环维黄杨星D对大鼠的肾脏毒性

目的观察环维黄杨星D(CVB-D)对大鼠的肾脏毒性及其可逆性。方法 120只大鼠随机分为正常对照组,CVB-D2.5,5和10mg·kg-1组,每组30只。CVB-D组大鼠分别ip给予CVB-D2个月,并于给药后第1和第2个月末每组各取10只大鼠的眼眶血分离血清,检测尿素氮(BUN)、肌酐(SCr)、TammHorsfall蛋白(THP)、β2微球蛋白(β2-MG);收集24h尿液检测N-乙酰-β-氨基葡萄糖苷酶(NAG)、微量白蛋白(mAlb)、免疫球蛋白G(IgG)、视黄醇结合蛋白(RBP)、β2微球蛋白(β2-MG)和转铁蛋白(TRF);并做肾脏组织病理学检测。作为恢复期观察,停药4周后每组另10只大鼠做同样检查。结果与正常对照组相比,ip给予大鼠CVB-D1个月后,大鼠血清中的β2-MG明显升高(P<0.01),CVB-D5和10mg·kg-1组的THP含量明显降低(P<0.01),CVB-D10mg·kg-1组大鼠血清中BUN含量升高(P<0.01);同时,CVB-D10mg·kg-1组大鼠尿液中NAG,TRF,β2-MG和IgG含量显著升高,CVB-D5和10mg·kg-1组尿液mAlb含量及RBP含量均显著升高(P<0.05,P<0.01)。持续给药2个月后,CVB-D5和10mg·kg-1组大鼠血清中β2-MG含量显著升高(P<0.05),CVB-D5mg·kg-1组BUN含量明显升高(P<0.05),CVB-D10mg·kg-1组THP含量显著降低(P<0.05);同时,CVB-D10mg·kg-1组大鼠尿液中NAG和IgG含量明显升高(P<0.05,P<0.01),CVB-D5和10mg·kg-1组β2-MG和TRF含量明显升高(P<0.01);病理组织切片显示CVB-D2.5mg·kg-1组部分动物肾小球及肾小管出现坏死的现象,CVB-D5和10mg·kg-1组部分动物出现组织自溶现象。在恢复期,血清及尿液中仍有部分指标显著高于正常对照组,病理组织切片显示CVB-D组仍有部分肾单位出现肾间质内少量炎细胞浸润或不同程度淤血的现象。结论长期应用CVB-D可能引起大鼠肾毒性,且病变在停药后不能彻底恢复。     

丹参多酚酸盐对肾间质纤维化模型大鼠的改善作用及机制研究

目的:研究丹参多酚酸盐对肾间质纤维化(RIF)模型大鼠的改善作用及可能机制。方法:将50只雄性SD大鼠按体质量随机分为正常组、模型组、氯沙坦组(阳性对照组,9 mg/kg)和丹参多酚酸盐低、高剂量组(18、36 mg/kg),每组10只。除正常组外,其余各组大鼠均灌胃腺嘌呤250 mg/kg建立RIF模型。造模结束后,各给药组大鼠灌胃相应药物,正常组和模型组大鼠灌胃等体积生理盐水,灌胃体积均为10 mL/kg,每天1次,连续30天。末次给药后,采用酶联免疫吸附测定法检测大鼠血清中肌酐(Scr)、尿素氮(BUN)和尿液中24 h尿蛋白(24 h UPro)水平;采用苏木精-伊红染色法和Masson染色法分别观察大鼠肾组织病理学特点和纤维化情况,对肾小管损伤、肾小球硬化程度进行评分并计算肾组织阳性染色面积百分比;采用免疫组化法和Western blot法分别测定大鼠肾组织中Wnt蛋白(Wnt5a、Wnt5b)、β-联蛋白(β-catenin)的表达水平。结果:与正常组比较,模型组大鼠Scr、BUN、24 h UPro水平和肾小管损伤评分、肾小球硬化评分、肾组织阳性染色面积百分比以及Wnt5a、β-catenin蛋白的表达水平均显著升高(P<0.05),Wnt5b蛋白的表达水平显著降低(P<0.05);显微镜下可见大鼠肾组织出现系膜增生、纤维组织增多、炎性细胞浸润等病理学变化。与模型组比较,氯沙坦组和丹参多酚酸盐低、高剂量组大鼠的上述指标均显著改善(P<0.05),且丹参多酚酸盐的作用具有一定的剂量依赖性趋势。结论:丹参多酚酸盐对腺嘌呤致RIF模型大鼠具有改善作用,其机制可能与抑制Wnt/β-catenin信号通路有关。     

