吡格列酮对阿霉素致肾小球硬化大鼠肾脏氧化应激的影响

目的 观察吡格列酮(胰岛素增敏剂)对阿霉素致肾小球硬化大鼠肾脏氧化应激的影响.方法 经单侧肾切除加上重复注射阿霉素诱导,建立肾小球硬化大鼠模型,Wistar大鼠32只随机分为假手术对照组,阿霉素致肾小球硬化模型组和吡格列酮治疗组,治疗组大鼠,于第1次尾静脉注射阿霉素后给予吡格列酮10 mg·kg-1·d-1灌胃治疗,共12周.治疗12周末,测定各组大鼠24 h尿蛋白排泄量、尿肌酐、血清肌酐及尿素氮;进行肾脏病理学检查,计算肾小球硬化指数(GSI);检测肾组织和尿中丙二醛(MDA)的含量及肾组织超氧化物歧化酶(SOD)与谷胱甘肽过氧化物酶(GSH-Px)的活性.结果 吡格列酮治疗组,24h尿蛋白排泄量、血清肌酐及尿素氮等与模型组比较均有不同程度的改善(P＜0.05),肾小球硬化程度也明显减轻(P＜0.05),治疗组肾组织和尿中的MDA含量明显低于模型组,SOD与GSH-Px活性明显高于模型组(P＜0.05).结论 吡格列酮能抑制阿霉素致肾小球硬化大鼠肾脏氧化应激反应,对该模型大鼠具有肾脏保护作用.     

曲尼司特对阿霉素肾病大鼠肾脏TIMP-1、FN表达的影响

目的研究曲尼司特对阿霉素肾病肾小球硬化大鼠的肾脏保护作用,并探讨其可能的机制。方法SD大鼠24只,随机分为正常对照组、模型组、曲尼司特组和安博维组,采用单侧肾切除加尾静脉注射阿霉素的方法建立阿霉素肾病模型。观察各组大鼠24h尿蛋白定量、BUN、Scr及肾脏病理的改变。应用免疫组化方法测定肾组织TIMP-1、FN的表达。结果曲尼司特能减少阿霉素肾病大鼠的尿蛋白,延缓Scr上升;减轻基质增生和肾小球硬化;下调阿霉素肾病大鼠肾组织中TIMP-1、FN的表达。结论曲尼司特可能通过下调阿霉素肾病大鼠肾组织中TIMP-1、FN的表达,调节细胞外基质的生成与降解,从而减轻肾脏病理损害,发挥其肾脏保护作用。     

补肾活血祛风方对阿霉素肾病大鼠的干预研究

目的:探讨补肾活血祛风方对阿霉素肾病大鼠蛋白尿及病理组织结构的影响。方法:两次尾静脉注射盐酸多柔比星(阿霉素),制备肾病综合征(nephrotic syndrome,NS)阿霉素大鼠模型。造模成功的大鼠再随机分为4组:模型组、激素组、补肾活血祛风方组和激素+补肾活血祛风方组。另设空白组。在造模成功后各干预组开始灌胃给药,模型组给予蒸馏水灌胃,空白对照组不予干预。第8周后测各组大鼠24尿蛋白定量、光镜和电镜观察肾组织病理结构变化。结果:与空白组比较,模型组大鼠24 h尿蛋白升高;病理可见肾小球萎缩、肾小管上皮细胞萎缩半部分肿胀、间质纤维组织增生等。与模型组比较,激素组24h尿蛋白均降低(P0.05);各干预组大鼠肾脏病理不同程度改善,其中激素组病理病变最轻。结论:补肾活血祛风方可减轻阿霉素肾病大鼠的肾脏病理损害,降低24h尿蛋白定量。     

