About this Journal Submit a Manuscript Table of Contents
ISRN Nephrology
Volume 2013 (2013), Article ID 612675, 5 pages
http://dx.doi.org/10.5402/2013/612675
Research Article

Sex-Related Difference in Nitric Oxide Metabolites Levels after Nephroprotectant Supplementation Administration against Cisplatin-Induced Nephrotoxicity in Wistar Rat Model: The Role of Vitamin E, Erythropoietin, or N-Acetylcysteine

1Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan 81745, Iran
2Department of Physiology, Isfahan University of Medical Sciences, Isfahan 81745, Iran

Received 22 January 2013; Accepted 14 February 2013

Academic Editors: C. Musso and A. H. Tzamaloukas

Copyright © 2013 Mehdi Nematbakhsh and Zahra Pezeshki. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background. Nitric oxide (NO) concentration in serum is altered by cisplatin (CP), and NO influences CP-induced nephrotoxicity. The effect of nephroprotectant agent supplementation (vitamin E, human recombinant erythropoietin (EPO), or n-acetylcysteine (NAC)) on the NO metabolites levels after CP administration in the two genders was determined. Methods. Sixty-four adult Wistar rats were randomly divided into 10 groups. Male and female rats in different groups received vehicle (saline), CP (7 mg/kg) alone, CP plus EPO (100 IU/kg), CP plus vitamin E (250 mg/kg), and CP plus NAC (600 mg/kg). CP was administrated as a single dose, but the supplementations were given for a period of 7 days. Results. In male rats, the serum levels of total NO metabolites (NOx) and nitrite were increased significantly ( ) by CP. However, vitamin E significantly reduced the serum levels of these metabolites, which was increased by administration of CP ( ), and such findings were not observed for female rats. The EPO or NAC did not influence NO metabolites neither in male rats nor in female rats. Conclusion. Although vitamin E, EPO, and NAC are reported to be nephroprotectant agents against CP-induced nephrotoxicity, only vitamin E could reduce the level of all NO metabolites only in male rats.

1. Introduction

Cisplatin (CP) is the most common antitumor drug in clinic. The most common side effect of CP is nephrotoxicity. However, hepatotoxicity and testicular toxicity are also frequently observed. CP is a platinum compound, which is accompanied by decrease in glomerular filtration rate (GFR), increase in blood urea nitrogen (BUN) and serum levels of creatinine, and tubular injury [13]. CP may disturb endothelium and endothelial function [47]. Nitric oxide (NO) is a marker of endothelial function. However, some studies documented that administration of CP increases the serum level of NO [8, 9], and on the other hand, increase of NO level may promote CP-induced nephrotoxicity [8]. NO is synthesized from the amino acid L-arginine by the endothelial NO synthase (eNOS) in endothelium. It is documented that L-arginine as precursor of NO has protective role against CP-induced nephrotoxicity [1, 3]. Some paradoxes could be seen here; CP may increase NO [1, 2], NO may promote CP-induced nephrotoxicity [8], and NO donates agents attenuating CP-induced nephrotoxicity [10].

NO is not a stable molecule, and its half life in circulation is considerably short, but it is rapidly oxidized to nitrite and nitrate that are considered as NO metabolites. The sum of NO metabolites called , and all , nitrite ( ), and nitrate ( ) are considered as endogenous NO products [11, 12]. However, it has been shown that nitrite is a good marker for endothelial NO production, while plasma nitrate levels are influenced by a variety of NOS-independent factors [1215]. Among the NO metabolites, nitrite is a major oxidative metabolite, which was implicated to be an indicator of NOS activity. It has been shown that up to 70%–90% of plasma nitrite is derived from eNOS activity in fasted subjects [16]. Furthermore, NOS inhibition in humans, pigs, dogs, and mice significantly decreases the plasma nitrite concentration [17]. Another point is gender. NO production is also reported to be gender related [1823], and accordingly, it is important to know which types of NO metabolites form NO system (nitrite, nitrate, or ) during CP therapy and which types of NO metabolites are influenced by CP in the two sexes.

