泽泻水提物对正常大鼠利尿活性及肾脏髓质AQP2作用研究

目的研究泽泻水提物的利尿活性及对肾脏髓质水通道蛋白2（AQP2）的调节作用。方法筛选合格利尿大鼠30只,分为生理盐水组、呋塞米组、泽泻100mg/kg组、泽泻500mg／kg组、泽泻1000mg／kg组,每组6只。观察单次及连续8次给予泽泻水提物后大鼠尿量,尿Na^＋、尿K^＋,尿Cl^-的水平,使用RT—PCR方法观察肾脏髓质AQP2 mRNA的相对表达含量。结果单次及连续8次给予正常大鼠泽泻水提物均可显著增加尿量,升高尿Na^＋、尿K^＋,尿Cl^-水平;8次给予正常大鼠泽泻水提物后显著降低大鼠肾脏髓质AQP2 mRNA相对含量表达。结论泽泻水提物具显著利尿活性,其利尿活性与降低肾脏髓质AQP2作用有关。     

雌激素对海水淹溺型肺损伤大鼠肺组织水通道蛋白表达影响的研究

目的 观察雌激素对海水淹溺型肺损伤大鼠肺组织水通道蛋白表达的影响.方法 90只健康雄性SD大鼠随机分为三组,即对照组、海水淹溺组及雌激素治疗组.海水淹溺组用气管吸入海水法建立模型;对照组除不吸入海水外,其他处理同海水淹溺组;雌激素治疗组在海水吸入后30 min给予腹腔注射17β-雌二醇5 mg/kg.分别于海水致肺损伤后1、2、4 h时间点取大鼠颈动脉血做血气分析观察动脉血氧分压(PaO2)的变化,测肺组织湿重/干重(W/D)比值,光镜下观察肺组织病理变化情况,采用RT - PCR方法检测AQPs mRNA的表达.结果 成功复制了大鼠海水淹溺型肺损伤模型:海水淹溺组在吸入海水后PaO2显著下降,各时间点PaO2显著低于对照组.雌激素治疗组PaO2显著上升,各时间点均高于海水淹溺组.海水淹溺组W/D比值显著高于正常对照组及雌激素治疗组.光镜下可见海水淹溺组肺组织有灶性出血,肺泡腔内渗出增多、少量中性粒细胞浸润和肺泡间质稍有增厚;对照组未见明显病理变化;雌激素治疗组肺组织充血、水肿有所减轻.海水淹溺组肺组织AQP1 mRNA及AQP5 mRNA表达高于对照组,AQP3 mRNA及AQP4 mRNA无明显变化;雌激素治疗组AQP1 mRNA及AQP5 mRNA表达减少.结论 吸入海水可引起大鼠肺组织AQP1 mRNA及AQP5 mRNA表达增加,但对AQP3 mRNA及AQP4 mRNA表达无明显影响.雌激素通过抑制海水吸入引起的大鼠肺组织AQP1 mRNA及AQP5 mRNA表达上调,影响大鼠海水淹溺型肺损伤时肺组织水的转运.     

肝硬化腹水大鼠水通道蛋白的表达

目的 :探讨肝硬化腹水大鼠模型中水通道蛋白的变化及其作用方法采用改良的CCl4肝硬化腹水大鼠模型 ,通过免疫组织化学及半定量RT -PCR ,检测肾脏 (皮质和髓质 )中水通道蛋白AQP1和AQP2的表达以及脏层腹膜中AQP1的表达 ,并与正常对照组大鼠相比较。结果 :(1)免疫组织化学显示 ,AQP1主要表达在肾脏近曲小管上皮细胞的刷状缘和髓襻降支细段上皮细胞的顶质膜 ,AQP2主要表达在肾脏的远曲小管与集合管 ,肝硬化腹水组与正常组比较 ,皮质、外髓及内髓的AQP1和AQP2的表达均显著增加 (P <0 .0 1)。在两组中 ,AQP1均仅表达在脏层腹膜中若干小血管壁中 ,两组之间无显著差异 (p >0 .0 5 )。 (2 )半定量RT -PCR显示 ,肝硬化腹水组与正常组相比 ,在肾皮质和髓质中 ,AQP1mRNA、AQP2mRNA表达升高 (P <0 .0 1)。AQP1mRNA在两组的脏层腹膜中的表达无显著差异 (p >0 .0 5 )。结论肝硬化伴腹水大鼠模型中肾脏AQP1及AQP2的表达升高 ,与肝硬化腹水情况下水的重吸收增加有关。     

