Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation

Nitric oxide (NO) regulates vascular tone and mitochondrial respiration. We investigated the hypothesis that there is reduced NO concentration in the renal cortex of diabetic rats that mediates reduced renal cortical blood perfusion and oxygen tension (P O2). Streptozotocin-induced diabetic and control rats were injected with l-arginine followed by Nomega-nitro-L-arginine-metyl-ester (L-NAME). NO and P O2 were measured using microsensors, and local blood flow was recorded by laser-Doppler flowmetry. Plasma arginine and asymmetric dimethylarginine (ADMA) were analyzed by high-performance liquid chromatography. L-Arginine increased cortical NO concentrations more in diabetic animals, whereas changes in blood flow were similar. Cortical P O2 was unaffected by L-arginine in both groups. L-NAME decreased NO in control animals by 87 +/- 15 nmol/l compared with 45 +/- 7 nmol/l in diabetic animals. L-NAME decreased blood perfusion more in diabetic animals, but it only affected P O2 in control animals. Plasma arginine was significantly lower in diabetic animals (79.7 +/- 6.7 vs. 127.9 +/- 3.9 mmol/l), whereas ADMA was unchanged. A larger increase in renal cortical NO concentration after l-arginine injection, a smaller decrease in NO after L-NAME, and reduced plasma arginine suggest substrate limitation for NO formation in the renal cortex of diabetic animals. This demonstrates a new mechanism for diabetes-induced alteration in renal oxygen metabolism and local blood flow regulation.     

罗格列酮对2型糖尿病大鼠肾脏的抗氧化保护作用

目的观察新型胰岛素增敏剂罗格列酮对2型糖尿病（DM）大鼠肾脏的抗氧化保护作用。方法将30只雄性Wistar大鼠随机分为3组：正常对照组、DM组和罗格列酮治疗组,每组10只。药物干预8周后,检测各组大鼠空腹血糖（FBG）、血胰岛素、总胆固醇（TC）、三酰甘油（TG）、血肌酐（SCr）、24h尿白蛋白排泄率（UAE）及肾组织中丙二醛（MDA）含量及铜／锌-超氧化物歧化酶（Cu／Zn-0D）、过氧化氢酶（CAT）、谷胱甘肽过氧化酶（GSH—Px）活性,同时留取肾组织做HE、PAS染色行病理检查。结果与对照组相比,DM组大鼠FBG、TC、TG、UAE均升高（P〈0．05）,系膜密度和肾小球基底膜厚度均增加（P〈0．05）;与DM组相比,罗格列酮治疗组FBG、TC、TG差异无统计学意义（P〉0．05）,SCr、UAE及肾组织MDA含量降低（P〈0．05）,肾组织Cu／Zn-SOD、CAT、GSH—Px活性升高（P〈0．05）,肾组织病理表现改善。结论罗格列酮对DM大鼠肾脏有保护作用,其机制可能与抑制肾组织氧化应激反应有关。     

针刺对光老化大鼠皮肤组织CAT、GSH-Px和H2O2影响的实验研究

目的:研究针刺对UV照射引起的皮肤光老化大鼠皮肤组织中过氧化氢酶(CAT)、谷胱甘肽氧化酶(GSH-Px)和过氧化氢(H2O2)的含量的变化,探讨针刺对抗皮肤光老化的作用机理。方法:将大鼠随机分成4组,除正常组外,其余各组模拟日光中UV(UVA+UVB)照射,造成皮肤光老化模型,每次造模前,针刺组给予电针刺激,阳性对照组采用VE涂抹造模部位,15周后对比各组生化指标结果。结果:模型组与正常组比较大鼠皮肤组织中CAT、GSH-Px活性明显降低,H2O2含量明显增加(P<0.05);针刺组与模型组比较CAT、GSH-Px活性增加,H2O2含量明显降低(P<0.05),与VE组比较无统计学意义(P>0.05)。结论:针刺可延缓UV引起的大鼠皮肤光老化,能增强皮肤组织中CAT、GSH-Px活性,降低H2O2含量。     

Reversal of renal lesions following interruption of nitric oxide synthesis inhibition in transgenic mice.

