ENaC and its regulatory proteins as drug targets for blood pressure control

Hypertension is a serious medical problem affecting millions of people worldwide. A key protein regulating blood pressure is the Epithelial Na(+) Channel (ENaC). In accord, loss of function mutations in ENaC (PHA1) cause hypotension, whereas gain of function mutations (Liddle syndrome) result in hypertension. The region mutated in Liddle syndrome, called the PY motif (L/PPxY), serves as a binding site for the ubiquitin ligase Nedd4-2, a C2-WW-Hect E3 ubiquitin ligase. Nedd4-2 binds the ENaC-PY motif via it WW domains, ubiquitylates the channel and targets it for endocytosis, a process impaired in Liddle syndrome due to poor binding of the channel to Nedd4-2. This leads to accumulation of active channels at the cell surface and increased Na(+) (and fluid) absorption in the distal nephron, resulting in elevated blood volume and blood pressure. Compounds that destabilize cell surface ENaC, or enhance Nedd4-2 activity in the kidney, could potentially serve as drug targets for hypertension. In addition, recent discoveries of regulation of activation of ENaC by proteases such as furin, prostasin and elastase, which cleave the extracellular domain of this channel leading to it activation, as well as the identification of inhibitors that block the activity of these proteases, provide further avenues for drug targeting of ENaC and the control of blood pressure.     

脑梗死患者血压分期目标调控的研究

目的 探讨脑梗死患者血压分期目标调控的效果.方法 将400例脑梗死患者完全随机分为研究组和对照组,各200例.2组基本二级预防措施一致.研究组实施血压分期目标调控,对照组目标血压在140/85 mm Hg左右.随访至2010年12月,对2组患者的机能健康水平和终点事件分别进行评定.结果 至2010年12月,按牛津残障评分表进行机能健康水平分级,研究组0级96例(48.0％)、1级62例(31.0％)、2级18例(9.0％)、3级12例(6.0％)、4级4例(2.0％)、5级5例(2.5％)、6级3例(1.5％),再发梗死20例(10.0％);对照组0级44例(22.0％)、1级24例(12.0％)、2级26例(13.0％)、3级25例(12.5％)、4级22例(11.0％)、5级29例(14.5％)、6级30例(15.0％),再发梗死78例(39.0％).2组机能健康水平比较,研究组优于对照组,差异有统计学意义(P＜0.05).2组再发梗死情况比较,研究组少于对照组,差异亦有统计学意义(P＜0.05).结论 脑梗死患者血压的分期目标调控有效.     

Neurochemical control of cerebral blood circulation

A neurochemical approach to a study of the mechanisms by which cerebral circulation is controlled made it possible to discover the capability of GABA, GHBA, gamma-butyrolactone and pyrrolidone-2 to enhance cerebral circulation, to relax and enlarge an isolated flap of the cerebral arteries. GABA and specific GABA-receptors were found in the tissues of the walls of the cerebral arteries. Glutamate decarboxylase and GABA-transaminase were discovered in the cerebral vessels, with the endothelial and muscle layers of the arterial walls showing the highest GABA-transaminase activity. It is evident that as regards certain biochemical characteristics there is a definite similarity between GABA-ergic neurons and tissues of cerebral artery walls, which may ensure similar and undirectional neurochemical reactions in the brain and in the walls of its arteries. The latter circumstance is responsible for the mechanisms that control the functioning of the cerebral vessels.     

Ion channels and the control of blood pressure

Ion channels exist in all cells and are enormously varied in structure, function and regulation. Some progress has been made in understanding the role that ion channels play in the control of blood pressure, but the discipline is still in its infancy. Ion channels provide many different targets for intervention in disorders of blood pressure and exciting advances have been made in this field. It is possible that new drugs, as well as antisense nucleotide technology or gene therapy directed towards ion channels, may form a new class of treatments for high and low blood pressure in the future.     

Identification of the ligand binding sites and novel drug target molecules by photoaffinity labeling

Photoaffinity labeling is a useful and reliable method for 1) the identification of the ligand-target receptor and 2) the structural investigation of its binding site. Using photoaffinity labeling techniques, the binding sites of four typical calcium antagonists, 1,4-dihydropyridines, benzothiazepines, phenylalkylamines, and benzothiazines, were successfully identified within the primary structure of the skeletal muscle calcium channels. The results confirm pharmacological observations of the four antagonists, which had been proposed to interact allosterically with each other. Secondarily we demonstrated that human glutathione S-transferase class pi (GST pi) is specifically photolabeled by the antidiabetic agent sulfonylurea glibenclamide (GB) and it also inhibits the enzyme activities of glutathione conjugation by GB in a competitive manner for glutathione. These results indicate that GST pi is another target molecule of sulfonylurea since a subunit of ATP-sensitive potassium channels is well known to be a sulfonylurea receptor. This review focuses on photoaffinity labeling techniques as a useful tool for drug discovery and development.     