丹参水提液对染镉大鼠肾损伤的干预作用

目的探讨丹参水提液对染镉大鼠肾损伤的干预作用及其可能的作用机制。方法健康Wistar大鼠,雌雄各20只,鼠龄6周。适应性喂养1周,随机分组,空白组8只,模型组32只,空白组腹腔注射生理盐水5 m L/(kg·d),模型组以2.8 mg/(kg·d)氯化镉溶液腹腔注射。连续造模4周,观察大鼠一般情况,检测大鼠肾功能指标、肾脏组织病理改变。造模成功后,将模型组随机分为给药组、阴性、阳性对照组及空白对照组。给药组[丹参水提液高剂量2.7 g/(kg·d)、丹参水提液低剂量1.35 g/(kg·d)]灌胃,阳性对照组亚硒酸钠溶液0.05 mg/(kg·d)灌胃,阴性及空白对照组给予同体积生理盐水2.7 m L/(kg·d)。各组治疗10周,实验终末收集血清、尿液,并留取肾脏组织,待检测。结果丹参水提液低、高剂量组24 h尿量低于阴性对照组,而血清超氧化物歧化酶(SOD)明显升高,丙二醛(MDA)显著降低,总抗氧化能力(T-AOC)增强明显,血尿素氮、血清肌酐含量降低,尿蛋白(β2-MG)含量下降。病理切片可见阴性对照组肾脏近曲小管上皮细胞浑浊、肿胀变性、坏死;丹参水提液低、高剂量组血清、皮质镉含量低于阴性对照组;丹参水提液低、高剂量组凋亡率低于阴性对照组。结论丹参水提液能加速体内镉代谢,可有效干预镉致肾损伤,有助于延缓慢性肾功能衰竭,改善肾功能,保护肾脏。     

罗布麻水提物对获得性无助抑郁模型大鼠行为学的影响

目的：建立大鼠获得性无助模型评价药物抗抑郁作用，并观察口服罗布麻叶水提物在该模型上的抗抑郁效应。方法：采用微机程序控制的大鼠穿梭箱反应仪。给予不可逃避的足底电击建立获得性无助模型，进行条件性回避反应训练，测定大鼠的逃避失败次数。结果：模型对照组动物的逃避失败次数比正常组动物显著增加，罗布麻叶水提物60mg／kg在第4天显著减少逃避失败次数，罗布麻叶水提物120mg／kg在第3天、第4天均显著减少逃避失败次数。结论：在大鼠获得性无助模型上，罗布麻叶水提物口服给药时具有抗抑郁活性。     

七叶皂苷钠对模拟高原低氧大鼠脑损伤的干预作用及对水通道蛋白4表达的影响

目的 探讨七叶皂苷钠对模拟高原低氧大鼠脑损伤的干预作用及对水通道蛋白4(AQP4)表达的影响.方法 40只SD大鼠随机均分为正常对照组、高原低氧致脑损伤组、七叶皂苷钠干预组.将大鼠放置在模拟海拔6000 m高原环境中,每6 h舱外以20 m/min 运动2 h,重复三次致大鼠脑损伤.脑损伤后干预组给予尾静脉推注5 mg/kg七叶皂苷钠,高原低氧致脑损伤组尾静脉推注5 mg/kg生理盐水,分别观察各组脑组织病理切片、含水量、TNF-α含量和AQP4蛋白在脑组织中的定位及表达情况.结果 病理切片显示,大鼠高原脑损伤后立即给予七叶皂苷钠干预,脑损伤程度显著减低.免疫组化示,AQP4蛋白主要在脑组织星形胶质细胞、小胶质细胞胞浆中呈阳性表达,且干预组较脑损伤组AQP4蛋白表达量显著降低;与正常组比较,脑损伤组12 h脑含水量、TNF-α含量和AQP4蛋白表达显著升高,干预组12 h脑含水量、12 h TNF-α含量和6、12 h AQP4蛋白表达较脑损伤组显著降低.结论 七叶皂苷钠通过抑制TNF-α及下调AQP4表达,从而有效改善高原脑损伤程度.     

