A comparison effects of l-citrulline and l-arginine against cyclosporine-induced blood pressure and biochemical changes in the rats / Comparación de los efectos de L-citrulina y L-arginina frente a la presión arterial inducida por ciclosporina y los cambios bioquímicos en ratas

Objective: The use of cyclosporine A (CsA) is associated with different adverse effects including hypertension and nephrotoxicity. The present study aimed to compare the inhibitory effects of l-arginine & l-citrulline on CsA-induced blood pressure and biochemical changes in the serum of rats. Methods: Thirty-six rats were divided into 6 groups received daily: (1) 1ml distilled water, (2) 200mg/kg l-citrulline IP, (3) 25mg/kg CsA SC, (4) CsA+l-citrulline with the same dose of the former groups, (5) 200mg/kg l-arginine IP and (6) l-arginie+CsA with the same doses of group 4 for 7 days. Results: The changes in the blood pressure, heart rate, creatinine, BUN, glucose and C-reactive protein (CRP) of the serum were determined in the treated animals. Significant (p<0.001) increase was shown in the blood pressure and heart rate of CsA treated rats compared to the control group. There were also a significant (p<0.05) increase in the creatinine, BUN and glucose, but a decrease in the CRP value in the CsA-treated group. However, l-citrulline significantly (p<0.001) inhibited the changes in the blood pressure and heart rate in CsA-treated as well as it was able to reduce blood pressure in non-treated group significantly (p<0.01). l-citrulline also inhibited the increased levels of BUN and creatinine induced by CsA, while, l-arginine was able to prevent the increased blood pressure and creatinine occurs after administration of CsA. Conclusions: These findings suggest that the l-citrulline is more efficient than l-arginine against the adverse effects induced by cyclosporine. (AU)

Objetivo: El uso de ciclosporina A (CsA) está asociado a diferentes efectos adversos que incluyen hipertensión y nefrotoxicidad. El objetivo del presente estudio es comparar los efectos inhibitorios de L-arginina y L-citrulina en la presión arterial inducida por CsA, y los cambios bioquímicos a nivel sérico en ratas. Métodos: Se dividieron 36 ratas en 6 grupos, que recibieron diariamente: 1) 1ml de agua destilada, 2) 200mg/kg de L-citrulina IP, 3) 25mg/kg de CsA SC, 4) la misma dosificación que los grupos anteriores de CsA+L-citrulina, 5) 200mg/kg de L-arginina IP y 6) la misma dosificación que el grupo 4 durante 7 días de L-arginina+CsA. Resultados: Se determinaron los cambios de presión arterial, frecuencia cardiaca, creatinina, BUN, glucosa y proteína C reactiva (PCR) a nivel sérico, en los animales tratados. Se observó un incremento significativo (p<0,001) de presión arterial y frecuencia cardiaca en las ratas tratadas con CsA en comparación con el grupo control. También se produjo un incremento significativo (p<0,05) de los niveles de creatinina, BUN y glucosa, y una reducción del valor de PCR en el grupo tratado con CsA. Sin embargo, L-citrulina inhibió significativamente (p<0,001) los cambios de presión arterial y frecuencia cardiaca en las ratas tratadas con CsA, y también pudo reducir la presión arterial de manera considerable en el grupo no tratado (p<0,01). L-citrulina inhibió también los niveles incrementados de BUN y creatinina inducidos por CsA, y L-arginina fue capaz de impedir la incidencia del incremento de presión arterial y creatinina tras la administración de CsA. Conclusiones: Estos hallazgos sugieren que L-citrulina es más efectiva que L-arginina frente a los efectos adversos inducidos por ciclosporina. (AU)

A comparison effects of l-citrulline and l-arginine against cyclosporine-induced blood pressure and biochemical changes in the rats.