上海市某社区签约患者抗高血压药物应用及血压控制情况调查分析

目的:调查塘桥社区卫生服务中心高血压签约患者抗高血压药物应用情况,了解用药趋势、治疗费用和血压控制效果,为合理用药、签约医师诊疗工作效果评估、优化卫生资源分配提供参考.方法:收集2012-2015年高血压签约患者,均为每半年周期内有连续5个月以上有效血压测量者,其中2012、2013、2014和2015年入选患者分别为3663、4333、4079和2423例.分析患者的就诊情况、抗高血压用药情况和血压控制情况.结果:①签约患者应用抗高血压药的金额呈逐年上升趋势,从2012年的468.85万元上升至2015年的607.51万元,其中应用最多的是钙离子拮抗剂,连年稳居第一,血管紧张素II受体拮抗剂和 β 受体阻滞剂的用量亦逐年上升.②签约患者的血压有效控制达标率高于60.00％.结论:塘桥社区卫生服务中心签约患者的抗高血压药总体用药结构基本合理,抗高血压药治疗费用可控,血压控制有效.     

动态血压监测氨氯地平控制血压及其晨峰的疗效

目的：采用动态血压监测（ABPM）观察氨氯地平（络活喜）对1、2级原发性高血压患者服药后血压和血压晨峰（MBPS）程度的影响。方法：对入选的150例1、2级高血压患者口服氨氯地平,服用前及8周后应用ABPM评价血压和血压晨峰程度的变化。结果：150例高血压患者治疗8周后,无论收缩压还是舒张压与治疗前比较,均明显下降（P〈0.05）;MBPS（＋）的患者减少,MBPS（-）的患者增多,治疗前后频数比较,差异有显著统计学意义（P〈0.01）。结论：苯磺酸氨氯地平不仅能有效控制24h血压,而且还能降低血压晨峰程度。     

医院-社区综合管理模式对高血压患者服药依从性及血压控制效果的影响

目的通过建立医院．社区综合管理模式。提高患者在生活方式、血压监测、药物选择、服药依从性等方面的认知,并对其血压进行干预,提高血压控制效果及血压达标率,改善患者的生存质量;并将医院-社区双向管理模式向其他医院、社区推广。方法通过自行设计的血压监测的认知与依从性量表,首先了解东莞市石排镇1745名高血压患者的基本情况,随机抽取500名患者作为干预组,指导调整生活方式、血压监测、合理选药、加强服用药物的依从性;剩余高血压患者作为对照组,不做任何干预;定期每半月对两组血压情况、服药情况进行详细记录。随访1年,重新对血压进行评价,并对血压控制效果进行比较。结果经过医院-社区综合管理模式的干预,干预组患者在生活方式的调整、血压监测、药物选择、服药依从性等方面的认知明显提高,血压控制效果及血压达标率较前明显增高。结论通过医院-社区综合管理模式,能够提高患者在生活方式、血压监测、选择药物、服药依从性等方面的认知,明显提高患者血压控制效果及血压达标率,有效改善患者的生存质量;医院-社区综合管理模式在高血压病防治中值得向基层医院、社区推广应用。     

左旋四氢巴马汀的降压效应及对冠脉循环的影响

目的：研究左旋四氢巴马汀（１－ＴＨＰ）对自发性高血压大鼠（ＳＨＲ）及对麻醉犬冠脉循环的影响,以便为拓展１－ＴＨＰ的临床新用途提供实验依据。方法;ＳＨＲ清醒状态下测尾动脉血压,麻醉犬开胸分离冠状动脉左旋支,放置探头测量冠脉血流量,同步测量动脉血压和记录Ⅱ导程心电图,抽取股动脉血测定血氧。结果：１－ＴＨＰ能降低ＳＨＲ的血压,同样亦可降低麻醉的血压,且能引起犬冠脉血流量呈短暂增加,并可较持久降低冠脉阻力     

