阻塞型睡眠呼吸暂停低通气综合征患者肾素、血管紧张素水平的研究

目的:探讨阻塞性睡眠暂停低通气综合征(OSAHS)患者血液中的肾素、血管紧张素水平异常和高血压之间关系。方法:选取住院接收治疗的100例患者,将患者随机分成两组,观察组患者伴有高血压,共50例,对比组非OSAHS患者,共有50例。对两组患者均采取晨起觉醒时抽静脉血2ml,用放射免疫法检测肾素、血管紧张素,分析采集数据,通过样本结果的分析、比较两组患者检测结果的差异性。结果:经过检验发现观察组患者血浆肾素、血管紧张素水平明显高于对照组(P<0.05)。结论:OSAHS伴有高血压患者,肾素、血管紧张素-醛固酮系统(RAAS)过度激活,睡眠觉醒、OSA可导致患者交感神经的兴奋,导致RAAS系统的激活,释放的儿茶酚胺、肾素、血管紧张素Ⅱ、醛固酮可导致患者血压的上升。

充血性心力衰竭患者血钠水平与神经内分泌激素及脑钠肽水平关系的临床研究

目的探讨充血性心力衰竭患者血钠水平与血浆肾素(PRA)、血管紧张素Ⅱ(AngⅡ)、醛固酮(ALD)及脑钠肽(BNP)水平的关系。方法 73例NYHAⅡ、Ⅳ级住院患者按血清钠水平分为正常血钠组(41例)和低血钠组(32例),测定并比较两组患者的血浆PRA、AngⅡ、ALD及BNP水平,并分析血清钠水平和上述指标的相关性;根据心功能级别分为心功能Ⅱ级组(20例)、Ⅲ级组(22例)和Ⅳ级组(31例),并分别进行组间血钠、PRA、AngⅡ、ALD、BNP水平比较。结果①与正常血钠组相比,低血钠组的心力衰竭患者血浆PRA、AngⅡ、ALD、BNP水平均显著升高;②相关分析显示,血钠与血浆PRA、AngⅡ、ALD、BNP呈显著负相关;③与心功能Ⅱ组比较,心功能Ⅲ、Ⅳ组的血浆PRA、AngⅡ、ALD、BNP水平显著升高,而血钠水平显著降低(P<0.05)。结论慢性充血性心力衰竭患者血钠水平与PRA、AngⅡ、ALD、BNP水平呈负相关,可能促进慢性心力衰竭患者血浆PRA、AngⅡ、ALD、BNP分泌增加。

Meta-analysis of effects of obstructive sleep apnea on the renin-angiotensinaldosterone system

Background Obstructive sleep apnea （OSA） is the most common cause of resistant hypertension, which has been proposed to result from activation of the renin-angiotensin-aldosterone system （RAAS）. We meta-analyzed the effects of OSA on plasma levels of RAAS components. Methods Full-text studies published on MEDL1NE and EMBASE analyzing fasting plasma levels of at least one RAAS component in adults with OSA with or without hypertension. OSA was diagnosed as an apnea-hypopnea index or respiratory disturbance index 〉 5. Study quality was evaluated using the Newcastle-Ottawa Scale, and heterogeneity was assessed using the 12 statistic. Results from individual studies were synthesized using inverse variance and pooled using a random-effects model. Subgroup analysis, sensitivity analysis, and meta-regression were performed, and risk of publication bias was assessed. Results The meta-analysis included 13 studies, of which 10 reported results on renin （n = 470 cases and controls）, 7 on angiotensin II （AnglI, n = 384）, and 9 on aldosterone （n = 439）. AnglI levels were significantly higher in OSA than in controls [mean differences = 3.39 ng/L, 95% CI： 2.00-4.79, P 〈 0.00001], while aldosterone levels were significantly higher in OSA with hypertension than OSA but not with hypertension （mean differences = 1.32 ng/dL, 95% CI： 0.58-2.07, P = 0.0005）. Meta-analysis of all studies suggested no significant differences in aldosterone between OSA and controls, but a significant pooled mean difference of 1.35 ng/mL （95% CI： 0.88-1.82, P 〈 0.00001） emerged after excluding one small-sample study. No significant risk of publication bias was detected among all included studies. Conelusions OSA is associated with higher AnglI and aldosterone levels, espe- cially in hypertensive patients. OSA may cause hypertension, at least in part, by stimulating RAAS activity.

