Role of vascular K(ATP) channels in blood pressure variability after sinoaortic denervation in rats

Aim:

To investigate the role of ATP-sensitive potassium (K_ATP) channels on blood pressure variability (BPV) in sinoaortic denervated (SAD) rats.

Methods:

SAD was performed on male Sprague-Dawley rats 4 weeks before the study. mRNA expression of Kir6.1, Kir6.2 and SUR2 in aorta and mesenteric artery was determined using real-time quantitative polymerase chain reaction, and confirmed at the protein level using Western blotting and laser confocal immunofluorescence assays. Concentration-response curves of isolated aortic and mesenteric arterial rings to adenosine and pinacidil were established. Effects of K_ATP channel openers and blocker on BPV were examined in conscious SAD rats.

Results:

Aortic SUR2 expression was significantly greater, while Kir6.1 was lower, in SAD rats than in sham-operated controls. In contrast, in the mesenteric artery both SUR2 and Kir6.1 expression were markedly lower in SAD rats than controls. For both arteries, Kir6.2 expression was indistinguishable between sham-operated and SAD rats. These findings were confirmed at the protein level. Responses of the aorta to both adenosine and pinacidil were enhanced after SAD, while the mesenteric response to adenosine was attenuated. Pinacidil, diazoxide, nicorandil, and glibenclamide significantly decreased BPV.

Conclusion:

These findings indicate that expression of vascular K_ATP channels is altered by chronic SAD. These alterations influence vascular reactivity, and may play a role in the increased BPV in chronic SAD rats.     

Functional roles of KATP channels in vascular smooth muscle

1. ATP-sensitive potassium channels (K(ATP)) are present in vascular smooth muscle cells and play important roles in the vascular responses to a variety of pharmacological and endogenous vasodilators. 2. The K(ATP) channels are composed of four inwardly rectifying K+ channel subunits and four regulatory sulphonylurea receptors. The K(ATP) channels are inhibited by intracellular ATP and by sulphonylurea agents. 3. Pharmacological vasodilators such as cromakalim, pinacidil and diazoxide directly activate K(ATP) channels. The associated membrane hyperpolarization closes voltage-dependent Ca2+ channels, which leads to a reduction in intracellular Ca2+ and vasodilation. 4. Endogenous vasodilators such as calcitonin gene-related peptide, vasoactive intestinal polypeptide, prostacylin and adenosine activate K(ATP) by stimulating the formation of cAMP and increasing the activity of protein kinase A. Part of the mechanism of contraction of endogenous vasoconstrictors is due to inhibition of K(ATP) channels. 5. The K(ATP) channels appear to be tonically active in some vascular beds and contribute to the physiological regulation of vascular tone and blood flow. These channels also are activated under pathophysiological conditions, such as hypoxia, ischaemia, acidosis and septic shock, and, in these disease states, may play an important role in the regulation of tissue perfusion.     

Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow

Members of the transient receptor potential (TRP) channel superfamily are present in vascular smooth muscle cells and play important roles in the regulation of vascular contractility. The TRPC3 and TRPC6 channels are activated by stimulation of several excitatory receptors in vascular smooth muscle cells. Activation of these channels leads to myocyte depolarization, which stimulates Ca2+ entry via voltage-dependent Ca2+ channels (VDCC), leading to vasoconstriction. The TRPV4 channels in arterial myocytes are activated by epoxyeicosatrienoic acids, and activation of the channels enhances Ca2+ spark and transient Ca2+-sensitive K+ channel activity, thereby hyperpolarizing and relaxing vascular smooth muscle cells. The TRPC6 and TRPM4 channels are activated by mechanical stimulation of cerebral artery myocytes. Subsequent depolarization and activation of VDCC Ca2+ entry is directly linked to the development of myogenic tone in vitro and to autoregulation of cerebral blood flow in vivo. These findings imply a fundamental importance of TRP channels in the regulation of vascular smooth muscle tone and suggest that TRP channels could be important targets for drug therapy under conditions in which vascular contractility is disturbed (e.g. hypertension, stroke, vasospasm).     

