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

Abstract

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 eect of a single injection of native lowdensity lipoprotein (LDL) on endothelium function and the serum level of ADMA and the eect of probucol on endothelium function and ADMA level in rats. 2Endothelial injury was induced by intravenous injection of LDL at the dose of 2, 4, or 6 mg kg 71 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 concentrationdependent manner. Inhibition of vasodilator responses to acetylcholine by LDL was abolished in the presence of L-arginine (3610 74 M). Serum levels of ADMA and MDA were signi®cantly elevated in the rats pretreated with LDL, while serum level of nitrite/nitrate was markedly decreased. 4 Pretreatment with probucol signi®cantly improved endothelium-dependent relaxation, decreased concentrations of ADMA and MDA and increased nitrite/nitrate level in the rats treated with LDL. A similar eect 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 eect of probucol on endothelial cells is related to reduction of ADMA concentration.

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

“…Statins are known to correct endothelial dysfunction 30,85 and recently Simvastatin was shown to increase eNOS activity and ameliorate vasospasm 56 . Yet another cholesterol-lowering drug, probucol, was shown to promote functional reendothelization of stripped aorta 48 and to preserve endothelial vasodilatory functions by reducing ADMA levels 38 . Thus, we used probucol, a drug with high octanol/water partition coefficient (logP=10.91) 85 assuring significant penetration of the blood-brain barrier, to inhibit increased ADMA levels in CSF after SAH and prevent development of vasospasm in a primate model of SAH 73 .…”

Role of Asymmetric Dimethylarginine in Inflammatory Reactions by Angiotensin II

“…There is evidence that an increase in ADMA is related to oxidative stress, and treatment with antioxidants, e.g. vitamin E, probucol, daviditin A and pyrrolidine dithiocarbamate, decreases both lipid peroxide and ADMA levels [26,27,28,29,30,31]. It was reported that Ang II can enhance the activity of NADPH oxidase and lead to marked ROS generation in cultured endothelial cells [32] and L6 myotubes, which is blocked by ARB losartan or the NADPH oxidase inhibitor apocynin [33].…”

Effect of supplementation with B vitamins and antioxidants on levels of asymmetric dimethylarginine (ADMA) and C-reactive protein (CRP): a double-blind, randomised, factorial design, placebo-controlled trial

“…Therefore, the attenuation of DDAH activity by oxidative stress [8], whereby a cysteine molecule held in an activated state in the tertiary structure of the enzyme is inactivated by oxidation, may lead to an accumulation of ADMA. Antioxidants have been shown to decrease ADMA levels in cultured human endothelial cells [9] and in vivo rats exposed to native low-density lipoprotein [10]. Consequently, antioxidant therapy may reduce ADMA levels by attenuating the effects of oxidative stress.…”