The angiotensin Ⅱ type 1 receptor and receptor-associated proteins

The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl- terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxy1-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.

Angiotensin-（1-7）： new perspectives in atherosclerosis treatment

Angiotensin （Ang）-（1-7） is recognized as a new bioactive peptide in renin-angiotensin system （RAS）. Ang-（1-7） is a counter-regulatory mediator of Ang-II which appears to be protective against cardiovascular disease. Recent studies have found that Ang-（1-7） played an important role in reducing smooth muscle cell proliferation and migration, improving endothelial function and regulating lipid metabolism, leading to inhibition of atherosclerotic lesions and increase of plaque stability. Although clinical application of Ang-（1-7） is restricted due to its pharmacokinetic properties, identification of stabilized compounds, including more stable analogues and specific delivery compounds, has enabled clinical application of Ang-（1-7）. In this review, we discussed recent findings concerning the biological role of Ang-（1-7） and related mechanism during atherosclerosis development. In addition, we highlighted the perspective to develop therapeutic strategies using Ang-（1-7） to treat atherosclerosis.

Time to re-evaluate effects of renin-angiotensin system inhibitors on renal and cardiovascular outcomes in diabetic nephropathy

The use of renin-angiotensin system(RAS) inhibitors, such angiotensin converting enzyme inhibitors/angiotensin-Ⅱreceptor blockers, to slow progression of chronic kidney disease(CKD) in a large group dominated by elderly people in the real world is not supported by available evidence. Large-scale clinical trials had many faults,among them a lack of focus on the elderly. However,it would be difficult to conduct clinical trials of a similar scale in elderly CKD patients. Besides, progression ofkidney disease is often slow in elderly persons, and the vast majority of older adults with CKD will die before reaching end stage renal disease. Moreover, since it is not clear that progression of kidney disease, and even of proteinuric diabetic nephropathy, is not inhibited through the use of RAS inhibitors, the most patientcentric goal of therapy for many elderly individuals should be individualized.

Association of cardiovascular system medications with cognitive function and dementia in older adults living in nursing homes in Australia

Objective To examine associations between cardiovascular system medication use with cognition function and diagnosis of dementia in older adults living in nursing homes in Australia. Methods As part of a cross-sectional study of 17 Australian nursing homes examining quality of life and resource use, we examined the association between cognitive impairment and cardiovascular medication use （identified using the Anatomical Therapeutic Classification System） using general linear regression and logistic regression models. People who were receiving end of life care were excluded. Results Participants included 541 residents with a mean age of 85.5 years （± 8.5）, a mean Psychogeriatric Assessment Scale–Cognitive Impairment （PAS-Cog） score of 13.3 （± 7.7）, a prevalence of cardiovascular diseases of 44% and of hypertension of 47%. Sixty-four percent of participants had been diagnosed with dementia and 72% had received cardiovascular system medications within the previous 12 months. Regression models demonstrated the use of cardiovascular medications was associated with lower （better） PAS-Cog scores [Coefficient （β） = -3.7; 95% CI： -5.2 to -2.2; P 〈 0.0001] and a lower probability of a dementia diagnosis （OR = 0.44; 95% CI： 0.26 to 0.75, P = 0.0022）. Analysis by subgroups of medications showed cardiac therapy medications （C01）, beta blocking agents （C07）, and renin-angiotensin system agents （C09） were associated with lower PAS-Cog scores （better cognition） and lower dementia diagnosis probability. Conclusions This analysis has demonstrated an association between greater cardiovascular system medication use and better cognitive status among older adults living in nursing homes. In this population, there may be differential access to health care and treatment of cardiovascular risk factors. This association warrants further investigation in large cohort studies.