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。     

上肢有创血压与无创血压的差异分析

目的研究桡动脉有创动脉压与肱动脉无创动脉压之间的差异及其影响因素。方法对入住ICU的60例患者进行IABP与NBP的同步测量。结果收缩压均值,右侧IABP最高,左侧NBP最低。NBP与IABP收缩压测量值之间分组比较,PPI<0.45时NBP9.38%>IABP;0.45≤PPI≤0.55时NBP42.59%>IABP;PPI>0.55时NBP58.82%>IABP。结论在临床实践中,NBP与IABP的实际差异与理论相比有所不同。监测血压时应首选右臂,应用IABP时使用方波试验来判断IABP值的准确性;使用NBP时应对患者的血管硬化程度进行评估。     

Baroreflex control of sympathetic nerve activity and blood pressure variability

1. The simultaneous recording of blood pressure (BP) and renal sympathetic nerve activity (RSNA) in conscious sinoaortic baroreceptor denervated rats has revealed that the sympathetic component of the baroreceptor reflex both limits the amplitude of slow BP fluctuations and generates a faster BP oscillation (approximately 0.4 Hz in rats), the so-called Mayer wave. 2. Using BP and RSNA time series collected in conscious baroreceptor denervated rats and parameters of the transfer function relating RSNA to BP, it has been possible to predict BP and RSNA variabilities actually observed in baroreceptor-intact rats. The most accurate simulation was obtained when the baroreflex gain was set at 20-30% of a critical value leading to the production of self-sustained oscillations of BP and RSNA at Mayer wave's frequency. 3. Recent studies performed on conscious rats have indicated that the gain of the RSNA-BP baroreflex function curve is altered during sleep-wake cycle, grooming, exercise and exposure to environmental stress. These observations raise the possibility that the sympathetic baroreflex sensitivity might be continuously modulated as part of normal behavioural responses. 4. To examine this hypothesis, a method has been developed to obtain a continuous index of sympathetic baroreflex sensitivity. The method is based on the calculation of the gain of the transfer function relating RSNA oscillations to the BP pulse at heart rate frequency. This new spontaneous index correlates with the baroreflex gain measured by the vasoactive drug injection technique and is inversely related to overall indices of BP variability. In addition, it shows large, spontaneous variations over time.     

对106例高血压病人动态血压控制状况调查

目的:了解高血压病人24 h动态血压的控制状况.方法:以2010年1月-2011年3月在上海市嘉定区中医医院住院的、接受24 h动态血压监测的106例高血压病人为观察对象,分为糖尿病组(n=34)和非糖尿病组(n=72),对监测结果进行回顾性分析.结果:病人的24 h平均收缩压、日间平均收缩压、夜间平均收缩压,糖尿病组分别为(143±21.2)、(144±20.2)、(142±25.4) mmHg,非糖尿病组分别为(133±21.8)、(134±21.7)、(131±23.3) mmHg,糖尿病组显著高于非糖尿病组(P＜0.05).糖尿病组各项降压指标达标率均低于非糖尿病组;两组的收缩压和夜间血压下降比例达标率均低于本组的舒张压下降达标率.两组间抗高血压药物应用情况无显著性差异.结论:需加强对合并糖尿病高血压病人各时段收缩压和夜间血压的控制,重视动态血压监测对降压治疗的指导作用.     