OBJECTIVE: The use of cyclosporine A (CsA) is associated with different adverse effects including hypertension and nephrotoxicity. The present study aimed to compare the inhibitory effects of l-arginine &l-citrulline on CsA-induced blood pressure and biochemical changes in the serum of rats. METHODS: Thirty-six rats were divided into 6 groups received daily: (1) 1ml distilled water, (2) 200mg/kg l-citrulline IP, (3) 25mg/kg CsA SC, (4) CsA+l-citrulline with the same dose of the former groups, (5) 200mg/kg l-arginine IP and (6) l-arginie+CsA with the same doses of group 4 for 7 days. RESULTS: The changes in the blood pressure, heart rate, creatinine, BUN, glucose and C-reactive protein (CRP) of the serum were determined in the treated animals. Significant (p<0.001) increase was shown in the blood pressure and heart rate of CsA treated rats compared to the control group. There were also a significant (p<0.05) increase in the creatinine, BUN and glucose, but a decrease in the CRP value in the CsA-treated group. However, l-citrulline significantly (p<0.001) inhibited the changes in the blood pressure and heart rate in CsA-treated as well as it was able to reduce blood pressure in non-treated group significantly (p<0.01). l-citrulline also inhibited the increased levels of BUN and creatinine induced by CsA, while, l-arginine was able to prevent the increased blood pressure and creatinine occurs after administration of CsA. CONCLUSIONS: These findings suggest that the l-citrulline is more efficient than l-arginine against the adverse effects induced by cyclosporine.

Erythropoietin attenuates experimental haemorrhagic shock-induced renal damage through an iNOS- dependent mechanism in male Wistar rats.

AIM: Erythropoietin (EPO) is shown to exert protective effects on different tissues in haemorrhagic shock (HS) states. Nitric oxide (NO), as a multifunctional signaling molecule, is implicated in diverse physiologic and pathologic processes. In order to understand the exact mechanism of EPO protection, in this study we evaluated the role of different NOS enzymes in the EPO signaling pathway in male rats. METHODS: Rats were randomized to five groups: 1) Sham, 2) HS 3) EPO 4) L-NAME, a non-specific NOS inhibitor 5) 1400W, a specific iNOS inhibitor. HS was induced by withdrawal of 50% of total blood volume. After 2h, resuscitation was performed with the shed blood and Ringer's lactate. In group 3, rats were treated with EPO (300IU/kg, i.v.) over 10min before HS induction. In the L-NAME and 1400W groups, L-NAME (10mg/kg, i.p.) and 1400W (2mg/kg, i.p.) were administered 30min before EPO injection. Blood and kidney tissue samples were obtained 3h after resuscitation. RESULTS: EPO increased the survival rate and significantly improved kidney function and histology compared to the HS group. There were less renal oxidative stress, apoptosis and systemic inflammatory responses in the EPO group. EPO increased eNOS and more abundantly iNOS mRNA expressions. L-NAME and 1400W significantly abolished all beneficial effects of EPO. CONCLUSION: In this in vivo animal model, we showed that EPO administration prior to HS attenuates renal injury and dysfunction in rats. The protective effects of EPO may be mediated by nitric oxide and the expression of different NOS enzymes, especially iNOS isoform.

Administration of hydrogen sulfide protects ischemia reperfusion-induced acute kidney injury by reducing the oxidative stress.

BACKGROUND: Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury. Hydrogen sulfide (H2S) has been known as a novel gaseous signaling molecule. AIMS: The aim of this study was to investigate whether the efficacy of H2S in protecting against renal IRI is through its antioxidative effect. METHOD: In this study, rats were randomized into Sham, IR, or sodium hydrosulfide (NaHS, an H2S donor) groups. To establish a model of renal IRI, both renal arteries were occluded for 55 min and then declamped to allow reperfusion for 24 h. Rats in the NaHS group received intraperitoneal injections of 75 µmol/kg NaHS 10 min before the onset of ischemia and immediately after the onset of reperfusion. Sham group underwent laparotomy without cross-clamping of renal pedicles. After reperfusion, plasma and renal tissue samples were collected for functional, histological, and oxidative stress evaluation. RESULTS: The IR group exhibited significant rise in plasma creatinine, blood urea nitrogen (BUN), renal malondialdehyde (MDA) concentration, and significant reduction of renal superoxide dismutase (SOD) activity. Treatment with NaHS reduced the levels of plasma creatinine, BUN, renal MDA concentration, and increased SOD activity in the kidneys. NaHS improved renal histological changes in comparison to IR group. CONCLUSION: Our data demonstrated that H2S can protect against renal IRI and that its therapeutic effects may be mediated by reducing oxidative stress.

