选择性、非选择性内皮素受体拮抗剂对创伤性休克大鼠的影响

目的 探讨选择性、非选择性内皮素(ET)受体拮抗剂对创伤性休克大鼠的影响。方法 采用后肢创伤法建立创伤性休克大鼠模型,随机分为休克组、休克+BQ-123组和休克+PD142893组,分别于创伤前、休克末、复苏后 1、3、5 h检测血浆内皮素及骨骼肌、肝脏、小肠的组织氧分压,监测血流动力学变化并记录存活时间。结果 3组大鼠休克末及复苏后备时间点血浆内皮素浓度及组织氧分压较伤前差异有显著性(P<0.05),休克+BQ-123组于复苏后 1、3 h血浆内皮素浓度显著低于休克组(P<0.05),复苏后肝脏、小肠的组织氧分压较休克组显著升高(P<0.05),其 12、24 h存活率同休克组比较差异均有显著性(P<0.05)。结论 创伤性休克后血浆内皮素浓度显著升高,选择性ETA受体拮抗剂BQ-123可显著改善创伤性休克大鼠内脏组织氧分压,延长存活时间。     

波生坦对糖尿病高血压大鼠肾脏的保护作用

目的 观察内皮素受体阻为剂对糖尿病高血压大鼠的肾脏保护作用。方法 将自发性高血压大鼠建成链脲佐菌诱导的糖尿病模型,设ｂｏｓｅｎｔａｎ＋氨氯地平（ａｍｌｏｄｉｐｉｎｅ）组,ａｍｌｏｄｉｐｉｎｅ组,西拉普利组和非治疗组。４周后采用免疫组织化学和Ｗｅｓｔｅｒｎ ｂｌｏｔ方法观察肾脏细胞外基质和转化生长因子β１（ＴＧＦβ１）的改变。结果 与ＷＫＹ大鼠对照组相比,ＳＨＲ－ＤＭ大鼠２４小时尿蛋白出量增加,肌酐     

内皮素受体拮抗剂对肝硬化、门静脉高压大鼠内皮素受体mRNA表达的影响

内皮素(ET) 1是强力缩血管物质,在门静脉压力升高和维持中起重要作用[1] ,ET 1通过与其受体结合而发挥作用。ET受体至少可分为两种亚型,即ETA受体(ETRA)和ETB受体(ETRB) ,其中ETRB根据介导的舒张和收缩作用又分为ETRB1和ETRB2 [2 ] 。本实验旨在观察CCl4诱导的肝硬化、门静脉高压大鼠门静脉压力、肝组织ET受体mRNA表达的变化以及ETA受体拮抗剂(BQ 12 3 )、ETB受体拮抗剂(BQ 788)及两者联合应用对研究结果的影响。一、材料与方法1.实验对象:雄性SD大鼠,体重3 70～40 0 g ,参照文献[3 ]方法制备肝硬化、门静脉高压模型…     

内皮素受体拮抗剂对Fontan手术患者近期转归影响的前瞻性研究

目的研究内皮素受体拮抗剂对Fontan手术患者近期转归的影响。方法选取2009年1月至2010年12月于武汉亚洲心脏病医院行Fontan手术的患者39例,男25例、女14例,年龄2.5~18.0(8.02±4.98)岁。按照病案号单双号将患者分为内皮素受体拮抗剂组(波生坦组,n=16)和对照组(n=23)。波生坦组在术后3 d内按照推荐剂量开始灌胃(口服)波生坦,对照组不应用任何肺动脉高压靶向治疗药物,用药时间≥7 d。术后第10 d比较两组患者的死亡率等指标。结果波生坦组无死亡,对照组于术后第5 d死亡1例,两组术后死亡率差异无统计学意义(P0.05)。术后第10 d波生坦组患者在心功能、胸腔积液发生率、血管活性药物评分和血清B型脑钠肽、白蛋白、谷丙转氨酶方面均显著优于对照组(P0.05),而两组6分钟步行距离、经皮血氧饱和度、血白细胞、C反应蛋白、肌钙蛋白I、肌酐差异无统计学意义(P0.05)。结论内皮素受体拮抗剂能够改善患者Fontan术后的近期转归。     

