清醒大鼠动脉压力感受性反射的功能研究

本文综述本室近10年来对清醒自由活动大鼠动脉压力感受性反射(ABR)的功能性研究.首先,建立了ABR对血压的控制(ABR-BP)的测量方法.ABR-BP是与用经典方法测量的ABR功能(ABR-HP)不同的成份.其次,我们的研究表明ABR功能与高血压的器官损伤有关.损毁ABR功能可导致严重的器官损伤.该损伤的机制与血压波动性增高、肾素血管紧张素系统激活有关.酮色林能改善ABR功能.基于对酮色林研究的结果,我们提出改善ABR功能可作为改善某些心血管疾病预后的新策略.最后,提到了我们正在进行中的自发性ABR功能缺陷大鼠的培育.     

抗高血压新药依普沙坦

药效学　药效学体外研究表明,依普沙坦(eprosartan)以高亲和力与血管紧张素受体结合,此结合可被血管紧张素AT1选择性受体拮抗剂氯沙坦(losartan)钾盐置换,而与AT2选择性受体拮抗剂PD121981无关。动物体内研究表明,血压正常的清醒大鼠静注依普沙坦(0.01～0.3mg.kg-1),能剂量依赖性地使血管紧张素的量-效曲线平行右移;静注0.3mg.kg-1对交感神经激活所引起的压力反应具有抑制作用。依普沙坦经十二指肠给药(1.0～10mg.kg-1)能剂量依赖性地降低肾素依赖性高血压大鼠的平均动脉压长达90min。肾动脉狭窄的狗在30min内静脉推注依普沙坦(0.3～30mg…     

坎地沙坦对原发性高血压患者血压变异性及左室肥厚影响的研究

目的观察坎地沙坦对原发性高血压患者血压变异性及左室肥厚的影响以明确其心血管保护作用。方法选取该院2011年6月至2012年5月就诊的原发性高血压患者72例,给予坎地沙坦口服12周,比较治疗前后血压变异性及左心室质量指数的变化。结果治疗12周后,原发性高血压患者血压变异性明显减少(P0.05),同时左心室重量指数明显下降(P0.05)。结论坎地沙坦可减少原发性高血压患者血压变异性,并能逆转左室肥厚,从而具有改善左室功能和患者预后的作用。     

两种不同结构类型的钾通道开放剂埃他卡林和吡那地尔联合用药降压作用的特征

目的 :观察两种不同种类的钾通道开放剂(potassiumchannelopeners ,KCOs)埃他卡林 (iptakal im ,Ipt)和吡那地尔 (pinacidil ,Pin)联用降压作用的特征。方法 :用无创性套尾法观察药物对清醒大鼠血压和心率的影响。结果 :Pin在 2 .0和 4 .0mg·kg-1剂量下 ,可剂量依赖性降低清醒大鼠的血压 ,加快其心率。Ipt在 2 .0 ,4 .0和 8.0mg·kg-1剂量下 ,可剂量依赖性降低血压 ,但不影响心率。Ipt(2 .0～8.0mg·kg-1)与Pin(4 .0mg·kg-1)合用时 ,其降压作用产生协同效应 ,但加快心率的作用与Pin相同。结论 :Ipt和Pin降压特点不同 ,二者联用的降压作用增强。     

比较苯那普利和坎地沙坦单用或联用对自发性高血压大鼠心肌胶原纤维的影响

目的 比较研究苯那普利和坎地沙坦(均抗高血压药)单用或联用对自发性高血压大鼠(SHR)心肌胶原纤维的影响.方法 12周龄SHR给予苯那普利10 mg·kg-1·d-1或坎地沙坦4 mg·kg-1·d-1及半剂量联合治疗,12周后测定血清Ⅰ型前胶原羧基端肽(PICP)、Ⅲ型前胶原氨基端肽水平(PⅢNP)和心肌胶原浓度;用饱和苦味酸-天狼猩红染色,观察心肌纤维化程度;用透射电镜观察心肌胶原超微结构;提取Ⅰ型胶原并进行SDS-聚丙烯酰胺凝胶电泳.结果 苯那普利和坎地沙坦治疗后,血清PICP、PIIINP和心肌组织胶原浓度均明显降低,心肌间质及血管周围胶原均明显减少,SDS-PAGE显示Ⅰ型胶原水平均下调;两药联合应用具有协同作用.结论 苯那普利和坎地沙坦联用对改善高血压心肌胶原纤维总量与性质具有协同作用.     