表没食子儿茶素没食子酸酯对肾缺血再灌注损伤的保护作用

目的　探讨表没食子儿茶素没食子酸酯 (EGCG)对大鼠肾缺血再灌注损伤的影响。方法　通过结扎肾动脉 60min后再灌注 ,建立大鼠肾缺血再灌注损伤模型 ,给药组于结扎前后分别静脉给予 10mg·kg-1和 40mg·kg-1EGCG。化学法观察大鼠血清肌酐 (Scr)、尿素氮 (Bun)、丙二醛(MDA)含量 ,肾组织内MDA、活性氧 (ROS)含量和超氧化物歧化酶 (SOD)、Ca2 + ATP酶活性的变化 ,并观察肾组织的病理变化。结果　与模型对照组比较 ,40mg·kg-1的EGCG组可抑制由肾缺血再灌注引起的血清Bun、Scr、MDA含量和组织MDA、ROS含量的变化 ,增强SOD和Ca2 + ATP酶活性 ,减轻肾组织病理改变。结论　EGCG有保护大鼠肾缺血再灌注损伤的作用 ,其机制可能与抗自由基损伤和减少细胞内钙有关     

D-硝基精氨酸对小鼠肾损伤及氧化应激作用

目的研究D-硝基精氨酸(D-NNA)对小鼠的肾损伤及其氧化应激机制。方法 ICR小鼠ig给予D-NNA150,50和15 mg·kg-1,连续30 d。测定并计算肾系数;血液生化分析仪检测血清中肌酐(Crea)和尿素氮(BUN);分光光度法测定肾组织一氧化氮(NO),硫代巴比妥酸法测丙二醛(MDA)含量,比色法测定谷胱甘肽过氧化酶(GSH-Px)和超氧化物歧化酶(SOD)活性;观察肾病理组织学变化。结果与5%葡萄糖对照组相比,D-NNA 150,50和15 mg·kg-1组血清中BUN分别明显升高了83.6%,36.2%和27.4%(P<0.05),D-NNA150和50 mg·kg-1组血清中Crea分别明显升高了281.6%和10.6%(P<0.05);D-NNA150 mg·kg-1组肾系数和NO水平分别明显降低了5.6%和25.5%(P<0.05);D-NNA150和50 mg·kg-1组肾组织中MDA水平分别明显升高了69.0%和36.9%(P<0.01),SOD活性和GSH-Px活性分别明显下降了17.4%和17.7%,7.3%和13.7%(P<0.05);D-NNA150 mg·kg-1组病理检查可见肾小管损伤,嗜碱性变,萎缩或囊性扩张和间质炎性浸润,D-NNA50和15 mg·kg-1组出现炎症细胞浸润。结论 D-NNA对小鼠肾有一定的损伤作用,其作用机制可能与D-NNA的手性转化产物L-NNA导致NO合成减少,产生ROS有关。     

白芍总苷对糖尿病大鼠肾脏保护作用及部分机制

目的探讨白芍总苷(TGP)对糖尿病大鼠肾脏保护作用及部分机制。方法应用链脲佐菌素诱导大鼠糖尿病模型,同时每日灌胃给予TGP(50,100,200mg·kg-1,连续8wk。结果TGP给药呈剂量依赖性降低糖尿病大鼠AER的增加。TGP给药(50mg·kg-1)大鼠肾小球平均容量(VG)明显低于模型组,肾小管-间质损伤指数(TII)较模型组有所下降,但差异无统计学意义;TGP给药(100,200mg·kg-1VG与TII均明显低于模型组。模型组肾组织MDA含量明显高于对照组,TGP给药(200mg·kg-1)大鼠肾组织MDA含量明显低于模型组。Western blot显示模型组肾组织1α(IV)Ⅳ型胶原蛋白表达较对照组增加2.7倍,TGP给药(50、100、200mg·kg-1)8wk分别可使肾组织1α(IV)Ⅳ型胶原蛋白表达下降47.9%、60.4%与72.9%。模型组肾组织ICAM-1及TGFβ1蛋白表达明显高于对照组,TGP给药(50,100,200mg·kg-1)肾组织ICAM-1与TGFβ1蛋白表达明显低于模型组。结论TGP对糖尿病大鼠肾脏保护作用机制部分与其抑制肾组织中ICAM-1及TGFβ1蛋白表达有关。     