家庭自测血压对社区高血压患者血压控制和治疗依从性的影响

目的探讨家庭自测血压对社区高血压患者血压控制和治疗依从性的影响。方法选择2015年1月至2016年1月四川省广汉市10个社区卫生服务中心门诊的5 000例高血压患者作为研究对象,研究共分为3个阶段。第一阶段:患者进行高血压健康宣教以及药物干预,实施自我管理,患者在家自行检测血压并记录,定期至社区随诊,根据血压控制情况调整治疗方案;第二阶段:对于第一阶段血压控制未达标的患者实施专人跟踪管理,由社区安排专人定期对患者进行随访,主动保持联系并指导治疗;第三阶段:对于第二阶段血压控制仍未达标的患者,按随机数字表法分为观察组和对照组,对照组干预措施与第二阶段相同,观察组则采用家庭自测血压自动记录与分析系统对高血压患者进行管理,采用智诊通专业血压测量仪(欧姆龙HEM-7080-IC)在家测量血压。观察各阶段高血压患者血压控制达标情况,2组患者干预前后血压水平以及血压控制达标率,采用高血压治疗依从性量表对患者的治疗依从性情况进行评分。结果第一阶段血压控制达标率为53.65%,第二阶段血压控制达标率为45.41%,未达标的1 256例进入第三阶段。观察组收缩压、舒张压水平均明显低于对照组(P<0.05);观察组血压控制达标率为60.35%,显著高于对照组的35.67%(P<0.01);观察组遵医服药行为、不良服药行为、日常生活管理行为、研究嗜好管理行为及量表总分均明显高于对照组(P<0.05)。结论优化家庭自测血压能够有效提高社区高血压患者血压控制达标率,降低血压水平,提高患者治疗依从性,这对于促进家庭血压监测的健康发展,进一步提高高血压治疗率和控制率有重要意义     

Nitric oxide and sympathetic nerve activity in the control of blood pressure

1. Endothelial dysfunction marked by impairment in the release of nitric oxide (NO) is seen very early in the development of hypertension and is considered important in mediating the impaired vascular tone evident in essential hypertensive patients. 2. Recently, a hypothesis has emerged that NO acting as a neurotransmitter in the brain can modulate levels of sympathetic nerve activity and thereby blood pressure. The NO inhibition model of hypertension has been used to explore the possibility that a decrease in levels of NO can cause an increase in levels of sympathetic nerve activity that can mediate the hypertension. 3. In the present review, we examine the literature regarding the role of NO in setting the mean level of sympathetic nerve activity and blood pressure. Although the acute effects of NO inhibition are well understood, the chronic interaction between the sympathetic nervous system and NO has only been investigated using indirect measures of sympathetic nerve activity, such as ganglionic blockade. This has led to inconsistent results regarding the role of NO in modulating sympathetic nerve activity chronically. 4. Some of the conflicting results may be explained by differences in the 'background' levels of angiotensin (Ang) II. Evidence suggests that NO may interact with AngII and baroreceptor afferent inputs in the central nervous system to set the mean level of sympathetic nerve activity. 5. We suggest chronic NO inhibition can increase sympathetic nerve activity if baroreceptor input is intact and AngII levels are elevated. Although studies exploring the actions of NO or AngII in isolation are useful for gathering initial information, future studies should focus on their interactions and their role in setting the long-term levels of sympathetic activity and blood pressure.     

The importance of sustained blood pressure control

The case for antihypertensive drug regimens that produce consistent 24-h blood pressure control has largely been founded upon a series of epidemiological observations that were either cross-sectional or alternatively relatively small-scale follow-up studies. More recent data have unequivocally demonstrated, in a prospective study in hypertensive subjects with left ventricular hypertrophy, that the reduction in left ventricular mass index during the course of one year's antihypertensive treatment, was predicted much more closely by treatment-induced changes in ambulatory blood pressure than by changes in clinic blood pressure. This provides definitive and confirmatory data to support the aim of achieving blood pressure control, which is based upon a smooth and consistent antihypertensive effect over a full 24-h dosage interval. Regimens which provide such control may also offer the advantage of a sustained duration of effect beyond 24 h. This characteristic is attractive because even the most compliant patient may inadvertently miss at least one dose of medication each week. Evidence from a number of studies which have sought to mimic this pattern of suboptimal compliance by deliberately inserting a placebo phase into a steady-state treatment regimen, has clearly demonstrated the benefits of antihypertensive drugs with intrinsically long duration of action. Furthermore, there is evidence to suggest that following cessation of therapy there is a biphasic reversion of blood pressure towards baseline levels with a maintenance of a residual effect which is more pronounced with a long-acting agent when compared to a shorter-acting drug from the same therapeutic class. There is increasing evidence, albeit not derived from prospective outcome studies, that indicates that the benefits of antihypertensive therapy are likely to be maximized by treatment regimens which result in sustained blood pressure control.     