In order to attenuate CP-induced nephrotoxicity, many nephroprotectant agents such as vitamin E, human recombinant erythropoietin (EPO), and n-acetylcysteine (NAC) were subject of research in different models [2433]. Therefore, in the present study, we attempt first to find which metabolite, nitrite, nitrate, or , is disturbed by CP in the two genders and second to determine whether the protective role of vitamin E, EPO, or NAC against CP-induced nephrotoxicity is accompanied by changes of nitrite or nitrate levels.

2. Methods and Materials

2.1. Animals

The investigation was performed on 64 adult male (175–200 g) and female (150–180 g) Wistar rats (Animal Centre, Isfahan University of Medical Sciences, Isfahan, Iran). The rats were housed at a temperature of 23–25°C and had free access to water and rat chow. The research protocols were in advance approved by the Isfahan University Medical Sciences Ethics Committee.

2.2. Drugs

CP (cis-Diammineplatinum(II) dichloride, code P4394) and vitamin E from Sigma (St. Louis MO, USA), EPO from Janssen-Cilag (Czech Republic), NAC, as Flumil Antidote 20% from Pharmazam S. A. (Barcelona, Spain) were purchased.

Flumil Antidote 20% is the commercial name of NAC.

2.3. Experimental Protocol

The animals were randomly divided into 10 experimental groups. Groups 1 ( ) and 2 ( ) were assigned as male and female negative control groups that received vehicle (saline) alone during the study. Groups 3 ( ) and 4 ( ) were assigned as male and female positive control groups that received single dose of CP (7 mg/kg) and then were treated with vehicle ( 0.5 mL/day) every day for one week. Groups 5 (male, ) and 6 (female, ) received single dose of CP and then were treated with EPO (100 IU/kg/day, i.p.) every day for one week. The other groups received the same regimen as groups 5 and 6, except for vitamin E (250 mg/kg) instead of EPO, groups 7 (male, ) and 8 (female, ) or NAC (600 mg/kg), groups 9 (male, ) and 10 (female, ).

Seven days after CP administration, blood sample was obtained and the serum was collected from each blood sample and stored at −20°C until measurements.

2.4. Measurements

The NO stable metabolites (nitrite/nitrate, ) were measured in serum by an ELISA assay kit (Cayman Chemical Co.) that involves the Griess reaction.

2.5. Statistical Analysis

Data are expressed as mean SEM. The groups were compared by one-way analysis of variance (ANOVA) with regard to the serum levels of , nitrite, and nitrate. Post hoc testing was performed for intergroup comparisons using the least significant difference (LSD) test. values were considered statistically significant.

3. Results

3.1. Effect of CP on Serum , Nitrate, and Nitrite Levels

The serum levels of and nitrite were increased significantly ( ) by CP administration in male, while such finding was not obtained in female (Table 1). The data also indicated that the serum level of nitrate was increased by CP administration nonsignificantly. This finding revealed that alteration of serum NO metabolites ( and nitrite) after CP injection is gender related.

tab1
Table 1: Effect of CP on serum , nitrate, and nitrite levels in male and female rats. The data was compared between negative and positive control groups using Student’s -test.
3.2. Effect of EPO, Vitamin E, and NAC on Serum , Nitrate, and Nitrite Levels Increased by CP

The data are presented in Figure 1. In male, vitamin E significantly reduced the serum levels of and nitrite, which were increased by CP administration ( , Figure 1), while this was not observed in female. Although EPO and NAC are considered as nephroprotectant agents against CP-induced nephrotoxicity, these agents potentially could not reduce the CP-increased serum levels of and nitrite neither in male nor in female. This finding revealed that vitamin E is a more potent nephroprotectant agent in reducing nephrotoxicity via reduction of NO metabolites. However, this potential effect of vitamin E is gender dependent.

612675.fig.001
Figure 1: Effect of EPO, vitamin E, and NAC on CP-increased serum levels of , nitrate, and nitrite in male and female rats. The EPO, vitamin E, and NAC groups were compared with positive control group. (*) shows significant difference from control group ( ).

