Elsevier

Nitric Oxide

Volume 24, Issue 2, 15 March 2011, Pages 77-83
Nitric Oxide

Nitric oxide (NO) is associated with gentamicin (GENTA) nephrotoxicity and the renal function recovery after suspension of GENTA treatment in rats

https://doi.org/10.1016/j.niox.2010.12.001Get rights and content

Abstract

GENTA nephrotoxicity is likely to be caused, among other factors, by an increase of vasoconstrictors or a decrease of vasodilators such as NO. Few days after discontinuing GENTA treatment, the renal function is recovered, but if risk factors like advanced age, previous renal dysfunction, simultaneous use of other nephrotoxic drugs or dehydration are present, severe and progressive renal disease occurs. The aim of this study was to evaluate the renal function in rats during GENTA treatment and after its suspension as well as its relationship with NO. Rats were treated with water (vehicle, CTL) or GENTA (100 mg/kg BW) intraperitonially during 10 days; both n = 24. Twelve animals of each group were sacrificed after blood and 24 h urine were collected, and their kidneys were removed for histology. In another rats this procedure underwent after 20 or 30 days of GENTA suspension. GENTA treated group developed a marked decrease in renal function, characterized by an increased serum urea and decreased creatinine clearance; NO was increased in the serum and decreased in the urine; all P < 0.01 vs CTL. Acute tubular necrosis was confirmed in GENTA treated group. After GENTA suspension we observed a normalization of urea, creatinine clearance and serum and urinary NO; the histological lesions were also attenuated. We suggest that NO could play a role in GENTA induced nephrotoxicity and recovery. The understanding of this physiopathology could be an useful tool to prevent or blunt the nephrotoxicity progression, mainly when risk factors are present.

Introduction

GENTA is an antibiotic of the aminoglycoside family commonly used for the treatment of severe gram-negative bacterial infections. Its main side effect is nephrotoxicity which accounts for 10 to 20% of all cases of acute renal failure (ARF) according to experimental results [1].

Nephrotoxicity induced by GENTA is characterized by severe renal proximal tubular necrosis [2], [3], [4] and marked decline in glomerular filtration rate (GFR), mediated at least in part by a reduced ultrafiltration coefficient (Kf) and increased renal vascular resistance [5].

Many studies have been done to investigate the pathophysiology of this ARF, some of them suggesting the participation of the potent vasodilator nitric oxide (NO).

NO is produced by most cells of the human body and has as its substrate the l-arginine, which under the effect of nitric oxide synthase (NOS) generates l-citrulline and NO, that is quickly metabolized into nitrite (NO2-) and nitrate (NO3-) [6], [7]. NOS presents two isoforms: the constitutive (cNOS) and the inducible (iNOS), the latter can be induced by simple agents such as bacterial lipopolysaccharide (LPS), commonly associated with the induction of sepsis [8], [9].

Previous studies in our Laboratory demonstrated that GENTA decreases NO synthesis in renal vascular smooth muscle cells [10].

The aim of this study is to evaluate the NO synthesis and the renal function in rats, during GENTA treatment and after its suspension.

Section snippets

Methods

This study was approved by the “Ethics Committee” protocol #0039/07 of UNIFESP, Escola Paulista de Medicina, SP, Brazil.

Results

After 10 days of treatment, GENTA group developed a marked decrease in renal function, characterized by a significant increase of Crs (3.9 ± 0.5 vs CTL 1.0 ± 0.5 mg/dL; P < 0.05) and ureas (127.3 ± 3.4 vs CTL 48.8 ± 2.2 mg/dL; P < 0.05) and decreased Cr cl (0.5 ± 0.1 vs CTL 1.2 ± 0.1 mg/min; P < 0.05) and ureaur (46.1 ± 3.4 vs CTL 88.5 ± 4.1 mg/dL; P < 0.05) (Table 1). This group also presented an increased excretion of Na+ (8.1 ± 0.3 vs 2.3 ± 0.1 mM) and K+ (14.3 ± 0.5 vs 4.0 ± 0.4 mM) both P < 0.05 vs CTL (Table 2).

After 20 days of

Discussion

Acute renal failure is strongly associated with in-hospital mortality and morbidity and in spite of all efforts from researchers and clinicians over the understanding of its physiopathology, the possible means to prevent, attenuate or even shorten its progression, the mortality caused by ARF is still high, about 50%, comparable to data from 50 years ago.

Aminoglycoside antibiotics are commonly used for treatment of severe gram-negative bacterial infections [4]. Perhaps the most widely used drug

Conclusion

This study suggests that NO has a role in the ARF caused by GENTA in rats and it might be involved in the recovery phase when this drug is discontinued. The understanding of the physiopathology of GENTA induced ARF and its recovery phase could be a useful tool to prevent or to attenuate its nephrotoxicity, mainly in patients presenting risk factors like advanced age or previous renal damage.

Acknowledgments

This work was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) 04/08311-6 and FAP (Fundação de Apoio à Pesquisa da Universidade Federal de São Paulo). The authors thank Antonio C Seguro, M.D., Ph.D., Lúcia Andrade M.D., Ph.D. and Talita R Sanches B.Sc. from Nephrology Department, Universidade de São Paulo for Western blot analysis and Thiago S Rosa M.Sc., Marcos A Nascimento and Guilherme B Nogueira for technical assistance.

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