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PubMed1997

Extent of antioxidant protection of plasma LDL is not a predictor of the antiatherogenic effect of antioxidants.

Oxidation of LDL plays all important role in atherogenesis. The lag-time in the formation of conjugated dienes provides a sensitive measure of the resistance of plasma LDL to oxidation and is widely assumed to be an indicator of atherogenic risk. To test this assumption, we investigated whether different antioxidants yielding similar lag-times result in similar reduction of atherosclerosis. A 6-months intervention study was carried out in three groups of 10 LDL receptor-deficient rabbits each. Because previous studies indicated that antioxidants that reduce atherosclerosis resulted in very long lag-times, the first group was treated with an antioxidant combination containing 1,000 IU vitamin E, 0.05% probucol analogue (BM15.0639), and 0.025% probucol. The lag-times achieved throughout the intervention period by this combination (952 +/- 39 min) were matched in a second group (829 +/- 46 min) treated with a variable dose of probucol (0.0575-0.11%, average 0.091%). A third, untreated group served as a control. Plasma cholesterol levels of all groups were matched. Even though both treatments yielded similar antioxidant protection of plasma LDL, 0.091% probucol reduced aortic atherosclerosis by 51.7% compared to the untreated group (P < 0.005), whereas the antioxidant combination failed to reduce lesion formation. Thus, the lag-time is clearly not correlated with the antiatherogenic efficacy of different antioxidants. However, a weak correlation was found within the group treated with probucol only. Our results suggest that the degree of antioxidant protection of plasma LDL may not be a good indicator of the atherogenic risk, in general, and that probucol reduces atherogenesis by mechanisms not shared by all antioxidants.

Animals↗
PubMed2004

Pravastatin has an additional depressor effect in patients undergoing long-term treatment with antihypertensive drugs.

BACKGROUND: Statins have been reported to have direct vascular effects independent of cholesterol reduction. To assess the antihypertensive effect of statins, a crossover study was designed to compare the depressor effect of pravastatin and probucol in hypertensive patients undergoing long-term treatment with antihypertensive drugs. METHODS: The subjects enrolled in this study were 52 hypertensive patients (22 men and 30 women, mean age 62.8 +/- 9.3 years) who were treated with the same antihypertensive drugs for more than 1 year and had serum cholesterol levels of more than 5.69 mmol/L. In 26 subjects, pravastatin at a dose of 10 mg/d was given first for 6 months followed by treatment with probucol at a dose of 500 mg/d, and vice versa in the remaining 26 subjects. Serum lipids, apolipoproteins, glucose, and insulin were measured on the final day of the control period, and pravastatin and probucol treatments. The homeostatic model assessment insulin resistance index (HOMA-IR) was used to assess insulin resistance. RESULTS: The blood pressure decreased after pravastatin treatment (141.2 +/- 4.7/81.3 +/- 4.9 to 136.5 +/- 5.3/80.6 +/- 5.1 mm Hg, P <.001/.499), but did not decrease after probucol treatment (141.2 +/- 4.7/81.3 +/- 4.9 to 141.4 +/- 4.9/80.8 +/- 4.9 mm Hg, P =.832/.634). Total cholesterol decreased significantly after pravastatin (6.69 +/- 0.69 to 5.23 +/- 0.77 mmol/L, P <.001) and probucol treatment (6.69 +/- 0.69 to 5.53 +/- 0.64 mmol/L, P <.001). The HOMA-IR was decreased by probucol (1.92 +/- 0.78 to 1.57 +/- 0.59, P =.029), whereas pravastatin had no effect on HOMA-IR. CONCLUSIONS: It can be concluded that the depressor effect of pravastatin may have an additional benefit in the treatment of hypertensive patients with hyperlipidemia without any adverse effect on insulin sensitivity.

Adult↗
PubMed1995

Effects of anti-oxidant treatment on sciatic nerve dysfunction in streptozotocin-diabetic rats; comparison with essential fatty acids.

