title: Role of NO in cyclosporin nephrotoxicity: effects of chronic NO inhibition and NO synthases gene expression.
abstract: The role of nitric oxide (NO) during cyclosporin renal vasoconstriction was evaluated by glomerular hemodynamic and histological changes produced by chronic NO synthesis inhibition and neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) NO syntheses mRNA expression in renal cortex and medulla. Uninephrectomized rats treated during 7 days with vehicle (Veh), cyclosporin A (CsA) 30 mg/kg, CsA + nitro-L-arginine methyl ester (L-NAME), and Veh + L-NAME (10 mg/dl) in the drinking water were studied. Increase in arterial pressure and afferent and efferent resistances, as well as decrease in glomerular plasma flow, ultrafiltration coefficient, and single-nephron glomerular filtration rate were significantly greater with CsA + L-NAME than with CsA alone. The increase in afferent resistance was higher with CsA + L-NAME than with Veh + L-NAME. In addition, glomerular thrombosis, proximal tubular vacuolization, and arteriolar thickening were more prominent. In renal cortex, eNOS mRNA expression exhibited a 2.7-fold increase in CsA, whereas, in medulla, nNOS and iNOs expression were lower in CsA than in Veh, while eNOS tended to increase. Our results support the hypothesis that NO synthesis is enhanced at cortical level during CsA nephrotoxicity, counterbalancing predominantly preglomerular vasoconstriction. Higher NO production could be the result of increased eNOS mRNA expression.
authors.affiliation: Department of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico.
authors.forename: N A
authors.initials: NA
authors.lastname: Bobadilla
authors.forename: G
authors.initials: G
authors.lastname: Gamba
authors.forename: E
authors.initials: E
authors.lastname: Tapia
authors.forename: R
authors.initials: R
authors.lastname: García-Torres
authors.forename: A
authors.initials: A
authors.lastname: Bolio
authors.forename: P
authors.initials: P
authors.lastname: López-Zetina
authors.forename: J
authors.initials: J
authors.lastname: Herrera-Acosta
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000506:poisoning*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000506:poisoning*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009399:Nephrons / Q000187:drug effects*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D009569:Nitric Oxide; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester