Impaired heart function and noradrenaline release after ischaemia in stroke-prone spontaneously hypertensive rats

1. Stroke-prone spontaneously hypertensive rats (SHRSP) are a strain of rat that exhibit severely high blood pressure and stroke attacks at an early age, but their heart function in vitro has seldom been studied in detail. Although the activity of the sympathetic nervous system is known to increase after myocardial ischaemia, there is little information about the cardiac release of noradrenaline (NA) associated with heart function after ischaemia in SHRSP. The aim of the present study was to examine heart function and cardiac NA release after ischaemia in SHRSP. 2. Isolated hearts of 4- and 8-month-old SHRSP and age-matched Wistar-Kyoto (WKY) rats were perfused in a working heart preparation and were subjected to 30 min ischaemia followed by 30 min reperfusion. Heart function and coronary flow were monitored throughout the experiment. Coronary effluent was collected for determination of NA using high-performance liquid chromatography coupled with electrochemical detection. 3. Under baseline conditions, cardiac output of 4-month-old SHRSP was slightly but significantly decreased compared with that of WKY rats (P < 0.05), although coronary flow was maintained normally at this age. Eight-month-old SHRSP showed a further impairment of systolic heart function, with lower coronary flow and higher coronary vascular resistance under baseline conditions. Elevated left ventricular end-diastolic pressure was evident in SHRSP at both ages before ischaemia. Heart function was severely damaged after 30 min global ischaemia in SHRSP from both age groups. Stroke-prone spontaneously hypertensive rats also showed lower coronary flow and higher coronary vascular resistance during reperfusion. 4. Coronary NA was not detectable in WKY rats or SHRSP at 4 months of age under baseline conditions. In 8-month-old SHRSP, pre-ischaemic NA release was significantly higher than that in age-matched WKY rat controls. The concentration of NA in the coronary effluent of SHRSP during reperfusion was also significantly higher than that of WKY rats at both ages. 5. These data demonstrate that SHRSP have early impairment of both systolic and diastolic heart function compared with WKY rats. Severe damage of heart function and coronary flow after ischaemia in SHRSP was accompanied with an increased release of NA, which may play a harmful role in heart function impairment in SHRSP after ischaemia.     

Amlodipine ameliorates endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats

1. Endothelial dysfunction plays a critical role in the development and progression or pathogenesis of hypertension. Amlodipine, a calcium channel blocker, is an effective antihypertensive agent. We investigated the effects of amlodipine on endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats (SHR). 2. Eight-week-old SHR were treated with amlodipine (10 mg/kg per day) for 8 weeks. Control SHR and Wistar-Kyoto (WKY) rats were treated with saline. Systolic blood pressure (SBP) was measured by the tail-cuff method. Isometric tension changes of isolated mesenteric arterial rings were recorded continuously by a myograph system. Serum contents of malondialdehyde (MDA) and total nitrate/nitrite (NO(x) ) were determined. Vascular superoxide anion production was analysed with dihydroethidium (DHE) fluorescence. 3. The contractile responses to KCl and phenylephrine were greater in untreated SHR than in WKY. Acetylcholine (ACh)-induced relaxation was significantly impaired in untreated SHR. Amlodipine treatment reduced the contractions and improved relaxation to ACh. In WKY, relaxation to ACh was inhibited by N(G) -nitro-l-arginine methyl ester (l-NAME) and not changed by ascorbic acid. In untreated SHR, the response to ACh was unaffected by l-NAME, whereas it was improved by ascorbic acid. Amlodipine restored the inhibitory effect of l-NAME on ACh-induced relaxation, but ascorbic acid no longer exerted its facilitating effect. Amlodipine prevented the rise in SBP and ameliorated abnormalities in serum MDA and NO in untreated SHR. DHE assay showed an increased intravascular superoxide generation in untreated SHR, which was abrogated by amlodipine. 4. Treatment of SHR with amlodipine resulted in amelioration of endothelial dysfunction by anti-oxidant activity and improvement in NO availability.     