BACKGROUND: Renal fibrosis, a common complication of hypertension and diabetes is considered as a non-curable disease and is characterized by the abnormal accumulation of collagen I within the kidney. Chronic inhibition of nitric oxide (NO) synthesis is a model of hypertension associated with the development of nephroangiosclerosis. The present study investigated whether halt of NO inhibition leads to the regression of renal sclerotic lesions. METHODS: The NO deficiency (N(G)-nitro-L-arginine methylester; L-NAME) model of hypertension was applied in transgenic mice harbouring the luciferase reporter gene under the control of the collagen I-alpha2 chain promoter. RESULTS: Systolic pressure gradually increased following the administration of L-NAME, and reached 160 mmHg after 8-10 weeks. Activation of collagen I gene within the renal vasculature preceded the blood pressure increase and was accompanied by the appearance of sclerotic glomeruli and tubulointerstitial infiltration. After renal lesions had been established (20 weeks), animals were divided in three subgroups for an additional experimental period of 10 weeks: first group continued to receive L-NAME, in the second, L-NAME administration was stopped to allow endogenous NO synthesis and in the third the removal of L-NAME was combined with endothelin receptor antagonism. Removal of L-NAME decreased, without normalizing, systolic pressure and collagen I gene activity; renal morphology was substantially improved, and tubulointerstitial infiltration disappeared. Combination of L-NAME removal with endothelin antagonism normalized collagen I gene expression and further improved renal morphology without further decreasing blood pressure. CONCLUSION: Manipulating the balance between NO/vasoconstrictors in favour of NO could provide a curative approach against renal inflammatory and fibrotic complications associated to hypertension.     

Propofol attenuates reperfusion injury after testicular torsion and detorsion

Propofol, which is widely used as an intravenous anesthetic, has been shown to have an antioxidant activity on several tissues. This study was designed to investigate the prevention of reperfusion injury with propofol after testicular torsion. Five groups of rats (seven in each group) were used. Animals in the control group (group I) did not received any treatment, while animals in the sham group (group II) underwent scrotal incision and testicular fixation only. After 2 h of 720° left testicular torsion in groups III, IV and V, subsequent detorsion was done for 2 h in groups IV and V. Propofol (50 mg/kg) was injected transperitoneally 30 min prior to detorsion in group V. Both testicles in all rats were retrieved and tissue malondialdeyhde (MDA) level, which is a measure of the amount of free oxygen radicals, and enzymatic activity of xanthine oxidase (XO), which converts hypoxanthine to xanthine and uric acid were studied. In addition, tissue catalase (CAT) and glutathione peroxidase (GSH-Px) activities, which are endogenous scavenger enzymes, protecting tissues against free radicals, were studied. Additionally, histological evaluations were performed after hematoxylin and eosin staining. Testicular MDA levels, and XO and CAT activities were higher in the torsion group compared to sham control group (P<0.05). Detorsion caused a further increase in MDA levels, contrasting with a decrease in the levels of XO activity, while CAT activity was not changed. Pretreatment with propofol prevented a further increase in MDA levels and significantly decreased CAT activity following detorsion. GSH-Px activities were not effected either by torsion/detorsion or propofol pretreatment. Histologically, torsion caused some separation between germinal cells in the seminiferous tubules, which became much more prominent in the detorsion group and attenuated with propofol pretreatment. There was no significant change in any of the abovementioned enzymatic activities nor were there histopathological changes in the contralateral testicle in any groups. It is concluded that biochemically and histologically reperfusion injury occurs in the ipsilateral testis following detorsion up to 2 h. Preference of propofol for anaesthesia during the detorsion procedure may attenuate such reperfusion injury.     

The protective effect of ebselen on radiocontrast-induced nephrotoxicity

Aim: Radiocontrast-induced nephropathy has become one of the most important causes of renal acute failure. The most effective management of reducing the incidence of contrast nephropathy is to understand and prevent its causes. We aimed to investigate the protective role of ebselen against radiocontrast-induced nephrotoxicity in terms of tissue oxidant/antioxidant parameters and light microscopy in rats. Methods: Albino Wistar rats were randomly separated into four groups. The Group 1 rats were treated with sodium chloride as the control group, Group 2 with radiocontrast, Group 3 with radiocontrast plus ebselen, and Group 4 with ebselen alone. After 24 h, the animals over the experimental period were euthanized and blood samples were analyzed for blood urea nitrogen (BUN) and serum creatinine (Cr) levels. Kidney sections were analyzed for malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, as well as histopathological changes. Results: In the radiocontrast group, BUN, MDA, and GSH-Px levels increased while SOD activity decreased compared with the control group. These decays were improved by ebselen administration in the radiocontrast group. Significant histological deteriorations were observed in the radiocontrast group. We noted improvement in the histologic findings with ebselen administration. Conclusion: These results indicate that ebselen might produce a protective mechanism against radiocontrast-induced nephrotoxicity.     

