title: Dietary L-arginine and alpha-tocopherol reduce vascular oxidative stress and preserve endothelial function in hypercholesterolemic rabbits via different mechanisms.
abstract: Vascular oxidative stress brought about by superoxide radicals and oxidized low-density lipoproteins (oxLDL) is a major factor contributing to decreased NO-dependent vasodilator function in hypercholesterolemia and atherosclerosis. We investigated whether chronic administration of L-arginine (2% in drinking water) or of alpha-tocopherol (300 mg/day) improves endothelium-dependent vasodilator function and systemic NO production, reduces vascular oxidative stress, and reduces the progression of atherosclerosis in cholesterol-fed rabbits with pre-existing hypercholesterolemia. Systemic NO production was assessed as urinary nitrate excretion; oxidative stress was measured by urinary 8-iso-PGF2alpha excretion in vivo, by lucigenin-enhanced chemiluminescence of isolated aortic rings ex vivo, and by copper-mediated LDL oxidation in vitro. Endothelium-dependent relaxation was almost completely abrogated in cholesterol-fed rabbits. Urinary nitrate excretion was reduced by 46+/-10%, and 8-iso-PGF2alpha excretion was increased by 61+/-18% as compared to controls (each P <0.05). Vascular superoxide radical release stimulated by PMA ex vivo was increased by 273+/-93% in this group, and the lag time of LDL oxidation was reduced by 35+/-6% (each P <0.05). Treatment with L-arginine and alpha-tocopherol reduced intimal lesion formation (by 68+/-6 and 4+/-11%, respectively; P <0.05) and improved endothelium-dependent relaxation. Both treatments also normalized urinary 8-iso-PGF2alpha excretion. L-Arginine increased urinary nitrate excretion by 43+/-13% (P <0.05) and reduced superoxide radical release by isolated aortic rings to control levels, which was unaffected by vitamin E treatment. By contrast, vitamin E dramatically increased the resistance of isolated LDL to copper-mediated oxidation in vitro by 178+/-7% (P <0.05), which was only marginally prolonged by L-arginine. Intimal thickening was reduced by both treatments. We conclude that both L-arginine and alpha-tocopherol reduce the progression of atherosclerotic plaques in cholesterol-fed rabbits. However, while L-arginine increases NO formation and reduces superoxide release, alpha-tocopherol antagonizes mainly oxLDL-related events in atherogenesis. Thus, both treatments reduce urinary isoprostane excretion and improve endothelium-dependent vasodilation via different mechanisms.
authors.affiliation: Institute of Clinical Pharmacology, Hannover Medical School, Germany.
authors.forename: R H
authors.initials: RH
authors.lastname: Böger
authors.forename: S M
authors.initials: SM
authors.lastname: Bode-Böger
authors.forename: L
authors.initials: L
authors.lastname: Phivthong-ngam
authors.forename: R P
authors.initials: RP
authors.lastname: Brandes
authors.forename: E
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: A
authors.initials: A
authors.lastname: Mügge
authors.forename: M
authors.initials: M
authors.lastname: Böhme
authors.forename: D
authors.initials: D
authors.lastname: Tsikas
authors.forename: J C
authors.initials: JC
authors.lastname: Frölich
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology*; D002339:Carotid Arteries / Q000473:pathology; D004032:Diet; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004730:Endothelium, Vascular / Q000503:physiopathology*; D028441:F2-Isoprostanes; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation; D014810:Vitamin E / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D028441:F2-Isoprostanes; D008077:Lipoproteins, LDL; D009566:Nitrates; D013481:Superoxides; D014810:Vitamin E; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D001120:Arginine; D015237:Dinoprost