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Background: Renal hemodynamic is influenced by both gender difference and age. Also, the Mas receptor (MasR) as one of the depressor components of the renin-angiotensin system which has more expression in females could postpone some dysfunctions associated with age, although the association between MasR and age in renal vascular responses to angiotensin II (Ang II) in male and female rats was well undefined. Therefore, the current study examined the effects of age and sex on systemic and renal vascular responses to graded doses of Ang II in Wistar rats with or without MasR antagonists (A779). Materials and Methods: Anesthetized Wistar male and female rats with two age ranges of 8-12 and 24-28 weeks were exposed to cannulate venous and arterial vessels. After stability, mean arterial pressure (MAP), renal perfusion pressure (RPP), renal vascular resistance (RVR), and renal blood flow (RBF) were measured in response to the infusion of Ang II with or without A779. Results: There were no significant differences in the base values of MAP, RPP, RBF, and RVR between the two genders in both the age ranges of 8-12 and 24-28 weeks. In addition, no significant gender difference was observed in the age ranges of the above mentioned parameters among the groups receiving vehicle or A779. Also, the infusion of vehicle or A779 could not significantly change the base values. On the other hand, the responses of RBF and RVR to Ang II revealed gender differences among 8-12-week groups (P < 0.05) but not in 24-28-week groups, while the blockade of MasR could not influence the responses in the age ranges. Conclusion: It was concluded that age could impress sex difference in RBF and RVR responses to Ang II infusion and that MasR alone could not participate in these responses. In other words, MasR is not active under normal and acutely elevated Ang II levels.
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Cisplatin (CP) as the most important anticancer drug has limited usage due to a lot of side effects such as nephrotoxicity. Additionally, nephrotoxicity is gender/sex-related. There is a variety of experimental studies in association with sex and CP-induced nephrotoxicity. Some studies have reported that female sex is resistant than male sex due to greater antioxidant defense and protective effects of estrogen in females. Other studies have indicated that males are less vulnerable than females due to CP high clearance. Also, various supplementations have revealed conflicting effects in males and females. It is uncovered that sex hormones have determinant roles on the conflicting effects. Some supplements could improve CP-induced nephrotoxicity, but several supplements intensified CP-induced nephrotoxicity, especially in female sex. On the other hand, major clinical studies introduced female gender as a risk factor of CP-induced nephrotoxicity. Although, rare studies evaluated the effect of various supplemental compounds on CP-induced nephrotoxicity in patients underwent CP therapy. Therefore, it requires further investigations to clarify the controversial subject of gender/sex and CP-induced nephrotoxicity in both clinic and laboratory.
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Cisplatin (CDDP) has been widely used as a chemotherapeutic agent for solid tumors. The most common side effect of CDDP is nephrotoxicity, and many efforts have been made in the laboratory and the clinic to employ candidate adjuvants to CDDP to minimize this adverse influence. Many synthetic and herbal antioxidants as well as trace elements have been investigated for this purpose in recent years and a variety of positive and negative results have been yielded. However, no definitive supplement has so far been proposed to prevent CDDP-induced nephrotoxicity; however, this condition is gender related and the sex hormone estrogen may protect the kidney against CDDP damage. In this review, the results of research related to the effect of different synthetic and herbal antioxidants supplements are presented and discussed with suggestions included for future work.
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BACKGROUND: Renal ischemia/reperfusion (I/R) injury may be related to activity of reninangiotensin system (RAS), which is gender-related. In this study, it was attempted to compare the effect of angiotensin II (Ang II) receptor type 1 (AT1R) blockade; losartan in I/R injury in male and female rats. MATERIALS AND METHODS: Male and female Wistar rats were assigned as sham surgery, control I/R groups treated with vehicle, and case I/R groups treated with losartan (30 mg/kg). Vehicle and losartan were given 2 hours before bilateral kidney ischemia induced by clamping renal arteries for 45 minutes followed by 24 hours of renal reperfusion. RESULTS: The I/R injury significantly increased the serum levels of blood urea nitrogen (BUN) and creatinine (Cr), and kidney tissue damage score in both genders. However, losartan decreased these values in female rats significantly (P < 0.05). This was not observed in male rats. CONCLUSION: Losartan protects the kidney from I/R injury in female but not in male rats possibly because of gender-related difference of RAS.