Curcumin protects against ischemia/reperfusion injury in rat kidneys

OBJECTIVES: Renal ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal allograft. We investigated the effect of curcumin on ischemia-reperfusion (I/R) injury and the antioxidant effects of curcumin in rats. METHODS: Thirty rats were randomly divided into five experimental groups (control, sham, curcumin, I/R and I/R+curcumin, n=6 each). Curcumin was administered (200 mg kg(-1)) orally to curcumin and I/R+curcumin groups for 7 days. Then, the rats were subjected to bilateral renal ischemia for 45 min and followed by reperfusion for 24 h. All rats were killed and kidney function tests, serum and tissue nitric oxide (NO), protein carbonyl (PC), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels were determined. Histopathological examinations were also performed. RESULTS: Curcumin significantly improved the urea and cystatin C levels in I/R+curcumin group compared to I/R group (p<0.05). Reduction of serum GSH-Px was significantly improved by curcumin (p<0.001), but SOD enzyme activity did not alter (p>0.05). Treatment with curcumin also resulted in significant reduction in serum and tissue MDA, NO and PC and for tissue that were increased by renal I/R injury (p<0.001 for serum and p<0.05 for tissue, respectively). In histological examination, the rats treated with curcumin had nearly normal morphology of the kidney. CONCLUSIONS: Based on our results, it can be concluded that curcumin protects the kidneys against I/R injury via its antioxidant effects.     

Lipid peroxidation and antioxidant enzymes in children with chronic renal failure

Increased lipid peroxidation (LP) has been observed in dialysis patients and in predialysis adults with advanced chronic renal failure (CRF). The aim of this study was to investigate whether predialysis CRF children have increased LP in plasma and red blood cells (RBC) and to evaluate the activity of the antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)] in RBC. Concentrations of selenium (Se), copper (Cu), and zinc (Zn)—cofactors of these enzymes—were determined both in erythrocytes and in plasma. LP was monitored by plasma and erythrocyte malonyldialdehyde (MDA) and by plasma organic hydroperoxide (OHP) concentrations. Forty-six predialysis children, aged 5–18 years, divided into two groups according to their serum creatinine levels [group I (n=14, mean serum creatinine 421.61±141.08 mol/l), group II (n=32, mean serum creatinine 174.94±45.50 mol/l)] and 27 age-matched healthy subjects were enrolled in the study. Significantly higher concentrations of plasma and erythrocyte MDA and plasma OHP, significantly lower activities of GSH-Px and CAT, and significantly lower concentrations of erythrocyte Se, Cu, and Zn and plasma Se and Cu were found in both groups of renal patients compared with controls. The SOD activity was reduced in both groups of CRF children. In group I the activity of SOD and GSH-Px was significantly lower than in group II. In summary, there is increased LP in plasma and RBC in children with predialysis CRF, even those patients with moderate renal insufficiency. The activity of the enzymatic antioxidant defense system is reduced in the RBC of predialysis patients. The antioxidant capacity is related to the severity of renal failure.     

Rosiglitazone,peroxisome proliferator receptor-gamma agonist,ameliorates gentamicin-induced nephrotoxicity in rats

Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe gram-negative infections. Reactive oxygen spaces (ROS) are important mediators of gentamicin-induced nephrotoxicity. Peroxisome proliferator-activated receptors (PPARs) have different activities including antioxidant properties. This study was performed to investigate the protective role of PPAR-γ agonist against GEN-induced nephrotoxicity. Male Wistar Albino rats were randomly divided into the following four groups, each of which consisted of six animals: (1) control; (2) intraperitoneally injected with GEN for 14 consecutive days (100 mg/kg/day); (3) treatment with rosiglitazone (RSG) via nasogastric gavage (10 mg/kg/daily for 14 days); (4) treatment with GEN + RSG combination for 14 day. Rats were decapitated on the 15th day and kidneys were removed. Urine was collected for every 24 h for the determination of daily urine volume. Urea, creatinine, Na⁺ and K⁺ levels were measured in blood. Malondialdehyde (MDA), reduced glutathion (GSH), and nitric oxide (NO) levels along with glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activities were determined in the renal tissue. Changes in body weight were recorded. GEN treatment was found to cause nephrotoxicity as evidenced by elevation of serum urea and creatinine levels. Renal impairment was also assessed by the renal histology. The significant decrease in GSH and increases in MDA and NO levels as well as a decrease in GSH-Px, CAT, and SOD activities indicated that GEN-induced renal damage was mediated through oxidative reactions. On the other hand, RSG administration protected kidney tissue against GEN-induced and free radical-mediated oxidative renal damage in rats.     