4. Discussion

The main findings of this research were as follows: and nitrite are increased by CP administration and vitamin E as a nephroprotectant agent reduces the NO metabolites. Since NO may promote CP-induced nephrotoxicity [8], it is important to know which one of the NO metabolites is suitable to monitor the NO bioavailability [12, 34], and also it is important to select the appropriate nephroprotectant supplementation to modulate NO metabolite levels after CP administration. It is well known that the levels of nitrate and total do not vary during pharmacological modulation of L-arginine-NO pathway [15], and oxidation of endogenous NO is one of the most important endogenous sources of [16]. Endogenous NO production is performed by NOS isoforms: constitutively active forms of eNOS, neuronal NO synthase (nNOS), and the inducible isoforms (iNOS). The relevant amount of NO in circulation is not from nNOS [35]. The iNOS is expressed by smooth muscle cells and macrophages [36] and may contribute to NO production under pathological conditions. However, selective inhibition of iNOS reduces CP-induced histological damage, renal dysfunction, oxidative stress, and nitrosative stress [37]. It is reported that nitrite is a suitable marker of NO formation [12], and variation of NOS activity is associated with direct parallel alteration of nitrite concentrations [13, 14] while up to 70%–90% of plasma nitrite is derived from eNOS activity [16]. Furthermore, NOS inhibition in humans, pigs, dogs, and mice significantly decreases the plasma nitrite concentration [17]. Therefore, although nitrite is the most important NO metabolite to monitor NO formation, it seems that vitamin E provides its antioxidant effect against CP-induced nephrotoxicity by reduction of both nitrite and nitrate in male, but not in female. Gender-related nitrate and nitrite levels have been reported in rat brain [38]. Watanabe et al. measured the serum levels of NO metabolites in 263 healthy subjects and obtained some different results for male and female subjects. Furthermore, the concentration was affected by age in women [39]. Other studies also demonstrated gender-related characteristics of NO system [1820, 4045]. Some other studies also reported the sex-based difference of CP-induced nephrotoxicity [4649]. Therefore, the influence of gender on both CP-induced nephrotoxicity and NO metabolite could be responsible for sex-based difference of NO metabolite change when supplementations such as vitamin E, EPO, or NAC are administrated to protect the kidney during CP therapy.

5. Conclusion

Although all vitamin E, EPO, and NAC have potentially antioxidant effect to be nephroprotectant against CP-induced nephrotoxicity, vitamin E could reduce the level of all NO metabolites which possibly are promotion marker of kidney toxicity after CP administration.

Acknowledgment

This research was supported by Isfahan University of Medical Sciences.