小儿急性肾衰的治疗

小儿急性肾衰的治疗要抓早(期)、抓少(尿期),其中早期腹膜透析最为有效。早期防治 1、补液:应酌情输液,输血或代用血浆制剂,尽早恢复血容量。可选用生理盐水1份与5～10％葡萄糖2份液15～20ml/kg,如果尿量增加可继续补充。 2、利尿疗法:此法多用于发生少尿48小时之内,甘露醇和速尿均具有扩张肾脏血管的作用,可以增加肾脏的血浆流量而增加肾小球滤过率,甘露醇并起渗透性利尿作用。 (1)甘露醇:量0.5～1g/kg,1/2小时滴完,如尿量不增,2～3小时后重复一次,尿量增加30～40ml/小时,应继续给予维持,直到尿量进一步较明显增加,但日用量不超过2～3g/kg。 (2)利尿剂:单用或/和甘露醇同用。速尿1～2mg/kg(5mg/kg),15～20分钟注完,2～3小时后疗效不显可加大量,可多次重复,最大量每天不超过200～300mg。利尿酸钠1～2mg/kg,15分钟滴完,2小时后尿量不大于30ml/小时,可重上量,二次无效不宜再用。可用利尿合     

SB203580减轻高原低氧大鼠脑水肿的实验研究

探讨SB203580对于高原低氧大鼠脑组织水通道蛋白1(AQP1)和水通道蛋白4(AQP4)表达及脑水肿的影响。方法 SPF级雄性SD大鼠54只,随机分为常压常氧对照组(sham组)、低压低氧模型组(HH组)和低压低氧+药物干预组(SB203580组)。应用低压低氧实验舱模拟高原环境,构建高原低氧大鼠脑损伤模型。SB203580组每日腹腔注射P38MAPK抑制剂SB203580(10 mg/kg),连续注射7 d。采用HE染色观察大鼠脑组织病理变化。干湿比重法测定脑组织含水量,荧光定量PCR法检测脑组织AQP1和AQP4 mRNA的表达。结果与对照组比较,低压低氧组大鼠脑组织含水量增加(P0.05),脑组织AQP1和AQP4表达显著升高(P0.01)。与低氧组比较,SB203580组大鼠脑含水量明显降低(P0.05),脑组织中AQP1和AQP4 mRNA表达显著降低(P0.01),脑组织的病理损伤较小。结论 SB203580可减轻高原低氧大鼠AQP1和AQP4mRNA表达及脑水肿。其机制可能与SB203580抑制P38MAPK信号通路的激活相关。     

急性肾损伤时水通道蛋白2及钠钾泵的表达

目的 探讨水通道蛋白2的表达及钠-钾-三磷酸腺苷酶在多器官功能障碍肾损伤发病机制中的作用,研究大鼠多器官功能障碍肾损伤与水通道蛋白2及钠-钾-三磷酸腺苷酶的表达.方法 选取健康大鼠72只,随机(随机数字法)分为对照组24只,脂多糖组48只,采用大鼠腹腔注射脂多糖5 mg/kg造成内毒素致多器官功能障碍动物模型,对照组仅作假手术处理.造模成功后6h、12h、24 h、2d、3d、5d分别处死动物,留取血液、尿量进行生化检测,并应用免疫组化法和RT-PCR技术检测肾组织内水通道蛋白2 mRNA及蛋白的表达水平.应用试剂盒测定钠-钾-三磷酸腺苷酶的含量及活性.结果 造模成功后致伤组大鼠尿量迅速减少,48 h后尿量增多.尿素氮、肌酐逐渐增高,48 h达高峰,此后逐渐下降.水通道蛋白2 mRNA及蛋白表达迅速减少,48 h降至最低,此后逐渐增多.钠-钾-三磷酸腺苷酶含量差异无统计学意义,但其活性在造模成功后明显降低,此后逐渐增高,但仍低于对照组.结论 大鼠多器官功能障碍综合征肾损伤模型中,水通道蛋白2是肾脏重吸收功能恢复的结构基础,钠-钾-三磷酸腺苷酶则直接参与或间接反映肾脏的能量代谢状态,只有在水通道蛋白2及能量代谢恢复后,大鼠的肾脏功能才能逐渐好转.     

