Dietary L-arginine and α-tocopherol reduce vascular oxidative stress and preserve endothelial function in hypercholesterolemic rabbits via different mechanisms

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-de pendent 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-PGF(2 alpha) 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-PGF(2 alpha) 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 41 +/- 11%, respectively; P < 0.05) and improved endothelium-dependent relaxation. Both treatments also normalized urinary 8-iso-PGF(2 alpha) 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. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.