无创性延迟肢体缺血预适应对糖尿病大鼠心肌缺血/再灌注氧化损伤的影响

目的:观察无创性延迟肢体缺血预适应(NDLIP)对糖尿病(DM)大鼠心肌缺血/再灌注氧化损伤的保护作用。方法:尾静脉注射链脲佐菌素(STZ)制备DM大鼠模型。将DM大鼠随机分成心肌缺血再灌注(I/R)、心肌缺血预适应(MIP)、无创性延迟肢体缺血预适应(NDLIP)组。通过3个循环的左后肢5 min缺血/5 min再灌注,每天1次,连续3 d,建立NDLIP模型。心肌冠状动脉左前降支(LAD)实施3次5 min缺血/5 min再灌注建立MIP模型。各组实施LAD 30 min缺血/120 min再灌注复制I/R模型。用BL-420E生物机能实验系统连续监测心电图(ECG),记录缺血期间室性心律失常(VA)的发生情况。TTC染色测定大鼠心肌I/R后梗死面积(IS)。检测心肌组织中总-超氧化物歧化酶(T-SOD)、锰-超氧化物歧化酶(Mn-SOD)活性及丙二醛(MDA)含量。结果:与I/R组相比,MIP组和NDLIP组室性早搏(VPC)出现时间明显推迟(P<0.01),持续时间明显缩短(P<0.01),室性心动过速(VT)和心室纤颤(VF)发生率都明显降低(P<0.05),IS明显缩小,梗死面积/危险区(IS/A...     

雷米普利对糖尿病大鼠心肌缺血/再灌注损伤的保护作用

目的研究雷米普利(RAM)对糖尿病大鼠心肌缺血/再灌注损伤的保护作用。方法链脲佐菌素致糖尿病大鼠被随机分为缺血/再灌注(I/R)、缺血预适应(IPC)和RAM3组。RAM组每天用RAM(1mg·kg-1)灌胃,IPC和I/R组用等体积生理盐水灌胃。4wk后各组动物均经历心肌缺血/再灌注损伤,IPC组于缺血前行心肌缺血预适应。连续监测心电图,检测心肌梗死范围、心肌细胞凋亡、凋亡蛋白Bcl-2与Bax表达,光镜下观察心肌形态学改变。结果与I/R组比较,RAM及IPC组ST-段抬高幅度降低,室早出现时间推迟,持续时间缩短,室速、室颤发生率降低,心肌梗死范围缩小,心肌细胞凋亡减轻,Bcl-2/Bax比值升高。结论连续4wk应用RAM可减轻糖尿病大鼠心肌缺血/再灌注损伤。     

依达拉奉对大鼠脑缺血再灌注后自由基含量的影响

目的通过观察雄性大鼠脑缺血再灌注后SOD活力、MDA、NO的表达,探讨依达拉奉的脑保护作用。方法选用雄性SD大鼠30只,随机分为3组:假手术(SO)组、缺血再灌注(I/R)组和依达拉奉(ED)组,每组10只。建立大鼠右侧大脑中动脉闭塞局灶性脑缺血再灌注模型,用生化法测定3组脑缺血再灌注后SOD活力、MDA、NO含量。结果 ED组及SO组脑组织SOD活力均高于I/R组(P<0.05),MDA及NO含量显著低于I/R组(P<0.05)。结论依达拉奉能增强SOD活力、减少MDA及NO含量,改善自由基代谢,有效减轻缺血再灌注损伤后的脑损伤。     

无创性肢体缺血预适应增强大鼠缺血/再灌注损伤后心肌抗氧化能力

目的研究无创性肢体缺血预适应对心肌缺血/再灌注损伤的保护作用,并从氧化-抗氧化角度初步探讨其作用机制。方法大鼠被随机分为缺血/再灌注(I/R)、心脏缺血预适应(CIP)和肢体缺血预适应(LIP)3组。LIP组连续3d经历左后肢缺血预适应。d4,各组动物均经历心肌缺血/再灌注损伤,CIP组于缺血前行心肌缺血预适应。连续监测心电图变化,检测心肌梗死范围,测定心肌组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、黄嘌呤氧化酶(XOD)活性以及丙二醛(MDA)含量。结果与I/R组比较,LIP及CIP组ST-段抬高幅度降低,室早出现时间推迟,持续时间缩短,室性心律失常发生率降低,心肌梗死范围缩小,SOD、GSH-PX活性升高,XOD活性降低,MDA含量减少。结论LIP具有与CIP相似的心脏保护作用,其机制与增强心肌抗氧化能力有关。     

