Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production

Abstract

L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce intimal plaque area in cholesterol (Chol)-fed rabbits. We have studied endogenous NO production in such animals in vitro (endothelium-dependent relaxations) and in vivo (assessed by urinary NO₃⁻ excretion) before and during chronic oral adminstration of L-arginine and an inhibitor of NO synthesis, L-NAME. Vascular superoxide anion (O₂⁻) production of aortic rings was measured under basal conditions and following exposure to phorbol-myristate-acetate (PMA). Cholesterol feeding reduced endothelium-dependent relaxations and decreased urinary NO₃⁻ excretion. These effects were potentiated by administration of L-NAME. L-arginine partly restored endothelium-dependent relaxations and increased NO₃⁻ excretion. PMA-stimulated O₂⁻ production was increased in aortic rings from rabbits given cholesterol (+159 ± 28%; mean ± S.E.M.) or cholesterol + L-NAME (+149 ± 37%) as compared with controls (−22 ± 7%). In rabbits given cholesterol + L-arginine, O₂⁻ production was decreased to control levels (+14 ± 17%; P < 0.05). We conclude that the systemic synthesis of NO is impaired in cholesterol-fed rabbits, as indicated by the decreased urinary excretion of NO₃⁻. Enhanced O₂⁻ production may further contribute to the decreased biological activity of NO in hypercholesterolaemia. L-arginine restores endothelial function in hypercholesterolaemia by enhancing NO production and by protecting NO from early breakdown by O₂⁻.