慢肾灵颗粒剂治疗大鼠慢性肾功能衰竭的药效学研究

目的 观察慢肾灵颗粒剂(抗肾功能衰竭中药方剂)对柔红霉素所致大鼠慢性肾功能衰竭(CRF)的药效.方法 用单侧大鼠肾切除加尾静脉重复注射柔红霉素,建立CRF动物模型,降正常组外,将造模大鼠随机分为5组:模型组、阴性对照组(尿毒清颗粒2.3 g·kg-1)及大、中、小剂量(慢肾灵颗粒剂2.70、1.35、0.68 g·kg-1)实验组,观察慢肾灵颗粒剂对CRF大鼠肾脏的保护作用.结果 慢肾灵颗粒剂大、中剂量组的尿蛋白排泄量、血清肌酐、尿素氮水平均显著低于模型组;肾小球增生、硬化程度均显著轻于模型组.结论 慢肾灵颗粒剂能减轻CRF大鼠的肾脏损害,有效地延缓CRF的进展.     

小檗碱对2型糖尿病大鼠肾组织细胞周期蛋白依赖激酶9和细胞周期蛋白T1表达的影响(英文)

目的观察2型糖尿病大鼠肾组织细胞周期蛋白依赖激酶9(Cdk9)和细胞周期蛋白(cyclin )T1蛋白的表达及小檗碱的影响。方法小剂量注射链佐星(链脲菌素)加高糖高脂饲料喂养16周建立2型糖尿病大鼠模型,随后16周每天分别给予小檗碱75,150及300 mg·kg-1、非诺贝特100 mg·kg-1和罗格列酮4 mg·kg-1。处死大鼠后用HE染色检查肾组织结构和免疫组化技术检测Cdk9和cyclin T1的表达。结果糖尿病模型大鼠肾小球体积增大,部分系膜细胞增生和系膜区扩张,肾小球及肾小管基底膜增厚,肾重/体重比值增加;150及300 mg·kg-1小檗碱和罗格列酮能部分改善糖尿病性肾组织病变和降低肾重/体重比值。150及300 mg·kg-1小檗碱和罗格列酮都能明显恢复糖尿病肾组织中降低了的Cdk9和cyclin T1表达至接近正常水平。结论小檗碱通过调控肾组织Cdk9和cyclin T1的表达能部分改善实验性糖尿病大鼠肾组织病变。     

番茄红素抑制AGEs/RAGE信号通路对慢性肾功能衰竭大鼠血管钙化的影响

摘要：目的:探究番茄红素（Lyc）抑制糖基化终末产物（AGEs）/AGEs受体（RAGE）信号通路对慢性肾功能衰竭（CKF）大鼠血管钙化的影响。方法:48只大鼠随机分为正常对照组、模型组、阳性对照组(氯沙坦9 mg·kg-1)、Lyc低、高剂量组(10和20 mg·kg-1)及AGEs激动剂+Lyc高剂量组(AGEs-BSA 40 mg·kg-1+Lyc 20 mg·kg-1),每组8只。除正常对照组外,其余各组采用腺嘌呤喂食法制备大鼠CKF血管钙化模型。采用ELISA试剂盒检测血肌酐（SCr）和血尿素氮（BUN）含量;HE染色观察肾组织病理变化;比色法检测腹主动脉组织中钙含量;Von Kossa染色观察腹主动脉组织钙化情况;比色法检测腹主动脉组织中AGEs含量;Western blot检测腹主动脉组织中RAGE含量。结果:与正常对照组比较,模型组大鼠SCr和BUN含量显著增加（P＜0.05）;肾组织发生明显病理改变,肾小球内细胞数目增多、结构紊乱,肾小管扩张、坏死,肾皮质变薄、皮髓质界限不清,肾间质可见炎性细胞浸润及纤维化;腹主动脉组织中钙含量显著增加（P＜0.05）,同时中层可见大量黑色颗粒,发生明显钙化;腹主动脉组织中AGEs和RAGE含量均显著增加（P＜0.05）。与模型组比较,Lyc低、高剂量组大鼠SCr和BUN含量均显著减少（P＜0.05）;肾组织病理损伤减轻;腹主动脉组织中钙含量减少（P＜0.05）,同时钙化程度减轻;腹主动脉组织中AGEs和RAGE含量均显著减少（P＜0.05）,高剂量组变化更为显著。与高剂量组比较,AGEs激动剂+高剂量Lyc组大鼠上述情况有所逆转。结论:Lyc能够减轻CKF大鼠肾损伤,改善其血管钙化,可能通过抑制AGEs/RAGE信号通路而实现。     