Renal effects of HMG-CoA reductase inhibition in a rat model of chronic inhibition of nitric oxide synthesis

BACKGROUND/AIMS: In addition to their lipid-lowering effects, HMG-CoA reductase inhibitors (statins) induce a variety of pleiotropic actions that have been recently studied in the area of cardiovascular and renal protection. In the present studies we sought to determine whether statins retain beneficial effects in the experimental model of NO deficiency achieved by chronic administration of a pressor dose of L-arginine analogue N-nitro-L-arginine-methyl ester (L-NAME). METHODS: To address this issue, blood pressure (BP), renal function (GFR), and albuminuria were determined in rats treated for 4 weeks with L-NAME, L-NAME + atorvastatin (ATO), and in untreated controls. In addition, renal cortical protein expression of caveolin 1 (CAV1), vascular endothelial growth factor (VEGF), and activity of RhoA were also determined. RESULTS: L-NAME administration resulted in sustained elevation of BP, decreased GFR, and in higher albuminuria as compared to control animals. Co-administration of ATO with L-NAME normalized albuminuria and prevented decreases in GFR in L-NAME rats without having an impact on pressor effects of L-NAME. CAV1 protein expression was similar in all groups of rats. In contrast, VEGF expression and RhoA activity was increased in L-NAME-treated animals, and normalized with co-administration of ATO. CONCLUSION: Treatment with ATO exerts early nephroprotective effects in the NO-deficient model of hypertension. These effects could be mediated by amelioration of VEGF expression and reduction of RhoA activity.     

阻塞性黄疸时L-精氨酸对肾功能的保护作用

目的：研究阻塞性黄疸（OJ）时，L－精氨酸（L－Arg)对肾功能的保护作用。方法：胆总管结扎大鼠30只，随机分成生理盐水对照（NS）组、L－精氨酸（L－Arg)组和L－硝基精氨酸（L－NNA）组，每组10只。胆总管结扎后第2天起分别腹腔注射1ml NS、1ml L-Arg(500mg/kg)、1ml L-NNA(10mg/kg)，连用9d；假手术（SO）组用1ml NS腹腔注射。观察各组肾功能的变化，同时测定血和肾组织内皮素（ET）、一氧化氮（NO）水平、一氧化氮合酶（NOS）活性和丙二醛（MDA）的含量。并用图像分析检测ET1 mRNA和NOS mRNA表达的部位及量的变化。结果：用L－Arg后，血和肾组织NOS活性增加，肾组织ET1 mRNA表达减少，血和肾组织ET下降，NO升高；同时伴有内生肌酐清除率（Ccr)、肾皮质平均血流（RCBF）的升高，肾组织MDA含量降低。结论：L－Arg通过增强血和肾组织NOS活性来增加体内NO水平、抑制ET1 mRNA表达、降低体内ET水平，从而提高Ccr与RCBF，减轻阻塞性黄疸时的肾功能损伤。     

The correlation between serum levels of oxidative stress indicators and renal interstitial fibrosis in patients with IgA nephropathy