正常高值血压者血管结构的变化

目的利用无创方法探讨正常高值血压者血管结构的改变。方法试验分正常高值组（90例）及正常对照组（60例）。观察入选者的踝-臂血压比值（ABI）、颈动脉内中膜厚度（IMT）,同时均测定体重指数、腰臀围比值、心脏LVEF、E/A、空腹血糖、血脂四项等临场指标。结果正常高值组的甘油三酯（TG）和低密度脂蛋白胆固醇（LDL-C）比正常对照组高（P〈0.05）,其高密度脂蛋白胆固醇（HDL-C）比正常组低（P〈0.05）;LVEF在两组之间无显著差异（P〉0.05）;正常高值组的ABI、颈动脉IMT高于正常对照组,但其E/A低于正常对照组（均为P〈0.05）。结论正常高值血压者不仅存在血脂代谢异常及心脏舒张功能的下降,同时也存在血管结构的变化。     

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.     

Clinical significance of home blood pressure measurements for the prevention and management of high blood pressure

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高血压患者血压水平和脉压与脑卒中的关系

目的:探讨原发性高血压病不同收缩压、舒张压、脉压水平与脑卒中发生率的关系。方法:收集原发性高血压患者186例,其中单纯并发脑卒中者84例。按收缩压、舒张压、脉压的水平不同分别分为四组,观察各组脑卒中的发病率。结果:随着收缩压、舒张压、脉压水平的增高,脑卒中的发病率增加,P<0.05,有统计学意义。结论:在我国脑卒中是人群主要的病残和死亡原因。积极有效地降低血压水平及脉压差,是防治脑卒中的重要环节。     

Physiological sleep-dependent changes in arterial blood pressure: central autonomic commands and baroreflex control

Sleep is a heterogeneous behaviour. As a first approximation, it is subdivided objectively into two states: non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). The mean value and variability of arterial blood pressure (ABP) decrease physiologically from wakefulness to NREMS. In REMS, there may be a further decrease or increase in mean ABP as well as phasic hypertensive events, which enhance the variability of ABP. The reduced mean ABP during NREMS results from a decrease in either heart rate or sympathetic vasoconstrictor tone. During REMS, sympathetic activity to the different cardiovascular effectors undergoes a substantial repatterning. Thus, the mean ABP in REMS reflects a balance between changes in cardiac output and constriction or dilatation of different vascular beds. In both sleep states, the phasic changes in ABP are driven by bursts of vasoconstriction, which may be accompanied by surges of heart rate. The available evidence supports the hypothesis that the sleep-dependent changes in ABP, either tonic or phasic, result from the integration between cardiovascular reflexes and central autonomic commands that are specific to each sleep state.     

The calcium-sensing receptor and calcimimetics in blood pressure modulation

Calcium is a crucial second messenger in the cardiovascular system. However, calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular concentration (Ca(2+)(o)), the calcium-sensing receptor (CaR). The most prominent physiological function of the CaR is to maintain the extracellular Ca(2+) level in a very tight range by regulating the circulating levels of parathyroid hormone (PTH). This control over PTH and Ca(2+) levels is partially lost in patients suffering from primary and secondary hyperparathyroidism. Allosteric modulators of the CaR (calcimimetics) are the first drugs in their class to become available for clinical use and have been shown to successfully treat certain forms of primary and secondary hyperparathyroidism. In addition, several studies suggest beneficial effects of calcimimetics on cardiovascular risk factors associated with hyperparathyroidism. Although a plethora of studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. However, several studies point toward a possibility that the CaR might be involved in the regulation of vascular tone. This review will summarize the current knowledge on the possible functions of the CaR and calcimimetics on blood pressure regulation.     