Increases in interleukin-6 and interferon-gamma levels is progressive in immature rats with varicocele.

BACKGROUND: Pre-pubertal varicocele can result in hypotrophy of testes, progressive deterioration of Sertoli cells and spermatogonia cell number, decrease in seminiferous diameter and cause to sperm damage. AIMS: Because of detrimental time-dependent effects of varicocele, this study describes the effects of varicocele on the levels of interleukin-6 (IL-6) and interferon-gamma in serum and testis tissue, seminiferous tubules diameter, number of Sertoli and spermatogonia cells, testis and epididymis weight and volume and sperm indices in immature rats. METHODS: Thirty-six immature rats (5-6 weeks) were assigned into six groups: three sham groups and three varicocele groups. Serum, testis, and sperm samples were collected at 9, 11, and 13 weeks after induction of varicocele or sham operation to evaluate histological parameters and levels of cytokines. RESULTS: Varicocele significantly caused an increase in serum and testis IL-6 and interferon-gamma, compared to related sham groups and previous varicocele groups (P < 0.05). Varicocele significantly decreased Sertoli cells and spermatogonia cell number with increasing varicocele time (P < 0.05). In the evaluation of seminiferous tubules diameter, the external, internal, and epithelium diameter were decreased compared to sham-related groups and previous varicocele groups. In the all varicocele groups, all types of sperm motility decreased compared to the related sham-operated group (P < 0.05). CONCLUSIONS: This study suggests varicocele has a detrimental, time-dependent effect on cytokines levels and decreases Sertoli cells, spermatogonia cell number, seminiferous tubules diameter, and sperm indices.

Hepatoprotective effects of remote perconditioning during renal ischemia.

BACKGROUND: Novel treatment strategies are required to reduce the development of hepatic injury during surgical procedure in which renal ischemia/reperfusion (IR) is inevitable. Remote perconditioning (rPeC) has been proved to reduce the extent of kidney damages induced by renal IR injury. The aim of this study was to determine the protective effect of rPeC against hepatic injury caused by renal ischemia. METHODS: Male rats were subjected to the right nephrectomy and randomized as: sham, no additional intervention; IR, 45 min of left renal pedicle occlusion; rPeC, four cycles of 5-min limb IR administered at the beginning of renal ischemia. After 24-h of reperfusion, the plasma and tissue samples were taken. RESULTS: A significant improvement in hepatic functional injury and oxidative damages were observed in the rPeC group compared to the IR group. However, histological evaluation and plasma levels of TNF-α revealed no significant difference among groups. CONCLUSIONS: It is concluded that rPeC exerted protective effects on renal IR-induced hepatic injury as a remote organ. The protection may be a consequence of the reduction in oxidative stress in the liver. This simple approach may be a promising strategy against IR-induced remote organ damages in the clinical practice (Fig. 4, Ref. 23).

Renal oxidative injury after leukocyte transfer from ischemia-reperfusion-induced kidney damage in Balb/c mice.