曲尼司特对肾小球硬化大鼠肾脏的保护作用

目的 研究曲尼司特对阿霉素肾病肾小球硬化大鼠的.肾脏保护作用,并探讨可能的机制.方法 ♂SD大鼠24只,随机分为正常对照组、模型组、曲尼司特组和安博维组,采用单侧肾切除加尾iv阿霉素5 mg·kg-1的方法建立阿霉素致肾病模型.观察各组大鼠24 h尿蛋白定量、血清尿素氮(BUN)、Scr及肾脏病理的影响.应用免疫组化方法测定肾组织的结缔组织生长因子(CTGF)和TIMP-1的表达,应用原位杂交方法测定肾组织α-SMA mRNA的表达.结果 曲尼司特能减少阿霉素致.肾病大鼠的尿蛋白,延缓Scr上升;减轻基质增生和肾小球硬化;下调大鼠肾组织中CTGF、TIMP-1、α-SMA、mRNA的表达.结论 曲尼司特可能通过下调阿霉素致肾病大鼠肾组织中CTGF、TIMP-1的表达以及抑制肾脏细胞表型转分化,调节细胞外基质的生成与降解,从而减轻肾脏病理损害而发挥作用.     

苦参素对阿霉素肾病肾硬化大鼠细胞凋亡及Bax、Bcl-2表达的影响

目的 探讨苦参素对阿霉素肾病肾硬化大鼠细胞凋亡及凋亡相关蛋白Bax 和Bcl-2 表达的影响.方法 60只Wistar大鼠随机分为4组:正常对照组、氧化苦参碱50 mg·kg-1·d-1治疗组、氧化苦参碱100 mg·kg-1·d-1治疗组、模型组.分2次(间隔21 d)尾静脉注射阿霉素(每次2 mg/kg)构建肾病慢性病理进展模型.第2次注药后各干预组予以相应的药物进行灌胃,之后每8周每组杀鼠5只观察大鼠尿蛋白、血清指标、肾脏病理、肾组织细胞凋亡及Bax、Bcl-2蛋白的表达.动物实验时间27周.结果 各干预组比模型组尿蛋白排泄量明显减少,血肌酐和尿素氮水平下降,肾小球系膜增生、硬化程度及细胞凋亡明显减轻(P＜0.05或P＜0.01);肾小球内Bax蛋白沉积较模型组明显减少,Bcl-2蛋白的沉积较模型组明显增多(P＜0.01).结论 苦参素减轻阿霉素肾病鼠慢性肾脏损害的机理可能与其抑制肾脏细胞凋亡有关.     

罗格列酮减轻阿霉素肾病大鼠肾小球硬化的实验观察

目的观察罗格列酮干预治疗对单侧肾切除加重复阿霉素注射诱导的肾小球硬化大鼠肾脏的保护作用。方法建立单侧肾切除加重复阿霉素注射的肾小球硬化大鼠模型,分为罗格列酮治疗组和肾病组,设假手术组为对照组。检测各组大鼠第0、4、8、12周尿蛋白,并观察第12周肾组织病理改变,计算肾小球硬化指数。结果罗格列酮治疗组比肾病组尿蛋白排泄量明显减少(P<0.01),肾小球硬化程度明显减轻。结论罗格列酮对阿霉素肾病大鼠肾脏病变具有保护作用。     