无创性肢体缺血预适应增强糖尿病大鼠缺血/再灌注损伤后心肌抗氧化能力

目的研究无创性肢体缺血预适应对糖尿病大鼠心肌缺血/再灌注损伤的保护作用,并从氧化-抗氧化角度初步探讨其作用机制。方法大鼠经尾静脉一次性注射链脲佐菌素(STZ)造成急性糖尿病模型后,被随机分为缺血/再灌注(I/R)、心脏缺血预适应(CIP)和无创肢体缺血预适应(NLIP)3组。NLIP组连续3d经历左后肢缺血预适应。d4,各组动物均经历心肌缺血/再灌注损伤,CIP组于缺血前行心肌缺血预适应。连续监测血压和心电图变化,检测心肌梗死范围,测定心肌组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、黄嘌呤氧化酶(XOD)活性以及丙二醛(MDA)含量。结果成模动物表现出血糖明显升高,体重下降。与I/R组比较,NLIP及CIP组ST-段抬高幅度降低,室早和室速出现时间推迟,持续时间缩短,室性心律失常发生率降低,心肌梗死范围缩小,SOD、GSH-PX活性升高,XOD活性降低,MDA含量减少。结论NLIP对糖尿病大鼠具有与CIP程度相当的心脏保护作用,其机制与增强心肌抗氧化能力有关。     

无创性延迟肢体缺血预适应对大鼠脑缺血再灌注皮层的保护作用

目的：研究无创性延迟肢体缺血预适应（NDLIP）对大鼠脑缺血再灌注损伤的保护作用。方法：通过连续3d,每天1次3个循环左后肢无创性5min缺血、5rain再灌注,建立NDLIP模型。实验分4组：假手术组（sham）、缺血再灌注组（I／R）、早期脑缺血预适应＋I／R组（ECIP＋I／R）、NDLIP＋I／R组。观察其对脑缺血／再灌注的神经缺损症状,脑梗死范围,超氧化物歧化酶（SOD）,谷胱甘肽过氧化物酶（GSH—PX）活力,黄嘌呤氧化酶活力（XOD）,丙二醛（MDA）含量影响。结果：与I/R组相比,ECIP＋I／R组及NDLIP＋I／R组缺血1h,再灌注24h后评分有非常显著的降低;脑梗死范围显著减小。与I／R组比较,ECIP＋I／R组和NDLIP＋I／R组的T-SOD和Mn—SOD活力、GSH—PX活力均升高;XOD活力明显降低,MAD含量明显减少;ECIP＋I／R组和NDLIP＋I／R组间差异无统计学意义。结论：NDLIP可降低I／R对神经的损伤、减小脑梗死范围、提高脑组织抗氧化能力,减少I／R对脑组织的损伤。     

褪黑素对在体大鼠心肌缺血再灌注损伤的作用

目的　探讨外源性褪黑素(MLT)对在体大鼠心肌急性缺血再灌注损伤的保护作用。方法　36只大鼠随机分为对照组、缺血再灌注(I/R)组及缺血再灌注+褪黑素(I/R+MLT)组,I/R组及I/R+MLT组在体大鼠心脏左冠状动脉前降支完全阻断10min,再灌15min,术中监测记录心电及血流动力学的变化,随后测定局部受损心肌中MDA(丙二醛)的含量和SOD(超氧化物歧化酶)的活性并用电镜检查心肌结构。结果心脏血流动力学指标I/R+MLT组好于I/R组(P<0 .01);I/R组MDA的含量明显高于对照组及I/R+MLT组(P<0.01 ),SOD活性明显低于对照组及I/R+MLT组(P<0 .01),I/R+MLT组MDA含量及SOD活性与对照组无明显差异(P>0 .05);电镜下I/R组心肌细胞结构损伤明显,而I/RMLT组心肌细胞结构基本正常。结论　褪黑素对在体大鼠心肌急性缺血再灌注损伤具有保护作用,其作用与抗氧化损伤有关。     