次黄嘌呤与氧嗪酸钾不同剂量配伍制备高尿酸血症大鼠模型

目的确定次黄嘌呤与尿酸酶抑制剂氧嗪酸钾(OAPS)伍用制备高尿酸血症大鼠模型的合适剂量,为制备持续性高尿酸血症及痛风大鼠模型提供实验依据。方法给大鼠不同配伍剂量的次黄嘌呤(ig)与OAPS(sc)制备代谢性高尿酸血症大鼠模型,于造模后不同时间观察模型大鼠血清尿酸、尿素氮和肌酐水平。结果次黄嘌呤分别为125,250和500mg·kg-1,OAPS以25,50和100mg·kg-1与每个剂量的次黄嘌呤伍用造模。造模后3h血清尿酸和肌酐浓度均有所升高,造模后9h血清尿素氮浓度明显升高。在次黄嘌呤为500mg·kg-1,OAPS为100mg·kg-1时,造模后3,9和12h模型大鼠血清尿酸浓度分别为(781±167),(627±291)和(366±196)μmol·L-1,明显高于正常对照组(86±10),(75±16)和(80±15)μmol·L-1;造模后24h,血清尿素氮和肌酐水平〔(199±96)mg.L-1和(55±16)μmol·L-1〕均明显高于正常对照组〔(61±5)mg.L-1和(21±2)μmol·L-1〕。结论次黄嘌呤500mg·kg-1和OAPS100mg·kg-1伍用制备的代谢性高尿酸血症大鼠模型具有血清尿酸浓度高和维持时间长的特点。     

虫草菌丝对慢性肾功能衰竭大鼠微炎症反应的影响

目的考察慢性肾功能衰竭(CRF)模型大鼠肾脏组织NF-κB-p65与血清C反应蛋白(CRP)和白细胞介素6(IL-6)浓度的关系,并探讨虫草菌丝对NF-κB表达的抑制作用及其用于治疗微炎症反应的可能性。方法 50只雄性Wistar大鼠随机分为假手术组、模型组、四氢化吡咯二硫代氨基甲酸酯(PDTC)阳性对照组、虫草菌丝3和6g·kg-1治疗组。建模前1d各组大鼠尾静脉抽血,并留取24h尿液,第2天假手术组行假手术,其余4组切除右肾上、下两极约70%肾脏;10d后假手术组再次进行"假手术",其余4组再经左腹壁切除左肾,制备5/6肾切除CRF大鼠模型。建模2周后,PDTC组隔日ip给予PDTC0.01g·kg-1,虫草菌丝治疗组分别ig给予虫草菌丝3和6g·kg-1,每天1次,共12周;假手术组和模型组ig给予等体积生理盐水;给药12周后各组留取血样和24h尿液,处死大鼠取肾。ELISA法检测血清CRP和IL-6浓度,全自动生化仪检测血清肌酐浓度,考马斯亮蓝法测定24h尿蛋白,实时荧光定量RT-PCR法和免疫组织化学法检测肾组织NF-κB-p65mRNA和蛋白表达。结果①建模前,各组大鼠24h尿蛋白和血清肌酐浓度无明显差异;建模14周后,模型组、PDTC组、虫草菌丝3和6g·kg-1组24h尿蛋白和血清肌酐浓度较建模前均明显升高(P<0.01),模型组较假手术组亦明显升高(P<0.01);模型组大鼠肾组织均出现肾小球球囊粘连、局灶节段性硬化及肾小管灶状萎缩和代偿性肥大等CRF病理改变;给药12周后,PDTC组、虫草菌丝3和6g·kg-1组大鼠肾组织病理变化与模型组比较无明显改善,虫草菌丝3和6g·kg-1组24h尿蛋白和血清肌酐浓度明显降低(P<0.01)。②给药12周后,模型组与假手术组比较,血清CRP和IL-6浓度及肾组织NF-κB-p65mRNA和蛋白表达均明显升高(P<0.01),PDTC组、虫草菌丝3和6g·kg-1组与模型组比较均明显降低(P<0.01),虫草菌丝6g·kg-1组比3g·kg-1组降低更为明显(P<0.05)。③各组肾组织NF-κB-p65mRNA表达与血清CRP和IL-6浓度进行直线相关分析结果表明,假手术组肾脏NF-κB-p65mRNA表达与血清CRP和IL-6浓度之间无相关性,其余4组肾组织NF-κB-p65mRNA表达与血清CRP和IL-6浓度明显正相关(P<0.05,P<0.01)。结论 CRF大鼠肾脏NF-κB-p65表达与血清CRP和IL-6浓度正相关;虫草菌丝可抑制CRF大鼠肾脏NF-κB-p65mRNA和蛋白表达,对CRF大鼠微炎症反应具有一定的治疗作用。     