灯盏花素注射液对卒中相关性肺炎大鼠肺损伤及AQP1、AQP4、MMP-9表达的影响

目的探究灯盏花素注射液对卒中相关性肺炎大鼠肺损伤及水通道蛋白-1(AQP1)、水通道蛋白-4(AQP4)、基质金属蛋白酶9(MMP-9)表达的影响。方法将雄性SD大鼠按照随机数字表法分为假手术组(仅暴露颈总动脉,不阻断血管),模型组(脑缺血再灌注-肺损伤模型),灯盏花素注射液低、中、高剂量组(造模后尾静脉注射25mg/kg、50 mg/kg、100 mg/kg灯盏花素注射液)组,阳性组(造模后尾静脉注射1 mg/kg尼莫地平),每组15只。12周末,苏木精-伊红染色法(HE)观察大鼠肺部组织病理学变化,对各组肺组织大体以及病理形态进行评定,对大鼠肺组织湿干重(W/D)、氧合指数(OI)、动脉血氧分压(Pa O_2)进行测定;酶联免疫法测定肺组织超氧化物歧化酶(SOD)、丙二醛(MDA)水平,逆转录-聚合酶链反应(RT-PCR)与免疫印迹(WB)检测AQP1、AQP4、MMP-9表达。结果与假手术组相比,模型组大鼠肺组织大体分级、病理评分升高(P 0. 05);与模型组相比,阳性组、灯盏花素治疗组大鼠肺组织大体分级、病理评分均降低,具有剂量依赖性(P 0. 05)。与假手术组相比,模型组W/D、MDA升高,PaO_2、OI、SOD降低(P 0. 05);与模型组相比,阳性组、灯盏花素治疗组W/D、MDA降低,Pa O_2、OI、SOD升高,具有剂量依赖性(P 0. 05)。与假手术组相比,模型组AQP1、AQP4 mRNA及蛋白表达降低,MMP-9 mRNA及蛋白表达升高(P 0. 05);与模型组相比,阳性组、灯盏花素治疗组AQP1、AQP4 mRNA及蛋白表达升高,MMP-9 mRNA及蛋白表达降低,具有剂量依赖性(P 0. 05)。结论灯盏花素注射液对卒中相关性肺炎大鼠肺损伤具有一定的保护作用,其机制可能与上调AQP1、AQP4表达,下调MMP-9表达有关。     

Diuretic and hypotensive effects of Nigella sativa in the spontaneously hypertensive rat

Nigella sativa (ranunculaceae) is used in Arab folk medicine as a diuretic and hypotensive plant. We report here the diuretic and hypotensive effects of dichloromethane extract of Nigella sativa seeds in the spontaneously hypertensive rat (SHR). An oral dose of Nigella sativa extract (0.6 ml/kg/day) and furosemide (5 mg/kg/day) increased significantly the diuresis by 16 and 30 per cent respectively after 15 days of treatment; urinary excretion of Cl-, Na+, K+ and urea is also increased. Simultaneously, the mean arterial pressure decreased respectively by 22 and 18 per cent in the Nigella sativa treated rat and nifédipine treated rat (0.5 mg/kg/day). In conclusion, the diuretic activity observed in the SHR rat treated with Nigella sativa seeds may be partially responsible for its diuretic action; it seems that other pathways may also be involved in their cardiovascular effects.     

Renal and antihypertensive effects of a novel eukalemic diuretic, ICI 207,828.

ICI 207,828, an aminomethylphenol pyrazine derivative, produces water diuretic effects with only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. In the dog, ICI 207,828 reached maximum activity at a dose of 10 mg/kg, p.o. This was comparable to that of hydrochlorothiazide (HCTZ) at a dose of 5 mg/kg, p.o. or higher. In the rat, a dose of 30 mg/kg, p.o. of ICI 207,828 was comparable to the maximum of water diuretic and saluretic response obtained with HCTZ at a dose of 10 mg/kg, p.o. Based upon studies using in vitro amphibian models of the mammalian nephron, ICI 207,828 appeared to act on both the thick ascending limb of the loop of Henle and the late distal nephron. In the toad bladder preparation, ICI 207,828 inhibited Na+ transport when placed on either the mucosal (amiloride-like) or serosal (thiazide-like or loop diuretic-like) sides. This compound also inhibited Cl- transport in the toad cornea preparation (loop diuretic-like). ICI 207,828 did not change plasma K+ significantly in dogs dosed for 14 days at doses having diuretic effects (5 and 10 mg/kg, p.o., daily). In contrast, HCTZ consistently decreased plasma K+, whereas amiloride increased it significantly. ICI 207,828 demonstrated antihypertensive effects in spontaneously hypertensive rats. At 30 mg/kg, p.o., b.i.d., ICI 207,828 and HCTZ produced approximately equal antihypertensive activities during a 3 1/2-day treatment period. The pharmacological profile of ICI 207,828 indicates that this compound is a potent eukalemic diuretic and antihypertensive agent in animals.     