In Study 1, the effects of treatment of streptozotocin-diabetic rats with the antioxidants, probucol or vitamin E were compared. Untreated diabetic rats showed a reduction of 45% (p < 0.01) in nerve laser Doppler flux, which was used as an index of nerve blood flow. In diabetic rats treated with either probucol or vitamin E nerve Doppler flux was reduced by only 13 or 16%, respectively (p < 0.01 for either compared to untreated diabetic rats). A second study examined the effects of treatment with evening primrose oil either alone or in combination with probucol. Reduced nerve Doppler flux was reproduced in untreated diabetic rats (47%; p < 0.01). In parallel diabetic groups, nerve Doppler flux was reduced by only 14% with evening primrose oil alone and by 8% with evening primrose oil plus probucol (both p < 0.01 vs untreated diabetic rats). Both treatments were also associated with marked attenuation of motor and sensory nerve conduction velocity deficits. Measurements on plasma from rats showed normalisation of triglyceride levels by probucol treatment without an effect on those of cholesterol in Study 1. In Study 2, the converse was true for evening primrose oil treatment, whilst the combined treatment lowered both plasma triglycerides and cholesterol. This work indicates similar effects of antioxidants and evening primrose oil against reduced nerve Doppler flux and conduction velocity in diabetic rats, with dissimilar actions on plasma triglycerides and cholesterol.

Animals↗
PubMed2006

Molecular interaction among probucol/PVP/SDS multicomponent system investigated by solid-state NMR.

PURPOSE: Effects of polyvinylpyrrolidone (PVP) molecular weight on the solid-state intermolecular interactions among probucol/PVP/sodium dodecyl sulfate (SDS) ternary ground mixtures (GM) and the formation of nanoparticles were investigated by solid-state NMR spectroscopy. MATERIALS AND METHODS: Ternary GMs of probucol were prepared with PVP (K12, K17, K30 or K90) and SDS at a weight ratio of 1:3:1 and were ground for 15, 30 and 60 min. Solid-state interactions were evaluated using powder X-ray diffraction (PXRD) and solid-state cross polarization/magic angle spinning (CP/MAS) (13)C NMR spectroscopy. A high resolution scanning electron microscopy (SEM) was employed to observe nanoparticles of probucol in the GM. RESULTS: The solid-state (13)C CP/MAS NMR results indicate that the low molecular weight PVP interacts with probucol and SDS more strongly than the high molecular weight PVP in the ternary GM. This finding was consistent with the result that smaller drug nanoparticles were obtained using low molecular weight of PVP. SEM images of probucol/PVP K12/SDS confirmed the presence of nanoparticles (15-25 nm) in the GM. CONCLUSIONS: Grinding-induced solid-state interactions among drug, PVP and SDS could be detected using solid state (13)C NMR. The interactions in both probucol-PVP and PVP-SDS should occur simultaneously to generate nanometer-sized particles of probucol.

Magnetic Resonance Spectroscopy↗
PubMed2005

Na+/H+ exchange inhibition and antioxidants lack additive protective effects after reperfusion injury in the working heterotopic rat heart isograft.

BACKGROUND: The utility of combining strategies of myocardial protection was studied in intact rat hearts subjected to 1 hour of ischemia and 40 minutes blood reperfusion. METHODS: Lewis rats (n = 48) were divided into 4 transplant groups. Twenty-four hearts were arrested by coronary perfusion with hypothermic Celsior solution at 60 mm Hg. The aortic valve was punctured to introduce volume into the left ventricle (LV), and the hearts were abdominally isografted. Animals were either given both the antioxidant probucol (300 mg/kg) and the sodium-hydrogen exchange inhibitor cariporide (5 mg/kg) (CP; n = 6), just cariporide (CAR; n = 6), just probucol (PROB; n = 6), or neither drug (CON; n = 6). After 40 minutes of blood reperfusion, transplanted hearts were rearrested. The control recipients' native hearts (native; n = 6) were also arrested. Postmortem LV compliance relations and myocardial water content (MWC) were measured. RESULTS: Grafts protected by probucol were significantly more compliant than controls and significantly less compliant than grafts protected by cariporide alone and with both cariporide and probucol (p = 0.0001, analysis of variance). Compliance relations for CP overlapped those for CAR. All grafts were less compliant than natives. MWC was significantly greater in controls and PROB than in natives. CONCLUSIONS: Pretreatment with cariporide in the setting of ischemia-reperfusion injury provides greater protection against the development of diastolic abnormalities than probucol when Celsior solution is used for both arrest and preservation. In this model, there is no advantage to combining the drugs, supporting the hypothesis that there is an overlapping mechanism of protection.

