Nebivolol Ameliorates Cisplatin‐Induced Nephrotoxicity in Rats

Treatment with cisplatin is associated with dose‐limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a β₁‐adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor‐alpha, caspase‐3, angiotensin II and endothelin‐1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre‐treatment with N_ω‐nitro‐L‐arginine methyl ester, the non‐specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin‐induced nephrotoxicity that is most likely through its antioxidant, anti‐inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin‐1 levels.     

Dose‐Dependent Protection by Lipoic Acid against Cisplatin‐Induced Nephrotoxicity in Rats: Antioxidant Defense System

This study was designed to investigate the role of graded doses of lipoic acid pretreatment against cisplatin‐induced nephrotoxicity. Male Wistar rats were divided into six groups and treated as follows: 1) vehicle (saline) control; 2) cisplatin (16 mg/kg, intraperitoneally); 3) lipoic acid (100 mg/kg, intraperitoneally); 4) cisplatin plus lipoic acid (25 mg/kg); 5) cisplatin plus lipoic acid (50 mg/kg) and 6) cisplatin plus lipoic acid (100 mg/kg). Rats were sacrificed three days after treatment, and plasma as well as kidneys were isolated and analyzed. Plasma creatinine increased (677% of control) following cisplatin administration alone which was decreased by lipoic acid in a dose‐dependent manner. Cisplatin‐treated rats showed a depletion of renal glutathione (GSH), increased oxidized GSH and decreased GSH/GSH oxidized ratio (62%, 166% and 62% of control), respectively which were restored with lipoic acid pretreatment. Renal superoxide dismutase, catalase, glutathione peroxidase (GSH peroxidase) and glutathione reductase activities decreased (62%, 75%, 62% and 80% of control), respectively, and malondialdehyde content increased (204% of control) following cisplatin administration, which were restored with increasing doses of lipoic acid. The renal platinum concentration increased following cisplatin administration, which was possibly decreased by chelation with lipoic acid. The data suggest that the graded doses of lipoic acid effectively prevented a decrease in renal antioxidant defense system and prevented an increase in lipid peroxidation, platinum content and plasma creatinine concentrations in a dose‐dependent manner.     

Amelioration of Cisplatin Nephrotoxicity with Glycine: Dose Dependency in Rats

The effects of glycine (0·1-1·0 g μg kg^?1, i.v.) on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin (6·0 mg g kg^?1, i.v.) were investigated in the rat. Cisplatin produced decreases of 50% in the clearance of [³H] inulin (C_IN) and renal blood flow (RBF), 110 min following its injection. Glycine at a dose of 0·1 g kg^?1 produced no attenuation of the cisplatin-induced decrease in C_IN or RBF. Furthermore, this dose of glycine provided no significant protection of renal function over a 7-day period following cisplatin injection. By contrast, glycine at a dose of either 0·5 or 1·0 g kg^?1 markedly attenuated cisplatin-induced falls in C_IN and RBF, with the highest dose completely preventing any falls in these indices during the course of the experiment. Treatment with these higher doses of glycine produced prominent protection from the nephrotoxic actions of cisplatin, as evidenced by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, C_IN and the clearance of [¹⁴C]P-aminohippurate. The results of experiments with an intermediate dose of 0·25 g kg^?1 glycine revealed some degree of amelioration of acute renal haemodynamic effects of cisplatin, particularly with regard to C_IN; whilst in the nephrotoxicity study, 0·25 g kg^?1 glycine produced a modest but significant reduction in cisplatin-induced acute renal dysfunction. The results have revealed a clear association between the acute renal haemodynamic effects produced by glycine in cisplatin-injected rats with the longer-term renal protective effects of glycine in cisplatin nephrotoxicity. The findings indicate that glycine's ability to prevent the falls in RBF and glomerular filtration rate produced by cisplatin plays an important role in the protective effect of glycine in cisplatin-induced nephrotoxicity.     

Effect of Uric Acid on Gentamicin‐Induced Nephrotoxicity in Rats – Role of Matrix Metalloproteinases 2 and 9

