The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced nephrotoxicity in mice.
The nitric oxide (NO) donor, O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P450 enzymes to release NO in the liver and possibly other tissues. V-PYRRO/NO has been shown to be hepatoprotective, but little is known about its effect in the kidney, another organ rich in P450s. Thus, mice were given V-PYRRO/NO (0.4-5.4 mg/ml, 8 microl/h) before and/or after a nephrotoxic dose of acetaminophen (APAP; 600 mg/kg, i.p.) to examine its nephroprotective effects. V-PYRRO/NO administration significantly reduced APAP-induced nephrotoxicity in a dose- and time-dependent manner, as evidenced by mitigation of increased blood urea nitrogen levels and by amelioration of renal pathology, specifically interstitial congestion, proximal tubular cell degeneration and necrosis. The best protection was observed at the highest dose (5.4 mg/ml) and with V-PYRRO/NO pretreatment (4-16 h). Implanting V-PYRRO/NO pumps simultaneously with APAP also attenuated APAP nephrotoxicity. The protection is probably not due to a decreased APAP toxication metabolism, as similar depletion of renal glutathione levels was observed regardless of V-PYRRO/NO treatment. APAP-induced renal lipid peroxidation was reduced by V-PYRRO/NO, as determined by the concentrations of hydroxynonenals and malondialdehyde. In summary, this study demonstrates that the NO donor V-PYRRO/NO is effective in blocking APAP-induced nephrotoxicity in mice. The protection is probably due to multiple mechanisms involving attenuation of APAP-induced congestion and lipid peroxidation in the kidney.
Li
Chengxiu
C
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27706, USA.
Liu
Jie
J
Saavedra
Joseph E
JE
Keefer
Larry K
LK
Waalkes
Michael P
MP
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D001806:Blood Urea Nitrogen; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006651:Histocytochemistry; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008054:Lipid Peroxides / Q000378:metabolism; D051379:Mice; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*
D018712:Analgesics, Non-Narcotic; D008054:Lipid Peroxides; D020030:Nitric Oxide Donors; C107010:O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate; D011759:Pyrrolidines; D000082:Acetaminophen; D005978:Glutathione