Objective To investigate the relationship between serum levels of oxidative stress indicators and the degree of renal interstitial fibrosis in patients with IgA nephropathy (IgAN). Methods Seventy eight patients with confirmed primary IgAN in General Hospital of Ningxia Medical University from January 2013 to December 2014 were enrolled. The patients were divided into T0 group (n=30), T1 group (n=26) and T2 group (n=22) according to the grade of tubular atrophy/interstitial fibrosis of Oxford pathological classification criteria for IgAN in 2009. Meanwhile, thirty cases of health examiner were enrolled as control subjects. The levels of serum malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were detected by xanthine oxidase method, thiobarbituric acid spectrophotometry method, ultraviolet spectrophotometry method, chemical colorimetric method, respectively. The levels of serum advanced oxidation protein products (AOPPs), transforming growth factor beta 1 (TGF-β1), monocyte chemotactic protein 1 (MCP-1), transforming growth factor alpha (TGF-α), interleukin 6 (IL-6) and hypoxia inducible factor 1 alpha (HIF-1α) were detected by enzyme linked immunosorbent assay (ELISA) in all groups. Spearman correlation analysis was used to analyze the correlation between serum oxidative stress indicators and traditional risk factors of tubular atrophy/renal interstitial fibrosis. Multivariable linear regression analysis was used to analyze the correlation between oxidative stress indicators and degree of renal tubular atrophy/renal interstitial fibrosis. Results There were differences in serum levels of AOPPs, MDA, SOD, CAT and GSH-Px in IgAN patients with different degrees of renal interstitial fibrosis (all P﹤0.05). With the increase of renal interstitial fibrosis, the levels of AOPPs and MDA increased gradually, while the levels of SOD, CAT and GSH-Px decreased gradually. Serum AOPPs, MDA, SOD, CAT, GSH-Px concentration in IgAN patients were correlated with the mean arterial pressure (MAP), total blood protein (TP), albumin (Alb), Scr, uric acid (UA), 24-hour urinary protein volume and estimated glomerular filtration rate (eGFR). Multivariate regression analysis showed that the AOPPs levels of blood were positively correlated with MAP, Scr, UA and 24-hour urinary protein (all P﹤0.01), and negatively correlated with TP, Alb, eGFR (all P﹤0.05). The serum levels of AOPPs and MDA in IgAN patients were positively correlated with the levels of TGF-β1, MCP-1, TGF-α, IL-6 and HIF-1α. The levels of SOD, CAT and GSH-Px were negatively correlated with the levels of TGF-β1, MCP-1, TGF-α, IL-6 and HIF-1α. Multivariate stepwise regression analysis showed that the degree of renal interstitial fibrosis in IgAN patients was positively correlated with serum AOPPs level (β=0.285, P=0.001), negatively correlated with CAT (β=-0.346, P﹤0.001), GSH-Px (β=-0.303, P﹤0.001). Conclusions The level of serum oxidative stress in IgAN patients is elevated and positively correlated with the degree of renal interstitial fibrosis, suggesting that oxidative stress may be involved in the occurrence and development of renal interstitial fibrosis.     

Impaired antioxidant defence in guinea pig heart tissues treated with halothane

Purpose

To investigate the effects of halothane and halothane plus vitamin E treatment on myocardial free radical metabolism in guinea pigs.

Methods

Four groups of seven animals were studied; control, halothane, halothane plus vitamin E and vitamin E groups. In the halothane group, halothane 1.5% in oxygen was given for 90 min over three days. In the halothane plus vitamin E group, 300 rng · kg^?1 · day^?1 vitamin Eim was started three days before the first halothane treatment and continued for three days. Following sacrifice, the hearts were assayed for superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) and malondialdehyde (MDA) level was determined. Electron spin resonance (ESR) analysis and electron microscopy (EM) were also performed.

Results

In the halothane group, SOD activities and MDA concentrations were increased compared with control and GSH-Px and CAT activities were decreased. In the halothane plus vitamin E group, there were no differences in enzyme activity compared with halothane alone but the MDA level was decreased. In the vitamin E group, enzyme activities were increased compared with control. Mainly the CF₃CHCl radical was identified by ESR analysis in heart tissues exposed to halothane and the concentration of this radical was reduced by vitamin E. Electron microscopy showed cytoplasmic vacuolisation and dilation in sarcoplasmic reticulum in the heart tissues exposed to halothane: both were prevented by vitamin E.

Conclusion

Although halothane causes impairment in enzymatic antioxidant defence potential, due to lowered GSH-Px and CAT activity, and accelerates peroxidative reactions in the tissues affected, no subcellular damage occurred. Vitamin E may protect tissues against free radical attack by scavenging toxic free radicals formed in heart tissue during halothane anaesthesia.     