References

  1. F. Eshraghi-Jazi, M. Nematbakhsh, H. Nasri, et al., “The protective role of endogenous nitric oxide donor (L-arginine) in cisplatin-induced nephrotoxicity: gender related differences in rat model,” Journal of Research in Medical Sciences, vol. 16, no. 11, pp. 1389–1396, 2011.
  2. S. Saleh, A. A. Ain-Shoka, E. El-Demerdash, and M. M. Khalef, “Protective effects of the angiotensin II receptor blocker losartan on cisplatin-induced kidney injury,” Chemotherapy, vol. 55, no. 6, pp. 399–406, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Saleh and E. El-Demerdash, “Protective effects of L-arginine against cisplatin-induced renal oxidative stress and toxicity: role of nitric oxide,” Basic and Clinical Pharmacology and Toxicology, vol. 97, no. 2, pp. 91–97, 2005. View at Publisher · View at Google Scholar · View at Scopus
  4. R. Eguchi, Y. Fujimori, T. Ohta, K. Kunimasa, and T. Nakano, “Calpain is involved in cisplatin-induced endothelial injury in an in vitro three-dimensional blood vessel model,” International Journal of Oncology, vol. 37, no. 5, pp. 1289–1296, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. J. Nuver, E. C. de Haas, M. van Zweeden, J. A. Gietema, and C. Meijer, “Vascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro,” Oncology Reports, vol. 23, no. 1, pp. 247–253, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. M. Montiel, L. Urso, E. P. de la Blanca, S. Marsigliante, and E. Jiménez, “Cisplatin reduces endothelial cell migration via regulation of type 2-matrix metalloproteinase activity,” Cellular Physiology and Biochemistry, vol. 23, no. 4–6, pp. 441–448, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. H. Ito, T. Okafuji, and T. Suzuki, “Vitamin E prevents endothelial injury associated with cisplatin injection into the superior mesenteric artery of rats,” Heart and Vessels, vol. 10, no. 4, pp. 178–184, 1995. View at Publisher · View at Google Scholar · View at Scopus
  8. M. Ekor, G. O. Emerole, and E. O. Farombi, “Phenolic extract of soybean (Glycine max) attenuates cisplatin-induced nephrotoxicity in rats,” Food and Chemical Toxicology, vol. 48, no. 4, pp. 1005–1012, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. S. Y. Saad, T. A. O. Najjar, M. H. Daba, and A. C. Al-Rikabi, “Inhibition of nitric oxide synthase aggravates cisplatin-induced nephrotoxicity: effect of 2-amino-4-methylpyridine,” Chemotherapy, vol. 48, no. 6, pp. 309–315, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. B. C. Kone and C. Baylis, “Biosynthesis and homeostatic roles of nitric oxide in the normal kidney,” American Journal of Physiology, vol. 272, no. 5, part 2, pp. F561–F578, 1997. View at Scopus
  11. R. F. Eich, T. Li, D. D. Lemon et al., “Mechanism of NO-induced oxidation of myoglobin and hemoglobin,” Biochemistry, vol. 35, no. 22, pp. 6976–6983, 1996. View at Publisher · View at Google Scholar · View at Scopus
  12. I. F. Metzger, J. T. C. Sertorio, and J. E. Tanus-Santos, “Relationship between systemic nitric oxide metabolites and cyclic GMP in healthy male volunteers,” Acta Physiologica, vol. 188, no. 2, pp. 123–127, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Kelm, H. Preik-Steinhoff, M. Preik, and B. E. Strauer, “Serum nitrite sensitively reflects endothelial NO formation in human forearm vasculature: evidence for biochemical assessment of the endothelial L-arginine-NO pathway,” Cardiovascular Research, vol. 41, no. 3, pp. 765–772, 1999. View at Publisher · View at Google Scholar · View at Scopus
  14. P. Kleinbongard, A. Dejam, T. Lauer et al., “Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans,” Free Radical Biology and Medicine, vol. 40, no. 2, pp. 295–302, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. T. Lauer, M. Preik, T. Rassaf et al., “Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 22, pp. 12814–12819, 2001. View at Publisher · View at Google Scholar · View at Scopus
  16. N. S. Bryan, “Nitrite in nitric oxide biology: cause or consequence? A systems-based review,” Free Radical Biology and Medicine, vol. 41, no. 5, pp. 691–701, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. P. Kleinbongard, A. Dejam, T. Lauer et al., “Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals,” Free Radical Biology and Medicine, vol. 35, no. 7, pp. 790–796, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. S. B. Ahmed, N. D. L. Fisher, and N. K. Hollenberg, “Gender and the renal nitric oxide synthase system in healthy humans,” Clinical Journal of the American Society of Nephrology, vol. 2, no. 5, pp. 916–931, 2007. View at Publisher · View at Google Scholar · View at Scopus