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INTRODUCTION: Vanadium compounds are insulin like drugs which are accompanied with nephrotoxicity and hepatotoxicity as their major side effects. Aerobic exercise is well known as an approach to reduce the side effects of many drugs. OBJECTIVES: This study was designed to determine the role of aerobic exercise against vanadyl sulphate induced nephrotoxicity and hepatotoxicity in male rats. MATERIALS AND METHODS: Twenty-four male Wistar rats were randomly divided into three groups. Group I had aerobic exercise on a treadmill 5 days/week for 6 weeks. Group II received vanadyl sulphate (50 mg/kg/week; i.p.) for 6 weeks. Group III had combination of exercise and vanadyl sulphate therapy as groups 1 and 2. At the end of study, blood samples were obtained, and the animals were sacrificed for the tissues injury determination. RESULTS: Vanadyl sulphate alone increased serum levels of blood urea nitrogen (BUN), creatinine (Cr), and kidney weight (KW) and kidney tissue damage score (KTDS) (P<0.05). These observations revealed nephrotoxicity induced by vanadyl sulphate, although exercise training did not attenuate these results. In addition, vanadyl sulphate alone induced liver tissue damage score and exercise training intensified it insignificantly, while the serum levels of aspartate amino transferase and alanine amino transferase were greater in exercise alone group than others groups. CONCLUSION: Aerobic exercise could not attenuate vanadyl sulphate induced nephrotoxicity and hepatotoxicity. These findings must be considered when vanadyl sulphate is suggested as insulin like drug.
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INTRODUCTION: Cisplatin (CP) is a major antineoplastic drug for treatment of solid tumors. CP-induced nephrotoxicity may be gender-related. This is while gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the central nervous system that has renoprotective impacts on acute renal injury. OBJECTIVES: This study was designed to investigate the protective role of GABA against CP-induced nephrotoxicity in male and female rats. MATERIALS AND METHODS: Sixty Wistar male and female rats were used in eight experimental groups. Both genders received GABA (50 µg/kg/day; i. p.) for 14 days and CP (2.5 mg/kg/day; i. p.) was added from day 8 to the end of the study, and they were compared with the control groups. At the end of the study, all animals were sacrificed and the serum levels of blood urea nitrogen (BUN), creatinine (Cr), nitrite, malondialdehyde (MDA), and magnesium (Mg) were measured. The kidney tissue damage was also determined via staining. RESULTS: CP significantly increased the serum levels of Cr and BUN, kidney weight, and kidney tissue damage score in both genders (P<0.05). GABA did not attenuate these markers in males; even these biomarkers were intensified in females. Serum level of Mg, and testis and uterus weights did not alter in the groups. However, the groups were significantly different in terms of nitrite and MDA levels. CONCLUSION: It seems that GABA did not improve nephrotoxicity induced by CP-treated rats, and it exacerbated renal damage in female rats.
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Background. Gentamicin (GM) induced nephrotoxicity may be sex hormones related. The effects of sex hormones on GM induced nephrotoxicity in gonadectomized rats were investigated. Methods. Ovariectomized rats received 0.25, 0.5, or 1 mg/kg/week of estradiol (ES) alone or accompanied with 10 mg/kg/week of progesterone (Pro) for two weeks followed by GM (100 mg/kg/day) for 9 days. Castrated rats were also treated with 10, 50, or 100 mg/kg/week of testosterone (TS) for two weeks and then received GM. In addition, a single castrated group received 0.25 mg/kg/week of ES plus GM. Results. GM increased the serum levels of blood urea nitrogen (BUN) and creatinine (Cr) and kidney tissue damage score (KTDS) (P < 0.05). TS had no effect on the serum levels of BUN and Cr and KTDS, while low dose of ES intensified these parameters in male (P < 0.05). ES (0.5 mg/kg) without Pro ameliorated KTDS in female (P < 0.05) while ES (1 mg/kg) with or without Pro exacerbated the BUN values and Cr values, KTDS, and body weight loss (P < 0.05). Conclusion. ES (0.5 mg/kg) without Pro ameliorated kidney damage induced by GM in female while neither TS nor ES had beneficial effect on nephrotoxicity induced by GM in male, although ES aggravated it.
