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NDT Advance Access published online on October 12, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm691
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Preventive effect of nebivolol on contrast-induced nephropathy in rats

Omer Toprak1, Mustafa Cirit1, Mehmet Tanrisev1, Cevat Yazici2, Ozlem Canoz3, Murat Sipahioglu4, Atilla Uzum1, Rifki Ersoy1 and Eser Yildirim Sozmen5

1 Department of Nephrology, Ataturk Training and Research Hospital, Izmir, Turkey 2 Department of Biochemistry, Erciyes University School of Medicine, Kayseri, Turkey 3 Department of Pathology, Erciyes University School of Medicine, Kayseri, Turkey 4 Department of Medicine, Division of Nephrology, Erciyes University School of Medicine, Kayseri, Turkey 5 Department of Biochemistry, Ege University School of Medicine, Izmir, Turkey

Correspondence and offprint requests to: Correspondence and offprint requests to: Omer Toprak, MD, Ataturk Training and Research Hospital, Department of Nephrology, 35360 Izmir, Turkey. Tel: +90-505-4411635; Fax: +90-232-2434848; E-mail: info{at}omertoprak.com



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Conclusions
 References
 
Background. Altered renal vasodilatation and oxidative stress are important mechanisms of contrast-induced nephropathy (CIN). The aim of the present study was to assess the effect of nebivolol, a beta blocker, on prevention of CIN. We hypothesized that nebivolol may prevent CIN due to its renal vasodilatation and antioxidant effects.

Methods. Thirty-two Wistar-albino rats were divided into four groups (n = 8 each): control (C), contrast media (CM), nebivolol (N), and nebivolol + contrast media (NCM). CIN was induced by administration of intravenous high-osmolar contrast media diatrizoate (6 ml/kg) after 72 h of dehydration. Nebivolol (2 mg/kg) was given internally once daily for 5 days. Kidney function parameters, nitric oxide metabolites and oxidative stress markers were measured. Kidneys were excised for pathological evaluation.

Results. The decrease of creatinine clearance was 0.180 ± 0.11 mg/dl in CM, and 0.030 ± 0.10 mg/dl in NCM (P = 0.01). Microproteinuria was ameliorated using nebivolol (P = 0.001). Serum protein carbonyl content, malonyldialdehyde and kidney thiobarbituric acid-reacting substances levels were higher in CM than in C (P = 0.003, P < 0.001 and P = 0.034, respectively) and serum thiol was lower in CM than in C (P = 0.001). However, oxidative stress markers were similar in NCM and C. Diatrizoate decreased kidney nitrite levels, but nebivolol increased them (P = 0.027). Nebivolol attenuated the tubular necrosis, proteinaceous casts and medullary congestion, although significant protective effects, were observed in tubular necrosis (P = 0.001) and proteinaceous cast (P < 0.001).

Conclusion. This study demonstrated the protective role of nebivolol against CIN.

Keywords: contrast-induced nephropathy; contrast media; nebivolol; nitric oxide; oxidative stress



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Conclusions
 References
 
Radiological procedures that require intravascular administration of iodinated contrast media is becoming a great source of an iatrogenic disease known as contrast-induced nephropathy (CIN). In the United States, more than 10 million radiological examinations using iodinated contrast media are performed annually, and approximately 4 million of these procedures are cardiac catheterizations. CIN is independently associated with prolonged hospitalization, the potential need for renal replacement therapy, and increased mortality [1,2]. The incidence of high-risk patients for CIN, such as those with chronic kidney disease, diabetes mellitus, metabolic syndrome, hypertension and patients over 70 years of age, is increasing worldwide [3,4]. This means that CIN will be an important health problem in future. The incidence of CIN is up to 90% among high-risk patients [3].

There is still no universally accepted method for preventing CIN, except for extracellular volume expansion. CIN is still the third leading cause of hospital-acquired acute renal failure [5]. The proposed pathophysiologic mechanisms of CIN are outer-medullary hypoxia due to decreased renal blood flow secondary to renal artery vasoconstriction, tubular obstruction and direct tubular toxicity [6]. Also, decreased production of nitric oxide (NO) and increased oxidative stress play important roles in the pathogenesis of CIN [7,8].