  19. H. Higashino, H. Miya, H. Mukai, and Y. Miya, “Serum nitric oxide metabolite (NOx) levels in hypertensive patients at rest: a comparison of age, gender, blood pressure and complications using normotensive controls,” Clinical and Experimental Pharmacology and Physiology, vol. 34, no. 8, pp. 725–731, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. B. B. McGuire, R. W. G. Watson, F. Pérez-Barriocanal, J. M. Fitzpatrick, and N. G. Docherty, “Gender differences in the renin-angiotensin and nitric oxide systems: relevance in the normal and diseased kidney,” Kidney and Blood Pressure Research, vol. 30, no. 2, pp. 67–80, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Page, H. Reich, J. Zhou et al., “Endothelial nitric oxide synthase gene/gender interactions and the renal hemodynamic response to angiotensin II,” Journal of the American Society of Nephrology, vol. 16, no. 10, pp. 3053–3060, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. Y. R. Wang, C. H. Yen, Y. F. Sun, and Y. T. Lau, “Gender-dependent response in blood pressure changes following the inhibition of nitric oxide synthase,” Chinese Journal of Physiology, vol. 46, no. 2, pp. 91–94, 2003. View at Scopus
  23. K. Kauser and G. M. Rubanyi, “Gender difference in bioassayable endothelium-derived nitric oxide from isolated rat aortae,” American Journal of Physiology, vol. 267, no. 6, part 2, pp. H2311–H2317, 1994. View at Scopus
  24. F. Ashrafi, M. Nematbakhsh, T. Safari, et al., “A combination of vitamin C and losartan for cisplatin-induced nephrotoxicity in rats,” Iranian Journal of Kidney Diseases, vol. 6, no. 5, pp. 361–365, 2012.
  25. M. Nematbakhsh, F. Ashrafi, T. Safari, et al., “Administration of vitamin E and losartan as prophylaxes in cisplatin-induced nephrotoxicity model in rats,” Journal of Nephrology, vol. 25, no. 3, pp. 410–417, 2012. View at Publisher · View at Google Scholar
  26. S. Atasayar, H. Gürer-Orhan, H. Orhan, B. Gürel, G. Girgin, and H. Ozgunes, “Preventive effect of aminoguanidine compared to vitamin E and C on cisplatin-induced nephrotoxicity in rats,” Experimental and Toxicologic Pathology, vol. 61, no. 1, pp. 23–32, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. L. M. Antunes, J. D. Darin, and M. D. Bianchi, “Protective effects of vitamin C against cisplatin-induced nephrotoxicity and lipid peroxidation in adult rats: a dose-dependent study,” Pharmacological Research, vol. 41, no. 4, pp. 405–411, 2000. View at Publisher · View at Google Scholar · View at Scopus
  28. D. Appenroth, S. Fröb, L. Kersten, F. K. Splinter, and K. Winnefeld, “Protective effects of vitamin E and C on cisplatin nephrotoxicity in developing rats,” Archives of Toxicology, vol. 71, no. 11, pp. 677–683, 1997. View at Publisher · View at Google Scholar · View at Scopus
  29. A. M. Abdelrahman, S. Al Salam, A. S. Almahruqi, I. S. Al Husseni, M. A. Mansour, and B. H. Ali, “N-acetylcysteine improves renal hemodynamics in rats with cisplatin-induced nephrotoxicity,” Journal of Applied Toxicology, vol. 30, no. 1, pp. 15–21, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Nisar and D. A. Feinfeld, “N-acetylcysteine as salvage therapy in cisplatin nephrotoxicity,” Renal Failure, vol. 24, no. 4, pp. 529–533, 2002. View at Publisher · View at Google Scholar · View at Scopus
  31. D. Kong, L. Zhuo, C. Gao, et al., “Erythropoietin protects against cisplatin-induced nephrotoxicity by attenuating endoplasmic reticulum stress-induced apoptosis,” Journal of Nephrology, vol. 26, no. 1, pp. 219–227, 2012. View at Publisher · View at Google Scholar
  32. D. Zafirov, G. Petrusevska, A. Sikole et al., “Erythropoietin reduces cumulative nephrotoxicity from cisplatin and enhances renal tubular cell proliferation,” Prilozi, vol. 29, no. 2, pp. 167–183, 2008. View at Scopus