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INTRODUCTION: Excessive production of nitric oxide (NO) via inducible nitric oxide synthase (iNOS) is associated in renal ischemia reperfusion injury (IRI). OBJECTIVES: This study was designed to investigate the role of S-methylisothiourea (SMT) as selective inhibitor iNOS in renal IRI. MATERIALS AND METHODS: Male Wistar rats were subjected to 45 minutes of bilateral renal ischemia by occlusion of renal vessels of both kidney followed by 24 hours of reperfusion. Prior to renal IRI, the rats received either vehicle (saline, group 2) or SMT (50 mg/kg, group 3), and were compared with the sham-operated animals (group 1). At the end of reperfusion period, the rats were sacrificed for kidney tissue pathology investigation. RESULTS: Serum creatinine (Cr), blood urea nitrogen (BUN), nitrite levels, and kidney weight significantly increased in groups 2 and 3 (P < 0.05). Kidney tissue damage scores in groups 2 and 3 were also higher than that in the sham-operated group (P < 0.05). CONCLUSION: SMT not only prevent the kidney during IRI, but also promotes kidney function disturbance and severity of renal injury.
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BACKGROUND: The function of renin angiotensin system (RAS) is gender-related, and this system affects cisplatin (CP)-induced nephrotoxicity. In this study, we compared the effect of enalapril as an angiotensin-converting enzyme (ACE) inhibitor on CP-induced nephrotoxicity between male and female rats. MATERIALS AND METHODS: Sixty-two adult male and female Wistar rats were divided into eight groups. Both genders received CP (2.5 mg/kg, i.p.) and enalapril (30 mg/kg, i.p.) for 7 days in compared with CP alone or enalapril alone or vehicle alone treated groups. At the end of the experiment, blood samples were obtained, and the kidney tissue was investigated for histopathological changes. RESULTS: CP increased the serum levels of blood urea nitrogen and creatinine as well as kidney weight and kidney tissue damage score in both genders (P < 0.05). However, not only enalapril failed to ameliorate the aforementioned parameters in both genders, but also it intensified nephrotoxicity in females (P < 0.05). In addition, enalapril enhanced body weight loss induced by CP in females (P < 0.05). CP alone decreased kidney level of nitrite in both genders (P < 0.05) and enalapril could not reverse this decreasing. The combination of enalapril and CP significantly increased serum level of nitrite in females, but this was not observed in males (P < 0.05). CONCLUSION: Enalapril as an ACE inhibitor failed to ameliorate nephrotoxicity induced by CP in both male and female rats. In addition, enalapril aggravated CP-induced nephrotoxicity in female possibly due to gender-dependent RAS response.
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INTRODUCTION: Gentamicin (GM) as an antibiotic is used in clinic. However, its administration is limited by side effects such as nephrotoxicity. Herbal extracts could be used in therapeutic approaches. OBJECTIVES: The present study was planned to investigate whether pomegranate flower extract (PFE) could ameliorate GM-induced renal toxicity in male rats. MATERIALS AND METHODS: Twenty eight male Wistar rats were divided into 5 groups. Groups 1 and 2 respectively received PFE 25 and 50 mg/kg for 9 days. Groups 3, 4 and 5 received saline, PFE 25 mg/kg, and PFE 50 mg/kg for 9 days, respectively, and GM (100 mg/kg/day) was administered from day 3 on. Blood samples were obtained, and after sacrificing the animals, the kidneys were removed for histopathology investigations. RESULTS: GM alone increased the serum levels of creatinine (Cr) and blood urea nitrogen (BUN), and tissue damage and kidney weight (P < 0.05). However, administration of low dose of PFE accompanied with GM decreased these markers significantly (P < 0.05). Low dose of PFE also ameliorated weight loss induced by GM (P < 0.05). CONCLUSION: It is concluded that PFE 25 mg/kg is the effective dose to ameliorate nephrotoxicity induced by GM.
