title: Renal vascular function in hypercholesterolemia is preserved by chronic antioxidant supplementation.
abstract: Hypercholesterolemia impairs systemic vascular reactivity in response to endothelium-dependent vasodilators, which may be mediated partly through increased formation of lipid peroxides. However, it is unclear whether these pathophysiological mechanisms play a role in renal vascular impairment in experimental hypercholesterolemia. Hence, pigs were studied after a 3-mo normal (n = 7) or high cholesterol (HC) (n = 7) diet, HC diet supplemented daily with antioxidant vitamins E (100 IU/kg) and C (1000 mg; HC+vitamins, n = 5), or normal diet supplemented with vitamins (N+vitamins, n = 5). Renal blood flow was measured with electron-beam computed tomography before and during infusion of acetylcholine (Ach). Endothelial function, endothelial and inducible nitric oxide synthase (NOS), and nitrotyrosine immunoreactivity were studied in renal arteries ex vivo. Despite similar cholesterol levels, LDL oxidizability (lag time, malondialdehyde, and relative electrophoretic mobility) was increased in pigs that were fed the HC diet but was significantly decreased in pigs that were fed the HC+vitamins diet. Renal blood flow response to Ach was blunted in pigs that were fed the HC diet but was preserved in pigs that were fed the HC+vitamins diet. Maximal relaxation to Ach was attenuated in pigs that were fed the HC diet compared with those that were fed the normal diet (51.5 +/- 6.4% versus 97.0 +/- 2.9%; P < 0.01) but was preserved in pigs that were fed the HC+vitamins diet (103.1 +/- 3.0%; P = 0.39) and N+vitamins diet (87.7 +/- 3.0%; P = 0.1), as were relaxation responses to calcium ionophore A23187. Vascular smooth-muscle relaxation to diethylamine was enhanced in endothelium-denuded HC vessel but was restored in pigs that were on the HC+vitamins regimen. In HC, immuno-reactivity of endothelial NOS was decreased, that of inducible NOS was increased, and both were preserved in pigs that were fed the HC+vitamins and N+vitamins diets, whereas nitrotyrosine was not detected. The present study demonstrates that antioxidant intervention in experimental HC reduces LDL oxidizability and preserves renal vascular responses to endothelium-dependent vasodilators. Therefore, this beneficial effect potentially can protect the kidney from hypercholesterolemia-induced damage.
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.
authors.forename: John M
authors.initials: JM
authors.lastname: Stulak
authors.affiliation: Departments of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.affiliation: Departments of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Martin Rodriguez
authors.initials: MR
authors.lastname: Porcel
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: James A
authors.initials: JA
authors.lastname: Caccitolo
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Romero
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Hartzell V
authors.initials: HV
authors.lastname: Schaff
authors.affiliation: Department of Medicine, University of Naples, Italy and Department of Medicine, University of California, San Diego, California.
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
authors.affiliation: Department of Internal Medicine, Division of Hypertension, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics; D006937:Hypercholesterolemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000097:blood; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D012016:Reference Values; D012079:Renal Circulation / Q000187:drug effects*; D013552:Swine; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014810:Vitamin E / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D002791:Cholesterol, Dietary; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D014810:Vitamin E; D002784:Cholesterol; D006152:Cyclic GMP; D001205:Ascorbic Acid