Probucol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level

1 Oxide low-density lipoprotein (ox-LDL) is believed to play an important role in early events of atherogenesis, and asymmetric dimethylarginine (ADMA) is associated with the development of endothelial dysfunction. The present study examined the effect of a single injection of native low-density lipoprotein (LDL) on endothelium function and the serum level of ADMA and the effect of probucol on endothelium function and ADMA level in rats. 2 Endothelial injury was induced by intravenous injection of LDL at the dose of 2, 4, or 6 mg kg(-1) for 24, 48, or 72 h, and vasodilator responses to acetylcholine in the aortic rings and serum levels of ADMA, nitrite/nitrate (NO) and malondialdehyde (MDA) were determined. 3 Pretreatment with LDL markedly reduced endothelium-dependent relaxation in a concentration-dependent manner. Inhibition of vasodilator responses to acetylcholine by LDL was abolished in the presence Of L-arginine (3 x 10(-4) m). Serum levels of ADMA and MDA were significantly elevated in the rats pretreated with LDL, while serum level of nitrite/nitrate was markedly decreased. 4 Pretreatment with probucol significantly improved endothelium-dependent relaxation, decreased concentrations of ADMA and MDA and increased nitrite/nitrate level in the rats treated with LDL. A similar effect was seen in the rats pretreated with an antioxidant vitamin E. 5 These results suggest that a single injection of native LDL causes endothelial dysfunction by elevation of ADMA levels and that the protective effect of probucol on endothelial cells is related to reduction of ADMA concentration.