丹参多酚酸盐治疗早期慢性肾衰竭及对血浆ET-1和CGRP水平的影响

目的探讨丹参多酚酸盐在治疗早期慢性肾衰竭中的作用及机制。方法 54例患者随机分为2组,常规治疗组27例（简称常规组）;常规＋丹参多酚酸盐治疗组27例（简称研究组）。观察丹参多酚酸盐治疗前后肾功能、尿蛋白及血浆ET-1和CGRP水平的变化。结果 CRF患者血浆ET-1水平高于对照组,而血浆CGRP水平偏低;两者在治疗后均显著改善,但以研究组改善更为显著,与常规组治疗后比较,血浆ET-1水平降低（P〈0.05）,而血浆CGRP水平增高（P〈0.01）。CRF患者血浆ET-1水平与血清Scr、尿蛋白呈正相关;而血浆CGRP水平与后两者均呈负相关;血浆ET-1水平与CGRP呈负相关。丹参多酚酸盐治疗后,血浆ET-1水平与Scr、尿蛋白及血浆CGRP之间的相关关系和治疗前一致。结论丹参多酚酸盐能降低CRF患者血浆ET-1水平,增加血浆CGRP水平,减少尿蛋白,改善肾功能,故值得临床应用。     

凯时注射液与丹参多酚酸盐共同治疗慢性肾功能衰竭的临床分析

目的探究前列地尔注射液(商品名:凯时)与丹参多酚酸盐共同治疗慢性肾功能衰竭(CRF)的临床效果。方法126例CRF患者,按照随机数表法分为对照组与观察组,每组63例。对照组针对饮食进行合理控制,行优质低蛋白低磷饮食,观察组在对照组治疗基础上加以凯时注射液与丹参多酚酸盐进行治疗。对比两组患者治疗前后肾功能指标[血尿素氮(BUN)、血肌酐(Scr)、肌酐清除率(Ccr)]、临床疗效及不良反应发生情况。结果治疗后,两组患者BUN、Scr、Ccr水平均优于本组治疗前,且观察组优于对照组,差异均具有统计学意义(P<0.05)。观察组治疗总有效率95.24%显著高于对照组的82.54%,差异具有统计学意义(P<0.05)。对照组不良反应发生率6.35%显著低于对照组的20.63%,差异具有统计学意义(P<0.05)。结论在CRP的治疗中使用凯时注射液联合丹参多酚酸盐可使患者的肾功能指标得到显著改善,提高治疗有效率并减少不良反应的情况发生,值得推荐。     

川芎嗪对大鼠实验性慢性肾功能衰竭的治疗作用

目的 探讨川芎嗪对大鼠实验性慢性肾功能衰竭的治疗作用。方法 采用改良方法制造大鼠慢性肾功能衰竭模型：一次手术切除左例全部肾脏及右侧2／3肾脏，二周后测定大鼠血清肌酐和尿素氮含量，建立大鼠慢性肾功能衰竭模型。给予川芎嗪60mg／kg，1次／日口服，连续治疗100天。结果 川芎嗪可明显改善实验动物的肾功能，降低该模型肾皮质丙二醛含量并明显增加肾皮质SOD活性，还可增加该模型近曲小管细胞及远曲小管细胞cAMP含量。结论 提示川芎嗪治疗慢性肾功能衰竭的机理与其增加肾皮质SOD活性、降低肾皮质的脂质过氧化、并增加近曲肾小管细胞和远曲肾小管细胞cAMP含量有关。     

Changes of calcium content and plasma membrane Ca-ATPase activity in renal cortex of rats treated with stannous chloride

A single intraperitoneal (i.p.) injection of stannous chloride (3.0 mg Sn/ 100 g body weight) to rats markedly increases the calcium content of renal cortex and significantly decreases Ca-ATPase and alkaline phosphatase activities in the plasma membrane fraction of renal cortex. The results suggest that the calcium accumulation in the renal cortex is due partly to the inhibition of calcium efflux from the cells.     

