有氧运动对自发性高血压大鼠动脉平滑肌RhoA/Rho激酶活性的影响

目的:Ras同源基因家族成员A(Ras homolog gene family member A,Rho A)/Rho激酶信号通路介导钙敏化机制在血管平滑肌收缩过程中起着关键性作用,本研究观察有氧运动对自发性高血压大鼠(Spontaneously hypertensive rat,SHR)肠系膜动脉平滑肌中Rho A/Rho激酶活性变化的影响。方法:选用12周龄、雄性自发性高血压大鼠,随机分为高血压安静对照组(SHR-SED)和高血压有氧运动组(SHR-EX)。同时选用同龄雄性Wistar Kyoto(WKY)大鼠作为正常血压对照组。SHR-EX组大鼠进行跑台运动训练,运动方案为5 d/wk,坡度0°,20 m/min,60 min/day。8周后,取肠系膜动脉,离体微血管环张力测定肠系膜动脉收缩特性,用Pull down技术和western blot技术检测活化Rho A的表达。结果:(1)与WKY组相比,SHR-SED组收缩压显著升高,而SHR-EX组收缩压较SHR-SED组显著下降,但仍高于WKY组。(2)120 m M KCl可诱发各组肠系膜动脉收缩张力增加,其最大张力无显著差异,但NE(10-5M)诱发的收缩张力SHR-SED组>SHR-EX组>WKY组。(3)Rho激酶抑制剂Y-27632(3×10-8~10-5M)可诱导血管呈浓度依赖性舒张反应,且动脉对其敏感性SHR-SED组>SHR-EX组>WKY组。(4)与WKY组相比,SHR-SED组肠系膜动脉Rho AGTP蛋白表达相对含量显著升高,有氧运动显著抑制此变化。结论:有氧运动可改善SHR肠系膜动脉舒缩功能,减弱高血压对Rho A/Rho激酶活性的上调,提示运动对Rho A/Rho激酶信号通路的影响可能是运动降压的机制之一。     

醛固酮致自发性高血压大鼠心肌纤维化的作用机制

为探索醛固酮介导高血压心肌纤维化作用机制,测定了自发性高血压大鼠（ＳＨＲ）、醛固酮受体拮抗剂螺内酯预处理ＳＨＲ及正常血压大鼠录同培养时间点心肌细胞对＾Ｈ０ｐｒｏｌｉｎｅ掺入理、心肌胶原蛋白呈及丝裂素活化蛋白激酶（ＭＡＰＫ）活性等。结果表明,ＳＨＲ心肌胶原蛋白含量及ＭＡＰＫ生增加,其各时间点的＾３Ｈ－ｐｒｏｌｉｎｅ摄入量均高于治疗组和正常对照组。说明高血压心肌纤维化可能与醛固酮通过其受体介导心肌ＭＡ     

糜酶介导自发性高血压大鼠心肌纤维化的作用机制

目的:观察糜酶对自发性高血压大鼠(SHR)心肌纤维化的影响及作用机制。方法:采用RT-PCR检测心肌组织Ⅰ、Ⅲ型胶原和糜酶mRNA表达,Western blot检测转化生长因子β1(TGF-β1)和过氧化酶体增殖物激活受体α(PPARα)蛋白表达。结果:SHR组和糜酶抑制剂(CHI)组Ⅰ、Ⅲ型胶原mRNA、TGF-β1蛋白高于对照组,PPARα蛋白低于对照组(P<0.01,P<0.05)。SHR组糜酶mRNA高于对照组(P<0.01)。结论:糜酶参与心肌纤维化,其机制与TGF-β1蛋白上调、PPARα蛋白下调有关。     

洛丁新对UUO大鼠肾脏纤维化及其血液流变学的影响

目的观察洛丁新对单侧输尿管梗阻(UUO)致肾间质纤维化大鼠的肾脏纤维化及其血液流变学的影响。方法采用单侧输尿管结扎法复制单侧输尿管梗阻致大鼠肾间质纤维化模型,随机均分为模型组和洛丁新组、假手术组[给药14天后处死,肾组织病理切片,测定高、中、低切变率下的全血黏度(WBV)、血浆粘度(PV)和红细胞压积(HCT)等血液流变学指标,同时检测血清肌酐(SCr)、尿素氮(BUN)。结果与模型组对比,洛丁新组在肾间质纤维化面积、肾功能指标SCr、BUN和血流高、中、低切变率下的全血黏度(WBV)、血浆粘度(PV)、红细胞压积(HCT)等指标显著降低,P<0.05。结论洛丁新能改善UUO肾间质纤维化大鼠的血液流变性,具有抗肾间质纤维化的作用。     