钙离子拮抗剂与血管紧张素受体拮抗剂对血压晨峰现象影响的临床对照研究

目的研究不同钙离子拮抗剂与ARBs对轻中度原发性高血压血压晨峰现象的影响。方法 160例轻中度原发性高血压患者随机分为4组:苯磺酸氨氯地平组、非洛地平缓释剂组、硝苯地平控释片组、缬沙坦组,每组40例。服药8周后,分别比较不同降压药物对血压晨峰的影响。结果治疗8周后,各组观察指标(24hS BP、24hD BP、清晨自测SBP、清晨自测DBP)较治疗前均明显降低(P<0.05)。与缬沙坦组比较,对血压晨峰的控制苯磺酸氨氯地平组优于缬沙坦组,差异有统计学意义(P<0.05);硝苯地平控释片组对血压晨峰的影响优于缬沙坦组,差异有统计学意义(P<0.05);苯磺酸氨氯地平组对晨峰现象的影响优于非洛地平缓释剂组和硝苯地平控释片组,差异有统计学意义(P<0.05)。结论钙离子拮抗剂及缬沙坦均能有效控制血压晨峰现象,其中以苯磺酸氨氯地平对清晨血压控制的有效率最为理想。     

睡眠期呼吸暂停综合征患者血压和血流动力学变化动态监测的意义

目的：探讨睡眠呼吸暂停综合征（sleep apnea syndrome,SAS）患者血压和血流动力学变化动态监测的意义。方法：选取40例SAS患者组成观察组和30例同期健康查体者作为对照组。监测两组血压和血流动力学指标,并分析其与睡眠监测指标的关系。结果：与对照组比较,观察组血压、血流动力学指标、非快动眼睡眠期和快动眼睡眠期患者收缩压（SP）、舒张压（DP）、全血高切黏度（WBHSV）、全血低切黏度（WBLSV）、血浆黏度（PV）以及呼吸紊乱指数（RDI）均升高,而血氧饱和度（SaO2）则降低,差异有统计学意义（P〈0.05）。Pearson相关性分析结果显示,SP、DP、WBHSV、WBLSV均与RDI和SaO2〈90%次数呈正相关,而与SaO2则呈负相关。结论：SAS患者存在血压、血流动力学指标和凝血功能异常,在治疗的同时应控制高血压和血流动力学指标并进行抗凝治疗。     

无创血压袖带缠绕方向和位置对血压测量的影响

目的探讨无创血压袖带缠绕方向和位置对血压测量的影响。方法将96例危重患者进行自身对照研究,将传感器置于肱动脉上和上臂外侧,每次间隔5分钟,进行正向和反向测量血压,记录测量数值。结果不同组间收缩压、舒张压和平均乐总体比较差异无统计学意义（P〉0．05）,进一步行各组间多重比较差异无统计学意义（P〉0．05）。结论心电监护仪无创血压测量时,袖带的缠绕方向和位置不影响血压值的准确性。     

Identification of blood pressure control mechanisms by power spectral analysis

1. Blood pressure and organ perfusion are controlled by a variety of cardiovascular control systems, such as the baroreceptor reflex and the renin-angiotensin system (RAS), and by local vascular mechanisms, such as shear stress-induced release of nitric oxide (NO) from the endothelium and the myogenic vascular response. Deviations in arterial blood pressure from its set point activate these mechanisms in an attempt to restore blood pressure and/or secure organ perfusion. However, the response times at which different cardiovascular mechanisms operate differ considerably (e.g. blood pressure control by the RAS is slower than blood pressure control via the baroreceptor reflex). 2. Owing to these different response times, some cardiovascular control systems affect blood pressure more rapidly and others more slowly. Thus, identifying the frequency components of blood pressure variability (BPV) by power spectral analysis can potentially provide important information on individual blood pressure control mechanisms. 3. Evidence is presented that the RAS, catecholamines, endothelial-derived NO and myogenic vascular function affect BPV at very low frequencies (0.02-0.2 Hz) and that low-frequency (LF) BPV (0.2-0.6 Hz) is affected by sympathetic modulation of vascular tone and endothelial-derived NO in rats. In humans, LF BPV (0.075-0.15 Hz) is affected by sympathetic modulation of vascular tone and myogenic vascular function. The impact of the RAS and endothelial-derived NO on BPV in humans requires further investigation. 4. In conclusion, power spectral analysis is a powerful diagnostic tool that allows identification of pathophysiological mechanisms contributing to cardiovascular diseases, such as hypertension, heart failure and stroke, because it can separate slow from fast cardiovascular control mechanisms. The limitation that some cardiovascular control mechanisms affect the same frequency components of BPV requires the combination of blood pressure spectral analysis with other techniques.     