坎地沙坦联合氢氯噻嗪治疗老年高血压中血压变异性指标观察简

目的观察坎地沙坦联合氢氯噻嗪在老年高血压治疗中血压变异性的影响。方法将老年高血压患者60例随机分为3组,所有病例先停服原来的降压药2周。A组用坎地沙坦酯片8mg,每日1次;氢氯噻嗪片12．5mg,每日1次。B组用坎地沙坦酯片8mg,每日1次。C组用氢氯噻嗪片12．5mg,每日1次;尼群地平片10mg,每日2次。均口服给药,共进行8周治疗。进行治疗后的2～4周进行药物调整,若坐位舒张压不低于90mmHg,则进行剂量调整。坎地沙坦酯片和尼群地平片均将剂量翻倍,氢氯噻嗪剂量不变。所有病例在开始治疗的前1天和治疗的最后1天进行24h动态血压监测。结果3组给药方式的血压变异性（BPV）用药前后均有降低（P〈0．05）。从用药后的BPV情况分析,A组低于B组和C组（P〈0．05）;B组和c组相比,除了在24h收缩压变异（SBPV）、日间收缩压变异性（dSBPV）无统计学意义外,其他均低于C组,且有统计学意义（P〈0．05）。结论坎地沙坦联合氢氯噻嗪治疗老年高血压,血压变异性小。     

坎地沙坦和苯那普利治疗高血压病疗效的对比研究

目的评价坎地沙坦同苯那普利治疗高血压病的疗效及其对血脂、肾功能的影响。方法原发性高血压患者59例为治疗组给予坎地沙坦剂量8-16mg/d,对照组56例服用苯那普利,剂量10-20mg/d,均治疗6周。治疗前后所有参与者测血压和胆固醇、三酰甘油、肾功能。结果监测血压显示坎地沙坦组降压与苯那普利对照组无差异,对胆固醇、三酰甘油没有影响,有降低尿酸的作用,与对照组相比,咳嗽发生率低,并能改善肾功能及保护内皮细胞功能。结论坎地沙坦同苯那普利治疗轻、中度高血压病安全、有效,对血脂、肾功能无影响。坎地沙坦有降低尿酸的作用,咳嗽发生率低。     

坎地沙坦对动脉粥样硬化大鼠血脂和血管MMP-2、VEGF表达的影响

目的 探讨坎地沙坦对动脉粥样硬化(AS)大鼠血脂以及血管基质金属蛋白酶2(MMP-2)、血管内皮生长因子(VEGF)表达的影响.方法 饲喂高脂饲料建立AS大鼠模型.随机分为正常组(A组)、模型组(B组)、坎地沙坦低(1 mg·kg-1·d-1,C组)、中(5 mg·kg-1·d-1,D组)、高(10 mg·kg-1·d-1,E组)剂量组.12周后腹主静脉取血检测各组血脂;取腹主动脉标本采用免疫组化方法测定大鼠血管MMP-2和VEGF的表达.结果 与B组相比,C、D、E组血脂(胆固醇、甘油三酯、低密度脂蛋白)均降低(P<0.05,P<0.01),但无剂量依赖性;D、E组血管MMP-2、VEGF的表达减少(P<0.05).结论 坎地沙坦可降低AS大鼠的血脂和血管MMP-2、VEGF的表达.     

与氯少坦对照评价坎地沙坦西酯治疗轻 中度高血压的疗效和安全性

目的评价坎地沙坦西酯对轻、中度原发性高血压的降压疗效及安全性。方法采用随机双盲研究方法,坎地沙坦西酯和氯沙坦随机、双盲治疗轻、中度原发性高血压患者40例,男性30例,女性10例,年龄(46±6)岁,各组20例,给予双盲药坎地沙坦西酯8mg口服,每日1次,或氯沙坦50mg口服,每日1次;4周后根据血压情况决定维持原剂量或分别增加到12mg口服,每日1次,或100mg口服,每日1次;总疗程8周。结果坎地沙坦西酯治疗原发性轻、中度高血压8周末的显效率55%,总有效率75%,收缩压下降(20.0±12.5)mmHg,下降幅度为15.2%;舒张压下降(10.0±2.4)mmHg,下降幅度为10.8%,出现不良反应的发生率为5%。结论坎地沙坦西酯治疗轻、中度原发性高血压的短期疗效明显,每日1次,疗效持久稳定,不良反应少。     