  33. S. Yalcin, S. Muftuoglu, E. Cetin et al., “Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin,” Medical Oncology, vol. 20, no. 2, pp. 169–173, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. C. Baylis and P. Vallance, “Measurement of nitrite and nitrate levels in plasma and urine—what does this measure tell us about the activity of the endogenous nitric oxide system?” Current Opinion in Nephrology and Hypertension, vol. 7, no. 1, pp. 59–62, 1998. View at Publisher · View at Google Scholar · View at Scopus
  35. M. R. Adams, C. J. Forsyth, W. Jessup, J. Robinson, and D. S. Celermajer, “Oral L-arginine inhibits platelet aggregation but does not enhance endothelium-dependent dilation in healthy young men,” Journal of the American College of Cardiology, vol. 26, no. 4, pp. 1054–1061, 1995. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Miyoshi, Y. Li, D. M. Shih et al., “Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice,” Life Sciences, vol. 79, no. 6, pp. 525–531, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. Y. I. Chirino, J. Trujillo, D. J. Sanchez-Gonzalez et al., “Selective iNOS inhibition reduces renal damage induced by cisplatin,” Toxicology Letters, vol. 176, no. 1, pp. 48–57, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. D. Taskiran, F. Z. Kutay, E. Sozmen, and S. Pogun, “Sex differences in nitrite/nitrate levels and antioxidant defense in rat brain,” NeuroReport, vol. 8, no. 4, pp. 881–884, 1997. View at Scopus
  39. T. Watanabe, M. Akishita, K. Toba et al., “Influence of sex and age on serum nitrite/nitrate concentration in healthy subjects,” Clinica Chimica Acta, vol. 301, no. 1-2, pp. 169–179, 2000. View at Publisher · View at Google Scholar · View at Scopus
  40. J. A. González-Correa, M. M. Arrebola, J. Muñoz-Marín et al., “Gender differences in the effect of aspirin on retinal ischemia, prostanoid synthesis and nitric oxide production in experimental type 1-like diabetes,” Vascular Pharmacology, vol. 47, no. 2-3, pp. 83–89, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. N. M. Dietz, “Gender and nitric oxide-mediated vasodilation in humans,” Lupus, vol. 8, no. 5, pp. 402–408, 1999. View at Scopus
  42. J. F. Reckelhoff, B. S. Hennington, A. G. Moore, E. J. Blanchard, and J. Cameron, “Gender differences in the renal nitric oxide (NO) system. Dissociation between expression of endothelial NO synthase and renal hemodynamic response to NO synthase inhibition,” American Journal of Hypertension, vol. 11, no. 1, part 1, pp. 97–104, 1998. View at Publisher · View at Google Scholar · View at Scopus
  43. K. Abeyama, I. Maruyama, S. Suenaga, and T. Noikura, “Nitric oxide production in the lesions of temporomandibular disorders and gender differences in nitric oxide production,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, vol. 84, no. 4, pp. 330–331, 1997. View at Scopus
  44. M. Ding, J. L. Wong, N. E. Rogers, L. J. Ignarro, and R. R. Voskuhl, “Gender differences of inducible nitric oxide production in SJL/J mice with experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 77, no. 1, pp. 99–106, 1997. View at Publisher · View at Google Scholar · View at Scopus
  45. T. Hayashi, J. M. Fukuto, L. J. Ignarro, and G. Chaudhuri, “Gender differences in atherosclerosis: possible role of nitric oxide,” Journal of Cardiovascular Pharmacology, vol. 26, no. 5, pp. 792–802, 1995. View at Scopus
  46. M. Haghighi, M. Nematbakhsh, A. Talebi, et al., “The role of angiotensin II receptor 1 (AT1) blockade in cisplatin-induced nephrotoxicity in rats: gender-related differences,” Renal Failure, vol. 34, no. 8, pp. 1046–1051, 2012. View at Publisher · View at Google Scholar
  47. M. Nematbakhsh, Z. Pezeshki, F. Eshraghi-Jazi, et al., “Vitamin E, vitamin C, or losartan is not nephroprotectant against cisplatin-induced nephrotoxicity in presence of estrogen in ovariectomized rat model,” International Journal of Nephrology, vol. 2012, Article ID 284896, 10 pages, 2012. View at Publisher · View at Google Scholar
  48. M. Nematbakhsh, A. Talebi, H. Nasri, et al., “Some evidence for sex-based differences in cisplatin-induced nephrotoxicity in rats,” Clinical and Experimental Medical Letters, vol. 53, no. 1-2, pp. 29–31, 2012.
  49. D. Stakišaitis, G. Dudeniene, R. J. Jankunas, G. Graželiene, J. Didžiapetriene, and B. Pundziene, “Cisplatin increases urinary sodium excretion in rats: gender-related differences,” Medicina, vol. 46, no. 1, pp. 45–50, 2010. View at Scopus