波生坦治疗先天性心脏病术后肺动脉高压的前瞻性随机对照研究

目的 评价应用波生坦治疗婴幼儿先天性心脏病术后肺动脉高压的疗效.方法 30例术前合并肺动脉高压且手术治疗后仍有肺动脉高压的先大性心脏病病儿入选.所有病儿均在低温体外循环辅助下完成心内畸形根治术,术后1周行超声心动图检查,估测肺动脉收缩压＞30mm Hg者随机分配到波生坦治疗组(15例)及对照组(15例)中.研究周期12周,波生坦组:传统治疗+波生坦,波生坦给药方案:10～20 kg病儿,31.25 mg,每日1次(qd)4周,31.25 mg,每日2次(bid)8周;5～10 kg病儿,15.6 mg,qd(4周),15.6 mg,bid(8周);对照组:传统治疗(地高辛、双氢克脲塞).两组病例于术后13周接受门诊随访、调查问卷、超声检查和血液检查.比较两组心功能及临床症状,超声心动图评价血流动力学和肺动脉高压变化,以及血浆内皮素(Endothelin-1,ET-1)变化.结果 两组病例年龄、平均体重、病种分布、基线肺动脉收缩压力、基线血浆ET-1浓度均无统计学差异.心功能改善方而,依据NYHA心功能分级(级数增高定义为心功能恶化,降低则为心功能改善).波生坦治疗组93%的病儿心功能较基线水平改善Ⅰ级,无心功能恶化;对照组只有73%病儿心功能较基线水平改善Ⅰ级,13%病儿心功能较基线水平恶化Ⅰ级.将术后因心肺功能不全再入院及死亡定义为临床恶化,波生坦治疗组无再入院及死亡发生;而对照组13%的病儿发生了临床恶化(1例病儿术后11大死亡,1例病儿术后60天再入院).波生坦治疗组:基线(术后1周)肺动脉收缩压(48.5±9)mm Hg,治疗12周后(29.0±8.0)mm Hg,治疗前后差异有统计学意义(P＜0.01,95%CI:12～27);对照组:基线(术后1周)肺动脉收缩压(45.4±16)mm Hg,12周后(35.1±15.0)mm Hg手术前后差异无统计学意义(P＞0.1).两组之间比较,波生坦治疗组较对照组能更好的降低肺动脉压力(P＜0.05,95%CI:0.1～1 8.3).应用波生坦治疗后血浆ET下降(2.01±0.03)fmol/ml(1 fmol/ml=10-15mol/ml,P=0.03),对照组血浆ET升高(0.15±0.10)fmol/ml(P=0.77).波生坦组有2例肝脏转氨酶升高,停药后自然恢复正常,后未继续服药;无其他明显副作用.结论 波生坦治疗左向右分流的先天性心脏病术后残留肺动脉高压疗效明显,有助于病儿术后心功能及临床症状的恢复.     

内皮素受体拮抗剂对损伤脊髓早期保护作用

目的评价非选择性内皮素(ET)受体拮抗剂PD145065对损伤脊髓的保护作用,证实ET参与脊髓损伤(SCI)后继发损伤的假设并探讨其作用机制。方法压迫法致伤大鼠脊髓(50g,1min)。损伤前10min鞘内注射PD145065或生理盐水,观察脊髓血流(SCBF)、丙二醛(MDA)、细胞内钙(［Ca2+］i)、伊文思兰(EB)及水含量变化。结果伤区SCBF在伤后5min即有明显下降,为基线的(75.23±9.21)%,2h降为(57.06±7.35)%;伤区邻近血流下降较慢,伤后30min降为(79.82±7.98)%。伤区及邻近区伤后4h?SCBF都未恢复。伤段脊髓组织中MDA、［Ca2+］i、EB和水含量均高于假手术组(P＜0.05)。PD145065明显改善了伤区SCBF,消除了伤区邻近段SCBF的下降。PD145065预处理组脊髓中MDA、［Ca2+］i、EB和水含量均低于生理盐水组(P＜0.05)。结论PD145065对损伤脊髓早期有明显保护作用,ET及其受体可能通过多种途径参与SCI后的继发损伤。临床应用ET受体拮抗剂对SCI可能有治疗作用。     