Animals↗
PubMed2000

Effect of vitamin E on the development of atherosclerosis.

The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidised low density lipoproteins. Some epidemiological studies have shown an association between high dietary intake or high serum concentrations of vitamin E and lower rates of ischemic heart disease. Recently, the Cambridge Heart Antioxidant Study (CHAOS) reported strong protection by high vitamin E doses against the risk of fatal and non fatal myocardial infarction. Here we have shown that incubation of vascular smooth muscle cells in the presence of alpha-tocopherol resulted in inhibition of cell proliferation and protein kinase C activity. Since beta-tocopherol and probucol are not inhibitory, the effect of alpha-tocopherol is considered due to a non-oxidant mechanism. In order to understand the protective role of alpha-tocopherol against atherosclerosis in vivo the following rabbit studies were carried out. Atherosclerosis was induced by a vitamin E poor diet containing 2% cholesterol in a group of rabbit. The other groups had 2% cholesterol in the diet plus 50 mg/kg vitamin E i.m. or 1% probucol or 50 mg/kg vitamin E plus 1% probucol. After 4 weeks, aortas were removed and analysed by microscopy for atherosclerotic lesions. Samples of the media were analysed for protein kinase C activity. The aortas of cholesterol-fed rabbits showed typical atherosclerotic lesions, detected by microscopic examination, their media smooth muscle cells exhibited an increase in protein kinase C activity. Vitamin E fully prevented cholesterol induced atherosclerotic lesions and the induction of protein kinase C activity while probucol was not effective. These results show that the protective effect of vitamin E against hypercholesterolemic atherosclerosis is not produced by an other antioxidant such as probucol and, therefore, may not be linked to the antioxidant properties of this vitamin. The effects observed at the level of smooth muscle cells in vitro and ex-vivo suggests an involvement of signal transduction events in the protective effect of vitamin E against atherosclerosis.

Animals↗
PubMed2001

A dynamic in vitro lipolysis model. II: Evaluation of the model.

A lipolysis model was characterised and evaluated by investigating the composition of the aqueous phase and the concentration of probucol and danazol in the aqueous phase. Effects of bile salt levels at 5, 10, 20, and 30 mM were investigated. Samples were taken at 0%, 50%, 75% and 95% hydrolysis of the triglycerides, and the aqueous phases were isolated by ultra-centrifugation, whereby the concentrations of bile salts, fatty acids, mono-, di-, triglycerides, and drug substances were measured. At high Ca(2+)-concentrations, bile salts were believed to precipitate with Ca(2+). The concentration of lipolytic products (fatty acids + monoglycerides) was dependent on the bile salt concentration. The ratio between lipolytic product and bile salts was 1.55+/-0.09 (S.D.). This ratio is equivalent to mixed bile salt micelles and vesicles in equilibrium. The aqueous solubility of probucol and danazol was increased in the presence of bile salts. The concentration of danazol in the aqueous phase was dependent on the solubilisation capacity of the aqueous phase. In the case of probucol, the concentration in the aqueous phase was dependent on the partition of probucol between the aqueous phase and the remaining triglyceride phase. This difference between danazol and probucol was attributed to the effect of different lipophilicity.

Bile Acids and Salts↗
PubMed2003

Selective inhibition of endothelial and monocyte redox-sensitive genes by AGI-1067: a novel antioxidant and anti-inflammatory agent.