Water immersion induced alterations of plasma adrenaline and noradrenaline levels in patients with endstage renal failure (CRF) and in healthy persons

Water immersion (WI) induced alterations of adrenaline and noradrenaline levels were examined in 20 patients with chronic renal failure (CRF) and 15 healthy persons. In patients with CRF a significantly elevated mean arterial blood pressure (MAP), a markedly elevated plasma level of adrenaline but only a slightly elevated concentration of plasma noradrenaline were observed as compared with healthy persons. In all examined groups WI induced significant decrease of mean arterial pressure and plasma adrenaline and noradrenaline levels. In patients with CRF the WI induced a decrease of MAP and of plasma adrenaline was significantly more marked, while that of plasma noradrenaline was significantly less than in healthy persons. Results presented in this study suggest the existence of an impaired function of the sympathetic nervous system, mainly of the beta-adrenergic one in CRF.     

Carotid artery intima-medial thickness is increased in chronic renal failure

1. Chronic renal failure (CRF) is associated with rapidly progressive atherosclerotic vascular disease. In the present study, carotid arterial intima-medial thickness (IMT) was assessed in a large cohort of patients with CRF and matched controls and related to risk factors. 2. A total of 159 subjects with CRF (serum creatinine > or =0.40 mmol/L) aged > 50 years (mean (+/-SD) 63.8+/-7.7 years) and 159 healthy controls matched for age, sex and smoking status were studied. 3. The IMT was determined using B-mode ultrasound measurements of the far wall of both common carotid arteries and presented as the mean IMT. Fasting plasma homocysteine (tHcy) was measured in the CRF group. 4. Intima-medial thickness was significantly greater in CRF patients than controls (0.89+/-0.17 vs 0.73+/-0.13 mm, respectively) after matching for age, sex and smoking status. Heart rate and pulse pressure were also significantly increased. The tHcy was increased two-fold in the CRF group (27.7+/-11.3 micromol/L; normal < 13.0 micromol/L) and did not correlate with carotid IMT. 5. Compared with controls after adjusting for traditional risk factors, patients with CRF exhibit significantly increased IMT.     

肾通注射液对急性肾衰家兔内皮素和一氧化氮的影响

目的：探讨活血化瘀药肾通注射液对急性肾衰家兔肾血管活性物质的影响。方法：健康雄性大耳白兔40只，随机平分为正常组、模型组、肾通治疗组和丹参治疗组，分别观测各组血肌酐（Scr）、尿素氮（BUN）、24h尿蛋白排泄率、滤过钠排汇分数（FENa）、内生肌酐清除率（Ccr）、血Na^ 、K^ 以及内皮素（ET）和一氧化氮（NO）水平，同时检测肾组织ET（NET）和NO（NNO）含量变化。结果：急性肾衰家兔经肾通、丹参注射液治疗后，肾功能各项指标均有显著改善（肾通效果似优于丹参，但两者无显著性差异），肾血管活性物质产生明显变化，血ET显著下降，NO水平升高，肾局部ET和NO与模型组比较差异更为显著。结论：肾通注射液对急性肾衰有防治作用，广泛调节肾血管活性物质，特别是对肾局部ET和NO的调节从而显著改善肾血流动力学是其重要的作用机理之一。     

Bosentan improves renal regional blood flow in rats with experimental congestive heart failure

The effects of the mixed endothelin receptor antagonist bosentan on renal regional haemodynamics were investigated in rats with aorto-caval fistula, an experimental model of congestive heart failure. A matched group of normal rats served as control. Injection of bosentan (10 mg/kg i.v.) to the rats with decompensated congestive heart failure produced an increase in cortical (+20%) and medullary (+12%) blood flow, and a decrease in vascular resistance in the cortex (−30%) and medula (−23%), while reducing mean arterial pressure by approximately 10 mm Hg. In rats with compensated congestive heart failure and in normal animals, infusion of bosentan did not affect blood pressure and cortical perfusion. These findings indicate that 1) endothelin receptor blockade produces beneficial effects on renal haemodynamics in rats with experimental congestive heart failure and 2) endothelin-1 may be involved in the pathogenesis of renal hypoperfusion only in decompensated congestive heart failure.     