络活喜与洛汀新对自发性高血压大鼠肾脏的保护作用

 目的探讨钙离子拮抗剂一络活喜(Amlodipine)和血管紧张素转换酶阻滞剂—洛汀新(Benazepril)对高血压所致肾脏损害的保护作用。方法采用体外灌注法给药,27只自发性高血压大鼠(SHR)随机分为2个治疗组和1个非治疗组,用9只魏—凯二氏大鼠(WKY)作对照,观察治疗前后血压及肾功能变化情况,实验结束时取肾脏观察组织形态学变化。结果与非治疗组比较,2个治疗组能有效地降低SHR的血压,治疗后24h尿蛋白减少,肌酐清除率增加,肾脏组织形态学改变明显好于非治疗组。2个药物之间比较,洛汀新在减少尿蛋白方面优于络活喜,络活喜在减轻肾小球组织学改变方面优于洛汀新。结论洛活喜和洛汀新不仅能明显降低SHR血压,而且可以改善肾功能,减轻肾脏损害。     

有氧运动对高血压大鼠脑动脉平滑肌细胞STOCs的影响

目的:观察有氧运动对自发性高血压大鼠(SHR)脑动脉平滑肌细胞自发瞬时外向电流(STOCs)的影响。方法:选用雄性SHR 24只,随机分为高血压安静组(SHR-SED组)和高血压运动组(SHR-EX组),后者进行8周有氧跑台运动。另选用同龄雄性WKY大鼠12只作为正常血压对照组。8周后,取脑动脉,用酶消化法急性分离脑动脉平滑肌细胞。采用穿孔膜片钳实验记录各组大鼠脑动脉STOCs的变化。结果:(1)SHR-SED组基础收缩压显著高于WKY组,经过有氧运动训练后收缩压显著下降,但仍较WKY组高(P<0.01)。(2)STOCs具有明显的电压依赖性,可被1 m M caffeine激活而被100 n M IBTX阻断;(3)在相同钳制电位下,自发性高血压可以显著增加脑动脉平滑肌细胞的STOCs的幅值,而频率无显著性改变。(4)有氧运动显著降低由高血压导致的STOCs幅值增高,而对频率无显著性影响。结论:自发性高血压大鼠脑动脉平滑肌细胞STOCs的幅值显著增大,与高血压背景下大电导钙激活钾通道(BKCa)功能的代偿性增强有关;长期有氧运动可以显著抑制此增强效应,阻止高血压背景下的BKCa通道的病理性改变。     

金雀异黄素对肾小管间质纤维化模型大鼠肾组织DDR1、bFGF表达的影响

目的探讨DDR1在肾小管损伤及间质纤维化过程中的表达以及金雀异黄素在肾小管损伤及间质纤维化过程中对肾脏的保护作用及可能机制。方法采用单侧输尿管结扎致肾间质纤维化大鼠模型,将45只大鼠随机分为三组：假手术组、模型组、金雀异黄素干预组,分别于术后7d、14d、21d每组各处死5只大鼠,收集血清测定尿素氮（BUN）、血肌酐（Scr）水平,结扎侧肾组织行HE染色观察肾脏病理变化,Masson染色分析肾间质纤维化程度,免疫组化半定量检测各组大鼠肾组织DDR1、bFGF的表达。结果模型组DDR1、bFGF表达及肾间质纤维化程度明显高于假手术组,BUN、Scr水平显著升高（P〈0.01）;金雀异黄素干预组DDR1、bFGF表达及肾间质纤维化程度较模型组明显降低（P〈0.01或0.05）,部分时间段BUN、Scr水平有所下降（P〈0.05）。结论金雀异黄素可能通过降低DDR1及bFGF的表达而减轻肾小管损伤及间质纤维化程度。     