Nebivolol is a ß1-adrenergic receptor antagonist with vasodilator and antioxidant properties [9,10]. Based on these findings, we hypothesized that nebivolol may protect the kidney against CIN through its antioxidant and NO-mediated vasodilator action. We designed this experimental study to investigate whether nebivolol has an effective role in protection against the development of CIN.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Conclusions
 References
 
Animals
The experiments were conducted following the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. The study included 32 female Wistar-albino rats (6 weeks old), each weighing 168–221 g, which were born and bred in the Experimental and Clinical Research Center of Erciyes University. To collect 24 h urine and to record water intake, rats were kept in individual metabolism cages. Otherwise, they were kept in stainless steel cages, which were maintained on a 12-h-light/12-h-dark cycle at 22–25°C. The design and experimental procedures of the study were approved by the Animal Care Committee of Erciyes University School of Medicine (protocol number: 04/403).

Experimental design and drugs
Rats were divided into four groups (n = 8 each): control (C), contrast media (CM), rats treated with nebivolol (N), and rats treated with nebivolol and injected contrast media (NCM). Nebivolol (Vasoxen, Berlin-Chemie AG, Menarini Group, Germany) was given by oral gavage to the rats in groups N and NCM at a dose of 2 mg/kg once daily for 5 consecutive days (days 1 to 5). Ionic high-osmolar contrast medium, meglumine/sodium diatrizoate (Urografin 76%, Schering AG, Germany) at a dose of 6 ml/kg was administered intravenously into the tail vein at day 4 to groups CM and NCM under ether anaesthesia. Rats were given unlimited access to standard rat chow and were deprived of water from day 1 to day 4. Rats were weighed once a day. Drug administrations, blood samples and weighing were done between 9:00 and 10:00 a.m. to minimize circadian variation. Baseline blood samples were collected from the tail vein under ether anaesthesia and analyzed for serum blood urea nitrogen (BUN) and creatinine. The final blood sample was withdrawn from the abdominal aorta at the end of the study (day 6). Serum samples for thiol and urine samples for microprotein were studied on the same day. Other samples were kept at –70 °C until analyzed. Under general anesthesia using intraperitoneal injections of xylazine (Rompun®, Bayer, Istanbul, Turkey) at a dose of 10 mg/kg, and ketamine (Ketalar®, Pfizer, Istanbul, Turkey) at a dose of 75 mg/kg, both kidneys were excised. The right kidneys were preserved in phosphate-buffered 10% formalin, embedded in paraffin wax, and cut at 3 µm and stained with haematoxylin-eosin. The left kidneys were washed in ice-cold normal saline and placed in separate Eppendorf tubes and stored at –70°C until the day of analysis.

Induction of CIN
In a preliminary study of three rats, we found that complete anuria and a weight loss of approximately 20% occurred after a 72 h interval of water deprivation. We found tubular necrosis, tubular protein casts and medullar congestions in the kidneys following injection of high-dose diatrizoate (6 ml/kg) after the water deprivation period. Therefore, CIN was induced by a high-dosage of diatrizoate, after a 72 h dehydration period.

Biochemical studies and renal function assessment
The chemicals and kits were supplied from Sigma-Aldrich and Sigma Diagnostics (St. Louis, MO, USA). Serum and urinary creatinine measurements were performed with the Jaffe method and serum BUN measurements with the kinetic UV assay on an autoanalyzer. Plasma and urinary sodium were measured by a flame photometer. Microproteinuria was assayed using a determination kit and a Konelab 60i analyzer. Creatinine clearance (CrCl) was calculated by U x V/P [where U = urine creatinine (mg/dl), V = urine volume (ml/min/100g), and P = serum creatinine (mg/dl)], and was expressed as ml/min/100 g body weight. Fractional excretion of sodium (FENa) was calculated as FENa (%) = (urine sodium/plasma sodium) x (plasma creatinine/urine creatinine) x 100.

Measurement of total nitrite/nitrate levels in kidney
Nitrite and nitrate levels were determined spectrophotometrically based on the Griess reaction [11]. Nitrite reacts with sulfanilamide and N-(1-naphthyl) ethylendiamine to produce an azo dye detected at 540 nm, while nitrate is first reduced to nitrite by nitrate reductase (EC 1.6.6.2.) via a reaction in which it is coupled to the oxidation of ß-NADPH and detected at 340 nm. Sodium nitrite and nitrate solutions were used for standard measurements.