苯那普利对慢性肾衰合并肾性高血压患者的治疗作用与血浆神经肽Y相关性分析

目的 :探讨慢性肾衰 (CRF)合并肾性高血压患者使用苯那普利治疗前后血压、肾功能、血浆神经肽Y(NPY)含量的变化及其相关性。方法 :CRF合并肾性高血压患者 3 0例 ,使用苯那普利治疗前及用药 4wk后分别测定收缩压 (SBP)、舒张压 (DBP)、血肌酐 (Scr)、血浆NPY ;另采用本院核医学科血浆NPY正常值作对照。结果 :治疗前后血浆NPY水平均高于正常 (P <0 .0 1 )。治疗后与治疗前相比 ,NPY降低明显 (P <0 .0 1 ) ,SBP、DBP及Scr明显下降 (P<0 .0 1 ) ,且血浆NPY与SBP下降有显著相关性 (r=0 .67,P <0 .0 1 )、与DBP、Scr下降关系不明显 (P>0 .0 5 )。结论 :CRF合并肾性高血压患者使用苯那普利治疗后 ,血浆NPY、血压下降 ,肾功能改善     

Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites

BACKGROUND AND OBJECTIVES: Levosimendan is a calcium sensitiser developed for the treatment of congestive heart failure. It increases myocardial contractility, reduces the filling pressure and dilates both the peripheral and coronary vessels. The circulating metabolites of levosimendan, OR-1855 and OR-1896, are formed and eliminated slowly after intravenous administration of levosimendan. The aim of this study was to investigate the effect of impaired renal function and haemodialysis on the pharmacokinetics of levosimendan, OR-1855 and OR-1896. STUDY DESIGN: This study was an open-label, nonrandomised, phase I pharmacokinetic study. Levosimendan was administered as a single-dose infusion of 0.1 microg/kg/minute for 24 hours. The follow-up period lasted 3 weeks. STUDY SETTING: Twenty-fivepatients were included:12 patients with severe chronic renal failure (CRF) with creatinine clearance of < 30 mL/minute/1.73 m(2) and 13 patients with end-stage renal disease (ESRD) undergoing haemodialysis. A group of 12 healthy subjects served as controls. RESULTS: Levosimendan, the parent drug, was eliminated rapidly from the plasma after discontinuation of its infusion, with an elimination half-life (t(1/2)) [mean +/- standard error of mean] of 1.5 +/- 0.09 hours in ESRD patients undergoing haemodialysis, 1.0 +/- 0.2 hours in patients with severe CRF and 0.91 +/- 0.03 hours in healthy subjects. The t(1/2) of levosimendan was significantly longer (p < 0.001) in ESRD patients undergoing haemodialysis than in healthy subjects. The t(1/2) of OR-1855 and OR-1896 were 94.0 +/- 20.4 hours and 96.5 +/- 19.5 hours, respectively, in ESRD patients undergoing haemodialysis compared with 60.8 +/- 5.2 and 61.6 +/- 5.2 hours, respectively, in healthy subjects (p = not significant). The t(1/2) of OR-1855 was significantly longer (85.0 +/- 13.6 hours) in patients with severe CRF than in healthy subjects (60.8 +/- 5.2 hours, p < 0.05). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C(max)) of the metabolites were approximately 2-fold in patients with ESRD undergoing haemodialysis and patients with severe CRF compared with healthy subjects. The mean unbound fraction (f(u)) of levosimendan in plasma was approximately 2% in each study group, whereas the f(u) of the metabolites was considerably higher (63-70%). In contrast to levosimendan, the metabolites were dialysable, with dialysis clearance of approximately 100 mL/minute. The haemodynamic responses and adverse event profiles were similar in the study groups, with headache, palpitations and dizziness being the most frequently recorded adverse events. CONCLUSION: The t(1/2) of the levosimendan metabolites was prolonged 1.5-fold and their AUC and C(max) were 2-fold in patients with severe CRF and ESRD patients undergoing haemodialysis as compared with healthy subjects. These results suggest that the dose should be reduced when levosimendan is used for the treatment of congestive heart failure in patients with severe renal insufficiency.