茶多酚对大鼠肠缺血再灌注肠损伤的保护作用

目的:研究茶多酚(TP)对大鼠肠缺血再灌注(I/R)所致肠损伤的保护作用及其可能的作用机制,为其临床新用途提供实验依据。方法:大鼠随机分为肠I/R损伤对照组、假手术组及TP给药组(100,50,25和12.5 mg.kg-1),通过夹闭肠系膜上动脉1 h、再灌注2 h,建立肠I/R损伤模型。于缺血前20 m in舌下静脉注射药物,假手术组仅分离、不夹闭肠系膜上动脉。再灌2 h后,各组取血及中段小肠组织,测定血清及小肠组织中超氧化物歧化酶(SOD)、丙二醛(MDA)和一氧化氮(NO)含量,光镜下观察小肠组织形态学改变。结果:与假手术组相比,肠I/R损伤对照组血清及小肠组织中的SOD活力降低,MDA和NO含量升高,镜检发现小肠有明显组织形态学损伤。与肠I/R损伤对照组相比,TP组呈剂量依赖性增强SOD活力,减少MDA及NO含量,减轻小肠组织形态学损伤。结论:TP对肠I/R所致肠急性损伤有显著的及剂量依赖性的保护作用,可能与其自由基清除作用有关。     

大鼠急性肾缺血再灌注时心肌细胞氧化损伤及瑞芬太尼的干预作用

目的观察大鼠急性肾缺血再灌注时心肌细胞氧化损伤以及瑞芬太尼预处理对氧化损伤的干预作用。方法建立大鼠肾缺血再灌注损伤模型。将54只Wistar大鼠随机分为假手术组(Sham组)、缺血再灌注组(I/R组)、瑞芬太尼预处理组(R组)。Sham组只结扎单侧肾脏,另一侧只穿线不结扎;I/R组结扎右侧肾脏,动脉夹夹闭左侧肾蒂45min后开放,于再灌注30min、1、2、3h处死大鼠;R组为缺血前以1μg·kg-1·min-1微泵输注瑞芬太尼30min进行预处理,余同I/R组。分别检测各组大鼠心肌组织超氧化物歧化酶(SOD)活力、丙二醛(MDA)含量及谷胱甘肽过氧物酶(GSH-Px)活力变化。结果I/R组、R组与Sham组相比,心肌组织MDA含量升高,SOD、GSH-Px活力降低,且在1、2、3h时间点,差异均有统计学意义(P<0.05)。R组与I/R组比较,心肌组织MDA含量降低,SOD、GSH-Px的表达增高,且差异有统计学意义(P<0.05)。结论大鼠急性肾缺血再灌注可造成心肌细胞氧化损伤,而瑞芬太尼预处理可起到一定的保护作用。     

PI3K-Akt-HIF-α信号通路在右美托咪定减轻大鼠肝缺血/再灌注致肺损伤中的作用

目的:通过研究右美托咪定对大鼠肝缺血/再灌注致急性肺损伤中的作用及其可能作用机制.方法:建立大鼠肝缺血/再灌注肺损伤模型,以随机数字表法分为假手术组、肝缺血/再灌注组(I/R组)、I/R+右美托咪定组(D组)和I/R+右美托咪定组+wortmannin(DW组),通过ELISA和Western blot检测细胞炎症因子及PI3K-Akt-HIF-α信号传导通路蛋白的表达.结果:I/R组中MDA和MPO含量、 细胞炎症因子表达及p-Akt和HIF-α蛋白含量较假手术组均明显升高;D组中上述肺损伤指标较I/R组均显著下调;与D组相比,DW组中MDA和MPO含量、细胞炎症因子表达及p-Akt和HIF-α蛋白含量均上调.     