Aquaporin-2 excretion and renal function during the 1st week of life in preterm newborn infants

In many preterm infants, a characteristic pattern of fluid and electrolyte homeostasis occurs during the 1st week of life, consisting of three phases: prediuretic, diuretic, and postdiuretic. In this study, we evaluated the possible role of aquaporin-2 (AQP2) in renal concentrating ability and correlated it with other markers of the renal function in healthy preterm infants. Daily urine and spot blood samples were collected from 9 healthy preterm (32 +/- 1 weeks) infants at postnatal ages 1, 3, and 7 days. Urine and serum osmolality, creatinine, electrolytes, and AQP2 excretion were measured. All infants showed a significant (about 7%) weight loss on day 3 associated with a more than threefold increase in urine output without a significant change in fluid intake (diuretic phase). The creatinine clearance increased on day 3, indicating an increase in glomerular filtration rate. Interestingly, on day 3, the level of total excreted AQP2 (pmol/h) was significantly higher when compared to day 1 and day 7, and the same tendency was observed for urine osmolality. To conclude, the observed increase in urine osmolality and creatinine clearance during the diuretic phase, paralleled by an increase in total AQP2 excretion, suggests that AQP2 can contribute to the urinary concentrating ability early in postnatal life.     

Antagonism of metergoline on the diuretic effect of cyclazocine and U-50488 drugs with a kappa agonist activity

In rats receiving a normal saline load of 2.5 ml/100 g, sc, (moderately hydrated rats), injections of the serotonin (5-HT) antagonist, metergoline (0.25 - 1 - 4 mg/kg), resulted in a dose-dependent decrease in the urine output induced by a dose of 8 mg/kg of cyclazocine (a benzomorphan derivative, mixed kappa and sigma agonist) at the 2-h time period. The antagonist effect of metergoline (1 mg/kg) on cyclazocine doses ranging from 0.25 to 8 mg/kg, was observed only at 2 mg/kg higher doses. Other 5-HT receptor blockers, methysergide, pizotifen, cyproheptadine, caused a significant degree of antagonism. In rats receiving a saline load and a water load of 5.5 ml/100 g, ip (hyperhydrated rats), metergoline (1 mg/kg) completely antagonized the diuretic effect of cyclazocine (8 mg/kg) at the 4-h and 5-h time periods. Similarly, metergoline (1 and 4 mg/kg) administered in moderately hydrated rats, markedly decreased at the 2-h time period, the urine output produced by 5 mg/kg of U-50488 (a non benzomorphan derivative, highly selective kappa agonist), and in hyperhydrated rats, completely suppressed, at the 4-h and 5-h time periods the drug-induced diuresis. Metergoline administered alone had no effect on urine output in moderately hydrated rats or in hyperhydrated rats. These results suggest the hypothesis that 5-HT may be involved in the complex mechanisms of kappa agonist-induced diuresis in rats.     

A(1) receptor blockade induces natriuresis with a favorable renal hemodynamic profile in SHHF/Mcc-fa(cp) rats chronically treated with salt and furosemide.

