Effect of autacoid modulation on N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity.
N-(3,5-Dichlorophenyl)succinimide (NDPS) is an agricultural fungicide which has been shown to induce acute tubular necrosis. The purpose of the present study was to determine if creatinine clearance was altered early in the development of NDPS nephrotoxicity. This study also examined the effect of autacoid modulation on the renal effects induced by NDPS and two metabolites of NDPS, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA). In one set of experiments, male Fischer 344 rats (4 rats/group) were administered a single intraperitoneal (i.p.) injection of NDPS (1.0 mmol/kg) or vehicle and creatinine clearance was determined at 3 and 6 h post-treatment. NDPS administration resulted in a marked decrease in creatinine clearance at both time points. In a second set of experiments, rats (4-8 rats/group) were pretreated with the cyclooxygenase inhibitor indomethacin (3.0 or 5.0 mg/kg, i.p.) or the thromboxane synthase inhibitor dazmegrel (20 mg/kg, i.p.) 1 h before the i.p. administration of NDPS (0.2 or 0.4 mmol/kg), NDHS (0.05 or 0.1 mmol/kg), NDHSA (0.05 or 0.1 mmol/kg) or vehicle. Indomethacin pretreatment potentiated the nephrotoxic potential of NDPS and its two metabolites, while dazmegrel pretreatment attenuated NDPS nephrotoxicity without marked effects on NDHS or NDHSA nephropathy. These results indicate that renal hemodynamic changes occur early in the development of NDPS nephrotoxicity and that autacoids are important modulators of NDPS- and NDPS metabolite-induced renal effects.
Rankin
G O
GO
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755-9310.
Valentovic
M A
MA
Teets
V J
VJ
Nicoll
D W
DW
Anestis
D K
DK
Brown
P I
PI
D000818:Animals; D003404:Creatinine / Q000378:metabolism; D005659:Fungicides, Industrial / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007678:Kidney Glomerulus / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012079:Renal Circulation / Q000187:drug effects; D013386:Succinates / Q000633:toxicity*; D013388:Succinimides / Q000633:toxicity*
D005659:Fungicides, Industrial; D007093:Imidazoles; D013386:Succinates; D013388:Succinimides; C070526:N-(3,5-dichlorophenyl)-2-hydroxysuccinimide; C007352:N-(3,5-dichlorophenyl)succinimide; C039242:dazmegrel; C070595:N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid; D003404:Creatinine; D007213:Indomethacin