Efficacy and safety of a novel multi-electrode radiofrequency ablation catheter for renal sympathetic denervation in pigs

Objective To investigate the safety and efficacy of a self-developed novel multi-electrode radiofrequency ablation catheter （Spark） for catheter-based renal denervation （RDN）. Methods A total of 14 experimental miniature pigs were randomly divided into four groups （55°＆ 5-watt, 55°＆ 8-watt, 65°＆ 5-watt, and 65° ＆ 8-watt groups）. Spark was used for left and right renal artery radiofrequency ablation. Blood samples collected from renal arteries and veins as well as renal arteriography were performed on all animals before, immediately after, and three months after procedure to evaluate the effects of Spark on the levels of plasma renin, aldosterone, angiotensin I, and angiotensin II as well as the pathological changes of renal arteries. Results One pig died of an anesthetic accident, 13 pigs successfully underwent the bilateral renal artery ablation. Compared with basic measurements, pigs in all the four groups had significantly decreased mean arterial pres- sure after procedure. Histopathological analysis showed that this procedure could result in intimal hyperplasia, significant peripheral sympa- thetic nerve damage in the renal arteries such as inflammatory cell infiltration and fibrosis in perineurium, uneven distribution of nerve fibers, tissue necrosis, severe vacuolization, fTagmented and unclear nucleoli myelin degeneration, sparse axons, and interruption of continuity. In addition, the renal artery radiofrequency ablation could significantly reduce the levels of plasma renin, aldosterone, angiotensin I, and angio- tensin II in pigs. Conclusions The results suggest that this type of multi-electrode catheter-based radiofrequency ablation could effectively remove peripheral renal sympathetic nerves and reduce the activity of systemic renin-angiotensin system in pigs, thus facilitating the control of systemic blood pressure in pigs.

Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

AIM:To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS:Patients were allocated into two groups:outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA),Angiotensin(Ang) Ⅰ,Ang Ⅱ,and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation,hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components.RESULTS:PRA,Ang Ⅰ,Ang Ⅱ and Ang-(1-7) were signifi cantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang Ⅰ levels and between Ang Ⅱ and Ang Ⅰ were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang Ⅱ remained unchanged in splanchnic and peripheral circulation in patients under β-blockade,whereas the relationship between Ang Ⅱ and Ang Ⅰ was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation,cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. CONCLUSION:In LD group,propranolol treatment reduced RAS mediators,but did not change the ratio between Ang-(1-7) and Ang Ⅱ in splanchnic and peripheral circulation. Furthermore,the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.

Effects of angiotensin-Ⅱ receptor blockers on β-catenin expression in a rat model of experimental streptozotocin-induced early-stage of diabetic nephropathy

Objective： Diabetic nephropathy （DN） is one of the most common causes of end-stage renal failure. The pathogenesis of progressive renal injury is multifactorial and the mechanism by which hyperglycemia causes microangiopathy is still poorly understood. The WNT pathway is activated in DN and regulating β-catenin protein levels is referred to as the canonical Wntβ-catenin pathway. Because the renin angiotensin system has been reported to be an important contributory factor in the pathophysiology of DN, exogenous administration of angiotensin Ⅱ receptor antagonist may be beneficial in counteracting some biochemical or functional changes of DN. The aim of the study was to determine the β-catenin expression and the possible protective effects of irbesartan, an angiotensin Ⅱ type 1 receptor blocker （ARB） in a rat model of streptozotocin（STZ）-induced diabetic nephropathy. Methods： STZ-induced DN in rats was assessed biochemically by measuring urine volume, protein and creatinine clearance as well as Kidney weight/body weight （KW/BW） and the index of mesangial expansion. Three groups of male Sprague-dawley rats were used. The first group consisted of non-diabetic control rats （control）. The second group was the untreated diabetic rats（STZ＋vehicle）. The third group consisted of diabeti rats treated with irbesartan, 50 mg/kg for 12 weeks （STZ＋irbesartan）. Immunohistochemical stainings and real time PCR for β-catenin were performed in renal cortex of rat modals. Results： Marked hyperglycemia, polyuria, proteinuria, renal hypertrophy, mesangial matrix expansion and glomerular hyperfiltration were observed in STZ diabetic rats. The levels of microalbuminuria and KW/BW in the STZ＋irbesartan group were lower than those in the STZ＋vehicle group （P〈0.05）. The up-regulated immunostaining and mRNA expression of β-catenin were decreased in renal cortic of the Irbesartan-treated diabetic group, but there was no significant difference compared to the untreated diabetic group. Conclusion： The data suggest that irbesartan ameliorates proteinuria and renal hypertrophy, charactered damages of STZ-induced early-stage DN in rats, but its effective drug target is not to inhibit the up-regulated expressions of β-catenin.