Our goal was to test the hypothesis that A(1) receptor blockade induces diuresis/natriuresis with a favorable renal hemodynamic/cardiac profile in aged, lean SHHF/Mcc-fa(cp) rats, a rodent model of hypertensive dilated cardiomyopathy. Thirteen-month-old SHHF/Mcc-fa(cp) rats were pretreated for 72 h before experiments with furosemide (100 mg/kg by gavage 72, 48, and 24 h before experiments) to mimic the clinical setting of chronic diuretic therapy and were given 1% NaCl as drinking water to reduce dehydration/sodium depletion. Animals were instrumented for measurement of systemic and renal hemodynamics, renal excretory function, and cardiac performance, and baseline values were obtained during a 30-min clearance period. Animals then received either vehicle (n = 9), BG9719 [the S-enantiomer of 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)] xanthine (also called CVT-124)] (highly selective A(1) receptor antagonist; 0.1 mg/kg bolus + 10 microg/kg/min; n = 9) or furosemide (loop diuretic; 30 mg/kg; n = 8) and measurements were repeated during four subsequent clearance periods. Both BG9719 and furosemide increased urine volume and absolute and fractional sodium excretion. BG9719 increased renal blood flow and glomerular filtration rate, but did not affect fractional potassium excretion. Furosemide decreased renal blood flow and glomerular filtration rate and increased fractional potassium excretion. Neither drug altered afterload; however, furosemide, but not BG9719, decreased preload (central venous pressure and ventricular end diastolic pressure). Neither drug altered systolic function (+dP/dt(max)); however, furosemide, but not BG9719, attenuated diastolic function (decreased -dP/dt(max), increased tau). In the setting of left ventricular dysfunction, chronic salt loading and prior loop diuretic treatment, selective A(1) receptor antagonists are effective diuretic/natriuretic agents with a favorable renal hemodynamic/cardiac performance profile.     

Anti-Hyperglycemic,Anti-Hyperlipidemic and Antioxidant Potential of Alcoholic-Extract of Sida cordifolia (Areal Part) in Streptozotocin-Induced-Diabetes in Wistar-Rats

Sida cordifolia is a shrub found throughout the tropical and sub-tropical plains. All parts of the plant are used as anti-rheumatic, antipyretic, anti-asthmatic, laxative, diuretic, vasorelaxative, hypotensive, central nervous system depressant, antioxidant, analgesic and hypoglycemic. The present study was aimed to evaluate the hypoglycemic, anti-hyperlipidemic and antioxidant potential of alcoholic-extract obtained from areal part of S. cordifolia in streptozotocin-induced-diabetes in wistar-rats. Diabetes was induced with streptozotocin at the intra-peritoneal dose of 55 mg/kg. Diabetic rats were treated with alcoholic extract of S. cordifolia at dosage of 200, 400 mg/kg and glibenclamide (5 mg/kg) after sub-acute administration for 28 days. Alcoholic extract of S. cordifolia at 400 mg/kg significantly improved the body-weight whereas significantly decreased the blood glucose level in diabetic rats. However at 400 mg/kg, the alcoholic extract of S. cordifolia showed beneficial effect indicating significant decrease in total cholesterol, triglycerides, low density lipids, plasma-creatinine, plasma-urea nitrogen and lipid-peroxidation and a significant increase in high density lipid-level in diabetic rats. Interestingly at 400 mg/kg, a significant increase in antioxidant enzymes such as catalase and superoxide-dismutase-activity was seen in the diabetic rats. The dose 200 mg/kg of alcoholic extract of S. cordifolia showed non-significant change in diabetic rats. The above therapeutic-potential of alcoholic extract of areal parts of plant may be because of the presence of bioactive compounds such as glycosides, resins, alkaloids, sterols, saponins and flavonoids. Thus, the findings of the present study indicate that the alcoholic extract of S. cordifolia at dosage level of 400 mg/kg produces anti-diabetic effect in the streptozotocin-induced diabetes in wistar-rats.     

Additive diuretic effect of S-8666 during furosemide-induced diuresis in rats

In order to verify that the novel uricosuric loop-acting diuretic S-8666 has an additional site of action in the distal tubule, we investigated the additive diuretic effect of S-8666 during furosemide-induced diuresis in rats. Intravenous bolus injection of S-8666 (3-30 mg/kg) and trichlormethiazide (TCM) (1-10 mg/kg) caused dose-dependent increases in Na+ excretion during furosemide-induced diuresis (primary, 10 mg/kg i.v.; sustaining, 10 mg/kg/hr i.v.), whereas injection of furosemide (5 mg/kg) did not. Ca++ excretion was decreased by injection of each drug. A significant reduction in Ca++/Na+ was observed at all doses of S-8666 and TCM. Additional natriuretic and hypocalciuric effects were lower in the S-8666 than in the TCM group. From these observations we conclude that: 1) S-8666 has a natriuretic effect which is additive to that of furosemide; 2) S-8666 attenuates the calciuric effect of furosemide; and, 3) S-8666 may have an additional site of action in the distal tubule.     