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BACKGROUND: Renal ischemia-reperfusion (RIR) is the main cause of renal failure. The incidence of RIR injury seems to be gender-related due to female sex hormone; estrogen. This study was designed to investigate the protective role of estrogen against RIR injury in male and ovariectomized female rats. METHODS: Thirty-nine Wistar rats were used in this study as male and ovariectomized female rats in the sham-operated, RIR, and estradiol-treated plus RIR groups. The RIR was induced by clamping the renal vessels for 45 min and then 24 h of reperfusion. All animals finally were sacrificed for the measurements. RESULTS: The serum levels of creatinine and blood urea nitrogen and kidney tissue damage score significantly increased in both male and female RIR rats (P < 0.05). Estradiol however significantly attenuated theses parameters (P < 0.05) toward normal levels in female (P < 0.05), but not in male rats. Kidney weight increased in both genders and estradiol intensified it in the male rats (P < 0.05). Uterus weight was increased by estradiol in female rats (P < 0.05) and testis weight did not alter in male rats. CONCLUSIONS: Estradiol demonstrated a protective role against RIR injury in female rats; however, estradiol as an antioxidant could not protect the male kidney from RIR injury.
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BACKGROUND: Gentamicin (GM) is used as antibiotic for Gram-negative infections, but its administration is limited due to a side-effect of nephrotoxicity. It was attempted to investigate the effect of Althaea officinalis flower extract (AOFE) against nephrotoxicity induced by GM in male rats. METHODS: 30-year-old male Wistar rats were divided into five groups. Group 1 as a negative control group received AOFE 250 mg/kg/day. Groups 2-5 received saline, AOFE 50 mg/kg/day, AOFE 250 mg/kg/day, and AOFE 500 mg/kg/day for 9 days, respectively, and GM (100 mg/kg/day) was added from the 3(rd) day on. At the end of the experiment, blood samples were obtained, animals were sacrificed, and the kidneys were removed immediately. RESULTS: Gentamicin (in group 2) significantly increased serum levels of blood urea nitrogen and creatinine as well as the pathological damage score (P < 0.05) when compared with group 1. Low dose of AOFE did not decrease the nephrotoxicity induced by GM while the high dose of AOFE aggravated renal toxicity (P < 0.05). CONCLUSIONS: Although AOFE acts as an antioxidant, at the doses used in the current study did not ameliorate nephrotoxicity induced by GM.
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Background. Cisplatin (CDDP) is an anticancer drug, which is accompanied with major side effects including nephrotoxicity. We tested two doses of losartan (10 and 20 mg/kg/day) against nephrotoxicity in a rat model treated with daily administration of CDDP (2.5 mg/kg/day). Methods. Five groups of rats were examined. Groups 1 and 2 received losartan 10 and 20 mg/kg/day, i.p, for a period of 10 days. Group 3 received saline for 10 days, but from day 3 the animals received CDDP (2.5 mg/kg/day, i.p) for the next seven days. Groups 4 and 5 received treatment regimen the same as groups 1 and 2, but from day 3 they also received CDDP for the next seven days. At the end of the experiment, blood samples were obtained and the kidneys were removed to undergo pathological investigation and to obtain supernatant from homogenized tissue. Results. CDDP induced nephrotoxicity, but the serum levels of creatinine and blood urea nitrogen were not attenuated by losartan. The pathological findings confirmed that losartan did not have nephroprotective effect in this experimental model. Conclusion. According to the findings, losartan could not improve renal function impaired by toxicity induced by continuous doses of CDDP, and also it worsened the renal failure.
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Introduction. Rennin-angiotensin system and salt diet play important roles in blood pressure control. We hypothesized that the high-salt intake during pregnancy influences the degree of angiotensin-dependent control of the blood pressure in adult offspring. Methods. Female Wistar rats in two groups (A and B) were subjected to drink tap and salt water, respectively, during pregnancy. The offspring were divided into four groups as male and female offspring from group A (groups 1 and 2) and from group B (groups 3 and 4). In anesthetized matured offspring mean arterial pressure (MAP), heart rate and urine output were measured in response to angiotensin II (AngII) (0-1000 ng/kg/min, iv) infusion. Results. An increase in MAP was detected in mothers with salt drinking water (P < 0.05). The body weight increased and kidney weight decreased significantly in male offspring from group 3 in comparison to group 1 (P < 0.05). MAP and urine volume in response to AngII infusion increased in group 3 (P < 0.05). These findings were not observed in female rats. Conclusion. Salt overloading during pregnancy had long-term effects on kidney weight and increased sex-dependent response to AngII infusion in offspring (adult) that may reveal the important role of diet during pregnancy in AngII receptors.