Atherosclerosis is a disease of oxidative stress and inflammation. AGI-1067 [butanedioic acid, mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-,hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis (1,1-dimethylethyl)phenyl] ester] is a metabolically stable derivative of, yet pharmacologically distinct from, the antioxidant drug probucol. It is a member of a novel class of orally active, antioxidant, anti-inflammatory compounds termed vascular protectants and exhibits antiatherosclerotic properties in multiple animal models and in humans. To elucidate its antiatherosclerotic mechanisms, we have evaluated several cellular and molecular properties of AGI-1067 in vitro. AGI-1067 exhibited potent lipid peroxide antioxidant activity comparable with probucol yet demonstrated significantly enhanced cellular uptake over that observed with probucol. AGI-1067, but not probucol, inhibited basal levels of reactive oxygen species (ROS) in cultured primary human endothelial cells and both basal and hydrogen peroxide-induced levels of ROS in the promonocytic cell line, U937. Furthermore, AGI-1067 inhibited the inducible expression of the redox-sensitive genes, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1, in endothelial cells as well as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 production in peripheral blood mononuclear cells, whereas probucol had no effect. cDNA array hybridization experiments demonstrated that AGI-1067 selectively inhibited the expression of only a subset of TNF-alpha-responsive and nuclear factor-kappaB (NF-kappaB)-inducible genes in endothelial cells. The inhibitory effect of AGI-1067 on inducible VCAM-1 gene expression occurred at the transcriptional level, yet AGI-1067 had no effect on the activation of the redox-sensitive transcription factor NF-kappaB. These studies suggest that the anti-inflammatory and antiatherosclerotic properties of AGI-1067 may be due to selective inhibition of redox-sensitive endothelial and monocyte inflammatory gene expression. These studies provide a molecular basis for understanding the mechanism of action of this new class of therapeutic antiatherosclerotic compounds.

Active Transport, Cell Nucleus↗
PubMed1995

Effect of dietary antioxidants on the susceptibility to hepatic microsomal lipid peroxidation in the rat.

The inhibitory effect of probucol on ferrous-iron-induced microsomal lipid peroxidation was compared to that of alpha-tocopherol and butylated hydroxytoluene (BHT). Male Wistar rats were fed with diets containing 1% probucol, 0.2% BHT or 0.1% alpha-tocopherol for 30 days. There were no effects of dietary antioxidants on growth parameters, although liver weight was significantly higher in the BHT-fed rats. Probucol reduced serum levels of total and free cholesterol, while BHT feeding increased the concentrations of serum thiobarbituric-acid-reactive substances, HDL cholesterol and hepatic phospholipid. alpha-Tocopherol had no effect on these parameters. Incorporation of both, probucol and alpha-tocopherol, decreased the susceptibility of microsomes to lipid peroxidation in vitro, while BHT incorporation increased hepatic microsomal lipid peroxidation. These results suggest the possible usefulness of probucol for treatment of both hypercholesterolemia and elevated hepatic microsomal lipid peroxidation, while alpha-tocopherol decreases only an elevated lipid peroxidation. BHT works as a prooxidant.

Animals↗
PubMed1996

Effect of antioxidants alone and in combination with monounsaturated fatty acid-enriched diets on lipoprotein oxidation.

Previous studies have demonstrated that compared with more buoyant LDL, dense LDL (D-LDL) is more susceptible to oxidation and less readily protected from oxidation by antioxidant enrichment. However, diets enriched in monounsaturated fatty acids (MUFAs) appear particularly effective in protecting D-LDL from oxidation. We therefore evaluated in 12 non-insulin-dependent diabetes mellitus subjects the effects of supplementation with alpha-tocopherol (1600 IU/d) and probucol (1 g/d) alone and in combination with an MUFA-enriched diet on LDL and LDL subfraction susceptibility to oxidation and monocyte release of superoxide anion. Subjects received either alpha-tocopherol or probucol for 4 months, and during the fourth month both groups also received an MUFA-enriched diet. alpha-Tocopherol levels were significantly increased in LDL and LDL subfractions (P < .05) after 3 months of supplementation. MUFA-enriched diets led to further increases in alpha-tocopherol in LDL fractions in the alpha-tocopherol group as well as in those receiving probucol. In the alpha-tocopherol-supplemented group, lag times were increased significantly (1.6- to 2.0-fold) for all LDL fractions, although the absolute increase was least for D-LDL. Although probucol supplementation increased lag times of LDL and LDL subfractions three- to fourfold, D-LDL was still more readily oxidized. In both the alpha-tocopherol- and probucol-supplemented groups the benefit of adding MUFA-enriched diets was greatest for D-LDL, with further increases in lag time of 26% and 18%, respectively. Neither antioxidant supplementation nor the addition of an MUFA-enriched diet reduced unstimulated or phorbol ester-stimulated monocyte superoxide anion production. These data demonstrate the markedly different effects that antioxidants and diet may have on different LDL subfractions, which may be particularly important in individuals with non-insulin-dependent diabetes mellitus, who frequently have increased amounts of D-LDL.