Protection from renal ischemia reperfusion injury by an endothelin-A receptor antagonist BQ-123 in relation to nitric oxide production

The aim of this study was to investigate whether the protective effect of endothelin-A (ET(A)) receptor antagonist BQ-123 against renal ischemia reperfusion (I/R) injury is related to nitric oxide (NO) production. Sprague-Dawley rats were divided into six groups: control, I/R, N sup omega nitro-L-arginine methyl ester (L-NAME), BQ, BQ+L-NAME, BQ+L-NAME+L-Arg groups. After urethane anesthesia, 30min renal ischemia and 2h reperfusion were performed in all groups except control group. Mean arterial pressures (MAP) during reperfusion in all L-NAME-treated groups were higher than during pre-ischemia and ischemia, however, MAP at 60th and 120th minute of reperfusion in control and BQ groups were lower than during ischemia. MAP of L-NAME-treated groups were significantly higher than the other groups during reperfusion period. The I/R caused lipid peroxidation and protein oxidation, however, BQ-123 treatment prevented oxidant injury. The inhibition of NO production prevented effect of BQ-123 treatment. Also, BQ-123 treatment caused an increase in superoxide dismutase and catalase activities. Both BQ-123 and L-NAME treatments prevented high xanthine oxidase activity. BQ-123 prevented risen myeloperoxidase activity and L-NAME reversed this effect of BQ-123 just like the addition of L-arginine to the treatment altered the effect of L-NAME. The plasma BUN was affected as increasing manner from L-NAME treatments; on the other hand, plasma Cr and Na concentrations were affected as decreasing manner from BQ-123 treatments. ET(A) receptor antagonist BQ-123 may be revealed a protective agent against renal I/R injury with a possible secondary pathway via its antioxidant effects. We suggest that BQ-123 may mediate the protective effect via a NO-dependent mechanism.     

Role of endothelin ET(A) and ET(B) receptor subtypes in the regulation of intrarenal blood flow and oxygen tension in rats

The aim of the present study was to investigate the role of endothelin ET(A) and ET(B) receptors in the regulation of intrarenal blood flow and oxygen tension in normotensive Sprague-Dawley rats. Thiobutabarbital anaesthetized rats were divided into four groups (n = 6-9 per group): (i) saline (4 mL/kg per h); (ii) BQ123; (iii) BQ788; and (iv) BQ123 + BQ788. After baseline measurements, the ET(A) receptor antagonist BQ-123 (30 nmol/kg per min, i.v.) and/or the ET(B) receptor antagonist BQ-788 (30 nmol/kg per min, i.v.), was administered for a period of 60 min. Total renal blood flow (RBF), cortical and outer medullary perfusion (laser-Doppler flowmetry) and Po(2) (Clark-type microelectrodes) were analysed throughout. At baseline, there were no significant differences between groups in mean arterial pressure (MAP), RBF, cortical and outer medullary perfusion and Po(2). Infusion of BQ-788 reduced RBF, cortical perfusion and outer medullary Po(2) (P < 0.05) and increased renal vascular resistance (P < 0.05) compared with saline-treated and BQ123 + BQ788-infused groups. BQ-123 and coinfusion of BQ-123 + BQ-788 increased outer medullary perfusion compared with the saline-treated group (P < 0.05) without significantly affecting outer medullary Po(2) and MAP. Neither selective nor combined ET(A) and ET(B) receptor antagonism significantly affected renal cortical Po(2). In conclusion, in normotensive rats, ET(B) receptor antagonism caused renal vasoconstriction and reduced RBF and cortical perfusion. Furthermore, ET(B) receptor antagonism decreased outer medullary Po(2). These effects were mediated by ET(A) receptor activation and are not due to a lack of ET(B) receptor activation per se. Finally, BQ-123 increased renal outer medullary perfusion, suggesting a tonic vasoconstrictor effect of ET(A) receptors in the medulla of normotensive rats.     