Determination biomarkers of oxidative stress
We studied kidney thiobarbituric acid-reacting substances (TBARS) and serum malondialdehyde (MDA) as lipid peroxidation and serum thiol and protein carbonyl content (PCC) as protein oxidation markers. TBARS levels were measured by the method reported by Sozmen et al. [12]. Tissue samples were incubated with TBA working solution for 30 min at 95 °C and were calculated using a calibration curve constructed from 1,1,3,3 tetraethoxypropan. MDA levels were assayed using a spectrophotometric method described by Ohkawa et al. [13]. Sample absorbances were measured at 532 nm and calculated using the absorbance of the standard. Thiol levels were determined by the method of Hu et al. [14], based on the thiol-disulphide interchange reaction between thiols and 5,5’-dithio-bis-(2-nitrobenzoic acid). The evaluation was performed using a standard curve for glutathione. Sample absorbances were measured at 412 nm. Plasma PCC levels were measured by using the method of Reznick et al. [15]. Sample absorbances were measured at 360 nm, using the molar extinction coefficient of DNPH and using a Folin kit.

Kidney histology
The upper halves of the right kidneys were examined for histopathological changes under a light microscope as suggested by Yamasowa et al. [16]. Evaluations were made in a blind manner using an arbitrary scale. Tubular necrosis and proteinaceous casts were graded as follows: no damage (– or 0), mild (± or 1, unicellular, patchy isolated damage), moderate (+ or 2, damage less than 25%), severe (++ or 3, damage between 25 and 50%), and very severe (+++ or 4, more than 50% damage). The degree of medullary congestion was defined as follows: no congestion (– or 0), mild (± or 1, vascular congestion with identification of erythrocytes by x400 magnification), moderate (+ or 2, vascular congestion with identification of erythrocytes by x200 magnification), severe (++ or 3, vascular congestion with identification of erythrocytes by x100 magnification) and very severe (+++ or 4, vascular congestion with identification of erythrocytes by x40 magnification).

Statistical analysis
We used the unpaired Student's t-test for two-group comparison and one-way ANOVA, followed by Scheffe tests for multiple comparisons. Within-subject comparisons of continuous variables were carried out using a paired t-test. All tests were two-sided, and a p value of <0.05 was considered statistically significant. Analyses were performed with SPSS software version 13.0 for Windows (Chicago, IL, USA). Values were expressed as the mean ± SD.



   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Conclusions
 References
 
Baseline and follow-up characteristics of the rats
The rats tolerated the treatment well, and all survived until the end of the experiment. No statistically significant differences were observed for the baseline characteristics between the groups. After 3 days of dehydration, in all groups, water intake was increased almost 2.5-fold; all rats developed anuria, and they lost approximately 20% of their baseline body weight (P < 0.001 for each parameter). Before scarification, body weight, urine volume and water intake almost reached the baseline levels.

Renal function parameters
In all groups, CrCl decreased, serum BUN, serum creatinine, and urine microprotein increased on day 6 vs baseline. The absolute decrease of CrCl was significantly higher in in group CM than in the other three groups (P = 0.010, CM vs C and NCM; P = 0.012, CM vs N). Also, CrCl levels 2 days after the diatrizoate injection (day 6) was significantly lower in group CM than in group C (P = 0.038). The absolute increase in serum creatinine was significantly higher in group CM than in groups C and N (P = 0.016 and P = 0.008, respectively). Serum creatinine levels on day 6 were significantly higher in CM than in N and C (P = 0.027 and P = 0.048, respectively). We have not found any significant differences in BUN levels and FENa between the groups. On day 6, urine microprotein levels were significantly increased in group CM compared with groups C, N and NCM (P < 0.001, p < 0.001 and P = 0.001, respectively). Also levels increased significantly in group NCM compared with groups C and N (P < 0.001). The absolute change of the microprotein levels was higher in group CM than in groups C, N and NCM (P < 0.001, P < 0.001, and P = 0.002, respectively). Also, the absolute change of microprotein was higher in group NCM than in groups C and N (P = 0.032 and P < 0.001). Both the absolute change of microprotein and the microprotein levels on day 6 were higher in group C than in group N (P = 0.003 and P = 0.001, respectively) (Table 1).


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  		Table 1 Renal function parameters in the study groups

 
Nitrite/nitrate levels
Kidney nitrite levels in group N were significantly higher than those in groups CM, C and NCM (P < 0.001, P = 0.017 and P = 0.043, respectively). Also, the nitrite levels in NCM were higher than those in CM by Student's t-test (P = 0.027) (Table 2).