nCPAP治疗对阻塞性睡眠呼吸暂停综合征患者动态血压的影响

目的:探讨经鼻持续气道正压通气(nCPAP)治疗,对阻塞性睡眠呼吸暂停综合征(OSAS)合并高血压患者动态血压的影响。方法:22例男性患者行多导睡眠图(PSG)监测及动态血压检查确诊为OSAS合并高血压的患者,观察nCPAP治疗前后患者动态血压、多导睡眠图等多项指标变化。结果:nCPAP治疗后患者PSG参数明显改善:睡眠时最低SaO_2从(71.0±12.3)％上升到(91.7±7.3)％(P<0.01);RDI显著降低;同时24小时血压明显下降,治疗前血压(16.5±1.6/11.6±2.3Kpa),治疗后血压(13.7±1.5/9.3±1.4Kpa)(P<0.01)。结论:经鼻持续气道正压通气治疗阻塞性睡眠呼吸暂停综合征,不但可以纠正患者的呼吸暂停,改善临床症状,而且可能降低患者的血压。     

老年与青年高血压病患者脉压和血压变异性比较

目的 比较老年和青年高血压病患者动态血压的差异,为老年高血压病患者的治疗提供依据.方法 我院高血压科就诊的83例2周内未服药的高血压病患者,60岁≤年龄＜80岁患者40例作为老年组,18岁≤年龄≤30岁患者43例作为青年组.2组患者均进行24 h动态血压监测,并比较结果.结果 老年高血压组的动态脉压、动态脉压指数和24h收缩压变异系数明显高于青年高血压组[(61±12) mm Hg(1 mm Hg=0.133 kPa)比(52 ±9)mm Hg,(0.44±0.07)比(0.37±0.06),(11±2)％比(8±2)％,均P＜0.01];24 h平均舒张压和24h平均心率明显低于青年高血压组[(79±10) mm Hg比(88±12)mm Hg,(69±8)次/mint比(74±9)次/min,均P＜0.01].结论 老年高血压病患者主要以动态脉压增大和24h收缩压变异性升高为特点;而青年患者以24h平均舒张压升高为主.因此,临床对老年高血压病患者进行降压治疗时,选择的药物不仅要有效降低平均收缩压水平,还要改善脉压和血压变异性.     

Ion channels in toxicology

Ion channels play essential roles in human physiology and toxicology. Cardiac contraction, neural transmission, temperature sensing, insulin release, regulation of apoptosis, cellular pH and oxidative stress, as well as detection of active compounds from chilli, are some of the processes in which ion channels have an important role. Regulation of ion channels by several chemicals including those found in air, water and soil represents an interesting potential link between environmental pollution and human diseases; for instance, de novo expression of ion channels in response to exposure to carcinogens is being considered as a potential tool for cancer diagnosis and therapy. Non‐specific binding of several drugs to ion channels is responsible for a huge number of undesirable side‐effects, and testing guidelines for several drugs now require ion channel screening for pharmaceutical safety. Animal toxins targeting human ion channels have serious effects on the population and have also provided a remarkable tool to study the molecular structure and function of ion channels. In this review, we will summarize the participation of ion channels in biological processes extensively used in toxicological studies, including cardiac function, apoptosis and cell proliferation. Major findings on the adverse effects of drugs on ion channels as well as the regulation of these proteins by different chemicals, including some pesticides, are also reviewed. Association of ion channels and toxicology in several biological processes strongly suggests these proteins to be excellent candidates to follow the toxic effects of xenobiotics, and as potential early indicators of life‐threatening situations including chronic degenerative diseases. Copyright © 2010 John Wiley & Sons, Ltd.