Clinical pharmacology of furosemide in children: a supplement.

Furosemide is one of the most effective and least toxic diuretics used in pediatric practice. Experimental and clinical data suggest that adrenocorticosteroids and/or endogenous ouabain-like substances may play an important role in its diuretic effect. Also, the drug appears to have anti-inflammatory properties. In children with different diseases who received orally or intravenously 1 to 2 mg/kg doses of furosemide, a statistically significant positive linear relationship was found between the drug urinary excretion rate and the urine flow rate, but log dose-response curves to the drug were found to vary depending on the disease and the route of the drug administration. No sigmoid-shaped log dose-response curve (ie, one approaching a zero response at very low furosemide urinary excretion rates and a maximum response at very high excretion rates) was attained, which may suggest that the capacity of the kidney tubules to respond diuretically to the aforementioned doses of furosemide was not exceeded in these patients. However, in infants with different diseases and reasonably normal renal function who required administration of this diuretic, a very steep log dose-response curve to a 1 mg/kg intravenous dose of furosemide was found, which may suggest that higher doses may not result in a significant increase in diuretic response. The lowest mean furosemide urinary excretion rate and its concentration in urine associated with a significant diuresis were found to be 0.58 +/- 0.33 microg/kg/min and 24.2 +/- 10.5 microg/ml, respectively. Also, a significant correlation was found between the amount (in milligrams) of furosemide excreted in the urine during the first 6 hours after administration and the urine volume collected during that time. Patients with cystic fibrosis appeared to have a markedly more pronounced diuretic response to the average oral dose of 0.835 +/- 0.18 mg/kg than that reported in control children given 2 mg/kg. In children with acute renal failure caused by acute gastroenterocolitis or glomerulonephritis, a broad relationship was observed between a single intravenous dose and diuretic response after administration of furosemide (1.2 to 30.8 mg/kg). It was suggested that the total daily dose of the drug should not exceed 100 mg in these patients. Furosemide was found to be effective in management of bronchoconstriction accompanying chronic lung disease and narrowing of the upper respiratory airways; in hydrocephalus in infancy to avoid cerebrospinal fluid shunts; in some diagnostic procedures, such as an assessment of fetal and neonatal hydronephrosis; and in evaluation of different types of renal tubular acidosis. Among side effects accompanying clinical use of this drug were cholelithiasis in premature infants receiving total parenteral nutrition concomitantly with the diuretic; secondary hyperparathyroidism and bone disease in infants obtaining long-term furosemide treatment; and drug-induced fever.     

Effects of the V(2)-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats

This study was conducted to characterize the diuretic effect of OPC-41061, a nonpeptide vasopressin V(2)-receptor antagonist, and furosemide by administering each alone and in combination in conscious male rats. OPC-41061 at 1 and 10 mg/kg and furosemide at 10 and 100 mg/kg dose-dependently increased urine volume to the same extent. The high dose of OPC-41061 (10 mg/kg) markedly elevated electrolyte-free water clearance (E-CH(2)o) to a positive value. In contrast to OPC-41061, furosemide elevated only electrolyte clearance but not E-CH(2)o. The differences in diuretic profile reflected the changes in serum sodium and hormone levels. OPC-41061 dose-dependently elevated serum sodium concentration, but furosemide tended to decrease it. The high dose of furosemide (100 mg/kg) significantly elevated serum renin activity and aldosterone concentration, indicating that furosemide activated the renin-angiotensin-aldosterone system (RAA-system). On the other hand, OPC-41061 did not affect these parameters. When OPC-41061 was administered concomitantly with furosemide, OPC-41061 significantly increased urine volume and E-CH(2)o, and decreased urinary osmolality compared with furosemide alone. OPC-41061 dose-dependently elevated serum osmolality and sodium concentration even when administered in combination with the high dose of furosemide. These results suggest that OPC-41061 produces aquaresis leading to increased serum sodium without affecting the RAA-system. On the other hand, furosemide produced natriuresis, leading to decreased serum sodium level and activation of the RAA-system. It was also demonstrated that OPC-41061 produced an additive diuretic effect and elevated serum sodium level in the presence of furosemide.