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  		Table 2 Nitrite, nitrate and total nitrite/nitrate levels (nmol/mg protein) in the kidneys

 
Oxidative stress markers
In group CM, serum PCC and MDA were significantly increased (P < 0.001), and thiol levels were significantly decreased (P = 0.029) when compared with C. The TBARS levels were also increased in group CM when compared with C (P = 0.034). However, in group NCM, the levels of thiol, MDA and TBARS were similar when compared with group C. Also, the PCC levels were decreased in group NCM, but they were still higher than those in C (P = 0.002). Furthermore, the TBARS levels were significantly higher in NCM than in N (P = 0.026) and significantly lower in NCM than in CM (P = 0.032). In group N, the MDA level was significantly lower than in C and NCM (P = 0.022 and P = 0.001, respectively), (Table 3).


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  		Table 3 Oxidative stress markers of the study groups

 
Histopathologic findings
All rats in group CM developed tubular necrosis (Figure 1a, outer zone of medulla), proteinaceous casts (Figure 1b, inner zone of the medulla), and medullary congestion (Figure 1c, outer zone of medulla). Pre- and post-treatment with nebivolol (group NCM) attenuated the development of all these lesions, although significant protective effects were observed only in tubular necrosis (P = 0.001) and proteinaceous cast (P < 0.001), (Table 4). Also, the 5-day treatment with nebivolol (group N) attenuated the development of proteinaceous casts and medullary congestion, which developed secondary to dehydration (group C), although significant protective effects were observed only in proteinaceous casts (P = 0.019).


Figure 1
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  		Fig. 1 (a) Large proteinaceous casts in tubular lumens of a CM group rat. Tubules were dilated with numerous proteinaceous casts (HE stain, original magnification x100). (b) Outer medullary congestion in a CM group rat (HE stain, original magnification x200). (c) Tubular necrosis in a CM group rat (HE stain, original magnification x200).

 

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  		Table 4 Histopathological changes in the kidneys of the study groups

 
Discussion
The main novel findings in this first study which studied the effect of nebivolol on CIN are as follows: nebivolol (i) decreases the medullar congestion, protein casts and tubular necrosis which occurred secondary to contrast media, (ii) decreases the systemic and renal oxidative stress which occurred after contrast media administration, (iii) decreases the microproteinuria which occurred secondary to contrast media, (iv) increases the kidney nitrite level which decreased secondary to contrast media, and (v) decreases the microproteinuria and protein cast in kidney which occurred secondary to dehydration.

Current recommendations to decrease the risk of CIN include hydration with saline, avoiding high osmolar and high volume of contrast media, and avoiding nephrotoxic drugs. N-acetylcysteine, ascorbic acid and sodium bicarbonate treatments are fairly benign and inexpensive. Their use is therefore reasonable [5,17–20]. Outer-medullary hypoxia secondary to renal artery vasoconstriction, direct tubular toxicity, tubular obstruction, high osmolarity of the contrast medium and oxidative stress are suggested mechanisms underlying the pathogenesis of CIN [6]. In the present study, we chose nebivolol, a last-generation beta blocker, which is a selective ß1-adrenergic receptor antagonist, as a prophylactic agent for CIN for the following reasons: it leads to (i) an increase in the renal NO excretion [21], (ii) a significant increase in the renal plasma flow and glomerular filtration rate (GFR) [21], (iii) suppression of the renin-angiotensin aldosterone system and inhibition angiotensin II [21,22], and reduces endothelin-1 [23], and (iv) has an antioxidant effect [24]. All of them are related to the pathogenesis of CIN. Furthermore, the most common procedure associated with CIN is coronary angiography, and most of the patients who underwent coronary angiography have indication for the use of nebivolol. In clinical practice, nebivolol should be discontinued prior to the use of contrast medium in patients with asthma, decreased liver function, hypotension, cardiogenic shock and heart block. Also, it should not be used during pregnancy or breastfeeding.

Contrast media administration induces a decrease of the production of NO [7,25]. It has been demonstrated that nebivolol affected vasodilation through NO production, stimulated NO release, enhanced NO bioavailability and prevented NO deactivation [26]. In a rat study, treatment with nebivolol (2 mg/kg per day) induced a significant increase in renal NO excretion and, at a dose of 1 mg/kg, it significantly increased renal plasma flow and GFR [21]. The half-life of nebivolol is approximately 13 h [10]. Therefore, in our study, we gave nebivolol once daily at a dose of 2 mg/kg, and we found that the kidney nitrite levels, a major stable breakdown product of NO, were significantly lower in the CM group than in the NCM. This may explain why tubular necrosis, medullary congestion and tubular cast are less in group NCM than in CM.