内皮素受体拮抗剂改善皮瓣微循环实验研究

任何皮瓣一旦掀起,因手术创伤导致皮瓣血供、交感神经支配状况的改变,皮瓣微循环随之不可避免地发生一系列的生理病理变化,其最终转归是皮瓣能否成活和成活多少的内在原因。内皮素(ET)是1988年由Yanagisawa等从培养的猪主动脉内皮细胞的上清液中分离并命名,主要由血管内皮细胞合成,为目前所知最强的血管收缩活性肽,生物作用极其广泛。在应激、缺血、缺氧、酸中毒等病理条件下,均可刺激ET大量合成释放增加。已证实皮瓣掀起后ET合成、释放剧增,与皮瓣成活长度密切相关[1,2]。本实验拟研究皮瓣掀起后ET的动态变化,并探讨运用非选择性ET受…     

波生坦和依那普利对糖尿病大鼠肾脏中过氧化物酶体增殖物激活剂受体γ途径的作用

目的 探讨糖尿病状态下肾脏中过氧化物酶体增殖物激活剂受体(PPAR)γ途径的变化,以及此时应用内皮素受体拮抗剂bosentan和血管紧张素转化酶抑制剂enalapril对该途径的作用。方法采用单肾切除的小剂量链脲佐菌素(STZ)诱导的糖尿病大鼠模型,设非治疗组、bosentan治疗组、enalapril治疗组、两药合用组和单肾切除的对照组。分别采用免疫组织化学(组化)和RT-PCR等方法检测肾脏病变和PPARγ途径的情况,以及药物的作用。结果与糖尿病非治疗组相比,bosentan治疗组、enalapril治疗组和两药合用组的尿蛋白排泄量、肾小球细胞外基质(ECM)蛋白、肾脏转化生长因子(TGF)-β1和纤溶酶原激活物抑制物(PAI)-1的mRNA表达量均明显减少(P<0.01)。与正常对照组相比,4组模型动物肾脏PPARγ的mRNA表达量明显增加(P<0.01),而治疗组与非治疗组之间的PPARγ的mRNA表达量无明显变化。与正常对照组和非治疗组相比,肾脏的脂肪细胞-脂肪酸结合蛋白(A-FABP)的mRNA表达量在3个治疗组明显增加。与正常对照组相比,糖尿病非治疗组肾小球P-细胞外信号调节激酶(ERK)明显增加,而在3个治疗组则明显降低。结论 1型糖尿病大鼠肾脏内PPARγ的mRNA表达量明显增加,尽管bosentan和enalapril对此无明显作用,但两者都可以通过抑制ERK信号途径,增加PPARγ     

内皮素拮抗剂对创伤性休克大鼠的影响

目的　研究内皮素在创伤性休克过程中的意义 ,探讨咖啡酸拮抗内皮素对创伤性休克治疗的影响。方法　建立创伤性休克动物模型 ,根据应用咖啡酸的不同分为A组 (不用药 )、B组(创伤前用药 )、C组 (复苏即刻用药 )及D组 (复苏 3h用药 ) ,检测复苏后 5h血浆内皮素及组织氧分压 ,监测血液动力学变化并记录存活时间。结果　应用咖啡酸各组于复苏 5h血浆内皮素浓度均较A组低差异有显著性 (P <0 .0 5 ) ,复苏 5hB组的组织氧分压及平均存活时间较A组明显降低且有显著性 ,而D组同A组相比可明显改善组织氧分压 ,延长平均存活时间。结论　内皮素在休克早期对于维持血压有重要意义 ,早期应用咖啡酸拮抗内皮素反而使模型平均存活时间下降 ,而于休克后期应用咖啡酸拮抗内皮素可明显改善组织氧分压 ,延长模型存活时间。     

