Inhibition of nitric oxide synthase aggravates cisplatin-induced nephrotoxicity: effect of 2-amino-4-methylpyridine.
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 (NO(x)), 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 NO(x) 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.
Saad
Sherif Y
SY
Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. sherif_ibrahem@hotmail.com
Najjar
Tawfeeg A O
TA
Daba
Mohammed H
MH
Al-Rikabi
Ammar C
AC
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects*; D004357:Drug Synergism; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009336:Necrosis; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010847:Picolines / Q000494:pharmacology*; D010984:Platinum / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D010847:Picolines; C015672:2-amino-4-picoline; D010984:Platinum; D019001:Nitric Oxide Synthase; D002945:Cisplatin