坎地沙坦对自发性高血压大鼠胰岛素抵抗及血清脂联素的影响

目的：探讨血管紧张素Ⅱ受体拮抗剂坎地沙坦对自发性高血压大鼠（SHR）糖代谢及血清脂联素的影响。方法：SHR大鼠分为两组：高血压组（SHR,n=30）;坎地沙坦组（坎地沙坦,1mg·kg-1.d-1,n=30,灌胃法给药）,另设同种系WKY大鼠为对照组,给予同等量安慰剂,12周后分别用生化方法和放射免疫方法测定空腹血糖（FBG）和胰岛素水平（FINS）,计算IR指数（HOMA—IR）,用生化方法进行口服葡萄糖耐量试验（OGTT）,ELlSA分析法测定血清脂联素水平。结果：空腹血糖高血压组和对照组大鼠差异无统计学意义（P〉0．05）;空腹胰岛素水平和HOMA—IR与高血压组大鼠相比,对照组和坎地沙坦组要明显降低（P〈0．05）;OGTT结果显示,30min和120min血糖水平与高血压组相比,对照组和坎地沙坦给药组明显降低（P〈0．05）。血清脂联素的水平与高血压组相比,对照组和坎地沙坦大鼠明显较高（P〈0．05）。结论：血管紧张素Ⅱ受体拮抗剂坎地沙坦可以升高高血压血清脂联素水平,改善IR,降低30、120min餐后血糖水平。     

Ketanserin stabilizes blood pressure in conscious spontaneously hypertensive rats

1. It has been demonstrated that blood pressure variability (BPV) is increased in hypertension and related to organ damage. It will be important to lower BPV in the treatment of hypertension. The present study was designed to investigate the effect of ketanserin, a 5-HT2A receptor antagonist with a weak alpha1-adrenoceptor blocking effect, on BPV in conscious spontaneously hypertensive rats (SHR). 2. It was found that ketanserin decreased blood pressure (BP) and BPV in SHR when administered intravenously (3 mg/kg, i.v.). Ketanserin decreased BPV, but not the BP level, when administered intracerebroventricularly (50 microg/rat, i.c.v.). 3. Prazosin, an alpha1-adrenoceptor antagonist, lowered BP but did not affect BPV when given either i.v. (0.5 mg/kg) or i.c.v. (30 microg/rat). Ritanserin (0.625 mg/kg, i.v.; 40 microg/rat, i.c.v.), a 5-HT2A receptor antagonist, decreased BPV only when administered i.c.v. and did not modify the BP level. 4. Ketanserin enhanced arterial baroreflex function in SHR when given either i.v. or i.c.v. 5. The stabilizing effect of ketanserin on BP was persistent when administered intragastrically. This administration route is similar to oral administration clinically. 6. It is concluded that ketanserin is an antihypertensive agent with an effect of reducing BPV. This effect is mainly mediated by central 5-HT2A receptors and is probably attributable to the restoration of arterial baroreflex function.     

Restoration of arterial baroreflex function contributes to organ protection in spontaneously hypertensive rats treated with long-term hydrochlorothiazide mixture

1. Hydrochlorothiazide mixture (HCTM) is widely used in China for the treatment of hypertension. This mixture consists of hydrochlorothiazide, triamterene, reserpine, hydralazine and chlordiazpoxide, with small (one-third to one-fifth of normal) doses of each drug. The present study was designed to investigate the effects of this mixture on blood pressure, blood pressure variability (BPV), baroreflex sensitivity (BRS) and end-organ damage in spontaneously hypertensive rats (SHR). 2. The HCTM was mixed in the rat chow and rats were treated for 4 months. After treatment, rats were catheterized and their blood pressure, BPV and BRS were measured in the conscious state. Organ damage was examined after these measurements had been completed. 3. It was found that HCTM not only decreased blood pressure and BPV, but also ameliorated impaired BRS in SHR. The HCTM had an obvious effect on organ protection in SHR. 4. The HCTM prevented left ventricular hypertrophy and this effect was mainly related to a decrease in systolic blood pressure. The effects of HCTM on preventing renal atrophy were mainly determined by BRS. Baroreflex sensitivity was the most important determinant for predicting organ damage in HCTM-treated SHR. 5. In conclusion, long-term treatment of rats with HCTM prevented hypertensive organ damage. Restoration of arterial baroreflex function contributes to organ protection in SHR treated in the long term with HCTM.     