非选择性ATP受体拮抗剂对坐骨神经再生轴突诱向作用影响的实验研究

目的　探讨苏拉明对细胞外ATP的轴突化学性诱向作用的影响。　方法　选用SD雌性大鼠 10只 ,制作成鼠坐骨神经缺损模型 ,将“Y”形硅胶管单臂一侧与坐骨神经近断端行套入缝合。“Y”形硅胶管的两管臂远端用无损伤线交叉或平行缝合封闭 ,以区别实验侧和对照侧。与左侧坐骨神经套入缝合的硅胶管两壁内分别注入 1mmol/LATP、生理盐水 10 μl和 1mmol/LATP加 0 2mg/ml苏拉明 10μl;与右侧坐骨神经套入缝合的硅胶管硅胶管两壁内分别注入生理盐水 10 μl和 0 2mg/ml苏拉明 10μl。术后 8周取标本进行肉眼、光镜、电镜及图像分析系统观察和检测再生神经的形态、有髓纤维的数目、形态、髓鞘厚度等。　结果　含ATP组再生神经干内有髓纤维的数目 (2 2 46± 2 2 2 )明显多于含生理盐水组 (10 61± 161) ,后者又明显多于含苏拉明组 (2 66± 84)。ATP受体非特异性拮抗剂苏拉明能完全阻断细胞外ATP对外周神经再生轴突的诱向作用。单纯的苏拉明对再生轴突也具有非常明显的抑制作用。　结论　细胞外ATP通过受体介导外周神经再生轴突的诱向作用     

The Effects of Endothelin Receptor Blockade by Bosentan on the Healing of a Bowel Anastomosis in an Experimental Crohn’s Disease Model

Objective  It was previously described that endothelins may contribute to the pathogenesis of Crohn’s disease. In this study, it was aimed to investigate the effects of endothelin receptor blockade by bosentan on the healing of a bowel anastomosis in an experimental Crohn’s disease model. Material and Methods  Twenty-eight Sprague–Dawley rats were divided into four groups. Groups I and II were used as sham-operated and control groups, respectively. Bowel inflammation induced by intrajejunal injection of iodoacetamide in groups III and IV. Rats in group IV were treated with oral preparation of bosentan 60 mg/kg/day. Three days after induction of the inflammation, partial resection of test loop and anastomosis was performed. Re-laparotomy was performed, anastomosis bursting pressures and peritonitis scores were measured, and tissue samples were obtained for the measurements of tissue hydroxylproline level and mucosal damage index 4 days later. Results  The mean mucosal damage index and peritonitis score of group IV were significantly lower, and the mean tissue hydroxyproline level and anastomotic bursting pressure of group IV were significantly higher than those of group III. Conclusion  The blockade of endothelin receptors by bosentan decreases the severity of iodoacetamide induced intestinal inflammation, increases the wound healing in the inflamed intestinal tissue, and decreases the severity of peritonitis. This study was supported by The Coordination Committee of Scientific Researches and Projects of Fırat University.     

舒洛地特对糖尿病大鼠肾脏病变的影响

目的:探讨2种剂量舒洛地特对糖尿病大鼠肾脏病变的影响。方法:采用STZ(链尿佐霉素,60mg/kg)腹腔注射法构建1型糖尿病大鼠模型,随机分为4组:糖尿病组(DM组)、舒洛地特10mg·kg-1·d-1组(S10组)、舒洛地特20mg·kg-1·d-1组(S20组)、氯沙坦30mg·kg-1·d-1组(L组),每组各10只。另取10只未造模大鼠作正常对照组(N组)。干预12周后测体重、24h尿白蛋白定量、血糖、血肌酐、尿素氮及肾重,光镜、电镜观察肾组织形态、结构的变化。结果:同N组相比,DM组大鼠24h尿白蛋白定量、血肌酐及尿素氮显著增加(P<0.01),病理改变较明显。同DM组相比,治疗组(S10、S20及L组)大鼠24h尿白蛋白定量减少(P<0.05或P<0.01),但血肌酐及尿素氮下降差异无统计学意义(P>0.05);同S10组相比,S20及L组大鼠24h尿白蛋白定量减少(P<0.05)。光镜及电镜显示治疗组较DM组病理变化减轻,尤以S20及L组病变减轻明显。结论:舒洛地特可对糖尿病大鼠有肾脏保护作用,而20mg·kg-1·d-1较10mg·kg-1·d-1的剂量效果更好。     