Adult↗
PubMed1998

Vitamin E combined with selenium inhibits atherosclerosis in hypercholesterolemic rabbits independently of effects on plasma cholesterol concentrations.

Several antioxidants inhibit atherosclerosis. This study investigated the hypothesis that combining vitamin E, a lipophilic antioxidant, with vitamin C, a hydrophilic antioxidant, and/or selenium, a cofactor of peroxidases that detoxify lipid peroxides, would inhibit atherosclerosis more effectively than vitamin E alone. We also considered whether regional variation in inhibition of atherosclerosis by antioxidants would be associated with regional variation in aortic lipophilic antioxidants. Rabbits were fed an atherogenic diet (control) or an atherogenic diet supplemented with vitamin E, vitamins E and C, vitamin E+selenium, vitamins E and C+selenium, or probucol (positive control). Supplements were as follows: vitamin E, 146 IU/d; vitamin C, 791 mg/d; selenium, 22 microg/d; or probucol, 406 mg/d. Vitamin C did not influence atherosclerosis. After 22 weeks of treatment, rank order of aortic atherosclerosis was control>vitamin E (with or without vitamin C)>vitamin E+selenium (with or without vitamin C)>probucol. Antioxidant treatment reduced aortic cholesterol concentrations 21% to 56%, 29% to 86%, and 19% to 75% for the aortic arch, descending thoracic aorta, and abdominal aorta, respectively (P<0.025 to P<0.0003 by ANOVA), with slightly greatly reductions for areas of atherosclerotic lesions. Some treatments reduced plasma cholesterol concentrations, but none altered the distribution of cholesterol among lipoproteins. Corrected for differences in plasma cholesterol concentrations, aortic cholesterol concentrations were reduced up to 72% (P<0.02) by the antioxidant treatments, with equal reductions by vitamin E+selenium and by probucol. Aortic alpha-tocopherol standardized by aortic cholesterol as a measure of aortic lipids was lower in the abdominal aorta than in the aortic arch of rabbits not given alpha-tocopherol and increased relatively more in the abdominal aorta than in the aortic arch with alpha-tocopherol supplementation. The results of this study suggest that vitamin E+ selenium inhibited atherosclerosis as effectively as an equally hypocholesterolemic dose of probucol by a mechanism(s) that is in part independent of effects on plasma and lipoprotein cholesterol concentrations. The tendency for greater efficacy of antioxidant treatments in the abdominal aorta than aortic arch may relate to the lower concentrations of alpha-tocopherol in the abdominal aorta of unsupplemented rabbits.

Animals↗
PubMed2005

AGI-1067: a novel vascular protectant for prevention of restenosis.

OBJECTIVE: To review the synthesis, pharmacology, clinical trials, and adverse effects of AGI-1067, a novel agent for preventing restenosis. DATA SOURCES: Literature searches were conducted using MEDLINE (1966-July 2005) and International Pharmaceutical Abstracts (1970-July 2005) for English-language articles containing the search terms AGI-1067, AGI 1067, and probucol. In addition, bibliographies from relevant articles were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were reviewed for relevant information. Applicable information was included in this review. DATA SYNTHESIS: AGI-1067, a derivative of the lipid-lowering agent probucol, is the first of a new class of drugs termed vascular protectants. It has antioxidant and lipid-lowering effects. In addition, it inhibits inflammatory processes without resultant immunosuppression through its selective inhibition of vascular cell adhesion molecule-1 expression. AGI-1067 also exhibited anti-atherosclerotic effects in preclinical studies. Relatively short-term treatment with AGI-1067 showed positive results compared with probucol in preventing restenosis in patients undergoing percutaneous coronary intervention. AGI-1067 appears to be well tolerated and holds important advantages over probucol in that it has fewer adverse effects on high-density lipoprotein cholesterol and the QT interval. CONCLUSIONS: The favorable safety profile of AGI-1067 offers potential advantages over its precursor, probucol. Preclinical and clinical studies indicate that it possesses antioxidant, antiinflammatory, and lipid-lowering properties. Ongoing Phase II and III studies will determine AGI-1067's place in therapy for the prevention of restenosis and reduction in cardiovascular events in patients undergoing percutaneous intervention for coronary atherosclerosis.