Abstract: In this work, we aimed to study the effect of uric acid on gentamicin‐induced nephrotoxicity. Male Sprague‐Dawley rats were assigned to one of six groups (six rats each) which received intraperitoneal injections for 9 days: (S) saline; (UA) Uric acid alone; (G) Gentamicin alone; (G + UA) Gentamicin + uric acid; (G rec) Gentamicin recovery and (G + UA rec) Gentamicin + uric acid recovery. In (G rec) and (G + UA rec), rats recovered for 7 days after the last injection. Urine and blood samples were taken on day 0 and at the end of every stage. Kidneys were harvested for histological scoring, determination of renal malondialdehyde (MDA), zymography and western blots for matrix metalloprotease (MMP)‐2 and MMP‐9. Uric acid alone did not provoke changes in biochemical and histological parameters when compared to controls. Gentamicin alone increased significantly plasma creatinine and blood urea nitrogen and caused a moderate histological damage. When combined with uric acid, these conditions worsened. MMP‐9 activity and expression was decreased in rats from group G + UA as compared with rats from group G, while activity of MMP‐2 was similarly increased in both groups when compared to controls. The increase in renal MDA induced by gentamicin was not altered when it was combined with uric acid. During the recovery stage, all biochemical parameters returned to normal levels, though a trend for delay of tubular damage recovery was observed in group G + UA rec when compared with group G rec. The results indicate that uric acid worsens gentamicin‐induced nephrotoxicity. The mechanism is likely to implicate down‐regulation of MMP‐9.     

Sequential Study of the Chronic Nephrotoxicity Induced by Dietary Administration of Ethoxyquin in Fischer 344 Rats

Groups of 3-week-old male and female Fischer 344 rats were administered0.5% ethoxyquin-containing diet for varying periods of time,ranging from 4 weeks up to 18 months, to assess renal histopathology.The primary lesion observed was renal papillary necrosis inthe male rat, commencing as interstitial degeneration of thepapillary tip by 4 weeks exposure, and reaching a complete formof papillary necrosis by 24 weeks. The papillary necrosis inmale rats was consistently accompanied by active pyelonephritisaffecting the cortex, and urothelial hyperplasia in the renalpelvis. A marked sex difference was evident in that female ratsdeveloped papillary change at a later stage than males and thelesion never progressed beyond interstitial degeneration. Afurther sex difference associated with ethoxyquin treatmentwas the increasing cellular accumulation of lipofuscinrelatedpigment involving proximal tubules in female rats. Spontaneouschronic progressive nephropathy (CPN) was exacerbated by ethoxyquinin both males and females, but more so in the former. Proximaltubule hyperplasia was most frequently observed in ethoxyquin-treatedmales at the later sampling times. In all cases, such proliferativelesions were associated either with pyelonephritis or with themost advanced stages of CPN. Contrary to a previous report,there was no evidence that ethoxyquin directly induced preneoplasticrenal tubule hyperplasia.     

Effects of Anticonvulsants on Local Anaesthetic‐Induced Neurotoxicity in Rats

Abstract: The effects of various anticonvulsants on local anaesthetics procaine‐ and lidocaine‐induced convulsions were investigated in rats. Pretreatment with diazepam (2.5–5 mg/kg, intraperitoneally) and clonazepam (5–10 mg/kg, intraperitoneally) completely protected the rats against both local anaesthetic‐induced convulsions. Phenobarbital (12.5–50 mg/kg, subcutaneously) also significantly decreased the incidence of both convulsions and prolonged their latencies. Carbabazepine (10–40 mg/kg, intraperitoneally) did not completely repress both convulsions, but it prolonged their latencies. Phenytoin (5–20 mg/kg, intraperitoneally) and primidone (30–60 mg/kg, intraperitoneally) markedly enhanced both local anaesthetic‐induced convulsions, as shown by shortening of latency and increase in mortality. Valproate (100–200 mg/kg, intraperitoneally) produced a protective effect against procaine‐induced convulsions, while it strongly enhanced lidocaine‐induced convulsions. These results suggest that the benzodiazepines are effective drugs to prevent neurotoxicity induced by local anaesthetics, while phenytoin and primidone potentiate them.     

Gastroprotective Effect of Rutin against Indomethacin‐Induced Ulcers in Rats

Abstract: Several reports have indicated that indomethacin‐induced gastropathy is mediated through generation of free radicals, neutrophil infiltration and disturbance in nitric oxide production. Rutin is a potent antioxidant flavonoid. Recently, rutin was reported to inhibit neutrophil infiltration and to modulate nitric oxide production in gastric mucosa. Therefore, the aim of this study was to investigate the protective effect of rutin against indomethacin‐induced gastric injury. Accordingly, four groups of rats were used. The first three groups were injected orally with vehicle, rutin (200 mg/kg) and indomethacin (48 mg/kg) respectively. The fourth group was injected with rutin 1 hr before indomethacin. Animals were killed after 6 hr of indomethacin administration. Gastric juice acidity and gastric injury were evaluated directly. Moreover, the activities of myeloperoxidase, superoxide dismutase and the contents of reduced glutathione, thiobarbituric acid reactive substance and total nitrite/nitrate (as a marker of nitric oxide production) were determined in mucosal tissues. Indomethacin increased gastric ulcer index, gastric myeloperoxidase activity, gastric acidity and thiobarbituric acid reactive substance contents compared with control. On the other hand, indomethacin decreased glutathione, nitrite/nitrate contents and superoxide dismutase activity. Histopathological examination of the stomachs of indomethacin‐treated rats revealed degenerative changes in gastric tissues. Pre‐treatment with rutin protected gastric tissues against indomethacin‐induced gastropathy as demonstrated from reduction in the ulcer index, attenuation of histopathological changes and amelioration of the altered oxidative stress and biochemical parameters. These results indicate that rutin has a protective effect against indomethacin‐induced gastropathy probably through inhibiting neutrophil infiltration, suppression of oxidative stress generation and replenishing nitrite/nitrate levels regardless of gastric acidity.     

维生素C对顺铂所致大鼠肾损伤的保护作用

目的研究维生素C（Vit C）对顺铂所致肾损伤的保护作用,并探讨其可能的机制。方法将40只成年雌性SD大鼠按体重分成5组,分别为正常对照组（A组,生理盐水）、Vit C对照组（B组,500mg／kg）、顺铂化疗模型组（C组,6mg／kg）、顺铂（6mg／kg）＋Vit C（50mg／kg或500mg／kg）干预组（D1组及D2组）。腹腔注射Vit C进行前、中、后期全程保护,并于顺铂给药5d后采血处死动物,测定血清尿素氮（BUN）、肌酐（Cr）、肾皮质匀浆丙二醛（MDA）含量及谷胱甘肽过氧化物酶（GSH—Px）、超氧化物歧化酶（SOD）活力的变化。结果与C组相比,D1组及D2组的血清Cr及BUN、肾皮质匀浆MDA含量明显下降（P〈0．01或P〈0．05）,GSH—Px和SOD活力略有增加。结论Vit C可以减轻顺铂所致肾损伤,作用机制可能与其抗氧化作用和清除自由基活性密切相关。     

亚高原地区野百合碱诱导大鼠肺动脉高压模型的剂量研究

目的 探讨亚高原地区野百合碱(monocrotaline,MCT)诱导大鼠肺动脉高压模型的最佳剂量.方法 将从平原地区购买85只(♂)SD大鼠随机分为对照组、MCT-20 mg·kg-1组、MCT-30 mg·kg-1组、MCT-40 mg·kg-1组、MCT-50 mg·kg-1组、MCT-60 mg·kg-1组.除...     

加味黄连阿胶煎剂对顺铂所致肾毒性大鼠肾组织MMP-9表达的影响

目的探讨加味黄连阿胶煎剂对顺铂（DDP）所致大鼠肾毒性基质金属蛋白酶 9（MMP 9）表达的影响。方法SPF级雄性SD大鼠60只,随机分为正常对照组,模型组,硫代硫酸钠治疗组,加味黄连阿胶煎剂低、高剂量组,每组12只。除正常对照组大鼠尾静脉注射0.9%氯化钠溶液外,其他4组大鼠尾静脉注射DDP 5 mg•kg 1,每周1次,连续3周。硫代硫酸钠治疗组大鼠同时注射10%硫代硫酸钠,600 mg•kg 1;加味黄连阿胶煎剂各剂量组第一次尾静脉注射DDP后根据体质量分别给予0.5,1.5 g•mL 1加味黄连阿胶煎剂灌胃;正常对照组和模型组给予0.9%氯化钠溶液灌胃。均qd,连续8周。实验结束,剖取肾脏,行苏木精 伊红（HE）、PAS及免疫组织化学染色。结果与模型组比较,加味黄连阿胶煎剂各剂量组及硫代硫酸钠治疗组MMP 9平均吸光度显著升高,均差异有显著性或极显著性（P＜0.05或P＜0.01）,且加味黄连阿胶煎剂各剂量组优于硫代硫酸钠治疗组（均P＜0.05）,但加味黄连阿胶煎剂两剂量组间差异无显著性。结论加味黄连阿胶煎剂可显著改善DDP肾毒性大鼠肾功能,上调肾小管上皮细胞MMP 9表达,减轻DPP所致肾小管和肾间质损伤。     