泛影葡胺和碘曲仑对糖尿病大鼠肾毒性的比较

目的:观察高渗离子造影剂76%泛影葡胺和等渗非离子造影剂碘曲仑对糖尿病大鼠肾毒性的不同.方法:建立单侧肾切除糖尿病大鼠模型,模型建立8周后,禁水24 h,尾静脉分别一次性注射76%泛影葡胺和碘曲仑[10 ml/kg,3 gI(iodine)/10 ml].72 h后按不同要求留取血及组织标本,测定大鼠血肌酐和尿素氮,放射免疫法测定血及肾组织中ET的浓度,硝酸还原酶法测定NO水平,同时观察肾组织形态变化.结果:糖尿病大鼠血肌酐、尿素氮与正常组相比均明显增加(P<0.01),HOCM组血肌酐、尿素氮较DM组进一步升高(P<0.05),且HOCM组与DM组相比,ET水平升高、NO含量进一步减少(P<0.05),ET/NO比值显著增高(P<0.01),而IOCM组各项指标均较DM组变化不明显;形态学观察结果亦提示76%泛影葡胺引起的肾脏改变较明显.结论:高渗离子造影剂泛影葡胺可以引起糖尿病大鼠肾功能明显降低,而非离子等渗造影剂碘曲仑引起肾功能下降轻微,这可能与泛影葡胺导致了糖尿病大鼠肾组织ET/NO的严重失衡有关.碘曲仑在糖尿病大鼠较少引起造影剂肾病.     

Effect of the Endothelin Receptor Antagonist Bosentan on Postischemic Oxygen Supply of the Liver

Endothelin evokes strong and longlasting constriction of postischemic sinusoids, leading to microcirculatory disturbances and local hypoxia, thereby causing liver damage. The aim of the study wus to avoid the constrictive response of sinusoids by blocking endothelin receptors. In an in vivo ischemia-reperfusion model (21 female Wistar rats, 250–300 g) with portal decompression by a splenocaval shunt, hepatic ischemia was induced for 30 min by cross clamping of the hepatoduodenal ligament. The endothelin receptor antagonist bosentan (10 mg/kg bw IV) was administered before ischemia. The effect of the receptor antagonist was assessed by serum levels of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) that were determined prior to ischemia, 2 and 6 h postoperatively. The local tissue pO₂ was measured prior to inducing ischemia, 30 and 60 min after reperfusion. Application of 10 mg/kg bw endothelin receptor antagonist (ERA) intravenously did not influence the systemic blood pressure. The postischemic increase in serum ASAT and ALAT levels was diminished after receptor antagonist treatment (ASAT: p <. 05). Local postischemic hepatic tissue pO₂ was significantly decreased to 45% of basal values after 30 min and to 54.8% after 60 min of reperfusion (p <.05). Application of ERA results in a significant increase in local tissue pO₂ to 110.9% of basal values after 30 min and to 90.7% after 60 min of reperfusion (p <. 05). These data indicate that the endothelin receptor antagonist treatment results in a prevention of postischemic sinusoidal constriction avoiding hypoxia and leading to improved hepatocellular recovely     

缬沙坦对糖尿病大鼠肾皮质TGF-β1表达的影响

目的:探讨血管紧张素Ⅱ受体拮抗剂缬沙坦(Valsartan)对实验性糖尿病大鼠肾皮质TGF-β1表达的影响,为糖尿病肾病的防治提供实验性理论基础.方法:选择健康雄性SD大鼠24只,任取其中16只腹腔注射链脲佐菌素制成糖尿病大鼠模型.将糖尿病大鼠随机分为糖尿病缬沙坦治疗组(A组,8只,缬沙坦10 mg*kg-1*d-1灌胃);糖尿病对照组(B组,8只);其余8只为正常对照组(C组).分别于实验第6周末测定各组大鼠血糖、血肌酐、尿白蛋白排泄率,对肾脏标本进行光镜观察,用图像分析仪测量各组大鼠平均肾小球面积、平均肾小球体积.并取各组大鼠肾皮质提取RNA,用逆转录-PCR(RT-PCR)方法对肾皮质TGF-β1 mRNA表达进行半定量分析.结果:在糖尿病第6周末,B组上述指标较C组均有不同程度的升高(P＜0.01),而A组则显著低于同时期的B组.其中,A组、C组尿白蛋白排泄率始终无统计学差异,肾小球平均面积、平均体积A组显著低于B组(P＜0.01).RT-PCR半定量结果分析显示,B组TGF-β1 mRNA表达较A组、C组显著增高(P＜0.01),A组TGF-β1 mRNA表达较C组为高(P＜0.01),但仍较B组为低(P＜0.05).结论:缬沙坦能够抑制肾组织TGF-β1 mRNA的表达,减少糖尿病大鼠的尿白蛋白,减轻及延缓肾小球硬化,发挥保护肾脏的作用.     