Animals↗
PubMed2002

Prevention of restenosis with antioxidants: mechanisms and implications.

The aim of this review is to give an overview of the field of restenosis prevention with antioxidants, put in the perspective of their potential use for the prevention of atherosclerosis progression. Compelling evidence points to oxidative stress as an important trigger in the complex chain of events leading to atherosclerosis. There is also evidence that oxidative stress occurs early after angioplasty. Reactive oxygen species (ROS) can induce endothelial dysfunction and macrophage activation, resulting in the release of cytokines and growth factors that stimulate matrix remodeling and smooth muscle cell proliferation. The accumulation of new extracellular matrix and smooth muscle cells will result in the neointimal formation responsible for lumen narrowing after stent deployment and which contributes to that after balloon angioplasty. In addition, oxidation processes are involved in the cross-linking of collagen fibers, and this coupled with smooth muscle cell contraction and endothelial dysfunction may result in long-term vascular constriction or lack of adaptive vascular remodeling after balloon angioplasty. The powerful antioxidant probucol has been shown to prevent coronary restenosis after balloon angioplasty in the Multivitamins and Probucol (MVP) trial and other clinical studies. However, prolongation of the QT interval with probucol remains a long-term safety concern. AGI-1067, a metabolically stable analog of probucol, is a vascular protectant with strong antioxidant properties as potent to those of probucol. There has been no evidence of prolongation of the QT interval with AGI-1067 in initial clinical studies. The anti-restenosis properties of AGI-1067 are being assessed in the Canadian Antioxidant Restenosis Trial (CART)-1. Considering that oxidative stress and inflammation may persist for a prolonged period after stent placement, treatment with AGI-1067 for the entire period of risk after percutaneous coronary intervention (PCI) [instead of only 4 weeks in CART-1] may result in enhanced protection against luminal renarrowing. This hypothesis will be tested in the randomized, multicenter CART-2 trial. AGI-1067 has been effective at preventing atherosclerosis in all tested animal models, including the low density lipoprotein receptor-deficient and apo-E knockout mice. This has potentially important implications, as PCI and local approaches to prevent restenosis such as coated stents are not expected to prevent atherosclerosis progression, myocardial infarction and cardiovascular death. As the ultimate goal of therapy for patients with coronary artery disease must remain prevention of disease progression and atherosclerosis-related events, CART-2 will test the value of AGI-1067 for the reduction of both post-PCI restenosis and atherosclerosis progression.

Angioplasty, Balloon, Coronary↗
PubMed1999

Inhibition of VCAM-1 expression in the arterial wall is shared by structurally different antioxidants that reduce early atherosclerosis in NZW rabbits.

We previously established that probucol decreases basal expression of VCAM-1 in the aorta of WHHL rabbits and inhibits the up-regulation of VCAM-1 expression that normally accompanies atherogenesis. To determine whether this effect is shared by other antioxidants in vivo, we now investigated whether a structurally unrelated antioxidant, vitamin E, also inhibits arterial VCAM-1 expression and whether the degree of VCAM-1 inhibition correlates with the reduction of atherosclerosis or the antioxidant protection of LDL. Atherogenesis and VCAM-1 mRNA and protein were determined in four groups of NZW rabbits (n = 6;-8) fed 0.5% cholesterol alone or supplemented with 0.1% vitamin E, a low dose (0.04;-0.075%) of probucol yielding the same degree of antioxidant protection of plasma LDL as vitamin E, or a high dose (0.5%) of probucol, and in normocholesterolemic rabbits. After 81 days, extensive atherosclerosis and a greater than 4-fold up-regulation of VCAM-1 mRNA was seen in rabbits on high cholesterol diet, mostly in the intima. Treatment with vitamin E, high-dose probucol, and low-dose probucol significantly decreased VCAM-1 mRNA by 49.0, 74.9, and 57. 5%, respectively, and reduced atherosclerosis in adjacent segments of the thoracic aorta to a similar degree as reported by previous studies. Immunocytochemistry confirmed that lesions of antioxidant-treated animals also contained less VCAM-1 protein. Neither the degree of VCAM-1 inhibition nor the extent of atherosclerosis correlated with the degree of antioxidant protection of plasma LDL.In summary, treatment with structurally unrelated antioxidants conveyed different degrees of antioxidant protection to plasma LDL but significantly reduced VCAM-1 expression in vivo and inhibited atherogenesis. This is consistent with the assumption that antiatherogenic effects of antioxidants may in part be mediated by interference with oxidation-dependent intracellular signaling.