Blunted Central Bromocriptine‐Induced Tachycardia in Conscious,Malnourished Rats

Abstract: Bromocriptine‐induced tachycardia, persisting after adrenalectomy, is mediated by central dopamine D₂ receptor stimulation through activation of the sympathetic outflow to the heart. The present study investigated the effects of malnutrition during pregnancy on bromocriptine‐induced tachycardia in adult conscious rats. Malnourished rats were obtained by feeding dams a multideficient diet (providing 8% protein) during mating and pregnancy. Birth weight was significantly reduced in malnourished rats when compared to control rats born to dams fed standard commercially diet (23% protein) during mating and pregnancy. Baseline mean aortic pressure and heart rate in malnourished rats were comparable to those of well‐nourished rats. Tachycardia (33±9 beats/min.), but not the hypotensive response to intravenous bromocriptine (150 μg/kg) was significantly reduced in malnourished rats, compared with control rats (70±10 beats/min.). In malnourished rats, pretreatment with intravenous domperidone (500 μg/kg) blocked the bromocriptine‐induced hypotension, without affecting the tachycardia. Neither cardiac vagal (40±6 beats/min.) nor sympathetic tone (76±6 beats/min.) was significantly altered by multideficient diet‐induced malnutrition (51±6 and 67±10 beats/min., respectively). In isolated perfused heart preparations from malnourished rats, positive inotropic response to isoproterenol (10^?8 to 10^?4 M) was not significantly different compared to that in control rats. In summary, malnutrition during foetal life blunted the bromocriptine‐induced tachycardia, an effect that could be related to central dopamine D₂ receptor desensitization rather than to impairment of autonomic regulation of the heart or cardiac β‐adrenoceptor desensitization.     

Protective Effect of Berberine on Cyclophosphamide‐Induced Haemorrhagic Cystitis in Rats

Abstract: The urotoxicity of cyclophosphamide and the protective effect of the herb berberine were investigated in this study. Administration of 150 mg/kg cyclophosphamide intraperitoneally caused a serious haemorrhagic cystitis in rats after 12 hr, including bladder oedema, haemorrhage, and dramatic elevation of nitric oxide metabolites (nitrite+nitrate) in urine and in plasma. To explore whether cyclophosphamide‐induced cystitis could be prevented by berberine, rats were pretreated with a single dose or two doses of berberine at 50, 100, or 200 mg/kg intraperitoneally then challenged with cyclophosphamide (150 mg/kg, intraperitoneally). The results indicated that pretreatment of rats with berberine could reduce cyclophosphamide‐induced cystitis in a dose‐dependent manner. Furthermore, we found that two doses of berberine showed greater protection against cyclophosphamide urotoxicity than when given a single dose. In addition, our data shows that a single dose of 200 mg/kg berberine, or two doses of 100, and 200 mg/kg berberine could completely block cyclophosphamide‐induced bladder oedema and haemorrhage, as well as nitric oxide metabolites increase in rat urine and plasma. In conclusion, our findings suggest that berberine could be a potential effective drug in the treatment of cyclophosphamide‐induced cystitis, and provides us with the bright hope in the prevention and treatment of cyclophosphamide urotoxicity.     

Chlorotrifluoroethylene Nephrotoxicity in Rats: A Subacute Study

Chlorotrifluoroethylene Nephrotoxicity in Rats: A Sub-acuteStudy. Buckley, L.A., Clayton, J.W., Nagle, R.B. and Gandolfi,A.J. (1982). Fundam. Appl. Toxicol. 2:181-186. Male Fischer-344rats were exposed via inhalation to a sublethal concentration(395 ppm ± 33 ppm; 1882 mg/m³) of the nephrotoxin chlorotrifluoroethylene(CTFE) for 4 h per day for 5 consecutive days. Within 1 dayafter the first exposure, rats exhibited diuresis, increasedwater intake, decreased urine osmolality, increased urinarylactic dehydrogenase activity and increased plasma creatinineand urea nitrogen. When animals were exposed repeatedly, valuesfor these parameters declined or returned to control levelsduring the exposure sequence in a manner comparable to ratsreceiving the single exposure. By the third day post exposure,coagulative necrosis involving primarily the pars recta, butextending to the pars convoluta, of the proximal tubule waspresent. Regeneration was apparent by the third day of exposure,and additional necrosis was minimal despite further exposures.Daily levels of urinary inorganic fluoride, an index of CTFEmetabolism, were increased to 3–6 µmoles/24 h/ratduring the exposure sequence which coincided with a brief elevationin serum fluoride at the end of each exposure. Adaptation toCTFE is evident either through changes in the metabolism ordisposition of CTFE or from a refractive property of the regeneratingtissue to CTFE.     