Endothelin Receptor Antagonism Attenuates Cardiomyocyte Apoptosis after Induction of Ischemia in Rats

Objective : Apoptosis has recently been implicated as a process that may contribute to loss of cardiomyocytes and to adverse myocardial remodeling in congestive heart failure (CHF). We investigated to what extent myocardial ischemia and CHF lead to induction of apoptotic gene programs and loss of cardiomyocytes through apoptosis, and subsequently to what extent the beneficial effects of endothelin (ET) receptor antagonism after myocardial infarction (MI) could be attributed to reduction of apoptotic cell loss in the myocardium. Design : Northern blot analysis, analysis of DNA fragmentation, and immunohistochemical analysis were performed after induction of MI in rats. Results : After induction of MI, the mRNA levels of the pro-apoptotic genes FAS, BAX, P53, and CASPASE-1 were significantly increased in the non-ischemic region of the left ventricle (LV) with highest levels of expression in the peri-infarct area. High levels of FAS, BAX, P53, and CASPASE-1 mRNA were also observed in the infarcted region. Concomitantly, numerous TUNEL-positive cells and internucleosomal degradation of DNA were found in tissue from the peri-infarct area and in the infarcted zone, indicating apoptotic cell death. Treatment with bosentan, a mixed ET A /ET B receptor antagonist, during the first 24 h after induction of MI significantly reduced the area of TUNEL-positive myocardium in the ischemic region (64 &#45 2% of LV circumference in the vehicle group vs 55 &#45 2% of LV circumference in the bosentan group, p < 0.05). Consistently, bosentan also caused a similar reduction of infarct size. Conclusion : Our data demonstrate activation of pro-apoptotic genes and provide evidence of cardiomyocyte apoptosis in the viable peri-infarct area and in the infarcted region after MI in rats. Intervention with bosentan may attenuate cardiomyocyte cell loss through apoptosis in the area at risk after induction of ischemia.     

Pretreatment of Donors with Endothelin Receptor Antagonist TAK-044 Improves Cardiac Functional Recovery Following Preservation with University of Wisconsin Solution

Objective : Previous studies suggest that endothelin-1 (ET-1) plays a role in myocardial ischemia/reperfusion injury. Although administration of an endothelin receptor antagonist to the recipient has been shown to improve myocardial function after ischemia/reperfusion in a rat heart transplantation model, the effect of administering an endothelin receptor antagonist to the donor has not yet been examined. This study was designed to investigate the effects of pretreating donors with an ET A /ET B endothelin receptor antagonist (TAK-044) on myocardial function after cold preservation of a rat heart. Design : Male rats were pretreated with normal saline (control group, n = 8), TAK-044 (TAK group, n = 8, 1 mg/kg). Following cardiac arrest using cardioplegia, we washed out the coronary vascular beds with cold University of Wisconsin solution followed by 6-h preservation. After preservation, the hearts were mounted on a Langendorff apparatus to estimate aortic flow (AF), coronary flow (CF), cardiac output (CO), systolic pressure (SP), heart rate (HR), and rate-pressure product (RPP: HR &#50 SP). The concentration of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) within the coronary perfusate during reperfusion was measured. Results : AF, SP, and CO were significantly greater in the TAK group than in the control group ( p = 0.0045, 0.004, and 0.0295, respectively). Conclusion : Pretreatment of donors with a nonselective endothelin receptor antagonist (TAK-044) improved cardiac functional recovery following preservation and may be beneficial for prolonged myocardial preservation.     

内皮素在大鼠梗阻性黄疸肝脏损伤中的作用

目的：观察大鼠胆管梗阻后内皮素在肝组织及血液中的分泌状况及甘胆酸的变化，探讨内皮素与甘胆酸之间的关系。方法：用放射免疫法观察大鼠胆管梗阻后5、10、15、20、25天时血及肝组织中内皮素含量，组织病理切片观察肝脏的病理改变。结果与结论：内皮素含量随梗阻性黄疸后时间延长而递增,与甘胆酸升高水平呈正相关（P＜0.01），说明内皮素可能是参与梗阻性黄疸致肝脏损伤的重要因素之一。