Effects of exercise training on nitric oxide synthase in the kidney of spontaneously hypertensive rats

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Comparative effects of tramadol on vascular reactivity in normotensive and spontaneously hypertensive rats

The aim of the present study was to determine the effects of tramadol on vascular reactivity in aortic rings from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Aortic rings, with or without endothelium, were obtained from male WKY rats and SHR (15-20 weeks old) and prepared for isometric tension recording. Aortic rings were precontracted with phenylephrine (10 micromol/L) or 40 mmol/L KCl and then exposed to cumulative concentrations of tramadol (0.1-1 mmol/L). Tramadol produced a concentration-dependent relaxation of precontracted aortic rings from WKY rats and SHR, which was not dependent on functional endothelium. Vascular relaxation was significantly greater in rings from SHR than WKY rats. The concentration of tramadol necessary to produce a 50% reduction of the maximal contraction to phenylephrine (IC(50)) in rings with and without endothelium from SHR was 0.47 +/- 0.08 and 0.44 +/- 0.03 mmol/L, respectively (P = 0.76). Tramadol attenuated the contracture elicited by Ca2+ in depolarized tissue, suggesting that it may inhibit L-type Ca2+ channels. However, pretreatment with nicardipine (1 micromol/L) prevented the relaxation induced by tramadol in aortic rings from WKY rats and partially reduced its inhibitory effect in aortic rings from SHR. 6. Pretreatment of endothelium-denuded aorta with glybenclamide (3 micromol/L), 4-aminopyridine (3 mmol/L), tetraethylammonium (3 mmol/L) and naloxone (100 micromol/L) did not affect tramadol-induced vasodilation of aortic rings from either WKY rats or SHR. Intravenous administration of tramadol (10 mg/kg) to conscious SHR significantly reduced both systolic and diastolic blood pressure from 171.4 +/- 5.3 to 129.3 +/- 5.3 (P = 0.002) and from 125.0 +/- 6.5 to 57.8 +/- 8.9 mmHg (P = 0.003), respectively.     

NADPH氧化酶对自发性高血压大鼠体内氧化应激的影响

目的考察NADPH氧化酶对自发性高血压大鼠体内氧化应激的影响。方法22wk龄自发性高血压大鼠(SHR)和正常血压WKY大鼠,采用尾套法测定血压,Greiss反应测定血清一氧化氮分泌量,ABTS和FRAP法进行血清总抗氧化能力测定,血管环舒缩测定来评价超氧阴离子清除剂超氧化物歧化酶(SOD)和NADPH氧化酶抑制剂夹竹桃麻素(Apo)对大鼠腹主动脉内皮依赖性舒张反应;采用RT-PCR考察内皮型一氧化氮合酶(eNOS)、NADPH氧化酶亚基p22phox以及NADPH氧化酶亚基gp91phox类似物nox4mRNA表达。结果与WKY大鼠相比,SHR血压升高,而血清总抗氧化水平及NO分泌量均降低。PCR显示SHR胸主动脉中eNOS及p22phoxmRNA表达与WKY大鼠相比差异无显著性,而nox4表达则升高。SHR腹主动脉内皮依赖性舒张反应与WKY相比降低,SOD或Apo均能明显逆转该变化。结论结果提示SHR体内氧化应激状态与NADPH氧化酶gp91phox类似物nox4mRNA过表达有关;NADPH氧化酶依赖性的氧化应激参与了SHR内皮功能障碍的发生发展;药理调节NADPH氧化酶功能或应用抗氧化治疗可明显改善SHR内皮依赖性舒张反应。     

Anticardiolipin antibodies in spontaneously hypertensive rats (SHR), stroke-prone SHR and normal Wistar rats

1. Anticardiolipin antibodies (ACA) can be detected in the serum of patients with autoimmune disturbances, ischaemic heart disease, myocardial infarction, neurological disorders and other medical conditions. Elevated values of these autoantibodies can be associated with recurrent fetal loss, arterial and venous thrombosis and thrombocytopenia. 2. In the present study, we investigated the presence of ACA in three rat strains, namely normal Wistar rats (WR), spontaneously hypertensive rats Okamoto-Aoki (SHR) and stroke-prone SHR (SHRSP). All animals were examined at four ages: 1, 4, 10 and 12 months of age. Anticardiolipin antibodies were determined by ELISA. 3. Anticardiolipin antibody levels in normal WR, which were used as controls, were lowest at 1 month and increased significantly from the 4th month on. At the prehypertensive age (1 month), ACA levels in SHR and SHRSP were significantly higher compared with control WR, decreased with age and were significantly lower at 4, 10 and 12 months compared with age-matched WR. 4. These differences may be a result of immunological disorders in SHR.     