Outer medullary congestion of the kidney is one of the vascular hallmarks of CIN. [27]. Tubular obstruction by proteins is associated with CIN [27]. One study has shown that after diatrizoate administration, five of the six rats developed a protein cast [28]. Compatible with the literature, we found that protein casts were significantly higher in the CM group, and after nebivolol treatment, the incidence of protein casts decreased. In our CIN model, we could not determine severe tubular necrosis probably due to the induction method. We have not used hard and invasive inductions of CIN, and this may explain why we have not seen severe tubular necrosis in the CM group.

Several experimental models have been used in the studies of CIN [7,18,29,30]. The experimental CIN model that we used in this study is relatively new. It has been shown that dehydration potentiates the vasoconstrictive effects of contrast media [30]. Also, the use of high-dose and high-osmolar-ionic contrast media, such as diatrizoate, are important risk factors for developing CIN [3]. Therefore, we used a prolonged dehydration period before the administration of high-dose diatrizoate. Severe protein cast, severe medullary congestion and moderate tubular necrosis were predicted, and this model in the CM group caused a significant decrease of CrCl. The advantages of our experimental CIN model are as follows: it is easy to prepare, involving no pharmacological pre-treatment and does not require any surgical procedures. The clinical impact of our animal model for human disease is as follows: we used an animal model where rats were deprived of water for several days and we used a high dose and high-osmolar contrast media. In spite of this high-risk situation for the development of CIN, nebivolol prevented the development of CIN, which was documented by histopathologic and laboratory findings. It means that nebivolol might be used in the prevention of CIN in high-risk patients for CIN.

In accordance with the literature, our data showed that diatrizoate administration significantly increased both renal and systemic oxidative stress. Similar to N-acetylcysteine and ascorbic acid, nebivolol produces systemic antioxidant effects. In human studies, it was shown that oxidative stress decreased after nebivolol treatment [31]. Our study demonstrated the protective role of nebivolol on oxidative stress. It has been known that proteinuria affects animals and human beings, following contrast agents [32]. We found that the absolute increase of the microprotein levels was higher in group CM than others. In accordance with this data, Carraro et al. showed that microproteinuria increased significantly after contrast administration [33]. There is no data on the antiproteinuric effect of nebivolol in literature. In rats, proteinuria is preceded by decreased NO synthesis and prevented by an NO donor [34]. The protective effects of nebivolol on renal tubules, the effect of nebivolol on kidney nitrite levels, and the antioxidant effect of nebivolol may explain the antimicroproteinuria in groups N and NCM.

Study limitations
Measurement of nitrites in urine is a much better indicator of renal NO system function. However, we have measured only kidney nitrite and nitrate levels. Also, we have not monitored the blood pressure and heart rate of the rats for technical reasons. In literature, there is no data about nebivolol preventing CIN. Therefore, to determine the treatment period of nebivolol was a problem in the present study. We pretreated the rats with nebivolol for 4 days and 1 more day after contrast administration. In an experimental study, it was shown that treatment with nebivolol for 7 days (10 mg/kg per day) increased NO bioavailability, and inhibited oxidative stress in angiotensin II-treated rats [35]. Perhaps administration of a single dose of nebivolol at the time of contrast administration could have a protective effect on the development of CIN.



   Conclusions
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Conclusions
References
 
The present experimental study demonstrated the protective role of nebivolol against CIN. Nebivolol leads to a decrease in the systemic and renal oxidative stress and an increase in renal nitrite production. In addition, contrast-induced proteinuria, proteinaceous cast and tubular necrosis are restored by nebivolol. Nebivolol prophylaxis may be useful in the prevention of CIN; further research on humans is needed.



   Acknowledgments
 
We would like to express our deep appreciation to Prof. Cengiz Utas and Associate Prof. Bulent Tokgoz for their assistance and technical support of this study. An abstract form of this study has been presented during the 3rd Clinical Vascular Biology Congress, Antalya, Turkey, from 25–29 April 2007. This study was supported by a research grant from the Turkish Society of Nephrology.

Conflict of interest. None of the authors have conflicts of interest to declare.



   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Conclusions
 References
 

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Received for publication: 17. 7.07
Accepted in revised form: 6. 9.07


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A. Maffei and G. Lembo
Nitric oxide mechanisms of nebivolol
Therapeutic Advances in Cardiovascular Disease, August 1, 2009; 3(4): 317 - 327.
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