Antioxidant activity of probucol and its analogs in hypercholesterolemic Watanabe rabbits

Abstract. This study investigates the hypothesis that lipid soluble antioxidants may increase the resistance of low-density lipoprotein (LDL) to oxidation and also enhance vascular endothelial responses in humans. In a double-blind parallel group study, 24 hypercholesterolaemic patients, already on treatment with simvastatin (20 mg day-'), were randomized to supplementary treatment with probucol (500 mg bd), vitamin E (400IU daily) or placebo for 8 weeks. Mean serum cholesterol before antioxidant treatment was 7.00mmoll-'. Resistance of LDL to oxidation by copper was increased by 830% in the probucol group and by 30% in the vitamin E group. However, thiobarbituric acid reacting substances in whole serum were not altered by either antioxidant. Probucol lowered HDLand LDL-cholesterol levels and increased the QT interval. Forearm vascular responses, as measured by venous occlusion plethysmography, to acetylcholine, glyceryl trinitrate and NG-monomethyl-L-arginine, were not significantly changed by antioxidant treatment. Probucol has a major, and vitamin E a minor, effect on LDL resistance to oxidation but neither compound appears to alter forearm vascular responses in vivo.

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“…5% water was used with an ultraviolet detector set at 245 nm. A probucol analogue (MDL27272) was used as an internal standard [21].…”

Section: Other Laboratory Methodsmentioning

confidence: 99%

The effect of probucol and vitamin E treatment on the oxidation of low‐density lipoprotein and forearm vascular responses in humans

McDowell¹,

Brennan

McEneny³

et al. 1994

Eur J Clin Investigation

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“…Seven rabbits in the probucol group were fed a high cholesterol diet plus 1% (wt/wt) probucol. 29 Seven rabbits in the SM group were fed a high cholesterol diet plus 5% (wt/wt) SM. The selection of SM dose was based on its antioxidant activity comparable to that of probucol in Cu 2ϩ -induced LDL oxidation (see Table 1).…”

Section: Animal Treatmentmentioning

confidence: 99%

Increase of Vitamin E Content in LDL and Reduction of Atherosclerosis in Cholesterol-Fed Rabbits by a Water-Soluble Antioxidant-Rich Fraction ofSalvia miltiorrhiza

Wu¹,

Hong²,

Lin³

et al. 1998

ATVB

147

111

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Abstract-Antioxidants that prevent LDL from oxidation may reduce atherosclerosis. Salvia miltiorrhiza Bunge is a Chinese herb widely used for the treatment of atherosclerosis-related disorders. Salvianolic acid B (Sal B), a water-soluble polyphenolic antioxidant isolated from the roots of this plant, was found to scavenge 1,1-diphenyl-2-picrylhydrazyl radicals and inhibit LDL oxidation more effectively than probucol. In order to evaluate the antiatherogenic potential, New Zealand White rabbits were fed for 12 weeks a normal diet, a high cholesterol diet, a high cholesterol diet containing 1% probucol, or a high cholesterol diet containing a 5% water-soluble extract of S miltiorrhiza (SM). Both SM and probucol feeding reduced plasma cholesterol. LDLs from the SM-treated group were more resistant to Cu 2ϩ -induced oxidation and contained more vitamin E (21.7Ϯ2.1 nmol/mol LDL cholesterol) than did LDLs from the high cholesterol diet group (9.6Ϯ1.8 nmol/mol LDL cholesterol) (PϽ.005). Endothelial damage, determined at week 6, was reduced by 53% in the SM group (PϽ.01). SM treatment reduced the atherosclerotic area in the abdominal aorta by 56% (PϽ.005) and cholesterol deposition in the thoracic aorta by 50% (PϽ.005). The severity of atherosclerosis in the SM group was significantly reduced after adjustment by using cholesterol exposure as an index of the cholesterol-lowering effect. This study concludes that the reduction of atherosclerosis by SM relies not only on its cholesterol-lowering effect but more heavily on its antioxidant potential to prevent endothelial damage and inhibit LDL oxidative modification in hypercholesterolemic animals. (Arterioscler Thromb Vasc Biol. 1998;18:481-486.)

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“…The progression of atherosclerotic lesions is counteracted by antioxidants such as probucol [12,13] and the LDL isolated from antioxidant-treated animals shows a reduced susceptibility to in vitro oxidation [13].…”

mentioning

confidence: 99%

Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

Cominacini

Garbin

Pastorino³

et al. 1997

Diabetologia

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Low density lipoprotein (LDL) oxidation is believed to play an important role in the development of atherosclerotic plaques [1][2][3][4][5]. This view is supported by LDL with characteristics similar to those of oxidatively modified LDL being present in atheromatous lesions [6]. Studies in cultured cells have demonstrated that oxidized LDL is chemotactic for monocytes and stimulates monocyte endothelial cell interaction [7,8]. It can also cause initial endothelial cell damage and increase uptake by scavenger receptors on macrophages, leading to cholesterol accumulation and foam cell formation [7,9].Oxidative modification of LDL is not likely to occur in circulation [3]. In view of the difficulties in identifying oxidized lipoprotein in plasma, many workers have attempted to analyse the oxidation susceptibility of isolated LDL particles in vitro [10,11]. If LDL can penetrate macrophages only after its modification [3], the ability of LDL to resist oxidation could be an Diabetologia (1997) Summary Troglitazone is a new oral antidiabetic agent able to reduce lipid peroxidation. In this study we evaluated its effect on the susceptibility of LDL and HDL to in vitro oxidation induced by copper ions and endothelial cells. In Cu ++ -induced LDL modification, different amounts of troglitazone were added to aliquots of the same pool of plasma with subsequent ultracentrifuge separation of LDL and HDL. Differences in LDL and HDL susceptibility to in vitro oxidation with Cu ++ were studied by measuring the changes in fluorescence intensity (expressed as lag phase). LDL derived from plasma incubated with different amounts of troglitazone were also incubated with umbilical vein endothelial cells (HU-VEC), the modification being monitored by LDL relative electrophoretic mobility and fluorescence. During Cu ++ -and HUVEC-induced LDL oxidation, the decay rate of vitamin E, and the potency of troglitazone as a radical scavenger in comparison with vitamin E were also studied. Troglitazone determined a significant, dose-dependent decrease in Cu ++ -induced LDL and HDL oxidation. Incubation with HUVEC was also followed by a progressive, significant decrease of LDL relative electrophoretic mobility and fluorescence intensity. During Cu ++ -and HU-VEC-induced-LDL modification, troglitazone significantly reduced the rate of vitamin E decay. In this study we also demonstrated that under the same oxidative stress, troglitazone was much more potent as a radical scavenger than vitamin E. In conclusion, the results demonstrate that troglitazone can reduce LDL and HDL in vitro oxidation and that, during this process, it can protect vitamin E. In addition to ensuring blood glucose control, the drug may therefore be useful in inhibiting lipoprotein peroxidation. [Diabetologia (1997)

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Antioxidant activity of probucol and its analogs in hypercholesterolemic Watanabe rabbits

Cited by 113 publications

References 6 publications

The effect of probucol and vitamin E treatment on the oxidation of low‐density lipoprotein and forearm vascular responses in humans

The effect of probucol and vitamin E treatment on the oxidation of low‐density lipoprotein and forearm vascular responses in humans

Increase of Vitamin E Content in LDL and Reduction of Atherosclerosis in Cholesterol-Fed Rabbits by a Water-Soluble Antioxidant-Rich Fraction ofSalvia miltiorrhiza

Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

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