Perinatal taurine exerts a hypotensive effect in male spontaneously hypertensive rats and down-regulates endothelial oxide nitric synthase in the aortic arch

Essential hypertension is considered to be a result of the interaction between genetic and environmental factors, including perinatal factors. Different advantageous perinatal factors proved to have beneficial long-lasting effects against an abnormal genetic background. Taurine is a ubiquitous sulphur-containing amino acid present in foods such as seafood. The antihypertensive effects of taurine have been reported in experimental studies and in human hypertension. We aimed to investigate the effects of perinatal treatment with taurine in spontaneously hypertensive rats (SHR), a known model of genetic hypertension. Female SHR were administered with taurine (3 g/L) during gestation and lactation (SHR-TAU). Untreated SHR and Wistar-Kyoto rats (WKY) were used as controls. Long-lasting effects in offspring were investigated. Addition of taurine to the mother's drinking water reduced blood pressure in adult offspring. No differences were observed in cardiac hypertrophy. Findings on morphometric evaluations suggest that perinatal treatment with taurine would be partially effective in improving structural alterations of the aorta. Modifications in gene expression of Bcl-2 family members and upregulation of endothelial nitric oxide synthase in the aorta of 22-week-old male offspring were found. No differences were observed on relative telomere length in different cardiovascular tissues between SHR and SHR-TAU. Altogether results suggest that taurine programming, albeit sex specific, is associated with gene expression changes which ultimately may lead to improvement of aortic remodelling and enhanced endothelial function because of augmented nitric oxide (NO) production.     

艾力沙坦钾单次给药对自发性高血压大鼠血压的影响

目的本实验通过观察艾力沙坦钾（allisartan potassium,ALS3K）对自发性高血压大鼠（spontaneously hypertensirerats,SHR）单次给药前后血压变化的情况,研究艾力沙坦钾对SHR的降压作用及量效关系。方法SHR随机分为7个组,每组9只。SHR麻醉状态下行股动脉插管并造胃瘘管,恢复1d后,动物在清醒自由活动状态下,由计算机连续记录每搏收缩压（systolicblood pressure,SBP）,舒张压（diastolic blood pressure,DBP）和心动间期（heart period,HP）。记录给药前1h内血压和心动间期作为给药前基础值。然后每组SHR经胃瘘管分别给予0．5％的羧甲基纤维素钠（sodium carboxymathyl cellulose,CMC-Na）、艾力沙坦酯（allisartan,ALS-3）2．5mg／kg、氯沙坦钾（losartan potassium,Los）2．5mg／kg和受试药品ALS3K各1．0、2．5、5．0、10mg／kg;给药后连续记录6hSBP、DBP和HP的变化。结果ALS3K在2．5mg／kg剂量开始明显降压,与给药前比较,SBP和DBP分别下降15、16mmHg（P〈0．01）;ALS3K5．0和10mg／kg降压效果与2．5mg／kg相近;各剂量对HP没有明显的影响。ALS-3以及Los在2．5mg／kg给药剂量下无明显的降压作用。结论ALS3K单次给药能平稳持久地降低SHR的血压,在一定剂量范围内有较好的量效关系。经过结构改造,ALS3K可以通过更低的给药剂量而获得比ALS-3更好的降压疗效。     

预适应减轻大鼠下肢缺血再灌注后的心肺损伤

目的 :观察预适应 (缺血及腺苷 )对大鼠下肢缺血再灌注后心、肺损伤的保护作用。方法 :雄性SD大鼠随机分为手术组 (Ⅰ ) ,缺血预适应组 (Ⅱ ) ,腺苷预适应组 (Ⅲ ) ,假手术组 (Ⅳ )。测定再灌注后的平均动脉压。终点取心、肺组织行测定心肌ATP酶 ,心、肺组织丙二醛 (MDA)及伊文氏兰含量。结果 :组Ⅰ ,Ⅲ再灌注后平均动脉压分别为 (8.1± 1.9)kPa ,(9.2± 2 .4 )kPa ,均显著低于组Ⅱ ,Ⅳ (P <0 .0 5 )。组Ⅰ心肌Ca2 + ATP酶活力为 (5 .0 2± 0 .2 1)U·mg- 1,低于余 3组 (P <0 .0 5 )。组Ⅰ心、肺组织MDA含量和肺伊文氏兰含量显著高于余 3组。结论 :预适应能改善大鼠下肢缺血再灌注后心、肺组织和功能损伤     

