原发性高血压与血浆肾素活性及血管紧张素原遗传关系研究

目的：分析血浆肾素活性（ＰＲＡ）、血浆血管紧张素原（ＡＯ）浓度与原发性高血压的关系。方法：在一个原发性高血压家系中随机抽取原发性高血压患者３１例（原发性高血压组）、正常血压者２５例（家系对照组），在６个正常对照家系中随机抽取２１例（正常对照组），测定ＰＲＡ、血浆ＡＯ及其它代谢因素。结果：调整年龄、性别、体重指数后原发性高血压家系内无论有无原发性高血压患者，ＰＲＡ均显著低于正常对照组（Ｐ＜００５）；原发性高血压组血浆ＡＯ显著高于正常对照组（Ｐ＜００５），高密度脂蛋白胆固醇显著低于正常对照组（Ｐ＜００５）。结论：具有原发性高血压遗传因素者无论是否患有原发性高血压均有显著的ＰＲＡ、血浆ＡＯ异常和其它代谢紊乱，这些异常可能在超重和原发性高血压发生前即已存在     

尿液水通道蛋白-2与低肾素型高血压关系的研究

目的探讨水通道蛋白-2（AQP2）与低肾素型高血压（LREH）发病机制的关系。方法选取LREH患者110例,分为1、2、3级高血压三个亚组,设置健康对照40例,间接ELISA法检测尿液AQP2浓度,放射免疫法检测血浆血管加压素（AVP）浓度,监测平均动脉压（MAP）,分析患者尿液AQP2浓度的变化及其与血浆AVP浓度、MAP之间的关系。结果LREH组不同血压级别三个亚组血浆AVP浓度、尿液AQP2浓度均高于健康对照组（t=2.99、t=3.01,P〈0.05）,并随血压级别升高而升高（P均〈0.05）;尿液AQP浓度与血浆AVP浓度、MAP之间彼此均呈正相关（r=0.862、r=0.694、r=0.797,P〈0.05）。结论LREH患者肾脏集合管主细胞内AQP2穿梭、表达的增加,可能与LREH的水钠潴留机制密切相关.     

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

Introduction: The current review aimed to outline the functions of the renin angiotensin system (RAS) in the context of the oxidative stress-associated liver disease.

Areas covered: Angiotensin II (Ang II) as the major effector peptide of the RAS is a pro-oxidant and fibrogenic cytokine. Mechanistically, NADPH oxidase (NOX) is a multicomponent enzyme complex that is able to generate reactive oxygen species (ROS) as a downstream signaling pathway of Ang II which is expressed in liver. Ang II has a detrimental role in the pathogenesis of chronic liver disease through possessing pro-oxidant, fibrogenic, and pro-inflammatory impact in the liver. The alternative axis (ACE2/Ang(1-7)/mas) of the RAS serves as an anti-inflammatory, antioxidant and anti-fibrotic component of the RAS.

Expert commentary: In summary, the use of alternative axis inhibitors accompanying with ACE2/ Ang(1-7)/mas axis activation is a promising new strategy serving as a novel therapeutic option to prevent and treat chronic liver diseases.     

Endogenous urocortins reduce vascular tone and renin-aldosterone/endothelin activity in experimental heart failure.

AIMS: To investigate the role of the endogenous urocortin peptides in heart failure (HF) through blockade of the corticotropin-releasing factor receptor 2 (CRF-R2). METHODS AND RESULTS: Eight sheep were administered the CRF-R2 antagonist CRF(9-41) (1.5 mg bolus) before (Normal) and after development of pacing-induced HF. Compared with controls, CRF(9-41) in HF significantly increased mean arterial pressure (MAP) (71+/-2 vs. 75+/-2 mmHg, P=0.0024) and calculated total peripheral resistance (CTPR) (33.3+/-5.2 vs. 39.4+/-5.9 mmHg/L/min, P=0.0455). Similar trends were observed in the Normal state (MAP 87+/-1 vs. 89+/-2 mmHg, P=0.0689; CTPR 21.9+/-2.0 vs. 24.4+/-2.4 mmHg/L/min, P=0.0731). Left atrial pressure was elevated similarly in both states (Normal P=0.0013; HF P=0.0298), whereas cardiac output tended to be reduced (Normal P=0.0614). CRF(9-41) increased plasma urocortin-I (Normal 10.3+/-0.8 vs. 19.8+/-1.3 pmol/L, P<0.001; HF 14.4+/-0.9 vs. 25.3+/-0.8 pmol/L, P<0.001), renin (Normal 0.34+/-0.06 vs. 0.41+/-0.02 nmol/L/hr, P=0.013; HF 1.14+/-0.29 vs. 1.57+/-0.36 nmol/L/hr, P=0.0326), aldosterone (Normal 370+/-62 vs. 563+/-99 pmol/L, P=0.0813; HF 662+/-141 vs. 1024+/-209 pmol/L, P=0.095), and endothelin-1 (HF 3.18+/-0.18 vs. 4.74+/-1.04 pmol/L, P=0.0087). MAP, CTPR, renin, and endothelin-1 responses to CRF-R2 antagonism were significantly greater in HF than in the Normal state (P=0.049, 0.0427, 0.0311, and 0.0412, respectively). CONCLUSION: These data suggest that the endogenous urocortin peptides contribute to the suppression of vascular tone and renin-angiotensin-aldosterone/endothelin activation in HF and thus, play a protective compensatory role in this disorder.     

Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIVAN mice. Interestingly, Angiotensin Receptor Type I (AT1R) blockade did not modulate renal tissue phosphorylation of mTOR in HIVAN mice; on the other hand, AT2R blockade attenuated renal tissue phosphorylation of mTOR in HIVAN mice. In vitro studies, both renin and Ang II displayed enhanced mouse tubular cell (MTC) phosphorylation of p70S6K in a dose dependent manner. HIV/MTC also displayed enhanced phosphorylation of both mTOR and p70S6K; interestingly this effect of HIV was further enhanced by losartan (an AT1R blocker). On the other hand, AT2R blockade attenuated HIV-induced tubular cell phosphorylation of mTOR and p70S6K, whereas, AT2R agonist enhanced phosphorylation of mTOR and p70S6K. These findings indicate that HIV stimulates mTOR pathway in HIVAN through the activation of renin angiotensin system via AT2R.     

组织中肾素—血管紧张素—醛固酮系统的实验研究

为了解组织中肾素－血管紧张素－醛固酮系统情况，用离体肾灌注、高效液相分析、放免检测、肾素基因保留时间（ＲＴ）－ＰＣＲ检测首次证明肾脏也可合成醛固酮。双肾切除３０小时使血浆肾素活性消失之后，用ＲＴ－ＰＣＲ技术表明血管仍可表达肾素ｍＲＮＡ，从而说明血管不同于心脏、具有独立的肾素合成能力。血管紧张素转换酶抑制剂培哚普利，不仅可抑制血管局部血管紧张素Ⅱ的生成，还可抑制血管醛固酮的合成，从而进一步解释培哚普利逆转血管重构的作用机理。     

Structure-Based Design of Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors

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Treatment with inhaled formulation of angiotensin-(1-7) reverses inflammation and pulmonary remodeling in a model of chronic asthma

Asthma is characterized by inflammation, pulmonary remodeling and bronchial hyperresponsiveness. We have previously shown that treatment with angiotensin-(1-7) [Ang-(1-7)] promotes resolution of eosinophilic inflammation and prevents chronic allergic lung inflammation. Here, we evaluated the effect of treatment with the inclusion compound of Ang-(1-7) in hydroxypropyl β-cyclodextrin (HPβCD) given by inhalation on pulmonary remodeling in an ovalbumin (OVA)-induced chronic allergic lung inflammation. Mice were sensitized to ovalbumin (OVA; 4 injections over 42 days, 14 days apart) and were challenged 3 times per week, for 4 weeks (days 21–46). After the 2nd week of challenge, mice were treated with Ang-(1-7) by inhalation (4.5 μg of Ang-(1-7) included in 6.9 μg of HPβCD for 14 days, i.e. days 35–48). Mice were killed 72 h after the last challenge and blood, bronchoalveolar lavage fluid (BALF) and lungs were collected. Histology and morphometric analysis were performed in the lung. Metalloproteinase (MMP)-9 and MMP-12 expression and activity, IL-5, CCL11 in the lung and plasma IgE were measured. After 2 weeks of OVA challenge there was an increase in plasma IgE and in inflammatory cells infiltration in the lung of asthmatic mice. Treatment with inhaled administration of Ang-(1-7)/HPβCD for 14 days reduced eosinophils, IL5, CCL11 in the lung and plasma IgE. Treatment of asthmatic mice with Ang-(1-7)/HPβCD by inhalation reversed pulmonary remodeling by reducing collagen deposition and MMP-9 and MMP-12 expression and activity. These results show for the first time that treatment by inhalation with Ang-(1-7) can reverse an installed asthma, inhibiting pulmonary inflammation and remodeling.     

慢性房颤犬心房肌肾素血管紧张素系统激活的影响及卡托普利的干预作用

目的探讨慢性房颤实验犬心房肌肾素血管紧张素系统(RAS)的影响及卡托普利的干预作用。方法健康杂种犬26只,随机分为三组：对照组(n=6),起搏组(n=11),治疗组(n=9)。起搏组和治疗组安置埋藏式高频率心脏起搏器(400次/min),快速起搏犬右心耳8周,治疗组于起搏前3 d至起搏后第8周每日口服卡托普利50 mg,每天两次。起搏8周后,两组分别处死动物,于左右心房、心耳及房间隔取材,测定心房组织血管紧张素Ⅱ(AngⅡ)含量及心房肌细胞内Ca~(2 )浓度。对照组未安置起搏器,与起搏、治疗组同步行相应检查。结果起搏8周后,起搏组、治疗组和对照组测得心房组织AngⅡ含量分别为(29．83±5．73)pg/ml,(13．23±3．15)pg/ml,(11．38±2．14)pg/ml。与对照组比较,起搏组AngⅡ含量明显增高(P＜0．01),而治疗组与对照组比较,差异无显著性(P＞0．05)。三组测得心房肌细胞内Ca~(2 )浓度分别为(35．32±4．88)μg/mg,(25．44±4．19)μg/mg,(24．06±3．51)μg/mg。与对照组比较,起搏组明显升高(P＜0．01),而治疗组没有(P＞0．05)。结论长期快速起搏实验犬心房组织AngⅡ含量增高、心房肌细胞内钙超载。卡托普利可阻滞慢性房颤实验犬心房组织RAS激活,阻止细胞内钙超载,从而消除房颤形成的基质。