ketanserin对慢性心肌梗死大鼠血流动力学的影响

目的　研究ketanserin对慢性心肌梗死大鼠血流动力学的影响。方法　设假手术组、心肌梗死组和心肌梗死治疗组。治疗组在冠脉结扎后饮水中给予ketanserin 10mg·kg-1·d-1,持续 4～ 5wk。在清醒自由活动条件下连续监测血压 ,并采用改良Symth法测定动脉压力感受性反射敏感性(BRS)。结果　与假手术组比较 ,心肌梗死大鼠血压下降、心动间期波动性 (HPV )升高、BRS降低 ,而血压波动性(BPV)和心动间期无明显改变。ketanserin长期治疗可降低心肌梗死大鼠的血压、BPV和改善BRS。心肌梗死组室性心律失常发生率为 60 % (12 / 2 0 ) ,经ketanserin治疗后降至2 8 6% (6/ 2 1)。治疗或未治疗心肌梗死大鼠如果存在心律失常 ,则HPV升高 ,否则正常。结论　ketanserin可能作为改善心肌梗死预后的治疗药物。心肌梗死大鼠HPV增加与心律失常有关     

Effects of ketanserin on hemodynamics and baroreflex effects in conscious spontaneously hypertensive rats

Ketanserin is an antihypertensive compound that binds to 5-HT2 receptors as well as to alpha 1-adrenoceptors. The relative importance of the two pharmacological interactions is still unclear. In the present study we compared the central hemodynamic effects of ketanserin with those of the alpha 1-adrenoceptor antagonist prazosin in conscious, unrestrained spontaneously hypertensive rats (SHR). Both drugs rapidly reduced mean arterial pressure (0.1 mg/kg prazosin, -22 +/- 3%; 3 mg/kg ketanserin, -27 +/- 4%) and total peripheral resistance (30 +/- 4 and 26 +/- 4%, respectively). The compounds differed with respect to their effects on heart rate and cardiac output, which increased following prazosin treatment and did not change following ketanserin administration. To investigate involvement of the baroreflex in the latter phenomenon, SHR were challenged with angiotensin II and sodium nitroprusside to increase and decrease blood pressure. Ketanserin did not influence bradycardia following elevation of blood pressure. However, reduction of blood pressure with nitroprusside following ketanserin treatment resulted in extreme vagal bradycardia. This phenomenon was not observed following administration of other antihypertensive agents or serotonin antagonists in SHR. We conclude that this latter interaction with the baroreflex is specific for ketanserin and that it may substantially contribute to its antihypertensive effect. The exact pharmacological mechanism underlying this effect is still under investigation.     

Effects of long-term treatment with ketanserin on blood pressure variability and end-organ damage in spontaneously hypertensive rats

It has been proposed that instability of blood pressure may produce organ damage. Ketanserin is an anti-hypertensive drug with an ability to reduce blood pressure variability (BPV) in acute experiments in spontaneously hypertensive rats (SHRs). The present work was designed to observe the effects of long-term treatment with ketanserin on BPV and end-organ damage in SHRs. Ketanserin was mixed in rat chow at an estimated dose of 10 mg/kg/d. After 5 months of drug administration, BP was continuously recorded in conscious, freely moving rats for 24 h. The heart, kidneys, and abdominal aorta were then isolated and examined by using histologic methods and computer image analysis. In another work, the effects of hydralazine (40 mg/kg/d, for 5 months) on BP, BPV, and organ damage were observed in SHRs. Ketanserin significantly decreased BP and BPV, ameliorated impaired arterial baroreflex function, and significantly prevented the target organs of SHRs from being damaged. This preventive effect was characterized by decrease in left ventricular hypertrophy, diminution of glomerulus damage, and amelioration in vascular lesion. Hydralazine decreased BP but did not lower BPV. No organ protection was found in hydralazine-treated rats. In conclusion, long-term treatment with ketanserin reduced hypertensive organ damage. Lowering BP, decreasing BPV, and ameliorating arterial baroreflex function may contribute together to this effect.     