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BACKGROUND: Tissue iron deposition may disturb functions of the organs. In many diseases like thalassemia, the patients suffer from iron deposition in kidney and heart tissues. Deferoxamine (DF) is a synthetic iron chelator and silymarin (SM) is an antioxidant and also a candidate for iron chelating. This study was designed to investigate the effect of DF and SM combination against kidney and heart iron deposition in an iron overload rat model. METHODS: Male Wistar rats were randomly assigned to 5 groups. The iron overloading was performed by iron dextran 100 mg/kg/day every other day during 2 weeks and in the 3(rd) week, iron dextran was discontinued and the animals were treated daily with combination of SM (200 mg/kg/day, i.p.) and DF (50 mg/kg/day, i.p.) (group 1), SM (group 2), DF (group 3) and saline (group 4). Group 5 received saline during the experiment. Finally, blood samples were obtained and kidney, heart and liver were immediately removed and prepared for histopathological procedures. RESULTS: The results indicated no significant difference in kidney function and endothelial function biomarkers between the groups. However, combination of SM and DF did not attenuate the iron deposition in the kidney, liver and heart. DF alone, rather than DF and SM combination, significantly reduced the serum level of malondialdehyde (P < 0.05). Co-administration of SM and DF significantly increased the serum level of ferritin (P < 0.05). CONCLUSIONS: DF and SM may be potentially considered as iron chelators. However, combination of these two agents did not provide a protective effect against kidney, liver and heart iron deposition.
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BACKGROUND: Nephrotoxicity is the major side-effect of cisplatin (CDDP), and it is reported to be gender-related. We evaluated the effects of pomegranate flower extract (PFE) as an antioxidant on CDDP-induced nephrotoxicity in female rats. METHODS: Twenty-three adult female rats in four groups treated as following. Groups 1 and 2 received PFE at doses of 25 and 50 (mg/kg/day), respectively, for 9 days, and from day 3 on, they also received cisplatin (CDDP) (2.5 mg/kg) daily. Group 3 was treated as group 1 expects saline instead of PFE, and group 4 received PFE (25 mg/kg/day) alone. RESULTS: Cisplatin alone increased the serum levels of blood urea nitrogen, creatinine, and nitrite; and kidney tissue damage score and kidney weight. However, PFE not only did not ameliorate the induced nephrotoxicity, but also aggravated renal tissue damage. CONCLUSIONS: Pomegranate extract as an antioxidant did not ameliorate CDDP-induced nephrotoxicity in female rats.
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BACKGROUND: Cisplatin (CP) is an important antitumor drug with serious side effects such as nephrotoxicity. Estrogens can affect CP-induced nephrotoxicity; however, the role of testosterone (TS), the main male sex hormone, is not clear. OBJECTIVES: This study aimed to investigate the effect of TS on CP-induced nephrotoxicity in castrated male rats. MATERIALS AND METHODS: A total of 54 male Wistar rats were castrated and allocated into eight groups. Groups 1 through 3 respectively received 10, 50, and 100 mg/kg/wk of TS and group 4 received sesame oil for four weeks; then all four groups received 2.5 mg/kg/d CP for one week. Groups 5 through 8 received the same treatment regimen as groups 1 through 4 during first four weeks but instead of CP, they received saline for one week. Then the animals were sacrificed for biochemical and histopathologic studies. RESULTS: CP increased the serum levels of blood urea nitrogen (BUN), creatinine (Cr), and malondialdehyde (SMDA) as well as kidney weight (KW), bodyweight (BW) loss, and kidney tissue damage score (KTDS). It significantly decreased the serum and kidney levels of nitrite and serum level of TS in comparison with the control group (P < 0.05). However, coadministration of CP and low dose of TS significantly decreased the serum levels of BUN as well as Cr and KTDS (P < 0.05). Administration of high-dose TS alone increased the SMDA level, KTDS, and KW while decreased the BW significantly (P < 0.05). CONCLUSIONS: It seems that testosterone in low dose, i.e. physiologic dose, protects kidneys against CP-induced nephrotoxicity; however, special care is needed in CP therapy of patients with high levels of TS.
