Rho激酶在高血压中的作用及其与容积调节性氯通道的关系

高血压血管平滑肌重构伴随Rho/Rho激酶通路的激活,抑制Rho激酶可逆转血管平滑肌增生以及血压升高。同时,在高血压中有容积调节性氯通道开放,这与Rho激酶通路激活有关。该文就高血压过程中Rho激酶与容积调节性氯通道的关系做一综述。     

美托洛尔治疗高血压心脏病心力衰竭的疗效观察

高血压是导致心力衰竭的常见病因之一，而高血压在向心力衰竭发展过程中左室重构是重要的环节。积极有效的血压达标治疗及逆转左室重构是减少和治疗高血压心脏病心力衰竭的关键。本文研究旨在长期追踪观察美托洛尔对高血压病性心力衰竭的远期预后。     

TMEM16A在脑血管重构中血管平滑肌细胞迁移的作用机制

目的探讨TMEM16A在脑血管重构中血管平滑肌细胞迁移的作用机制。方法采用Western印迹,质粒瞬时转染,流式细胞仪分析,荧光免疫染色等方法,在AngⅡ诱导高血压的血管平滑肌特异性过表达的小鼠及脑血管血管平滑肌细胞上研究。结果整体动物实验,在AngⅡ诱导高血压的血管平滑肌特异性过表达的小鼠(Tg)的脑血管重构过程TMEM16A能抑制脑基底动脉平滑肌细胞(BASMC)的迁移,细胞膜表面受体integrinβ3的表达,黏附斑的形成所需的FAK的磷酸化,MYPT1的磷酸化,细胞骨架收缩过程所需的MLC20的磷酸化,Rho A的活以及ROCK2的磷酸化。培养BASMCs上发现,Rho A/Rho kinse的信号通路介导TMEM16A对BASMCs迁移的调控:TMEM16A通过抑制Rho A的活性以及ROCK2和MYPT-1的磷酸化,进而抑制MLC20的磷酸化,从而抑制了BASMC的迁移;Ca~(2+)/camodulin的信号通路不参与TMEM16A对BASMCs迁移的调控:TMEM16A对MLCK的磷酸化无影响;integrinβ3/FAK的信号通路介导TMEM16A对BASMCs迁移的调控:TMEM16A通过抑制了integrinβ3的蛋白上调、FAK的磷酸化,进而抑制黏着斑的形成,同时抑制F-actin的表达以及伪足的形成,从而抑制了BASMCs的迁移。结论 TMEM16A通过抑制Rho A/Rho kinse和integrinβ3-FAK的信号通路从而抑制脑血管重构过程中BASMC的迁移。     

高血压致脑血管意外患者护理中家属需求分析

脑血管意外是高血压患者最为常见的并发症,其发病率在我国高血压死亡原因中居首位,年发病率高达217/10万,存活者的致残率超过80%.因此,对本病防治的意义重大.此外,对罹患本病的家属在治疗过程中所起的作用亦不可忽视.本文对高血压致脑血管意外患者护理中家属的需求进行调查分析,为临床护理提供参考.     

芪红口服液治疗瘀证型高血压病的临床研究

高血压病不仅是一种疾病,而且是多种心、脑血管疾病的重要病因和危险因素,导致心、脑、肾的结构破坏和功能衰竭,迄今仍是心、脑血管疾病死亡的主要原因之一.研究发现芪红口服液能抑制心肌细胞肥大和增生,逆转高血压心肌、间质及血管重构.     

医生应提醒患者合理摄入鸡蛋

在笔者临床实践过程中，常常听到医务人员在对患有高血压、脑血管疾病、糖尿病、冠心病、     

螺内酯对舒张功能不全老年女性高血压患者左心室重构及脑钠肽的影响

流行病学研究发现,人群中40%~50%心力衰竭的发生归因于高血压[1].目前普遍认为,心力衰竭首先经历舒张功能受损,之后发展成为舒张性心力衰竭,或合并有收缩性心力衰竭的混合性心力衰竭.高血压所致心脏、血管重构在此过程中起到重要作用.有研究发现脑钠肽(BNP)水平与左心室舒张功能的关系密切,可早期预测左心室舒张功能异常[1].女性绝经后高血压发生率明显增加,左心室舒张功能减退的发病率同样迅速增长[2,3],因此,逆转左心室重构、改善左心室舒张功能成为高血压治疗的重要目标.笔者对老年女性高血压患者加用螺内酯治疗,观察其对左心室重构及BNP的影响.     