长期高强度间歇训练加重自发性高血压大鼠心肌纤维化

目的:探讨中等强度持续训练(MICT)和高强度间歇训练(HIIT)对自发性高血压大鼠(SHR)心肌胶原代谢的影响及机制。方法:45只雄性SHR随机分为安静对照组(SHR-UT)、中等强度持续运动组(SHR-MT)和HIIT组(SHR-HT),同时将15只Wistar-Kyoto大鼠作为正常血压组(WKY)。WKY和SHRUT组大鼠保持安静状态,SHR-MT和SHR-HT组分别进行18周MICT或HIIT。末次实验后48 h利用超声心动图检测心脏结构与功能,Masson和HE染色进行组织病理学观察并分别获取心脏胶原容积分数(CVF)和心肌细胞横截面积(CSA),比色法测定心肌Ⅰ型胶原(ColⅠ)含量,RT-PCR法检测心肌胚胎基因[心钠素(ANP)和β-肌球蛋白重链(β-MHC)]mRNA表达量,Western blot法检测心肌基质金属蛋白酶-2(MMP-2)(包括64 kDa MMP-2和72 kDa MMP-2)、组织金属蛋白酶抑制物-2(TIMP-2)、转化生长因子-β1(TGF-β1)、结缔组织生长因子(CTGF)和α-平滑肌肌动蛋白(α-SMA)蛋白表达量。结果:与WKY组比...     

AT2受体对自发性高血压大鼠肾脏近曲小管上皮细胞AT1受体表达与功能的影响

目的 研究AT2受体激动剂CGP42112对自发性高血压大鼠(SHR)肾脏近曲小管上皮(RPT)细胞AT1受体的表达及功能的影响.方法 以RPT细胞株作为研究对象,采用不同浓度AT2受体激动剂CGP42t12(10-9～10-7mol/L)作用24h或同一浓度CGP42112(10-7mol/L)作用不同时间(8、16...     

应用超声背向散射积分技术评价糖尿病大鼠肾脏纤维化

目的 检测不同病程糖尿病大鼠肾脏背向散射积分(IBS),同时观察纤维化指标,探讨IBS与肾脏纤维化的关系.方法 腹腔注射链尿佐菌素(65mg/kg)建立SD大鼠糖尿病模型,于第4、12、24周测定肾皮质和肾髓质的IBS％,Masson染色观察血管周围胶原面积(PVCA)、肾小球胶原沉积评分(GCDS)、肾小管间质病变评分(TIDS),肾脏胶原蛋白(CollagenI、CollagenⅢ)免疫组织化学染色.心肌光镜与透射电镜观察,并与同龄正常大鼠进行比较.结果 ①与对照组相比:糖尿病组肾皮质、肾髓质的IBS％明显增高(P＜0.05);糖尿病组肾脏纤维化指标PVCA、GCDS、TIDS、Collagen Ⅰ、CollagenⅢ的表达均明显增高(P＜0.05);②肾皮质与肾髓质IBS％与PVCA、GCDS、TIDS、CollagenⅠ、CollagenⅢ表达呈正相关(P＜0.05);③电镜发现糖尿病组肾小球毛细血管基底膜弥漫性增厚,间质胶原增生.结论 糖尿病大鼠存在明显的肾脏纤维化,通过监测IBS可以监测糖尿病大鼠肾脏组织纤维化的程度.     

运动训练诱导自发性高血压大鼠生理性心脏肥大

 目的 观察规律运动训练对自发性高血压大鼠(SHR)心脏肥大的影响,探讨运动发挥心脏保护效应的可能机制。方法 30只SHR随机分为高血压运动组(SHR-Ex)和高血压对照组(SHR-C),15只健康Wistar大鼠作为正常血压对照组(NC)。SHR-Ex组大鼠进行8周游泳运动(每天60 min,5 d/周),SHR-C组和NC组在鼠笼内安静饲养。实验后,利用智能无创血压测试仪测量尾动脉血压,超声心动图监测心脏结构与功能,分离左心室并称重,HE和Masson染色分别获取心肌细胞横截面积(CSA)和胶原容积分数(CVF),Western Blot检测胚胎基因和心脏肥大信号途径蛋白表达量。结果 实验过程中,由于拒跑、死亡等原因共剔除7只大鼠,最终纳入38只,其中NC组15只、SHR-C组12只和SHR-Ex组11只。与NC组比较,SHR-C组大鼠出现向心性心脏肥大,心肌纤维化(CVF升高,P<0.05),心钠素(ANF)、肌球蛋白轻链-2(MLC-2)、钙调神经磷酸酶Aβ亚基(CNAβ)、PI3激酶p110α亚基[PI3-K(p110α)]和磷酸化Akt(p-Akt)蛋白表达量上调(P<0.05);与SHR-C组比较,SHR-Ex组发生离心性心脏肥大,心肌纤维化减轻(CVF下降,P<0.05),心功能增强(P<0.05),ANF、MLC-2和CNAβ蛋白表达量下调(P<0.05),PI3-K(p110α)和p-Akt的变化无统计学意义。结论 长期运动训练能够促进SHR由病理性心脏肥大向生理性心脏肥大转变,其机制可能与钙调神经磷酸酶信号途径活性下降有关。     