雷公藤多苷片对阿霉素肾病大鼠的保护作用

目的:利用阿霉素(ADR)肾病模型研究雷公藤多苷片对大鼠肾病综合征的治疗作用.方法:将50只SD雄性大鼠随机分成正常组、模型组、雷公藤多苷片低剂量组(7.5 mg/kg)、雷公藤多苷片中剂量组(15 mg/kg)和雷公藤多苷片高剂量组(30 mg/kg),每组10只.除正常组外,其余实验组大鼠均尾静脉一次性注射阿霉素6.5 mg/kg,正常组给予相应体积的生理盐水.造模成功后,各治疗组分别灌胃给予相应体积的雷公藤多苷片药液,正常组及模型组灌胃等体积的生理盐水.连续给药4周后,测定各组大鼠24 h尿蛋白及血清白蛋白(Alb)、总蛋白(TP)、总胆固醇(TC)、甘油三酯(TG)、肌酐(Cr)和尿素氮(BUN)的水平,结合肾脏组织病理形态学变化结果,观察不同剂量的雷公藤多苷片对鼠肾病综合征的治疗作用.结果:雷公藤多苷片具有减少阿霉素肾病大鼠蛋白尿、改善肾功能和低蛋白血症、调节血脂的作用,且作用具有剂量依赖性.雷公藤多苷片高剂量组在降低尿蛋白、升高血清Alb和TP、降低血清TG和TC、保护肾脏损伤等方面效果显著,对阿霉素(ADR)肾病模型具有显著的治疗作用.结论:雷公藤多苷片对阿霉素(ADR)肾病大鼠具有一定的治疗作用,且作用具有剂量依赖性.作用机制可能是减少阿霉素肾病大鼠尿蛋白、调节血脂、改善低蛋白血症以及对肾脏的保护作用.     

ARB和ACEI联合应用对阿霉素肾病大鼠肾小球bFGF的影响

目的:探讨ARB和ACEI联合应用对阿霉素肾病(AIN)大鼠肾小球碱性成纤维细胞生长因子(bFGF)表达的影响。方法:80只雄性Wistar大鼠,分为正常组、肾病对照组、缬沙坦组、联合组。一次性尾静脉注射阿霉素5mg/kg建立AIN模型。缬沙坦组予缬沙坦8mg/(kg·d)灌胃,联合组予缬沙坦8mg/(kg·d)和苯那普利3mg/(kg·d)灌胃。第3、7、14、28天检测各组大鼠24h尿蛋白定量,第28天检测血生化指标,用免疫组织化学法检测各组大鼠肾小球bFGF的表达,以彩色图像分析系统对bFGF的表达进行定量分析。结果:①各项生化指标比较:各治疗组情况均好于肾病对照组,且与正常组比较,差异有显著性;联合组与缬沙坦组比较,差异有显著性。②实验结束时缬沙坦组和联合组大鼠肾小球bFGF PI均较肾病对照组低,但较正常组高,差异均有显著性。其中以联合组的变化更显著。结论:ARB和ACEI联合应用能减少肾小球bFGF的表达;联合治疗的疗效优于单独应用,可获得相加的治疗效果,更有效地减轻蛋白尿,具有更好的肾脏保护作用。     

雷至胶囊治疗阿霉素肾病大鼠的实验研究

目的 探讨雷至胶囊对阿霉素肾病大鼠的治疗作用.方法 将大鼠随机分为正常组、模型组、雷至胶囊实验组、洛丁新组和雷至胶囊加洛丁新治疗组,尾静脉注射阿霉素6mg/kg.造成阿霉素肾病模型.观察24h尿蛋白定量、尿N-乙酰-葡萄糖苷酶fNAG)的改变和肾脏病理变化.结果 雷至胶囊加洛丁新治疗组尿蛋白含量、NAG酶明显降低,与模型组相比统计学差异显著(P<0.05);雷至胶囊加洛丁新治疗组与洛丁新组、模型组相比肾脏病理变化明显减轻.结论 雷至胶囊能增强对阿霉素肾病大鼠的治疗作用,保护肾功能.延缓.肾脏病变恶化速度.     