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BACKGROUND: Cisplatin (CP) therapy as the most common potent chemotherapeutic process is accompanied by nephrotoxicity. The diabetic state may protect rat kidney against this toxicity, and magnesium (Mg) on the other hand may reduce the glucose level in diabetic animals. OBJECTIVES: Current study was planned to investigate the effect of oral administration of magnesium supplementation on CP-induced nephrotoxicity in normal and Streptozocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Male Wistar rats were divided into seven groups and underwent two experiment protocols. As protocol 1, group 1 was considered as the sham group. Group 2 (CP group) received CP (2 mg/kg/d) for five consecutive days. Group 3 (CP + Mg group) received magnesium sulphate (MgSO4, 10 g/L added to the drinking water) for 10 days and then treated with CP from sixth day. As protocol 2, animals received a single dose of STZ (65 mg/kg i.p.). Three days after diabetes induction, animals were divided into four groups; Groups 4 (D group), 5 (D + CP group), and 7 (D + Mg + CP group) followed the same manner as groups 1 to 3, respectively; and group 6 (D + Mg group) was treated with MgSO4 alone for 10 days. Finally, blood samples were obtained, and all animals were killed for kidney tissue investigation. RESULTS: CP administration in normoglycemic rats significantly elevated the serum levels of blood urea nitrogen (BUN) and creatinine (Cr) (P < 0.05). However, coadministration of CP and Mg statistically increased the serum levels of BUN and Cr in both normoglycemic and diabetic animals when compared to the rats treated with CP alone (P < 0.05), while the serum level of Mg was significantly increased in nondiabetic groups (P < 0.05). No significant changes were observed in serum and kidney levels of nitrite; as well as the testis weight between all normoglycemic groups, whereas Mg decreased kidney levels of nitrite in diabetic groups when accompanied by CP (P < 0.05). The kidney and serum levels of malondialdehyde (MDA) enhanced significantly in nondiabetic rats treated with Mg and CP (P < 0.05). Kidney tissue damage score (KTDS), kidney weight, and body weight loss were significantly different among normoglycemic groups (P < 0.05), and Mg promoted the KTDS in diabetic animals treated with CP. CONCLUSIONS: Oral Mg supplementation did not protect the CP induced nephrotoxicity in diabetic rats.
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BACKGROUND: Nephrotoxicity and hepatotoxicity are side effects of Cisplatin (CP) therapy. OBJECTIVES: We investigated the role of gender in CP-induced nephrotoxicity and hepatotoxicity. MATERIALS AND METHODS: Low dose of CP (1 mg/kg/day; ip) was administered daily to male and female Wistar rats for 15 consecutive days. Serum creatinine (Cr), blood urea nitrogen (BUN), malondialdehyde (MDA), nitric oxide (NO) metabolite, and magnesium (Mg) levels were determined. RESULTS: The percentage of weight loss and the serum levels of MDA and nitrite in male and female animals were not statistically different. However, the serum levels of BUN, Cr, Mg, and kidney MDA levels, and kidney weight and damage score were significantly greater in males than in females (P < 0.05). CONCLUSIONS: CP-induced nephrotoxicity is gender related for which the mechanisms should be determined.
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Objective. Nitric oxide (NO) has numerous important functions in the kidney. The role of NO in cisplatin (CP)-induced nephrotoxicity is not completely understood. This study was designed to determine the role of NO synthase inhibitor (L-NAME) on the severity of CP-induced nephrotoxicity in rats. Methods. Sixty four male (M) and female (F) Wistar rats were randomly divided into eight groups. The sham groups (group 1, male, n = 6 and group 2, female, n = 6) received saline. Groups 3 (male, n = 8) and 4 (female, n = 8) were treated with L-NAME (4 mg/kg, i.p.), and groups 5 (male, n = 8) and 6 (female, n = 8) received CP (3 mg/kg) for 7 days. Groups 7 (male, n = 8) and 8 (female, n = 8) were treated with L-NAME and CP for 7 days. Results. The CP-alone treated rats showed weight loss and increase in serum levels of blood urea nitrogen (BUN) and creatinine (Cr). Coadministration of L-NAME and CP did not improve weight loss, and it increased the levels of BUN and Cr in male but not in female rats (P < 0.05). CP alone increased kidney damage significantly (P < 0.05 ), however, the damage induced by combination of CP and L-NAME was gender-related. Conclusion. NOS inhibition by L-NAME increased CP-induced nephrotoxicity, which was gender-related.