Animals↗
PubMed1997

Lipid lowering: an important factor in preventing adriamycin-induced heart failure.

The contribution of lipid lowering in protection against adriamycin cardiomyopathy achieved by probucol, an antioxidant and a lipid-lowering drug, was assessed by comparing its beneficial effects with that of lovastatin, another lipid-lowering drug with no known antioxidant properties. Adriamycin (cumulative dose, 15 mg/kg body weight) was given to rats in 6 equal injections (intraperitoneally) over a period of 2 weeks. Probucol (cumulative dose, 120 mg/kg body weight) or lovastatin (cumulative dose, 48 mg/kg body weight) was given in 12 equal injections (intraperitoneally) before and concurrent with adriamycin. After 3 weeks of post-treatment with adriamycin, congestive heart failure, ascites, congested liver, and depressed cardiac function were seen. Adriamycin treatment decreased glutathione peroxidase activity and increased lipid peroxidation. Adriamycin increased plasma triglycerides, total cholesterol, and high- and low-density lipoproteins. Myocardial triglycerides and total cholesterol were also increased. Probucol completely prevented the development of congestive heart failure and normalized myocardial and plasma triglycerides and total cholesterol, and significantly decreased plasma high- and low-density lipoproteins. Lovastatin significantly attenuated but did not completely prevent cardiomyopathic changes due to adriamycin. Lovastatin decreased plasma total cholesterol and low-density lipoproteins as well as myocardial triglycerides and total cholesterol. Plasma triglycerides and high-density lipoproteins were still high in the adriamycin plus lovastatin group. Probucol improved glutathione peroxidase activity and reduced lipid peroxidation whereas lovastatin had no effect on these adriamycin-induced changes. These data suggest that adriamycin cardiomyopathy is associated with an antioxidant deficit as well as increased myocardial and plasma lipids. Complete protection by probucol against adriamycin-induced congestive heart failure may be due to the unique combination of its antioxidant and lipid-lowering properties.

Animals↗
PubMed1997

Increased oxysterol contents in diabetic rat hearts: their involvement in diabetic cardiomyopathy.

BACKGROUND: Abnormal lipid metabolism associated with diabetes mellitus has been proposed to be involved in the pathogenesis of diabetic cardiomyopathy. Oxysterols, oxidation derivatives of cholesterol, are known to be highly cytotoxic. OBJECTIVE: To monitor changes in myocardial oxysterols and to assess the effect of probucol, a lipid lowering agent, on myocardial lipids and oxysterols in diabetic rats. METHODS AND RESULTS: Streptozotocin-induced diabetic rats were divided into two groups; one group was put on a standard diet, and the other a diet containing 1% (weight/weight) probucol for eight weeks. Two oxysterols, 7 beta-hydroxycholesterol and 7-ketocholesterol, were identified in myocardium by capillary gas chromatography. Both 7 beta-hydroxycholesterol and 7-ketocholesterol were significantly increased in diabetic rats (49.9 +/- 9.4 ng/mg dry weight versus 5.8 +/- 1.2 in controls, P < 0.05; and 5.3 +/- 1.2 ng/mg dry weight versus 1.7 +/- 0.1 in controls, P < 0.01, respectively). Probucol reduced not only plasma lipids but also myocardial lipids except for cholesterol and sphingomyelin fractions. However, probucol did not improve insulin deficiency, glucose metabolism or myocardial oxysterol contents. CONCLUSIONS: This study demonstrated an increase in oxysterols in the myocardium of diabetic rats, suggesting that oxysterols may play a role in the development of diabetic cardiomyopathy. Probucol did not decrease the myocardial oxysterol content at the dose used in this study, suggesting that the increase in oxysterols may not be attributed to high circulating concentrations of lipids, but rather to disturbed myocardial metabolism due to insulin deficiency.