罗格列酮对阿霉素肾病大鼠足细胞nephrin表达的影响

目的建立阿霉素肾病模型,探讨罗格列酮对阿霉素肾病大鼠足细胞nephrin的表达的影响。方法21只大鼠随机分为3组。阿霉素肾病组和罗格列酮组大鼠予0.1%阿霉素溶液7 mg·kg~(-1)一次性尾静脉注射,罗格列酮组次日予罗格列酮5 mg·kg~(-1)·d~(-1)灌胃,每日1次,共8 wk。另外2组每日予等量自来水灌胃。检测各组大鼠24 h尿蛋白定量、血清清蛋白、血脂、肾功能及肾脏病理改变,并检测肾组织nephrin和TCFβ_1的表达。结果给药后2、4、6、8 wk,罗格列酮组大鼠24 h尿蛋白定量明显低于阿霉素肾病组(P<0.05),8 wk时其血清清蛋白高于阿霉素肾病组[(26.7±s 2.6)g·L~(-1)vs(21±4)g·L~(-1),P<0.05],血三酰甘油和胆固醇水平低于阿霉素肾病组(P<0.05)。与阿霉素肾病组比较,罗格列酮组大鼠肾组织中nephrin蛋白表达增高19%(P<0.05),而TGFβ_1蛋白表达明显降低(P<0.01),肾脏病理损害也明显减轻。结论罗格列酮可上调阿霉素肾病大鼠肾组织nephrin表达,减少尿蛋白排泄,抑制其TGFβ_1表达,从而减轻肾组织病理损害。     

黄芪甲甙对阿霉素心肌损伤的保护作用的研究

目的研究黄芪甲甙对阿霉素心肌损伤的保护作用。方法30只SD大鼠随机分为3组,对照组(C组),阿霉素组(ADR组),阿霉素+黄芪甲甙组(ADR+黄芪组)。观察大鼠心率和肝、肺干湿重比变化,检测心肌铜-锌-超氧化物歧化酶(CuZn-SOD)活力,半定量聚合酶链反应测定心肌CuZn-SOD基因表达及bcl-2,bax基因表达。结果与ADR组比较,ADR+黄芪组心率变化率明显下降(P<0.05),肝、肺干湿重比明显上升(P<0.05),心肌铜-锌-超氧化物歧化酶活力明显提高(P<0.05),铜-锌-超氧化物歧化酶基因表达增加(P<0.05),bcl-2基因表达增加而bax基因表达下降。结论黄芪甲甙对阿霉素心肌损伤有保护作用,其机制可能与其抑制氧化应激从而抑制心肌细胞凋亡有关。     

No toxicological effects on acute and repeated oral gavage doses of single-wall or multi-wall carbon nanotube in rats

Three female Crl:CD(SD) rats/group were dosed with single wall carbon nanotube (SWCNT) or multi wall carbon nanotube (MWCNT) four times by gavage at a total of 50 mg/kg bw or 200 mg/kg bw (four equally divided doses at one-hour intervals). Acute oral doses of SWCNT and MWCNT caused neither death nor toxicological effects, and thus the oral LD50 values for SWCNT and MWCNT were considered to be greater than 50 mg/kg bw and 200 mg/kg bw, in rats respectively. Five or ten Crl:CD(SD) rats/sex were dosed with SWCNT once daily by gavage at a dose of 0 (control), 0.125, 1.25 or 12.5 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 12.5 mg/kg bw/day groups). Six or twelve Crl:CD(SD) rats/sex were dosed with MWCNT once daily by gavage at a dose of 0 (control), 0.5, 5.0 or 50 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 50 mg/kg bw/day groups). Based on no toxicological effects, the no observed adverse effect levels (NOAELs) of repeated dose toxicity of SWCNT and MWCNT were considered to be 12.5 mg/kg bw/day and 50 mg/kg bw/day (the highest dose tested), respectively. It was suggested that SWCNT and MWCNT dosed by gavage reached the gastro-intestinal tract as agglomerates and were mostly excreted via feces.     

