Inhibition of Nitric Oxide Synthase Aggravates Cisplatin-Induced Nephrotoxicity: Effect of 2-Amino-4-Methylpyridine
| Autor: | Mohammed H. Daba, Ammar C. Al-Rikabi, Sherif Y. Saad, Tawfeeg A. O. Najjar |
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| Rok vydání: | 2002 |
| Předmět: |
Male
inorganic chemicals medicine.medical_specialty medicine.medical_treatment Intraperitoneal injection Antineoplastic Agents Kidney Nephrotoxicity Nitric oxide Necrosis chemistry.chemical_compound Internal medicine Drug Discovery medicine Animals Pharmacology (medical) Rats Wistar neoplasms Platinum Pharmacology Creatinine Body Weight Kidney metabolism Drug Synergism General Medicine Malondialdehyde female genital diseases and pregnancy complications Rats Infectious Diseases medicine.anatomical_structure Endocrinology Oncology chemistry Picolines Toxicity Nephritis Interstitial Cisplatin Nitric Oxide Synthase Injections Intraperitoneal |
| Zdroj: | Chemotherapy. 48:309-315 |
| ISSN: | 1421-9794 0009-3157 |
| DOI: | 10.1159/000069714 |
| Popis: | Background: Nitric oxide (NO) has been shown to play a role in maintaining normal renal function. However, the role of NO in cisplatin (CDDP)-induced nephrotoxicity is still unclear. The aim of the present work was to examine the effect of the NO synthase (NOS) inhibitor, 2-amino-4-methylpyridine, on the severity of CDDP-induced nephrotoxicity. Methods: Male Wistar rats were divided into six groups. Three control groups received plain drinking water or water containing 1.5% L-arginine. One of the two groups receiving plain water was treated with an intraperitoneal injection of 2-amino-4-methylpyridine (1 mg/kg in normal saline), and the other two control groups were injected intraperitoneally with normal saline. Another three groups were treated in the same manner and injected with CDDP (6 mg/kg, i.p.). CDDP was injected 1 h after 2-amino-4-methylpyridine treatment. Rats were sacrificed 7 days after CDDP treatment, and serum as well as kidneys were isolated and analysed. Results: CDDP-treated rats showed increases in the kidney weight as a percentage of the total body weight and serum creatinine and urea levels and decreases in serum albumin and calcium levels. Also, CDDP treatment induced reductions in the kidney total nitrate/nitrite (NOx), reduced glutathione (GSH) and glutathione peroxidase activity (GSH-Px) levels and an increase in the kidney malondialdehyde (MDA) production level. In contrast, 2-amino-4-methylpyridine treatment 1 h prior to CDDP injection induced marked exacerbation of CDDP-induced nephrotoxicity, as manifested by severe aggravation of the indices of nephrotoxicity. Also, 2-amino-4-methylpyridine plus CDDP-treated rats showed exaggeration of the reduction in the kidney total NOx content and GSH-Px activity and elevation of the kidney platinum accumulation level with normalization of the kidney MDA production level and rebound in the kidney GSH content. Histopathologically, CDDP-treated rats showed marked interstitial nephritis, tubular atrophy and tubular necrosis. However, treatment with 2-amino-4-methylpyridine 1 h prior to CDDP injection revealed marked exacerbation of CDDP-induced histopathological changes. Conclusions: The present findings suggest that NO plays a role in CDDP-induced nephrotoxicity. Administration of 2-amino-4-methylpyridine, an NOS inhibitor, exacerbates CDDP-induced nephrotoxicity. |
| Databáze: | OpenAIRE |
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