尿中性粒细胞明胶酶相关脂质运载蛋白对高血压早期肾损害的预测价值

 目的 探讨检测血和尿中性粒细胞明胶酶相关脂质运载蛋白(neutrophil gelatinase-associated lipocalin,NGAL)对高血压早期肾损害的预测价值。方法 435例高血压患者按照病程长短分为长病程组及短病程组,按照分级标准分为3级;135例健康体检者作为对照组。应用酶联免疫吸附方法检测尿NGAL浓度,同时测Scr、ACR、血β₂-mG及尿β₂-mG。结果 高血压各级、各亚组血、尿NGAL检测浓度均高于对照组,血和尿中NGAL浓度呈正相关,尿NGAL浓度可以反映血浓度,尿NGAL高血压1级(1.21±0.63)μg/L、短病程组(2.21±1.59)μg/L均高于对照组(0.58±0.32)μg/L( P＜0.05),高血压2级(1.93±1.86)μg/L,高血压3级(3.11±1.38)μg/L和长病程组(3.29±1.41)μg/L与对照组比较,差异有统计学意义(P均＜0.01);高血压3级较高血压1级尿NGAL浓度高,长病程组较短病程组高(P均＜0.05);尿NGAL与高血压级别、高血压病程和Scr均呈显著性正相关(r=0.415、0.427、0.540,P均＜0.05),与ACR、血β₂-mG、尿β₂-mG相关性不明显。结论 尿NGAL可作为诊断高血压性肾损害敏感而准确的早期标志物,有望用于临床监测。     

自发性高血压大鼠心肌血管内皮生长因子表达水平的检测

 目的探讨血管内皮生长因子(Vascular endothelial growth factor,VEGF)在自发性高血压大鼠(Spontaneously hyper-tensive rat,SHR)心肌细胞中的表达情况,分析其与高血压时心肌毛细血管稀少及微小动脉"重塑"(remodeling)的关系.方法应用免疫组化SP染色法及计算机图像分析技术,对幼年(6周,n=15)和成年(12个月,n=15)SHR大鼠及幼年(6周,n=10)和成年(12个月,n=10)同系正常血压对照组京都Wistar大鼠(Wistar-Kyoto,WKY)心肌VEGF蛋白的表达水平进行了定量分析.结果在4组大鼠心脏各部(心房肌、心室肌、房间隔、室间隔等)心肌细胞浆中及冠状动脉各级分支的血管平滑肌细胞中均见有阳性VEGF表达,6周龄、12个月龄WKY及6周龄SHR三组间表达水平差异无统计学意义(P＞0.05),而12个月龄SHR组表达水平较其他三组均高(P＜0.05).结论随着成年SHR大鼠血压的升高,心肌及血管平滑肌细胞中VEGF蛋白的表达水平上调,可能是对高血压所致的靶器官继发性毛细血管减少的一种代偿反应,高表达的VEGF可对抗由于缺氧诱导的内皮细胞凋亡,维持其存活,并促进微血管再生.     