降钙素基因相关肽介导吴茱萸次碱的降压作用

目的研究吴茱萸次碱在自发性高血压大鼠(SHR)的降压作用,并探讨其效应是否由降钙素基因相关肽(CGRP)介导。方法灌胃给予不同剂量吴茱萸次碱(10、20和40 mg.kg-1.d-1),连续给药14 d。测量大鼠动脉尾收缩血压,分离血浆检测CGRP浓度(放免分析法),切取胸腰段背根神经节检测CGRP mRNA的表达水平(RT-PCR法)。结果吴茱萸次碱能显著降低SHR血压,且呈剂量依赖性[对照组与3个剂量吴茱萸次碱组的血压分别为(187±4)、(168±6)、(153±2)和(143±5)mmHg]。吴茱萸次碱能同时剂量依赖性增加血浆CGRP浓度及上调背根神经节中CGRP mRNA的表达。氯沙坦也显著降低SHR动脉压[(187±4)vs(131±2)mmHg],但增加CGRP血浆浓度及上调CGRP mRNA的表达作用弱于吴茱萸次碱。结论吴茱萸次碱能显著降低SHR的血压,其机制与促进CGRP的合成与释放有关。     

银杏内酯B对自发性高血压大鼠左室肥厚及心肌纤维化的影响

目的:观察银杏内酯B对自发性高血压大鼠模型左室肥厚心肌纤维化的影响。方法:选择12周龄雄性SHR大鼠(二级)40只,随机分成4组,每组10只,分别为银杏内酯B大剂量组(YH,120 mg.kg-1.d-1)、银杏内酯B小剂量组(YL,60mg.kg-1.d-1)、氯沙坦组(LOS,30 mg.kg-1.d-1)和SHR大鼠模型对照组(SHR),以及周龄、性别相匹配的Wistar Kyoto(WKY)大鼠10只作为空白对照。每日灌胃给药一次,对照组给等量CMCNa溶液。治疗12周后尾袖法测定动脉血压,称量后处死。计算左室质量与体质量比(LVM/BW)。天狼星红染色,计算机图像分析计算心肌胶原容积分数。结果:给药后,YH、YL组大鼠SBP均明显低于SHR组(P<0.01),YH、YL2组组间比较无显著性差异;YH组大鼠给药前后SBP比较有显著差异(P<0.01),给药后明显低于给药前,而YL组给药前后比较无统计学意义。YH、YL组大鼠心肌胶原纤维含量均明显低于SHR组(P<0.01),YH、YL2组间比较无显著性差异。结论:银杏内酯B可以抑制SHR大鼠的心肌纤维化,改善高血压所致的心肌重塑。     

重组降血压肽缓释微球对自发性高血压大鼠的降压作用

目的考察重组降血压肽聚乳酸(rAHP-PLA)缓释微球对自发性高血压大鼠(SHR)的降压作用。方法采用口服和皮下注射两种给药方式,分别给予按体质量和血压均衡分组的自发性高血压大鼠rAHP-PLA缓释微球,空白组给予等量生理盐水。结果口服给予降血压肽缓释微球后10 h,自发性高血压大鼠的血压降至最低,且药效可以持续36 h;皮下注射rAHP-PLA缓释微球后30 h,血压降至最低,且可以持续约9 d。rAHP-PLA缓释微球对正常血压无影响。结论 rAHP-PLA缓释微球具有显著的降压效果,并有明显的缓释作用。     

Pressor and non-pressor effects of sodium loading on stroke in stroke-prone spontaneously hypertensive rats