老年高血压患者血压晨峰与心室重构的临床研究

目的研究老年高血压患者血压晨峰及心室重构特点,指导临床治疗工作。方法供收录了2010年10月至2011年10月,在我院接受治疗的60例老年高血压疾病患者,对其临床血压晨峰与心室重构情况进行分析,掌握临床疾病症状后制定医疗方案。结果老年高血压患者在血压晨峰过程中以出现心室重构现象,需及时采取有效的措施进行治疗,以免引发严重性疾病而导致死亡。结论掌握老年高血压患者血压晨峰特点,可指导临床治疗工作的开展。     

高血压合并脑血管意外的护理

脑血管意外是高血压患者最为常见的并发症,其发病率在我国高血压死亡原因中居首位.临床上在早诊断、早治疗的基础上,若能采取有效的护理措施将对高血压脑血管意外病人预后有积极的影响.     

试论心室重构及其药物逆转

重构（remodeling）由Baumbach等在1989年首次提出。高血压左室重构是心脏事件的重要独立危险因素,与心率失常,猝死,心力衰竭等密切相关。现已证明,在高血压情况下,心血管系统会发生相应的结构和功能的变化,这与高血压的预后密切相关。高血压时心脏的前后负荷增加,血流动力学改变伴随神经—内分泌异常,左心室肥厚以及心腔扩大,此过程即为左心室重构。本文就心室重构的机制及其药物逆转做一综述。     

Volume‐regulated chloride channels and cerebral vascular remodelling

• 1 Transmembrane Cl^? transport through volume‐regulated Cl^? channels (VRCC) is implicated in cell cycle control and the proliferation of vascular smooth muscle cells (VSMC). In cerebrovascular VSMC, volume‐regulated Cl^? movement is enhanced with the severity of cerebrovascular remodelling induced by hypertension.
• 2 Expression of the ClC‐3 chloride channel, a potential molecular candidate for the VRCC, is significantly increased with the progression of VSMC proliferation, but is decreased in apoptosis.
• 3 In the present review, we summarize recent findings regarding the functional role of volume‐regulated ClC‐3 chloride channels in VSMC proliferation, apoptosis and cerebrovascular remodelling during the development of hypertension. In addition, we discuss the relationship between the channel and intracellular signalling pathways, including the production of reactive oxygen species and the phosphorylation of Akt.
• 4 Recent studies strongly suggest that VRCC/ClC‐3 is involved in the regulation of both cell proliferation and apoptosis. These findings suggest that ClC‐3 chloride channels may be potential new targets for the prevention of the cerebrovascular remodelling that occurs during the development of hypertension.

     

心房颤动离子通道重塑机制

心房颤动(atrial fibrillation,AF)是临床上常见的持续性快速心律失常.心房电重塑的主要机制是离子通道的重塑.其中,在影响心房电重望的过程中,不同的钠离子通道、钾离子通道和钙离子通道均具有重要作用.离子通道的变化既是AF的结果,又是维持AF的电生理基础.     

Cardiomyocyte Ca<Superscript>2+</Superscript> overload in atrial tachycardia: is blockade of L-type Ca<Superscript>2+</Superscript> channels a promising approach to prevent electrical remodeling and arrhythmogenesis?

Electrical remodeling paradigm has important implications for the understanding of atrial fibrillation (AF) and improvement of current treatment. Cardiomyocyte Ca²⁺ overload is generally accepted as the initiating signal for the tachycardia-induced changes in atrial electrical properties (electrical remodeling). The precise role of cardiomyocyte Ca²⁺ overload in AF-related ion channel alterations that contribute to AF maintenance is not fully understood. Clinically, patients with AF are often treated with Ca²⁺ channel blockers such as verapamil to control their ventricular rate and to improve the success rate of cardioversion procedures. However, verapamil may produce an increased L-type Ca²⁺ channel current (I_Ca,L) that may reinforce Ca²⁺ overload thereby promoting AF in the atrium. Ca²⁺ channel blockers which target T-type Ca²⁺ channels in addition to I_Ca,L (for instance, efonidipine) may be more efficient at preventing Ca²⁺ overload and arrhythmogenic electrical remodeling, but the potential benefits of these drugs have usually been tested in experimental models where drug administration preceded the initiation of electrical remodeling. Studies in animal models with established atrial tachycardia remodeling and in patients with AF are clearly warranted to prove the efficacy of Ca²⁺ channel blockers that additionally target T-type Ca²⁺ channels.     

Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction

Loss of energy supply to neurons during stroke induces a rapid loss of membrane potential that is called the anoxic depolarization. Anoxic depolarizations result in tremendous physiological stress on the neurons because of the dysregulation of ionic fluxes and the loss of ATP to drive ion pumps that maintain electrochemical gradients. In this review, we present an overview of some of the ionotropic receptors and ion channels that are thought to contribute to the anoxic depolarization of neurons and subsequently, to cell death. The ionotropic receptors for glutamate and ATP that function as ligand-gated cation channels are critical in the death and dysfunction of neurons. Interestingly, two of these receptors (P2X7 and NMDAR) have been shown to couple to the pannexin-1 (Panx1) ion channel. We also discuss the important roles of transient receptor potential (TRP) channels and acid-sensing ion channels (ASICs) in responses to ischemia. The central challenge that emerges from our current understanding of the anoxic depolarization is the need to elucidate the mechanistic and temporal interrelations of these ion channels to fully appreciate their impact on neurons during stroke.     

多机制多通路参与哮喘新说

目的哮喘发病机制十分复杂,涉及许多方面,对哮喘发病机制的最新研究成果进行综述。方法参阅国外公开发表的相关文献26篇,从炎症及神经体液机制、气道高反应性及气道重塑机制、主要的离子通道等方面阐述了哮喘的发病机制。结果哮喘的发生发展涉及支气管炎症、机体的免疫反应、神经体液信号分子、平滑肌细胞膜及浆膜钙离子通道和钾离子通道等。结论对哮喘发病机制的阐明将为其治疗提供新的思路,同时也为抗哮喘药物的研发奠定基础。     

An assessment of the present and future roles of non-ligand gated ion channel modulators as CNS therapeutics

Few approved drugs have, as their primary known mechanism of action, modulation of non-ligand gated ion channels. However, these proteins are important regulators of neuronal function through their control of sodium, potassium, calcium and chloride flux, and are ideal candidates as drug discovery targets. Recent progress in the molecular biology and pharmacology of ion channels suggests that many will be associated with specific pharmacological profiles that will include both activators and inhibitors. Ion channels, through their regulation by G-proteins, are a major component of the final common pathway of many drugs acting at classical neuronal receptors. Thus, targeting of the ion channels themselves may confer different profiles of efficacy and specificity to drug action in the brain and spinal cord. Three areas for drug discovery are profiled that the authors consider prime targets for ion channel based therapies, anticonvulsant drugs, cognition enhancing drugs and drugs for improving neurone survival following ischaemia.     

The ClC-3 chloride channels in cardiovascular disease

ClC-3 is a member of the ClC voltage-gated chloride (Cl(-)) channel superfamily. Recent studies have demonstrated the abundant expression and pleiotropy of ClC-3 in cardiac atrial and ventricular myocytes, vascular smooth muscle cells, and endothelial cells. ClC-3 Cl(-) channels can be activated by increase in cell volume, direct stretch of β1-integrin through focal adhesion kinase and many active molecules or growth factors including angiotensin II and endothelin-1-mediated signaling pathways, Ca(2+)/calmodulin-dependent protein kinase II and reactive oxygen species. ClC-3 may function as a key component of the volume-regulated Cl(-) channels, a superoxide anion transport and/or NADPH oxidase interaction partner, and a regulator of many other transporters. ClC-3 has been implicated in the regulation of electrical activity, cell volume, proliferation, differentiation, migration, apoptosis and intracellular pH. This review will highlight the major findings and recent advances in the study of ClC-3 Cl(-) channels in the cardiovascular system and discuss their important roles in cardiac and vascular remodeling during hypertension, myocardial hypertrophy, ischemia/reperfusion, and heart failure.     