Effect of zelandopam, a dopamine D1-like receptor agonist, in puromycin aminonucleoside nephrosis rats

The present experiment was designed to investigate the role of peripheral dopamine D1-like receptors and to evaluate the prophylactic effect of zelandopam, a dopamine D1-like receptor agonist, on puromycin aminonucleoside (PA)-induced nephrosis in rats. Rats were divided into six groups (n=10 per group): 0.9% saline-injected rats (control); PA-injected rats (PAN); PA-injected rats treated with the selective dopamine D1-like receptor agonist zelandopam (30, 100, 300 mg/kg p.o. twice a day); PA-injected rats treated with prednisolone (1 mg/kg p.o. once a day). Nephrosis was induced in rats with a single intravenous injection of PA at a dose of 50 mg/kg. The effects of zelandopam and prednisolone in PA nephrosis rats were evaluated before injection of PA and at 7 and 14 days after injection. PA-induced nephrosis was characterized by an increase in urinary protein excretion (proteinuria) and plasma total cholesterol. Zelandopam dose-dependently attenuated the increase in proteinuria and total cholesterol. Prednisolone significantly attenuated the increase in proteinuria and total cholesterol and resulted in a significant decrease in body weight. The present study demonstrates for the first time that zelandopam, a selective dopamine D1-like receptor agonist, is effective in blunting the development of PA-induced nephrosis, and that the effects of zelandopam are dose dependent.     

Subchronic oral toxicity of 4-chloro-alpha, alpha, alpha-trifluorotoluene in Sprague-Dawley rats

The subchronic oral toxicity of 4-chloro-alpha, alpha, alpha-trifluorotoluene (CTT) was assessed in Sprague-Dawley rats. Four groups of six male and six female rats were treated daily for 28 days, by gavage, with doses of 0, 10, 100 and 1000 mg CTT/kg body weight using olive oil as a vehicle. No clinical signs were observed, other than salivation in the high-dose group in the last week. The males of this group showed a significant decrease in body-weight gain without a concurrent decrease in food consumption. In males, there were significant dose-dependent increases in blood cholesterol and triglycerides, suggestive of alterations in lipid metabolism. The females showed only a small dose-related increase in serum lactate dehydrogenase. Specific histological alterations were found in the males given 1000 mg/kg/day, namely hyaline droplet nephrosis, along with a significant increase in relative kidney weight, and an increase in lipid vacuoles in the adrenal cortex. Slight nephrosis was also observed in males given 100 mg/kg. Both male and female rats showed a significant increase in relative liver weight at a dose of 1000 mg CTT/kg. CTT appears to have a low subchronic oral toxicity. Neither pathological nor biochemical alterations were found at 10 mg/kg body weight/day and this can be defined as the no-observable-effect level (NOEL).     

不同输注途径移植骨髓间充质干细胞对阿霉素肾病大鼠疗效初探

【摘要】目的探索骨髓间充质干细胞（BMSCs）经不同输注方式移植入阿霉素慢性肾病大鼠体内对肾损伤的影响。方法SD大鼠左侧肾切除后以2.5mg/kg剂量给大鼠尾静脉注射阿霉素,1次/周,连续2次,慢性肾病模型成功后,将成模大鼠36只随机均分为3组：阿霉素慢性肾病对照（ADR）组、干细胞经肾动脉移植（M-A）组、干细胞经外周静脉移植（M-V）组,另选12只正常大鼠设正常对照（N）组。BMSCs经体外培养后,以2×10⁶个/mL经肾动脉注射到M-A组大鼠体内,2×10⁶个/mL经尾静脉注射到M-V组大鼠体内,2周后再次同样方法注射等量BMSCs。检测移植当周、移植后1周、2周大鼠血尿素氮、血肌酐、24h尿蛋白、24h尿微量蛋白,末次注射干细胞后第1周于激光聚焦显微镜下观察大鼠肾脏病理和干细胞在肾脏内分布情况。结果M-A组、M-V组和ADR组在各观察时点血尿素氮、血肌酐、24h尿蛋白总量、24h尿微量蛋白均明显高于N组（P＜0.01）。移植后1、2周M-A组的24h尿微量蛋白低于ADR组（P＜0.01）,且M-A组的血肌酐较ADR组和M-V组均降低（P＜0.01）。移植后1周,M-A组24h尿蛋白、24h尿微量蛋白明显低于M-V组（P＜0.01）;但2周时尿蛋白和微量蛋白与M-V组的差异无统计学意义。结论BMSCs移植可以改善阿霉素慢性肾病的肾损伤情况,在BMSCs移植后一段时间,BMSCs经肾动脉移植的效果优于经外周静脉移植。     