1. Aetiological studies have shown that sodium loading increases both blood pressure and death from stroke. The present study was designed to investigate the pressor and non-pressor effects of sodium loading on stroke in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Eighty-five female SHRSP were used. Forty-nine SHRSP, aged 5 months, were randomly divided into two groups with or without sodium loading and their survival times were recorded. Thirty-six SHRSP, aged 3 months, were randomly divided into two groups and were instrumented to determine blood pressure, heart period and baroreflex sensitivity (BRS) after 4 months of sodium loading or normal rat chow. After determination of BRS, blood samples were collected for the measurement of tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and angiotensin (Ang) II and brains were dissected for light microscopic examination. 3. Over the 15 month period, the mortality of control SHRSP was 37.5%, which reached 80.0% in the sodium loading group. Compared with the control group, blood pressure was increased but BRS was significantly decreased (P < 0.001) in sodium-loaded rats. Levels of IL-1beta, IL-6 and AngII were all significantly increased (P < 0.05) in the sodium-loaded rats. Sodium loading also markedly increased the number of cerebral aneurysms. Multivariate regression analysis showed that IL-6 was the most significant factor related to aneurysm formation. 4. Sodium loading increases death from stroke in SHRSP. The increased blood pressure, impaired BRS, inflammatory reaction and the formation of cerebral aneurysms may contribute to the development of stroke.     

盐酸埃他卡林对自发性高血压大鼠肾组织细胞外基质降解系统的影响

目的观察埃他卡林(iptakalim hydrochloride,Ipt)对自发性高血压大鼠(spontaneously hyper-tensiverats,SHR)肾组织细胞外基质降解系统的影响。方法SHR于第12周龄进入实验,实验分组如下Ipt1、3、9mg·kg-1·d-1剂量组,苯那普利(benazepril)3mg·kg-1·d-1治疗组及SHR空白对照组,另设同月龄同种属正常血压大鼠(Wistar Kyotorat,WKY)为正常对照组,灌胃给药每天1次,持续给药12周,应用免疫组织化学和RT-PCR技术,观察埃他卡林对高血压大鼠肾组织Ⅳ型胶原(Col-Ⅳ)、转化生长因子β1(TGF-β1)、基质金属蛋白酶(MMPs)及其抑制物(TIMPs)表达的影响。结果埃他卡林长期降压治疗同时上调肾组织局部MMP-9mRNA和蛋白水平,同时一致性降低TIMP-1、TGF-β1及Ⅳ型胶原转录和蛋白水平。结论埃他卡林对肾脏靶器官的保护作用机制可能通过抑制肾脏局部TGF-β1表达,纠正MMP-9/TIMP-1失衡,从而促进细胞外基质的降解,减少细胞外基质的积聚。     

Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.     

Increased pressor responses to physostigmine in spontaneously hypertensive rats

Summary Intravenous injection of physostigmine evoked a pressor response in unanaesthetized rats. Spontaneously hypertensive rats (SHR) showed increased pressor responses, but the responses were within normal limits in renal hypertensive and DOCA-saline hypertensive rats. The pressor effect in SHR was abolished by the i.v. injection of atropine sulphate but not by the i.v. injection of atropine methyl bromide. After inhibition of the peripheral muscarinic receptors by atropine methyl bromide, oxotremorine also produced a pressor response in unanaesthetized rats. In contrast to the pressor effect of physostigmine, there was no difference between the oxotremorine-induced pressor response of SHR and that of normotensive Wistar-Kyoto rats. The pressor effect of oxotremorine in SHR was blocked by the i.v. injection of atropine sulphate.     

缬沙坦对自发性高血压大鼠血管结构和舒缩功能的影响

目的观察缬沙坦对自发性高血压大鼠(SHR)的血压、血管功能和结构的影响.方法30只12 wk龄雄性SHR,随机分成3组,每组10只缬沙坦大剂量组(30 mg*kg-1*d-1);缬沙坦小剂量组(10 mg*kg-1*d-1); SHR模型对照组,另设同龄雄性正常血压WKY大鼠作为正常对照组(n=10).用无创法测定尾动脉收缩压及心率,至给药 4 wk 处死.测定胸主动脉、肠系膜动脉分支第三级血管壁(中膜)/腔面积比,并采用平衡记录仪记录离体的动脉环对血管活性药物去甲肾上腺素(NE)和硝普钠反应的敏感性.结果与模型组相比,大、小剂量缬沙坦均能降低SHR血压,肠系膜动脉壁肥厚明显改善(P＜0.01);大剂量明显减少主动脉腔壁比(P＜0.01),小剂量缬沙坦也可减少腔壁比,但无统计学意义;大、小剂量均能使胸主动脉及肠系膜动脉对硝普钠的舒张敏感性增加 (P<0.05),对NE收缩的敏感性降低(P<0.05).结论缬沙坦能改善SHR的非内皮依赖性血管舒张功能,使SHR血管对循环〗活性物质的异常反应改善,并抑制SHR的血管壁变厚.