Effect of habitual exercise on urinary liver‐type fatty acid‐binding protein levels in middle‐aged and older adults

The purpose of this study was to examine the effect of habitual exercise on urinary liver‐type fatty acid‐binding protein (L‐FABP), which can reflect the degree of various stresses on renal proximal tubule related to the progression of renal disease, in middle‐aged and older adults. Cross‐sectional and interventional approaches were used to comprehensively achieve this purpose. In the cross‐sectional study, we investigated the relationship between physical activity levels and urinary L‐FABP levels in 130 middle‐aged and older adults. In the interventional study, subjects (n =31) were divided into two groups: exercise (n =19) and control group (n =12), whereby we examined the effects of 12‐week aerobic exercise training on urinary L‐FABP levels. The cross‐sectional study showed that the urinary L‐FABP levels were significantly lower in the higher physical activity group than in the lower physical activity group (P <.05). In the interventional study, 12‐week aerobic exercise training significantly decreased urinary L‐FABP levels (P <.01). Furthermore, the relative changes in urinary L‐FABP levels were significantly correlated with the relative changes in physical activity levels and mean arterial pressure after intervention (r =−.374 and r =.530, respectively). Our results revealed that the urinary L‐FABP levels were lower in the higher physical activity individuals, and aerobic exercise training decreased urinary L‐FABP levels. These results suggest that habitual exercise appears to be associated with a decrease in the degree of several stresses on renal proximal tubule and to be beneficial for kidney health in middle‐aged and older adults.     

Short-term cessation of statin therapy does not alter aerobic exercise performance in physically active middle-aged adults

Objectives: Physically active adults may be especially vulnerable to the adverse muscular side effects of statins. We determined if short-term cessation of statin therapy would improve aerobic exercise performance in middle-aged adults engaged in regular aerobic exercise training. Methods: Physically active middle-aged adults on statin therapy ≥6 mo (n = 16; 58 ± 10 y) or not taking lipid-lowering medications (controls) (n = 19; 51 ± 9 y) completed a peak oxygen consumption (VO_2peak) and time to exhaustion test on a cycle ergometer 2-7 d apart. Tests were repeated following 1 mo of statin cessation or a 1 mo period for controls. Questionnaires were administered to assess exercise history and muscle complaints. Results: Statin users reported little or no muscle complaints and participation in aerobic exercise was similar between groups (p≥0.13). The lower VO_2peak (37.3 ± 9.0 vs. 43.1 ± 4.9 ml/kg/min; p = 0.02) and time to exhaustion (21.9 ± 4.4 vs. 26.0 ± 6.3 min; p = 0.04) in statin users versus controls did not persist after controlling for age (p≥0.08). Aerobic exercise performance did not change with 1 mo of statin cessation (p≥0.54). No changes were observed in controls when tests were repeated 1 mo later (p≥0.38). Conclusion: Short-term cessation of statin therapy does not alter maximal aerobic capacity or aerobic endurance in physically active middle-aged adults with few or no statin muscle complaints.     

Effects of intense aerobic exercise and/or antihypertensive medication in individuals with metabolic syndrome

We studied the blood pressure lowering effects of a bout of exercise and/or antihypertensive medicine with the goal of studying if exercise could substitute or enhance pharmacologic hypertension treatment. Twenty‐three hypertensive metabolic syndrome patients chronically medicated with angiotensin II receptor 1 blockade antihypertensive medicine underwent 24‐hr monitoring in four separated days in a randomized order; (a) after taking their habitual dose of antihypertensive medicine (AHM trial), (b) substituting their medicine by placebo medicine (PLAC trial), (c) placebo medicine with a morning bout of intense aerobic exercise (PLAC +EXER trial) and (d) combining the exercise and antihypertensive medicine (AHM +EXER trial). We found that in trials with AHM subjects had lower plasma aldosterone/renin activity ratio evidencing treatment compliance. Before exercise, the trials with AHM displayed lower systolic (130 ± 16 vs 133 ± 15 mm Hg; P  = .018) and mean blood pressures (94 ± 11 vs 96 ± 10 mm Hg; P  = .036) than trials with placebo medication. Acutely (ie, 30 min after treatments) combining AHM +EXER lowered systolic blood pressure (SBP ) below the effects of PLAC +EXER (−8.1 ± 1.6 vs −4.9 ± 1.5 mm Hg; P  = .015). Twenty‐four hour monitoring revealed no differences among trials in body motion. However, PLAC +EXER and AHM lowered SBP below PLAC during the first 10 hours, time at which PLAC +EXER effects faded out (ie, at 19 PM ). Adding exercise to medication (ie, AHM +EXER ) resulted in longer reductions in SBP than with exercise alone (PLAC +EXER ). In summary, one bout of intense aerobic exercise in the morning cannot substitute the long‐lasting effects of antihypertensive medicine in lowering blood pressure, but their combination is superior to exercise alone.