Quercetin ameliorates methotrexate-induced renal damage,apoptosis and oxidative stress in rats

Abstract

Background: In the present study, the protective and therapeutic effects of quercetin (QE) on renal injury induced by methotrexate (MTX) have been examined. Materials and methods: A total of 24 male rats were divided into the following three groups: control group, MTX group, and MTX?+?QE group. Rats in MTX group received 20?mg/kg of single dose of MTX, while those in MTX?+?QE group received 20?mg/kg of single dose MTX, in addition to 15?mg/kg of QE administered 30?min prior to MTX and in the following 5-day period as a single daily dose. At the end of the experimental period, renal tissues were removed for histopathological and biochemical assessments. Results: Light microscopic examination showed a disruption of the renal structure in rats in MTX group in the form of tubular degeneration and dilation, with shedding of the tubular epithelial cells into the lumen. QE treatment was associated with less marked degenerative changes, with a similar histological appearance to that of controls. Furthermore, QE treatment resulted in decreased the number of apoptotic cells. Biochemical assessments showed significantly higher malondialdehyde (MDA) levels in MTX group as compared to control and MTX?+?QE groups. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) levels showed a significant decrease in MTX group as compared to controls. However, QE significantly suppressed MDA level, compensated deficits in the anti-oxidant defenses [reduced SOD, GSH-Px, and CAT levels] in kidney tissue resulted from MTX administration. Conclusions: In conclusion, renal toxic effects of MTX may be alleviated by QE.     

Protective effects of some antineoplastic agents on ischemia-reperfusion injury in epigastric island skin flaps

Neutrophil depletion has a beneficial effect on ischemic myocardium and skeletal muscle upon reperfusion. Antineoplastic agents reduce blood neutrophils effectively, and lead to neutrophil depletion. The purpose of this study was to investigate the effects of four antineoplastic agents in low doses (cyclophosphamide, cisplatinum, mitomycin-C, and 5-fluorouracil) on ischemia-reperfusion injury, using an epigastric island skin-flap model in rats. Fifty male Sprague-Dawley rats, weighing 250-300 g, were randomly divided into five groups, each consisting of 10 rats: control, cyclophosphamide, cisplatinum, mitomycin-C, and 5-fluorouracil groups. Epigastric island skin flaps (measuring 3.5 x 4 cm) were raised and subjected to 10 h of in situ ischemia, followed by 7-day reperfusion and evaluation. Treatment with antineoplastic agents (cyclophosphamide, cisplatinum, mitomycin-C, and 5-fluorouracil) was used to introduce neutropenia. Complete blood counts, cutaneous bleeding time, and skin-flap survival were evaluated. Additionally, levels of malonyldialdehyde (MDA), nitric oxide (NO), glutathione (GSH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were measured from extracted skin tissue. Numbers of leukocytes and platelets were decreased in all experimental groups. However, neutropenia and thrombocytopenia were not seen. Cutaneous bleeding activity was prolonged in all experimental groups, but not above the normal value. MDA and NO levels were found to be lower in all four antineoplastic agent groups than in the control group, while GSH, GSH-Px, and SOD enzyme activities were significantly higher (P < 0.05). However, MDA and NO levels were significantly decreased in the cyclophosphamide and 5-fluorouracil groups, as compared to the cisplatinum and mitomycin-C groups (P < 0.01). Also, GSH, GSH-Px, and SOD enzyme activities were significantly increased in the cyclophosphamide and 5-fluorouracil groups, compared to the other two antineoplastic agent groups (P < 0.01). We conclude that antineoplastic agents have beneficial effects on ischemia-reperfusion injuries when their doses are carefully adjusted, by decreasing the number of leukocytes and platelets, and altering the activity of free oxygen radicals.     

Effects of endurance training on antioxidant defense mechanisms and lipid peroxidation in testis of rats

Male rats were equally divided into trained rest (TR), trained exhaustive exercise (TE), untrained rest (UR), and untrained exhaustive exercise (UE). Endurance training consisted of treadmill running for 1.5 h/d, 5 days a week for 8 weeks reaching the speed of 2.1 km/h at the fortieth week. For acute exhaustive exercise, graded treadmill running was conducted reaching the speed of 2.1 km/h at 95th min, 10% uphill, continued until exhaustion. Testicular tissue malondialdehyde (MDA), antioxidant potential (AOP) levels, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST), glutathione reductase (GR) and catalase (CAT) activities were determined. There was a slight decrease, but not significant, in the SOD activity in UE group compared to TE and TR groups. Activity of GSH-Px decreased in the UE group compared to UR, TR and TE groups. Acute exhaustive exercise did not affect testicular tissue GSH-Px activity in trained rats. Testicular tissue GST activity of the UE group was similar to TE group, but lower than UR and TR groups. In UE group, testicular tissue AOP values were lower than UR, TR and TE groups. The oxidative effects of acute exhaustive exercise on the rat testis decreased with endurance training. Endurance training prevents oxidative injuries by eliminating oxygen radicals and inhibiting lipid peroxidation via preventing decreases in antioxidant enzyme activities.     