Protection by Hydrogen Against Gamma Ray‐Induced Testicular Damage in Rats

The aim of this study was to investigate the possible protective role of hydrogen‐rich saline solution (HRSS) and WR‐2721 on the testicular damage induced by irradiation. Sprague‐Dawley rats were randomly divided into four groups. Group I served as control group. Rats in group II were exposed to the irradiation. The animals in group III and IV were injected intraperitoneally with HRSS (5 ml/kg) and WR‐2721 (200 mg/kg), respectively, 15 min. before the start of gamma irradiation. Testis weight, testis dimensions, sperm count, sperm motility, apoptosis index and biochemical assays were assessed after a 4‐day initiation of irradiation. Testis weight, testis dimensions, sperm count, sperm motility in group II were significantly lower compared with those in the control group, whereas they were higher in the HRSS and WR‐2721 group. Apoptosis index was significantly increased in group II. Treatment of rats with HRSS and WR‐2721 significantly reduced the apoptosis index. On the other hand, irradiation markedly decreased activities of SOD. Activities of SOD were significantly improved when treated with HRSS and WR‐2721. Significant increase in the MDA level was observed in group II. MDA levels of group III and IV were significantly lowered when compared with group II. HRSS also played a significant role in the recovery of serum testosterone levels. The results from this experimental study suggest that hydrogen has a possible protective effect against radiation‐induced testicular damage.     

Protective Effects of Glycyrrhizin on Gentamicin‐Induced Acute Renal Failure in Rats

Abstract: The aim of this study was to investigate the effects of glycyrrhizin (200 mg/kg/day) on renal function in association with the regulation of aquaporin 2 water channel in rats with gentamicin (100 mg/kg/day)‐induced acute renal failure. Polyuria in rats with gentamicin‐induced acute renal failure was associated with down‐regulation of renal aquaporin 2 in the inner and outer renal medulla, and cortex. Glycyrrhizin administration restored the expression of aquaporin 2 with paralleled changes in urine output. Changes in renal functional parameters, such as creatinine clearance, urinary osmolality, and solute‐free reabsorption, accompanying acute renal failure were also partially restored after administration of glycyrrhizin. Histological changes in rats with gentamicin‐induced acute renal failure were also abrogated by glycyrrhizin treatment. The above results suggest that glycyrrhizin treatment could ameliorate renal defects in rats with acute renal failure induced by gentamicin.     

Skeletal Muscle Atrophy Induced by Intramuscular Repeated Dose of Botulinum Toxin Type A in Rats

Botulinum toxin type A was intramuscularly administered to Sprague–Dawley rats once a day for 28 days at doses of 1, 3, and 9 ng kg^?1 day^?1 to investigate the possibility of unanticipated toxicity of repeated dose. A dose-related decrease in body weight gain was noted and lasted throughout the 4-week recovery period. Paralytic gait was a common clinical sign observed in the animals dosed at ≥3 ng kg^?1 day^?1 and muscle atrophy at 9 ng kg^?1 day^?1. Decreased creatinine was monitored in both males and females treated at 9 ng kg^?1 day^?1. Microscopic examination of the quadriceps femoris muscle, the test article application site, confirmed the muscle atrophy with a decrease in myofiber diameter and an increase of myofiber nuclei and intermyofiber connective tissue. Although antibody against botulinum toxin type A was detected in the sera from both males and females at 9 ng kg^?1 day^?1, no immunogenicity-related changes or lesions were noted. In conclusion, no other side effects of the botulinum toxin type A injection except the decrease in body weight gain and the muscle atrophy at the administration site were noted in the 28-day intramuscular repeated dose study.     

Renoprotective Effects of Sesamol in Ferric Nitrilotriacetate‐Induced Oxidative Renal Injury in Rats

Abstract: The present study was designed to investigate the renoprotective effect of 3,4‐methylenedioxyphenol (sesamol) on ferric nitrilotriacetate‐induced renal toxicity. Rats were pretreated with sesamol (2, 4 and 8 mg/kg, p.o.) 30 min. prior to administration of ferric nitrilotriacetate (8 mg iron/kg, i.p.) to determine the blood urea nitrogen and serum creatinine levels along with renal oxidative stress. Challenge with ferric nitrilotriacetate markedly increased the blood urea nitrogen and serum creatinine levels, which was coupled with a marked lipid peroxidation, reduced activity of glutathione and decreased total nitric oxide levels in rat kidneys. It also produced significant renal morphological alterations and increased serum tumour necrosis factor‐alpha levels. Pretreatment with sesamol significantly reduced the serum creatinine and blood urea nitrogen levels, lipid peroxidation, restored levels of reduced glutathione and increased total renal nitric oxide levels. It also attenuated the increased tumour necrosis factor‐alpha levels and restored the normal morphology of the kidneys. Present findings strongly suggest the pivotal role of oxidative stress in the ferric nitrilotriacetate‐induced renal dysfunction and points towards the renoprotective potential of sesamol in oxidative renal pathologies.