左心室质量(LVW)、全心质量(HW)以及二者与体质量(BW)的比值。采用放射免疫测定法检测血浆醛固酮(Ald)及血管紧张素Ⅱ(AngⅡ)的含量。以蛋白印迹杂交的方法,测定心肌组织中Cain表达的变化。结果:与假手术组比较,手术组大鼠的LVW/BW及HW/BW比值显著增加(P0.05)、血浆Ald和AngⅡ的水平、及Cain的表达的显著增加(P0.01);而与手术组比较,螺内酯组大鼠的LVW/BW比值显著减少(P0.05)、血浆AngⅡ的水平及Cain的表达均显著减少(P0.01)。结论:通过一肾一夹手术,诱导机体内源性Ald和AngⅡ增加,导致大鼠心肌肥厚反应的发生。同时,机体内源性Cain表达的增加,以抑制CaN信号通路介导的心肌肥厚反应。螺内酯通过阻断Ald与其受体结合,可以抑制心肌肥厚的发生。     

肝素结合表皮生长因子在高血压大鼠心肌表达及氯沙坦对其影响

目的探讨肝素结合表皮生长因子(HB-EGF)在自发高血压大鼠(SHR)心肌表达情况及氯沙坦对其影响.方法取16只8周龄自发性高血压大鼠,随机分为两组,每组8只:氯沙坦干预组,给予氯沙坦30 mg/kg*d溶于饮水灌胃治疗;SHR阳性对照组给予正常饮水.另有8只同龄同源雄性正常血压Wistar-kyoto大鼠(WKY)组作为正常对照组.实验周期12周.观察血压、左室重量/体重(LVW/BW);逆转录多聚酶链反应(RT-PCR)和免疫组化实验检测各组大鼠HB-EGF mRNA的表达情况.结果正常对照组和氯沙坦组血压和LVW/BW均底于SHR阳性对照组;SHR阳性对照组HB-EGF mRNA表达均高于正常对照组和氯沙坦组;氯沙坦组HB-EGF mRNA表达高于正常对照组.结论肝素结合表皮生长因子在自发高血压大鼠组表达明显增加而氯沙坦能部分阻断HB-EGF mRNA的表达提示HB-EGF mRNA可能在高血压发生发展过程中起了一定作用.     

缬沙坦对肾性高血压大鼠心肌肥厚及富脯氨酸蛋白酪氨酸激酶表达的影响

背景和目的富脯氨酸蛋白酪氨酸激酶(Pyk2)是一种新发现且活跃的酪氨酸蛋白激酶,该酶能催化多种含 SH 同源域2的底物蛋白磷酸化,参与细胞的生长、增殖和分化。本文以肾性高血压大鼠(RHR)为模型,研究心肌中 Pyk2的表达情况,探讨缬沙坦逆转左室重构的可能机制。方法制备两肾一夹肾性高血压大鼠模型;将大鼠随机分为假手术组、模型组和缬沙坦组[术后第29天给予缬沙坦30 mg/(kg·d)];分别于术前及术后第1、4、8和12周测定动脉血压和心肌肥厚指数,用免疫印迹法检测心肌组织中 Pyk2及其磷酸化表达。结果术后4周已发生心肌肥大,8～12周心肌肥大进一步加重,缬沙坦能显著降低肾性高血压大鼠的血压,并能有效抑制心肌肥厚的形成(P<0.01);术后大鼠心肌组织 Pyk2活性逐渐增加(1周时,P<0.05,4、8、12周时 P<0.01);缬沙坦降低Pyk2及其磷酸化表达水平,与同周龄模型组相比差异有非常显著意义(P<0.01)。结论 Pyk2及磷酸化在 RHR心肌绀织内表达增高,且与心肌肥厚相关;缬沙坦能下调 Pyk2的表达和磷酸化变化。这可能是血管紧张素Ⅱ受体拮抗剂逆转心肌肥厚重构的机制之一。     

缬沙坦对肾性高血压大鼠心肌肥厚及富脯氨酸蛋白酪氨酸激酶表达的影响

背景和目的 富脯氨酸蛋白酪氨酸激酶(Pyk2)是一种新发现且活跃的酪氨酸蛋白激酶,该酶能催化多种含SH同源域2的底物蛋白磷酸化,参与细胞的生长、增殖和分化.本文以肾性高血压大鼠(RHR)为模型,研究心肌中Pyk2的表达情况,探讨缬沙坦逆转左室重构的可能机制.方法 制备两肾一夹肾性高血压大鼠模型;将大鼠随机分为假手术组、模型组和缬沙坦组[术后第29天给予缬沙坦30 mg/(kg·d)];分别于术前及术后第1、4、8和12周测定动脉血压和心肌肥厚指数,用免疫印迹法检测心肌组织中Pyk2及其磷酸化表达.结果 术后4周已发生心肌肥大,8～12周心肌肥大进一步加重,缬沙坦能显著降低肾性高血压大鼠的血压,并能有效抑制心肌肥厚的形成(P＜0.01);术后大鼠心肌组织Pyk2活性逐渐增加(1周时,P＜0.05,4、8、12周时P＜0.01);缬沙坦降低Pyk2及其磷酸化表达水平,与同周龄模型组相比差异有非常显著意义(P＜0.01).结论 Pyk2及磷酸化在RHR心肌组织内表达增高,且与心肌肥厚相关;缬沙坦能下调Pyk2的表达和磷酸化变化.这可能是血管紧张素Ⅱ受体拮抗剂逆转心肌肥厚重构的机制之一.     