The present study investigates the role of leukocyte transfer in the induction of kidney damage from mice that have undergone a severe renal ischemia-reperfusion insult into the intact recipient mice. First, Balb/c (inbred) mice were subjected to either sham operation (Sham donors) or bilateral renal IR injury (60 min ischemia-3 h reperfusion, IR donors). Leukocytes were isolated from blood and were transferred to two recipient groups: intact recipient mice received leukocytes from Sham donor group (Sham recipient) or from IR donor group (IR recipient). After 24 h, recipient mice were anesthetized for sample collections. Renal malondialdehyde increased and total glutathione concentration and superoxide dismutase activity decreased significantly in the IR recipient group compared to the Sham recipient group. BUN and plasma creatinine were significantly different between donor groups, but these parameters were not significantly different in the two recipient groups. In the IR donor group, there have been extensive changes in renal tissues comparing to Sham including severe destruction of the tubules, necrosis and tubular obstruction plus tubular flattening. IR recipient kidneys showed significant differences from their corresponding Sham group, demonstrating some degrees of injury including loss of brush borders from proximal tubules, cellular vacuolation and flattening of the tubules. However, less tissue damage was seen in this group comparing to IR donor kidneys. These findings showed that leucocytes transferred from post-ischemic mice induced oxidative stress and consequent damage to native kidneys, suggesting a role of leucocytes in the oxidative processes of reperfusion injury.

Effect of vitamin E therapy on serum uric acid in DOCA-salt-treated rats.

Uric acid is considered as an antioxidant in the blood. Despite its proposed protective properties, elevated plasma uric acid has been associated with hypertension in a variety of disorders. The purpose of this study was to investigate the relationship between the increase of arterial blood pressure and the changes in serum uric acid, measured during the gradual development of experimental hypertension in deoxycorticosterone (DOCA)-salt-treated rats. Blood pressure was monitored by tail-cuff method, urinary and plasma uric acid was measured by autoanalyzer during the induction of hypertension in 1-, 2-, 3- and 4-week DOCA-salt-treated Sprague-Dawley rats. Vitamin E (200 mg/kg/day/gavage) was co-administered with DOCA-salt for 4 weeks. From the first week of DOCA-salt treatment, rats exhibited marked increases in blood pressure. DOCA-salt treatment also resulted in a significant increase in serum uric acid and a significant decrease in urinary uric acid at the end of the first week. These changes in serum and urinary uric acid remained until the 4th week of DOCA-salt treatment but blood pressure continued to increase throughout the study. Vitamin E treatment increased urinary excretion of uric acid and decreased blood pressure and serum uric acid in DOCA-salt-treated rats. These data suggest that enhanced serum uric acid may be a contributing factor to the onset of hypertension in DOCA-salt-treated rats. A uricosuric effect is suggested for vitamin E in the treatment of hypertension.

Hepatic changes during various periods of reperfusion after induction of renal ischemia in rats.

BACKGROUND: Recent studies have suggested that ischemic damage to the kidneys causes liver tissue alterations. Thus, the morbidity and mortality in patients with acute renal failure (ARF) may be related to liver complications as well as to renal injury. The aim of the present study was to assess the hepatic changes during various periods of reperfusion after induction of renal ischemia. METHODS: Forty male rats were subjected to either a sham operation or to a 45-minute ischemia followed by 1, 3, 6, or 24 hours of reperfusion. Arterial pressure was continuously monitored. Blood samples were drawn to measure serum creatinine and blood urea nitrogen (BUN). RESULTS: We evaluated hepatic concentrations of interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha. Ischemia reperfusion (IR) caused significant reductions in renal function as demonstrated by increased values of serum creatinine and BUN. These rats also showed significant increases in hepatic TNF-alpha and IL-10 concentrations. The most significant changes among inflammatory factors in the liver were observed at 3 hours of reperfusion: TNF-alpha, 616 +/- 41 vs 215 +/- 16, and IL-10, 926 +/- 73 vs 125 +/- 34, pg/100 mg tissue (P

Effect of bicarbonate administration on cyclosporine-induced nephrotoxicity in rats.