Theophylline-induced mesenteric periarteritis in F344/N rats

The toxicity and carcinogenic potential of theophylline (an alkaloid bronchodilator drug) was investigated in male and female F344/N rats in 16-day, 14-week, and 2-year gavage and feeding studies. In 16-day studies, rats were fed diets containing 0, 500, 1000, 2000, 4000, and 8000 ppm of theophylline or given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), and 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. In 14-week studies, rats were fed diets containing 0, 1000, 2000, and 4000 ppm theophylline or given 0, 37.5, 75, and 150 mg/kg body weight theophylline in corn oil by gavage. In 2-year gavage studies, rats were given 0, 7.5, 25, and 75 mg/kg body weight in corn oil. In 16-day gavage studies, treatment-related periarteritis occurred in arteries of the pancreas and adjacent to the mesenteric lymph nodes of early death male and female rats given 400 mg/kg once daily. In the 14-week studies, treatment-related periarteritis occurred at similar sites and in male rats exposed to 75 and 150 mg/kg, and in all exposed female rats (gavage studies), in females exposed to 1000 ppm, and in both sexes exposed to 2000 and 4000 ppm (feeding studies). In the 2-year study, chronic periarteritis was significantly increased only in the males receiving 75 mg/kg of theophylline. The adventitia, media and intima of medium- and large-sized mesenteric arteries were involved. Similar to other vasodilator chemicals, the pathogenesis of theophylline-induced vascular lesions may be a consequence of hemodynamic changes induced in the vascular wall. Received: 11 May 1998 / Accepted: 6 July 1998     

Cardiotoxicity study of ME2303 with the interval intravenous injections to rats

Cardiotoxic effects of ME2303 were studied upon interval intravenous administrations to rats in comparison with those of doxorubicin (ADR). ME2303 at two dose levels of 3 and 9 mg/kg/day or ADR at a dose levels of 3 mg/kg/day was injected once a week for 3 weeks to female Sprague-Dawley rats (SPF) of 5-weeks of age. ADR depressed body weight gain, decreased food intake and increased water intake. Microscopic observation on the myocardial tissues revealed that ADR caused necrosis and cell infiltration, edema and disarrangement of myofibrils in some of ADR-treated rats. On the other hand, ME2303 showed no significant effects except that some decrease of food intake was observed at a dose level 9 mg/kg/day. No changes in left ventricular functions were observed in perfused hearts isolated from ADR- or ME2303-treated rats. However, about 133 ng/g of ADR remained in the hearts even at 1 week after the final administration whereas ME2303 or its metabolites were not detected, suggesting that ADR may cause disturbance of ventricular function and more cardiomyopathy after a longer term than 1 week following the final administration. These results suggest that the cardiotoxicity of ME2303 is weaker than that of ADR in rats.     

Encephalopathy in rats and nephropathy in rats and mice after subchronic oral exposure to benzaldehyde