Noradrenaline as a putative neurotransmitter mediating hypotension-induced Fos-like immunoreactivity inthe supraoptic nucleus of the rat

Hemorrhage or hypotension induces extensive Foslike immunoreactivity in the magnocellular neurosecretory cells in the supraoptic nucleus of the hypothalamus in rat, especially in the vasopressin neurons. The present study was to explore the neurotransmitter mediating this effect. Microinfusion of the alpha-adrenergic blocker into the supraoptic nucleus reduced the hypotension-induced Fos, whereas beta-antagonist did not affect it significantly. Alpha1- and alpha2-antagonist, prazosin and yohimbine,both reduced the Fos-positive cell counts. However, the effective dosage of yohimbine was much larger. Alpha1-agonist, methoxamine, induced abundant Fos-like immnnoreactivity in the vasopressin cells in this nucleus,while beta-and alpha2-agonist did not elicit such effect.Administration of the noradrenergic re-uptake inhibitor,desipramine, to this nucleus to locally accumulate the spontaneously released noradrenaline from the nerve terminals also induced Fos expression, mostly in the vasopressin cells.

The expression of AT1 receptor on hepatic stellate cells in rat fibrosis induced by CCl_4

Objectives To assess the effect of an ACE inhibitor and an Ang Ⅱ type 1 (AT1) receptor antagonist on preventing hepatic fibrosis induced by CCl4 in rats and to investigate whether there is the expression of AT1 receptors on hepatic stellate cells.Methods Studies were conducted in male Sprague-Dawley rats. Except for model group and control group, in three treated groups, either enalapril (5?mg/kg), or losartan (10?mg/kg), or enalapril+losartan were given to the fibrotic rats (daily gavage). Saline vehicle was given to the control group. After 6 weeks, liver fibrosis was assessed directly by hepatic morphometric analysis. The expression of AT1 receptors and α-smooth muscle actin (α-SMA) in liver tissue and isolated hepatic stellate cells (HSC) were detected by immunohistochemical techniques. Results Compared with the fibrosis in rats of the model group, rats treated with either enalapril or losartan, or a combination of two drugs, showed a limited expansion of the interstitium (P<0.05), but no significant difference was observed among the three treated groups (P>0.05). The expression of AT1 receptors was found in abundance in the fibrotic interstitium of the fibrotic rats, whereas in the normal control rats they were limited to the vascular wall. AT1 receptors were also expressed on activated HSC in culture plates. Conclusions Angiotensin-converting enzyme inhibitors and AT1 blockers might slow the progression of hepatic fibrosis. Activated HSCs expressed AT1 receptors. Activation of RAS might be related to hepatic fibrogenesis induced by CCl4.

Novel treatment options for portal hypertension

Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications,such as variceal bleeding,ascites or hepatic encephalopathy.As such,clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis.At present,non-selective bblockers,vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia.In contrast,safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue.In recent years,several preclinical and clinical trials have focused on this latter component and other therapeutic avenues.In this review,we highlight novel data in this context and address potentially interesting therapeutic options for the future.

Cell cycle regulator geminin is dispensable for the proliferation of vascular smooth muscle cells

The proliferation of vascular smooth muscle cells(VSMCs) plays a major role in the pathogenesis of many cardiovascular diseases.Geminin regulates DNA replication and cell cycle progression and plays a key role in the proliferation of cancer cells.We therefore hypothesized that geminin regulates the proliferation of VSMCs.The present study demonstrates that the level of geminin expression was low in quiescent VSMCs(approximately 90% and 10% of cells in the G1 and in S/G2/M phases of the cell cycle,respectively),increased as more cells entered in S/G2/M,and then decreased as cells exited S/G2/M.Further,angiotensin II and norepinephrine stimulated expression of geminin in VSMCs.However,the DNA content,nuclear morphology,percentage of cells at different stages of the cell cycle,and rate of proliferation of VSMCs from which geminin was either depleted or overexpressed were all similar.These findings indicate geminin functions differently in VSMCs than it does in cancer cell lines and that it may provide a target for treating cancers without affecting normal cells.