Physical training increases renal injury in rats with chronic NOS inhibition

Nitric oxide (NO) is involved in regulation of vascular tone and renal hemodynamics. Inhibition of NO synthase (NOS) by Nomega-nitro-L-arginine methyl ester (L-NAME) promotes systemic hypertension and glomerular damage. Exercise is effective in reducing elevated blood pressure in hypertensive individuals and rats treated with L-NAME. We investigated the effects of regular aerobic exercise on renal injury in hypertensive rats with NOS inhibition. Adult Wistar rats were divided into four groups: sedentary or exercising, nonhypertensive (two groups) and hypertensive, sedentary or exercising (two groups). Treadmill running exercise was prolonged for 4 weeks (60 min.day(-1), 5 days/week, 20 m.min(-1), no incline), and hypertension was induced by L-NAME given orally to rats for 4 weeks (25 mg.kg(-1).day(-1) in drinking water). Blood pressure was monitored at baseline and then once a week throughout L-NAME administration. Kidney sections were examined for renal histopathology. Hypertensive animals exhibited elevated blood pressure, and exercise partly prevented this elevation. Renal injury observed as arteriolar wall thickening, focal tubular atrophy, and interstitial inflammatory infiltration was apparent in hypertensive animals, and exercise induced further renal damage in hypertensive animals. The present training protocol exacerbates renal insufficiency in NOS-blockage hypertension in rats.     

Deoxycorticosterone suppresses the effects of losartan in nitric oxide-deficient hypertensive rats

Chronic inhibition of the renin angiotensin system prevents increased BP and renal injury in N(G)-nitro-L-arginine methyl ester (L-NAME) hypertension. However, a relationship between plasma renin activity and the protective effect of chronic angiotensin II (Ang II) blockade has not been established. With this background, this study was undertaken to evaluate how the chronic administration of deoxycortisone acetate (DOCA) modifies the effects of losartan on BP, renal injury, and other variables in L-NAME hypertensive rats. The following groups were used: Control, DOCA, L-NAME, L-NAME + losartan, L-NAME + DOCA, and L-NAME + DOCA + losartan. Tail systolic BP was measured twice a week. After 4-wk evolution, mean arterial pressure and metabolic, morphologic, and renal variables were measured. The final mean arterial pressure values were 116 +/- 6 mmHg for control, 107 +/- 2 mmHg for DOCA, 151 +/- 5 mmHg for L-NAME, 123 +/- 2 mmHg for L-NAME + losartan, 170 +/- 3 mmHg for L-NAME + DOCA, and 171 +/- 5.5 mmHg for L-NAME + DOCA + losartan. Losartan prevented microalbuminuria, hyaline arteriopathy, and glomerulosclerosis of L-NAME hypertension but was ineffective in L-NAME + DOCA-treated rats. Plasma protein was significantly reduced in the L-NAME + DOCA group when compared with control and L-NAME groups, whereas no significant differences were observed in the other groups. Plasma renin activity was suppressed in the DOCA (0.55 +/- 0.2) and L-NAME + DOCA (0.60 +/- 10.2) groups but unsuppressed in the L-NAME + DOCA + losartan group (5.8 +/- 1). The conclusion is that DOCA blocks the preventive effect of losartan on the increased BP and renal injury of L-NAME hypertension, which suggests that DOCA transforms L-NAME hypertension into an Ang II-independent model of hypertension. These data also suggest that losartan prevents L-NAME hypertension by blocking the activity of systemic Ang II.     