Male and female Fischer 344 rats and B6C3F1 mice were treated daily (5 days/wk) with benzaldehyde by gavage either in 12 doses of 0 (vehicle control), 100 (rats only), 200, 400, 800, 1600 or (for mice only) 3200 mg/kg body weight/day (followed by 2 days' observation without treatment), or for 90 days in doses of 0, 50, 100, 200, 400 or 800 mg/kg/day (rats) or 0, 75, 150, 300, 600 or 1200 mg/kg/day (mice). In the acute studies, benzaldehyde induced deaths and decreased body-weight gain in both sexes of rats given 800 or 1600 mg/kg/day and caused deaths in both sexes of mice given 1600 or 3200 mg/kg/day. In the 90-day studies, deaths occurred in both sexes of rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Body-weight gain was depressed in male rats on 800 mg/kg/day, in male mice on 600 mg/kg/day and in female mice on 1200 mg/kg/day. Necrotic and degenerative lesions were seen in the cerebellar and hippocampal regions of the brain in both sexes of rats given 800 mg/kg/day, but not in mice. Renal tubular necrosis occurred in male and female rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Mild epithelial hyperplasia or hyperkeratosis of the forestomach was seen in male and female rats on 800 mg/kg/day. In this limited study, the no-observed-toxic-effect doses of benzaldehyde administered by gavage were 400 mg/kg/day in male and female rats, 300 mg/kg/day in male mice and 600-1200 mg/kg/day in female mice.     

A 90-day toxicological evaluation of Compound 1080 (sodium monofluoroacetate) in Sprague-Dawley rats.

Groups of Sprague-Dawley rats received sodium monofluoroacetate (Compound 1080) at 0.025, 0.075, and 0.25 mg/kg by oral gavage once daily for 90 days and were then euthanized. The control and 0.25 mg/kg/day groups included additional rats of each sex that were treated for 90 days, then maintained without treatment for a further 56-day recovery period. Microscopic changes were restricted to the testes and the heart, and were seen only in males dosed with 1080 at 0.25 mg/kg/day and included severe hypospermia in the epididymides, severe degeneration of the seminiferous tubules of the testes, and cardiomyopathy. Sperm evaluation indicated severe decreases in all three sperm parameters evaluated (concentration, % motile, and % abnormal) at 0.25 mg/kg/day. There were no microscopic changes or 1080-related effects on sperm parameters at 0.025 and 0.075 mg/kg/day. The no observable effects level (NOEL) for rats administered 1080 via oral gavage for 90 days was 0.075 mg/kg/day. The lowest observable effects level (LOEL) dose was 0.25 mg/kg/day. After dosing with the LOEL dose of 0.25 mg/kg/day, mean concentrations of 1080 in rat plasma were 0.26 micro g/ml at 1 h and 0.076 microg/ml at 12 h. Rat urine collected from the same animals contained 0.059 microg/ml.     

Comparison of the cardioprotective and renoprotective effects of the L/N‐type calcium channel blocker,cilnidipine, in adriamycin‐treated spontaneously‐hypertensive rats

Cilnidipine is an L/N‐type calcium channel blocker (CCB). The effects of cilnidipine on N‐type channels give it unique organ‐protective properties via the suppression of hyperactivity in the sympathetic nervous system (SNS) and renin‐angiotensin‐aldosterone system (RAAS). In the present study, we compared the effects of cilnidipine and amlodipine (an L‐type CCB) on cardiac and renal functions in spontaneously‐hypertensive rats injected with adriamycin (ADR). After the weekly administration of ADR for 3 weeks, spontaneously‐hypertensive rats were orally administered cilnidipine (20 mg/kg per day), amlodipine (3 mg/kg per day), or vehicle once daily for 4 weeks. A control group received saline rather than ADR, followed by vehicle for 4 weeks. Cilnidipine and amlodipine produced similar reductions in blood pressure after 4 weeks. Cilnidipine ameliorated ADR‐induced heart and kidney damage, whereas amlodipine slightly improved cardiac echocardiographic parameters, but did not protect against ADR‐induced renal damage. Cilnidipine (but not amlodipine) suppressed the reflex SNS and RAAS hyperactivity caused by their antihypertensive effects. Furthermore, cilnidipine and amlodipine treatment decreased the urinary levels of adrenocortical hormones. The protective effects of cilnidipine against ADR‐induced renal and cardiac dysfunction might be associated with its blockade of N‐type calcium channels, in addition to its pleiotropic actions, which include the inhibition of the RAAS.