BACKGROUND: Cyclosporine (CsA) is known to cause metabolic and distal tubular acidosis. There is some evidence that CsA reduces net HCO(3)(-) absorption. The aim of this study was to elucidate whether bicarbonate administration prevented CsA-induced functional or structural nephrotoxicity. METHODS: Seven days after uninephrectomy, 20 rats were divided into 4 groups. NaHCO(3) (0.28 mol/L) was added in drinking water for 7 days, whereas control rats received regular tap water. The bicarbonate pretreated rats were administered either CsA (50 mg/kg intraperitoneally) or vehicle daily for a week. At the end of the procedure, animals were placed in metabolic cages for 24 hours after which we measured creatinine clearance (Ccr), urinary total proteins, pH, and N-acetyl-beta-D-glucosaminidase (NAG) activity. The kidney was fixed in formaldehyde. RESULTS: Ccr was significantly affected by the administration of CsA. The effects of CsA on serum pH and HCO(3)(-) concentration were prevented by pretreatment with NaHCO(3). However, it did not affect the CsA-induced increased urinary NAG activity or decreased Ccr. There was no protection of CsA-induced changes in renal tissues by NaHCO(3). CONCLUSION: Overall NaHCO(3) administration did not prevent CsA-induced changes in Ccr and NAG activity. These data suggested involvement of factors other than acid-base status in CsA-induced nephrotoxicity. However, correction of acidosis should still be considered for patients receiving CsA because acidosis exacerbates tissue damage.

Changes in serum and renal vitamin E levels in deoxycorticosterone acetate-salt hypertensive rats.

BACKGROUND: Hypertension is an important risk factor for the progression of chronic renal disease, which may result in the development of end-stage renal disease. Since reactive oxygen species are implicated in the induction of hypertension, antioxidants have been used to reduce blood pressure and renal impairment in animal models and in human hypertension. However, the available data are not conclusive. METHODS: To investigate oxidative stress in hypertension, we evaluated renal and serum vitamin E levels as the most effective antioxidant to reduce lipid peroxidation by high-performance liquid chromatography among rats subjected to deoxycorticosterone acetate (DOCA)-salt treatment for 4 weeks. Renal levels of malondialdehyde (MDA) as a marker of cell lipid peroxidation were also assayed in treated rats. Systolic blood pressure (SBP) was measured in conscious rats by the tail-cuff method using a PowerLab/4sp data acquisition system. RESULTS: SBP increased significantly in DOCA-salt-treated rats compared to the sham group after 4 weeks of treatment. Serum vitamin E levels were significantly lower and renal MDA concentrations significantly higher in treated compared to sham rats. However, renal vitamin E levels were also significantly higher among treated compared to sham rats. DISCUSSION: Decreased plasma vitamin E levels and increased renal MDA levels show systemic and local oxidative stress in DOCA-salt-treated rats. However, the higher renal vitamin E level suggested a local compensatory mechanism. Vitamin E administration might be appropriate, as significant decreases in vitamin E levels were observed in the serum of DOCA-salt-treated rats.

An ophthalmological complication: central serous chorioretinopathy in a renal transplant recipient.

BACKGROUND AND OBJECTIVE: Ophthalmological complications in transplanted recipients often due to underlying disorders or drug use consist of anterior segment and posterior segment complications. Among the posterior complications, Central serous chorioretinopathy (CSCR) is related to high-dose steroids, stress, or cyclosporine and usually has a good outcome. The aim of this study was to report a case of CSCR as an ophthalmologic complication of renal transplantation. CASE REPORT: A 36-year-old man hospitalized for the treatment of rejection suffered severe visual loss in both eyes. After examination and fluoresein angiography, we diagnosed CSCR due to high-dose steroid therapy for rejection. With tapering of the drug and after about 3 months, visual acuity became normal. CONCLUSION: Visual acuity changes must be followed up carefully in all transplant recipients, but CSCR usually has a good prognosis. If it does not improve, retinal laser therapy is needed.