Animals↗
PubMed2005

Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy.

The current study investigated the phosphorylation of mitogen-activated protein kinases (MAPKs) as well as pro- and anti-apoptotic proteins in adriamycin (ADR)-induced cardiomyopathy (AIC) and heart failure in rats. Modulatory effects of antioxidant probucol on the activation of MAPKs were also examined. Male rats were administered with ADR (15 mg/kg body wt ip, over 2 wk) with and without probucol (120 mg/kg body wt for 4 wk ip). Hearts from these animals were studied at 1- to 24-h as well as at 3-wk posttreatment durations. In the 3-wk group, ADR depressed cardiac function, increased left ventricular end-diastolic pressure (LVEDP), and caused dyspnea and mortality. These changes were prevented by probucol. Phosphorylation of extracellular signal-regulated kinase (ERK)1/2, in the early stage of AIC, showed a biphasic response, with a maximum increase to 513% seen at 4 h, followed by a decrease to 66.8% at 3 wk after the last injection of ADR. Phosphorylation of p38 and c-Jun NH(2)-terminal kinases (JNKs) showed a steady increase through 2, 4, and 24 h and 3 wk (116% to 148%). In gene microarray analysis at 3 wk (heart failure stage), mRNA expression for both ERK1/2 and p38 kinases was decreased, whereas JNK mRNA was undetectable. Probucol completely prevented these MAPK changes. Activation of caspase-3 as well as the increase in the ratio of Bax to Bcl-xl were seen at early time points (1-24 h) as well as in the heart failure stage (3 wk). It is suggested that a transient increase in ERK1/2 at a shorter interval indicate an early adaptive response, and failure of this response corresponded with heart failure. In contrast, a gradual and persistent increase in p38 and JNK MAPKs as well as in caspase-3 and the Bax-to-Bcl-xl ratio may contribute in the initiation of apoptosis and progression of heart failure. Because probucol modulated changes in cellular signaling pathways and cardiac function, it is likely that oxidative stress plays a key role in AIC and heart failure.

Animals↗
PubMed1992

[Studies on atherosclerosis with an animal model].

Atherosclerosis is a fundamental cause of life-threatening disorders, such as ischemic heart disease or stroke. Therefore, prevention and treatment of atherosclerosis is a matter of importance. In atherosclerotic lesions, there are many foam cells which contain large amounts of cholesteryl ester. In particular, most of these foam cells in the early stage of atherosclerosis derive from monocytes/macrophages. Today, foam cell transformation of macrophages in subendothelial space is considered to occur by a mechanism in which macrophages take up oxidized low density lipoprotein. We have already discovered that atherosclerosis of Watanabe heritable hyperlipidemic rabbits, an animal model for hereditary hyperlipidemia and severe atherosclerosis, could be prevented by probucol. This drug was originally developed as an antioxidant, and the mechanism of prevention of atherogenesis with this drug is considered that it prevents oxidative modification of LDL. On the other hand, probucol also causes regression of xanthoma in patients with familial hypercholesterolemia. This effect implies that probucol can be effective for treatment of atheromatous lesions, because xanthoma is a lesion which consists of macrophage-derived foam cells. However, the precise mechanism of probucol in causing regression of xanthoma has not been clarified. Considering these observations, we paid special attention to the oxidative modification of high density lipoprotein (HDL). HDL makes contact with foam cells in subendothelial space and stimulates efflux of cholesterol. This is the very place where oxidative modification of LDL is considered to occur. Therefore, it is rational to attempt to determine what would happen when HDL is oxidized and whether probucol could prevent oxidative modification of HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