Dose- and time-dependency of the dilator effects of the endothelin antagonist, BQ-123, in the human forearm

Aims Endothelin-1 is a potent endogenous vasoconstrictor that acts on the endothelin A (ET_A ) receptor. The dose-response and time-course of the dilator effect of the ET_A receptor antagonist, BQ-123, was investigated in the forearm of healthy volunteers.
Methods Forearm blood flow was measured using mercury-in rubber strain gauge venous occlusion plethysmography.
Results Following intra-arterial infusion of BQ-123 (50  nmol  min⁻¹ ) for 5  min, forearm blood flow increased by approximately 60% over the next 60 minutes; lower doses were without significant effect. The degree of dilatation was similar to that observed in previous studies using 20-fold larger doses.
Conclusions This study confirms that basal endothelin-1 has a role in the physiological regulation of vascular tone. It is possible that at low doses, BQ-123 might be a more sensitive pharmacological tool for the detection of abnormal endothelin-1 mediated constriction.     

非诺贝特对全脑缺血/再灌注损伤大鼠的保护作用

目的探讨非诺贝特对大鼠全脑缺血/再灌注损伤(I/R)的保护作用及机制。方法采用双侧颈总动脉夹闭合并低血压方法建立全脑缺血/再灌注大鼠模型。药物非诺贝特(fenofibrate,FF;33、100、300mg.kg-1)在缺血前30min灌胃给药,PPARα受体拮抗剂MK886(6mg.kg-1)在给予非诺贝特300mg.kg-1前腹腔注射。Morris水迷宫测定大鼠空间学习能力变化,病理切片HE染色观察海马神经元形态结构变化,免疫组化染色检测海马组织核转录因子NF-κBp65蛋白的表达,生化酶学方法观察超氧歧化酶(SOD)活性、丙二醛(MDA)含量变化,酶联免疫吸附法(ELISA)检测细胞因子IL-1β、IL-6、IL-10、TNF-α含量变化。结果非诺贝特能明显缩短全脑缺血/再灌注大鼠的寻台潜伏期,减轻全脑缺血/再灌注大鼠海马神经元损伤,降低海马神经元NF-κB p65蛋白表达,明显阻遏缺血/再灌注大鼠海马IL-1β、IL-6、TNF-α、MDA含量的升高和IL-10含量及SOD活性的降低;预先给予MK886能取消非诺贝特的作用。结论非诺贝特对缺血/再灌注脑损伤有明显保护作用,其机制与激活PPARα,抑制NF-κB活性,抑制CNS炎症反应和氧化应激有关。     

By regulating IP3/PKC/TRPV4 pathway hyperoside induces endothelium-dependent vasodilatation in rat basilar artery following four vessel occlusion ischemia reperfusion

OBJECTIVE To investigate regulatory effects of hyperoside(Hyp) on IP3/PKC/TRPV4 pathway in rat cerebral basilar artery(CBA) subjected to global cerebral ischemia-reperfusion(I/R). METHODS The model of global cerebral I/R in rats was established by four-vessel occlusions methods. The treated rats were administrated with Hyp(50 mg·kg~(-1)) group, Hyp(50 mg·kg~(-1))+HC-067047(10 mg·kg~(-1)), Hyp(50 mg·kg~(-1))+2 APB(2 mg·kg~(-1)), Hyp(50 mg·kg~(-1))+Bis I(2.5 mg·kg~(-1)), Hyp(50 mg·kg~(-1))+ 2 APB(2 mg·kg~(-1))+Bis I(2.5 mg·kg~(-1)). Hematoxylin-eosin(HE) and Nissl staining were performed and the contents of methane dicarboxylic aldehyde(MDA), neuron-specific enolase(NSE), S100β and the activity of lactic dehydrogenase(LDH) in serum were measured by enzyme-linked immunosorbnent assay(ELISA).The specific blocker N-nitro-L-arginine-methyl-ester(L-NAME) and indomethacin(Indo) were used to delete the prostacyclin(PGI2) and nitric oxide(NO) dependent relaxation. The protein expression level of TRPV4 was detected by Western blotting.Ca~(2+) intensity in vascular smooth muscle cells was measured by confocal laser scanning microscope and flow cytometry was performed to observe the apoptosis of CBA endothelial cells after in vivo administration. RESULTS Hyp induced a dose-dependent relaxation of CBA in IR rats via a PGI2 and NO independent manner, as evidenced by alleviated pathological changes and up-regulated expression of TRPV4 protein in the endothelial cells from cerebral vessels. Hyp significantly reduced the contents of MDA, NSE, S100β and the activity of LDH in serum and decreased the fluorescence intensity of Ca~(2+) in cerebral vascular smooth muscle cells by in vivo administration. The apoptotic rate of endothelial cells in Hyp treated group was significantly less than that in IR group. CONCLUSION Hyp does in fact ameliorate I/R injury by regulating IP3/PKC/TRPV4 pathway.     