Ketanserin-induced baroreflex enhancement in spontaneously hypertensive rats depends on central 5-HT(2A) receptors

1. Ketanserin may influence baroreflex function by blocking 5-HT(2A) receptors and/or alpha(1)-adrenoceptors through central and/or peripheral mechanisms. 2. In the present study, we tested the hypothesis that the baroreflex sensitivity (BRS)-enhancing effects of ketanserin are mediated by central 5-HT(2A) receptors in spontaneously hypertensive rats (SHR). 3. Using a conjugate of a monoclonal antibody to the serotonin reuptake transporter (SERT) and the toxin saporin (anti-SERT-SAP), which specifically eliminates the neurons that express SERT, the effects of ketanserin (0.3 and 3.0 mg/kg, i.g.) on BRS, blood pressure (BP), heart period (HP) and blood pressure variability (BPV) were compared between conscious intact SHR and SHR pretreated with anti-SERT-SAP. 4. Immunochemistry showed that, 2 weeks after intracerebroventricular injection of the toxin, 5-HT expression was strikingly attenuated in the brain, whereas values of BRS, BPV and BP were similar to those in the sham group. In intact SHR, 0.3 mg/kg ketanserin significantly improved BRS (191% control) and reduced BPV without affecting BP; at 3.0 mg/kg, ketanserin significantly increased BRS (197% control) and decreased BPV and BP. In toxin-pretreated SHR, only the high dose of ketanserin improved BRS (132% control), neither of the ketanserin doses reduced BPV, but both significantly decreased BP. 5. We conclude that the BRS-enhancing effects of ketanserin are mediated largely by central 5-HT(2A) receptors, whereas the antihypertensive effect of ketanserin persists even after destruction of serotonergic neurons in the central nervous system.     

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.     

噻嗪类利尿剂对自发性高血压大鼠内皮型一氧化氮合酶和内皮素-1表达影响的研究

目的研究噻嗪类利尿剂治疗自发性高血压大鼠时对其内皮型一氧化氮合酶和内皮素-1表达的影响,从而探讨其降压的可能分子机制。方法15只自发性高血压大鼠随机分为3组,分别经胃管给予氢氯噻嗪(HCTZ,10 mg.kg-1.d-1)、吲哒帕胺(IND,0.625 mg.kg-1.d-1)和等量去离子水。每周测血压1次,4 wk后处死动物,分别用RT-PCR和W estern B lot法检测组织中内皮素-1和内皮型一氧化氮合酶mRNA和蛋白质的表达。结果氢氯噻嗪和吲哒帕胺用药1 wk后SHR的血压降低,2wk时降压幅度达到显著水平(P<0.05)。同时两种利尿剂均可在蛋白质水平上调内皮型一氧化氮合酶的表达,在mRNA水平下调内皮素-1的表达。结论噻嗪类利尿剂可能通过上调内皮型一氧化氮合酶及下调内皮素-1而起到调节血压与改善血管内皮功能作用。     

尼群地平和卡托普利协同降低去窦弓神经大鼠血压波动性的作用

目的研究联合应用尼群地平和卡托普利可能具有的协同降低去窦弓神经大鼠血压及血压波动性的作用。方法以去窦弓神经大鼠为模型分别测定单次给予尼群地平或卡托普利及尼群地平与卡托普利联合应用后清醒自由活动大鼠的动脉血压、心动周期、血压波动性及心动周期波动性;采用概率和法计算尼群地平和卡托普利联合应用后对大鼠血压及血压波动性的作用。结果单用尼群地平5mg.kg-1或卡托普利100mg.kg-1能明显降低去窦弓神经大鼠的收缩压和舒张压,两药合用后降压作用明显加强,计算所得q值分别为1.23和1.38;单用尼群地平能显著降低去窦弓神经大鼠的收缩压波动性和舒张压波动性,单用卡托普利后对去窦弓神经大鼠的收缩压波动性和舒张压波动性没有明显影响,两药合用后可以显著降低大鼠的收缩压和舒张压波动性,q值分别为1.20和1.38;尼群地平和卡托普利无论是单用还是合用对去窦弓神经大鼠的心率及心率波动性都没有显著影响。结论尼群地平和卡托普利联合应用后具有协同降低和稳定去窦弓神经大鼠血压及血压波动性的作用。