title: Comparison of acute and chronic antioxidant interventions in experimental renovascular disease.
abstract: Reactive oxygen species (ROS) can modulate renal hemodynamics and function both directly, by leading to vasoconstriction, and indirectly, by inducing renal inflammation and tissue growth. The involvement of oxidative stress in the pathogenesis of renovascular disease (RVD) is increasingly recognized, but the relative contribution of long-term tissue injury to renal dysfunction remains unclear. We hypothesized that functional and structural alterations elicited by oxidative stress in RVD would be more effectively modulated by chronic than by acute antioxidant intervention. Renal hemodynamics and function were quantified in vivo in pigs using electron-beam computed tomography at baseline and after vasoactive challenge (ACh and sodium nitroprusside); after 12 wk of RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7); RVD acutely infused with the SOD-mimetic tempol (RVD+tempol, n = 7); RVD chronically supplemented with antioxidant vitamins C (1 g) and E (100 IU/kg; RVD+vitamins, n = 7); or control (normal, n = 7). Renal tissue was studied ex vivo using immunoblotting and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate were similarly decreased in all RVD groups. ACh-stimulated RBF remained unchanged in RVD, increased in RVD+tempol, but further increased (similarly to normal) in RVD+vitamins (P < 0.05 vs. RVD). Furthermore, RVD+vitamins also showed a decreased presence of superoxide anion, decreased NAD(P)H-oxidase and nitrotyrosine expression, increased endothelial nitric oxide synthase expression, and attenuated renal fibrosis. Chronic antioxidant intervention in early RVD improved renal hemodynamic responses more effectively than acute intervention, likely due to increased nitric oxide bioavailability and decreased structural injury. These suggest that chronic tissue changes play an important role in renal compromise mediated by oxidative stress in RVD.
authors.affiliation: Div. of Hypertension, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Chade
authors.forename: James D
authors.initials: JD
authors.lastname: Krier
authors.forename: Martin
authors.initials: M
authors.lastname: Rodriguez-Porcel
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Breen
authors.forename: Michael A
authors.initials: MA
authors.lastname: McKusick
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000208:Acute Disease; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use; D015153:Blotting, Western; D002908:Chronic Disease; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D005919:Glomerular Filtration Rate / Q000502:physiology; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D012078:Renal Artery Obstruction / Q000503:physiopathology; D012079:Renal Circulation / Q000187:drug effects; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000627:therapeutic use; D013552:Swine; D014057:Tomography, X-Ray Computed; D014665:Vasodilator Agents / Q000494:pharmacology; D014810:Vitamin E / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; D014665:Vasodilator Agents; D014810:Vitamin E; D009599:Nitroprusside; D013482:Superoxide Dismutase; D000109:Acetylcholine; D001205:Ascorbic Acid; C001803:tempol