Effect of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide on renal function and hemodynamics in the anesthetized rat.
The experimental agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is a nephrotoxicant in the Fischer 344 rat. NDPS induces nephrotoxicity via metabolic bioactivation to one or more metabolites. Both N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA), oxidative metabolites of NDPS, are more potent nephrotoxicants than the parent compound. Preliminary studies in our laboratory indicate that altered renal hemodynamics may contribute to the mechanism of NDPS-induced nephrotoxicity. However, it is not known if NDPS affects renal hemodynamics prior to or after altering tubular function. In this study, male Fischer 344 rats (275-300 g) were anesthetized with urethane (1.5 g/kg, i.p.) and prepared for renal function experiments. Renal blood flow (RBF), glomerular filtration rate (GFR), urine flow rate (V) and fraction of GFR excreted as urine (V/GFR) were determined during eight 30 min intervals following NDHS (0.2 or 0.4 mmol/kg, i.p.) or vehicle (sesame oil, 2.5 ml/kg, i.p.) treatment. NDHS (0.2 or 0.4 mmol/kg) decreased GFR while urine flow rate and V/GFR were increased compared to vehicle-treated controls. These alterations in renal function were evident by 2 h post NDHS (0.4 mmol/kg) and by 3 h post-NDHS (0.2 mmol/kg) treatment. RBF of rats receiving NDHS (0.2 or 0.4 mmol/kg) tended to decrease post-NDHS treatment; however, this decrease was not significant. Results of this study indicate that NDHS (0.2 or 0.4 mmol/kg) initially alters renal function by reducing the tubular reabsorption of glomerular filtrate prior to a reduction of GFR and RBF.
Department of Pharmacology, Marshall University School of Medicine, Huntington, West Virginia 25755-9310.
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005659:Fungicides, Industrial / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology / Q000652:urine; D008297:Male; D008954:Models, Biological; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D012079:Renal Circulation / Q000187:drug effects; D013388:Succinimides / Q000378:metabolism / Q000633:toxicity*; D014563:Urodynamics / Q000187:drug effects
D005659:Fungicides, Industrial; D013388:Succinimides; C070526:N-(3,5-dichlorophenyl)-2-hydroxysuccinimide