普罗布考防治大鼠顺铂急性肾损伤的实验研究

目的：复制大鼠顺铂急性肾损伤模型,研究氧化应激与核转录因子Sp1及凋亡的关系;探讨普罗布考对顺铂急性肾损伤的保护作用及作用机制。方法：24只SD雄性大鼠被随机分为生理盐水对照组、顺铂模型组、普罗布考干预组、普罗布考对照组,每组6只;检测尿N-乙酰-β-D-氨基葡萄糖甘酶（NAG）、血清肌酐（Scr）、血尿素氮（BUN）、肾组织匀浆液丙二醛（MDA）和谷胱甘肽过氧化物酶（GSH-Px）,光镜观察肾脏病理改变;采用免疫组化染色检测肾组织Sp1蛋白表达;采用TUNEL染色检测肾小管上皮细胞凋亡。结果：与生理盐水对照组和普罗布考对照组相比,顺铂模型组大鼠血清BUN和Scr,尿NAG酶,肾脏组织匀浆MDA含量显著升高,肾组织匀浆GSH-Px活力显著下降（P〈0.01）;肾脏指数、肾小管损伤分数和肾小管上皮细胞凋亡百分比均明显增加（P〈0.01）;肾组织Sp1蛋白的表达上调。采用普罗布考干预后血清BUN和Scr,尿NAG酶,肾脏组织匀浆MDA含量显著下降（P〈0.05）;肾组织匀浆GSH-Px活力显著升高;肾脏指数、肾小管损伤分数和肾小管上皮细胞凋亡百分比均明显降低（P〈0.01）;肾组织Sp1蛋白的表达下调。结论：氧化应激和核转录因子Sp1在顺铂所致大鼠肾毒性中起一定作用;普罗布考对顺铂所致大鼠肾毒性有保护作用,其机制可能与抗氧化、抑制肾小管上皮细胞凋亡、下调肾组织Sp1蛋白表达有关。     

褪黑素对梗阻性黄疸大鼠肝损伤保护作用的实验研究

目的探讨氧化性损伤在大鼠梗阻性黄疸肝功能损害发生中的作用以及褪黑素对其的保护作用。方法成年雄性SD大鼠64只,采用完全随机化法随机分为正常对照组（CN组,n=16）、假手术组（SO组,n=16）、胆总管结扎组（BDL组,n=16）和胆总管结扎＋褪黑素治疗组（BDL＋MT组,n=16）。应用胆总管结扎法建立梗阻性黄疸模型,褪黑素治疗组大鼠手术前1 d至手术后7 d连续腹腔注射褪黑素0.5 mg（/kg.d）,每日10∶00给药。分别于手术后第4 d和第8 d两个时间点采集标本,检测血浆中总胆红素（TBIL）、丙氨酸转氨酶（ALT）、门冬氨酸转氨酶（AST）、碱性磷酸酶（AKP）及γ-谷氨酰转肽酶（GGT）水平变化,比色法测定肝组织匀浆中丙二醛（MDA）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽（GSH）、谷胱甘肽过氧化物酶（GSH-Px）含量或活力变化,采用TUNEL法检测肝组织细胞凋亡,并计算肝细胞凋亡指数（AI）。结果与CN组和SO组比较,BDL组大鼠血浆TBIL、ALT、AST、AKP、GGT水平和肝组织MDA含量明显升高（P〈0.05,P〈0.01）,SOD、CAT、GSH-Px活力或GSH含量显著降低（P〈0.01）,AI增加（P〈0.01）;褪黑素治疗可使血浆TBIL、ALT、AST、AKP、GGT和肝组织MDA含量显著降低,SOD、CAT、GSH-Px活力或GSH含量明显升高（P〈0.01）,AI减少（P〈0.01）。BDL组肝组织MDA含量与血浆TBIL、ALT、AKP、AST、GGT水平均呈显著正相关（P〈0.01）,GSH、SOD、CAT、GSH-Px与血浆TBIL、ALT、AKP、ALT、AST水平分别均呈显著负相关（P〈0.01）;BDL组肝组织MDA含量的变化与AI呈正相关（P〈0.01）,而GSH含量及SOD、CAT、GSH-Px活力分别与AI呈负相关（P〈0.01）。结论大鼠梗阻性黄疸时,肝组织自由基大量产生介导的氧化性损伤及其细胞凋亡,参与了肝功能损害的发生、发展。褪黑素对大鼠梗阻性黄疸肝功能损害有一定程度的保护作用,其机制可能与其拮抗肝组织过氧化和细胞凋亡有关。