Simvastatin attenuated cerebrovascular cell proliferation in the development of hypertension through Rho/Rho-kinase pathway

The cerebrovascular remodeling is a prominent feature of hypertension and considered as a major risk of stroke. Statins may suppress the activation of the Rho/Rho-kinase pathway and have pleiotropic actions against the development of vascular remodeling. We hypothesized that the inhibition of the Rho/Rho-kinase pathway by simvastatin during hypertension could recuperate the pathological changes of basilar artery through the downregulation of cell proliferation. To resolve the problem, we used 2-kid, 2-clip rat as a hypertension model and evaluated the effect of simvastatin on the Rho/Rho-kinase pathway. In addition, we assessed the changes of the proliferation rate by CCK-8 assay in basilar artery smooth muscle cells. Our results from this study showed that a continuous increase in the plasma endothelin-1 (ET-1) concentration and the Rho/Rho-kinase activity was positively correlated with changes in blood pressure in the hypertensive rat. Simvastatin ameliorated the upregulated Rho/Rho-kinase activity and cell proliferation during hypertension. Moreover, simvastatin, the RhoA inhibitor C3, and the RhoA-kinase inhibitor Y27632 all attenuated the proliferation rate induced by ET-1 in basilar artery smooth muscle cells via the Rho/Rho-kinase signaling pathway. In conclusion, simvastatin attenuated ET-1-induced proliferation through the Rho/Rho-kinase signaling pathway in hypertensive rat basilar artery, and it may be an excellent reagent to protect vascular remodeling and stroke.     

Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of voltage-gated potassium channels

In this study, we pharmacologically characterized gambierol, a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Besides several other polycyclic ether toxins like ciguatoxins, this scarcely studied toxin is one of the compounds that may be responsible for ciguatera fish poisoning (CFP). Unfortunately, the biological target(s) that underlies CFP is still partly unknown. Today, ciguatoxins are described to specifically activate voltage-gated sodium channels by interacting with their receptor site 5. But some dispute about the role of gambierol in the CFP story shows up: some describe voltage-gated sodium channels as the target, while others pinpoint voltage-gated potassium channels as targets. Since gambierol was never tested on isolated ion channels before, it was subjected in this work to extensive screening on a panel of 17 ion channels: nine cloned voltage-gated ion channels (mammalian Na_v1.1–Na_v1.8 and insect Para) and eight cloned voltage-gated potassium channels (mammalian K_v1.1–K_v1.6, hERG and insect ShakerIR) expressed in Xenopus laevis oocytes using two-electrode voltage-clamp technique. All tested sodium channel subtypes are insensitive to gambierol concentrations up to 10 μM. In contrast, K_v1.2 is the most sensitive voltage-gated potassium channel subtype with almost full block (>97%) and an half maximal inhibitory concentration (IC₅₀) of 34.5 nM. To the best of our knowledge, this is the first study where the selectivity of gambierol is tested on isolated voltage-gated ion channels. Therefore, these results lead to a better understanding of gambierol and its possible role in CFP and they may also be useful in the development of more effective treatments.     

KATP通道开放剂吡那地尔对兔肺动脉平滑肌细胞增殖的影响

目的 :研究吡那地尔 (pinacidil,Pin)对内皮素 1(ET 1)诱导培养的兔肺动脉平滑肌细胞 (PASMC)增殖的影响。方法 :内皮素 1刺激培养兔PASMC增殖模型 ;以氚 胸腺嘧啶核苷 ([3 H] TdR)掺入法观察细胞增殖及脱氧核糖核苷酸 (DNA)合成 ;流式细胞仪技术检测兔PASMC细胞周期。结果 :吡那地尔可剂量依赖性的抑制内皮素 1所致的 [3 H] TdR掺入量增多 ,阻止兔PASMC由静止期 (G0 G1期 )进入DNA合成期 (S期 )和有丝分裂期 (G2 M期 )。ATP敏感性钾通道 (KATP)阻断剂格列本脲可拮抗吡那地尔对 [3 H] TdR掺入的抑制作用。结论 :吡那地尔可能通过激活KATP通道抑制内皮素 1诱导兔肺动脉平滑肌细胞的增殖 ,可望用于治疗肺动脉高压时所致的肺动脉重构。