雷米普利对兔心肌梗死后心室肌短暂外向钾电流变化的影响

目的探讨血管紧张素转化酶抑制剂雷米普利对兔心肌梗死后室性心律失常发生的影响及其可能机制。方法将24只家兔完全随机分为假手术组、心肌梗死组和雷米普利组,每组8只。3组均在无菌条件下开胸,其中心肌梗死组和雷米普利组分别结扎左冠状动脉前降支。雷米普利组术后第2天给予雷米普利1mg／（kg·d）灌胃,3组均喂养12周。3组家兔分别在心肌梗死前、心肌梗死后12周记录程序刺激诱发的室性心动过速／心室颤动（VT／VF）发生次数,并采用全细胞膜片钳技术记录短暂外向钾电流（Ito）的变化。结果心肌梗死后12周,雷米普利组VT／VF的发生次数明显低于心肌梗死组[（3．0±0．6）比（12．7±1．5）,P〈0．05];假手术组、心肌梗死组和雷米普利组Ito电流密度分别为（8．69±0．57）pA／pF、（4．71±0．43）pA／pF和（7．32±0．68）pA／pF,心肌梗死组显著高于假手术组及雷米普利组（P〈0．05）;雷米普利组与假手术组比较差异无统计学意义（P〉0．05）。结论长期服用雷米普利可明显降低家兔心肌梗死后VT／VF的发生,其机制可能与抑制家兔心肌梗死后It0有关。     

芝麻素与维生素E联用对代谢综合征

目的:观察芝麻素与维生素E联用对代谢综合征大鼠肾脏的保护作用并探讨两药联用的协同关系.方法:采用高脂高糖饮食24周诱导大鼠代谢综合征,第9周(57 d)口服含芝麻素(30 mg·kg~(-1)·d~(-1))、芝麻素+维生素E[(30+20)、(15+20)mg·kg~(-1)·d~(-1)]和维生素E(20mg·kg~(-1)·d~(-1))饲料16周.24周末称体重和左肾湿重;测血糖、血脂、血压、肾功能、肾皮质氧化和抗氧化指标;HE和Masson染色观察肾脏形态及胶原沉积;免疫组化法表达诱导型一氧化氮合酶和硝基酪氨酸.结果:(1)模型组肾功能明显损害,肾小球发生硬化和肾间质纤维化,并出现大量炎症细胞浸润,肾小球和肾间质胶原沉积,脂质过氧化物损伤因子MDA、NO_2~-/NO_3~-和OH~-含量升高,iNOS蛋白和硝基酪氨酸表达明显上调,抗氧化酶保护因子T-SOD、CAT、GSH-Px活性显著降低;(2)芝麻素+维生素E[(30+20mg/kg)]组能明显降低血糖、血脂和血压,提高肾皮质总超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化酶活性,减少丙二醛、NO_2~-/NO_3~-和羟自由基含量,下调诱导型一氧化氮合酶和硝基酪氨酸,减轻肾小球与肾间质胶原沉积,逆转肾小球硬化和肾间质纤维化,改善肾功能,并且优于单用芝麻素组和维生素E组(P＜0.01或P＜0.05).结论:芝麻素(30 mg/kg)与维生素E(20 mg/kg)联用具有协同抗氧化和抗代谢综合征大鼠肾脏损伤作用.