心舒康对肾性高血压大鼠血管紧张素Ⅱ受体1表达的影响

目的观察心舒康对肾性高血压大鼠血管紧张素Ⅱ受体1表达的影响。方法观察肾性高血压大鼠经心舒康治疗后的收缩压、左心室质量/体质量(LVW/BW)的变化。采用免疫组织化学法检测心肌组织血管紧张素Ⅱ受体1表达水平的变化。结果经中药复方心舒康治疗6周后,大鼠的收缩压明显降低,LVW/BW明显降低,左心室心肌组织中血管紧张素Ⅱ受体1的表达明显减少。结论心舒康能明显降低血压,能够降低LVW/BW,抑制心肌组织血管紧张素Ⅱ受体1的上调。     

氯沙坦对肾血管性高血压大鼠心肌细胞肿瘤坏死因子α表达的影响

目的观察氯沙坦对肾血管性高血压大鼠心肌细胞肿瘤坏死因子α(TNF-α)表达影响。方法实验采用两肾一夹(2K1C)的方法建立肾血管性高血压(RVH)大鼠模型,将大鼠随机分为假手术组、高血压模型组和高血压模型 氯沙坦治疗组(20mg/kg.d);用鼠尾动脉测压法记录每周血压变化,实验末取心脏,并计算心脏指数(CI:心肌重量/体重);ELISA法和免疫组织化学法分别测定各组心肌TNF-α的表达。结果氯沙坦能明显降低肾血管性高血压大鼠的血压(P<0.01)和CI(假手术组:2.86±0.37比高血压模型组:4.12±0.27比氯沙坦组:3.35±0.62,P<0.05)、显著抑制肾血管性高血压大鼠心肌TNF-α的表达[ELISA法:假手术组:1.1±0.1比高血压模型组:31.3±3.0比氯沙坦组:(2.3±0.2)ng/mg,P<0.05]。结论氯沙坦能有效逆转心室重构,其机制可能与降低心肌中TNF-α的表达有关。     

氯沙坦对肾血管性高血压大鼠心肌细胞肿瘤坏死因子α表达的影响

目的 观察氯沙坦对肾血管性高血压大鼠心肌细胞肿瘤坏死因子α(TNF-α)表达影响.方法实验采用两肾一夹(2K1C)的方法建立肾血管性高血压(RVH)大鼠模型,将大鼠随机分为假手术组、高血压模型组和高血压模型 氯沙坦治疗组(20 mg/kg·d);用鼠尾动脉测压法记录每周血压变化,实验末取心脏,并计算心脏指数(CI:心肌重量/体重);ELISA法和免疫组织化学法分别测定各组心肌TNF-α的表达.结果 氯沙坦能明显降低肾血管性高血压大鼠的血压(P＜0.01)和CI(假手术组:2.86±0.37比高血压模型组:4.12±0.27比氯沙坦组:3.35±0.62,P＜0.05)、显著抑制肾血管性高血压大鼠心肌TNF-α的表达[ELISA法:假手术组:1.1±0.1比高血压模型组:31.3±3.0比氯沙坦组:(2.3±0.2)ng/mg,P＜0.05].结论 氯沙坦能有效逆转心室重构,其机制可能与降低心肌中TNF-α的表达有关.     

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.     

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.     

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.     

Serological survey of HIV and syphilis in pregnant women in Madagascar

Objectives Peripartal transmission of human immunodeficiency virus (HIV) and Treponema pallidum, the causative agent of syphilis, leads to severe consequences for newborns. Preventive measures require awareness of the maternal infection. Although HIV and syphilis testing in Madagascar could be theoretically carried out within the framework of the national pregnancy follow‐up scheme, the required test kits are rarely available at peripheral health centres. In this study, we screened blood samples of pregnant Madagascan women for HIV and syphilis seroprevalence to estimate the demand for systemic screening in pregnancy. Methods Retrospective anonymous serological analysis for HIV and syphilis was performed in plasma samples from 1232 pregnant women that were taken between May and July 2010 in Ambositra, Ifanadiana, Manakara, Mananjary, Moramanga and Tsiroanomandidy (Madagascar) during pregnancy follow‐up. Screening was based on Treponema pallidum haemagglutination tests for syphilis and rapid tests for HIV, with confirmation of positive screening results on line assays. Results Out of 1232 pregnant women, none were seropositive for HIV and 37 (3%) were seropositive for Treponema pallidum. Conclusions Our findings are in line with previous studies that describe considerable syphilis prevalence in the rural Madagascan population. The results suggest a need for screening to prevent peripartal Treponema pallidum transmission, while HIV is still rare. If they are known, Treponema pallidum infections can be easily, safely and inexpensively treated even in pregnancy to reduce the risk of transmission.     

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.     

Variabilité des concentrations plasmatiques de l’angiotensinogène et risque d’hypertension artérielle chez le rat transgénique

Aim

Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5 mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors.

Methods

Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n = 3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction).

Results

At baseline, transgenic rats had +18 mmHg higher bood pressure and –8% lower body weight compared to non-transgenic rats (P < 0.05) without significant changes for the vehicle groups throughout the study (P > 0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P < 0.05) in transgenic and +25%, +5.3% and +6.7% (P > 0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P > 0.05).

Conclusion

Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.