从药品的流通特性看药品中间流通环节改革

文中从药品的流通特性入手,探讨药品中间流通环节的地位和要求,提出药品中间流通环节改革的设想。药品中间流通环节应当向物流配送转向,还原药品中间流通环节的本来面目。为了实现这一转向,必须改革公立医院自行采购药品的模式,实行真正意义上的政府采购,即由政府部门按招标方式或其他方式向药品生产企业采购,由药品配送企业实施配送,原有药品批发企业向药品物流运营企业转变。     

血压昼夜节律变化与靶器官损害的关系

目的:探讨24h动态血压昼夜节律变化与原发性高血压患者靶器官损害的关系。方法:对140例原发性高血压患者进行24h动态血压监测,根据血压昼夜节律变化消失与否将其分为两组,对两组患者靶器官损害情况进行对比分析。结果:两组脑损害、左室肥厚、心血管事件和肾功能损害的发生率差异有统计学意义(P<0.05)。结论:24h动态血压昼夜节律变化对高血压患者靶器官损害的影响不同,昼夜血压曲线消失与靶器官损害显著相关。     

Hypothesis: the systemic circulation as a regulated free-market economy. A new approach for understanding the long-term control of blood pressure

1. The purpose of the present paper is to discuss the long-term regulation of arterial blood pressure. Current thinking on the topic favours the theory that tight regulation is achieved through the action of a central (or primary) controller, usually assumed to be in either the brain or kidneys. 2. Here, an alternative explanation is considered; namely, that the average long-term level of arterial pressure is an emergent property of a decentralized control system. The goal of the system is to deliver nutrient-rich blood to distinct vascular regions based on their energy demand. 3. Specifically, the circulation is conceptualized as a free-market economy where tissues 'compete' for a scarce resource (the energy contained in blood) supplied by the heart-lung unit; the 'price' of the resource (analogous to the reciprocal of arterial pressure) is determined primarily by the dynamic relationship between supply and demand, not by a central mechanism. 4. Based on this concept of the circulation as an energy market, economic analogies are used to suggest novel mechanisms by which the brain and kidney may affect the long-term control of blood pressure. 5. Market-based control, a process derived from quantitative theoretical analysis of the performance of economic markets, is proposed as a new, potentially useful strategy for mathematically modelling the behaviour of the circulation.     

Cadralazine and chlorthalidone as a second-step drug with atenolol in hypertensive patients: Differences in blood pressure control during exercise

Summary The long-term efficacy of a new vasodilator, cadralazine (ISF 2469), and chlorthalidone have been compared in 20 hypertensive patients not adequately controlled by atenolol. After 4 weeks of treatment with atenolol 100 mg once daily, patients whose diastolic blood pressure was >95 mmHg were randomly divided into two groups to receive in addition to atenolol, either cadralazine 15 mg once daily or chlorthalidone 25 mg once daily. Both treatments were administered for 6 months. At the end of treatment with atenolol and after 3 and 6 months of combination therapy, blood pressure and heart rate were measured at rest and during bicycle exercise 24 h after the last dose. Compared to atenolol alone, both cadralazine and chlorthalidone caused a significant and similar reduction in resting blood pressure. Both groups showed an increase in diastolic blood pressure during exercise while receiving atenolol alone. The addition of chlorthalidone did not modify the pressor response to exercise, whereas patients taking cadralazine had a decrease in exercise diastolic blood pressure, which was fully evident after 6 months of therapy. The reduction in exercise diastolic blood pressure induced by cadralazine was proportional to the increase in exercise heart rate, suggesting a fall in peripheral vascular resistance. Chlorthalidone caused a significant increase in serum glucose and uric acid and a decrease in K⁺, whereas no change was observed during cadralazine It is concluded that cadralazine given once a day with atenolol has the same efficacy in controlling blood pressure at rest as the combination of atenolol and chlorthalidone, and in addition it improves the pressor response to dynamic exercise and does not cause unwanted metabolic effects.