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PubMed1991

Effects of probucol on plasma lipoprotein subfractions and activities of lipoprotein lipase and hepatic triglyceride lipase.

The effects of 12 weeks treatment with probucol on plasma lipoprotein subfraction levels and on LPL and HTGL activities were investigated. Plasma VLDL-C, VLDL-TG, VLDL-apo B levels were not changed. Probucol significantly reduced plasma IDL-C and IDL-apo B levels by 26.7% and 23.8%, respectively. Plasma cholesterol and apo B levels of large light LDL (LDL1) were decreased significantly by 27.8% and 23.2% by probucol treatment. Plasma cholesterol and apo B levels of small heavy LDL (LDL2) remained unchanged. Probucol markedly reduced plasma HDL2 levels. The reduction rates of plasma TC, TG and apo A-I levels of HDL2 were 43.0%, 43.6% and 47.0%. Probucol significantly decreased HDL3-C and HDL3-apo A-I levels by 18.0% and 19.2%. LPL activities in the post-heparin plasma were decreased significantly from 2.53 +/- 0.71 mumol free fatty acids (FFA)/ml/h to 1.71 +/- 0.71 mumol FFA/ml/h by probucol while HTGL activities remained unchanged. We conclude that probucol suppresses LPL activity and decreases plasma IDL, LDL1 and HDL2 levels due to disturbances of VLDL conversion to LDL1 via IDL and of HDL3 conversion to HDL2.

Aged↗
PubMed1992

Inhibition of intimal thickening of the carotid artery of rabbits and of outgrowth of explants of aorta by probucol.

The effect of administration of probucol in preventing intimal thickening of rabbit carotid artery after balloon catheter injury and the mechanism of action of the drug were studied. Groups of 6 male New Zealand-White rabbits were given normal diet (Group I), high cholesterol diet (Group II) or high cholesterol diet plus probucol (Group III) for 4 weeks. Balloon catheter injury was made in week 2 and animals were killed in week 4. No significant differences in the total cholesterol levels in Groups II and III were found in week 4. The medians of areas of the intimal layer in cross-sections of the carotid arteries of Groups I, II and III were 0.237, 0.475 and 0.309 mm2, respectively. Thus high-cholesterol diet increased the thickness of the intimal layer and probucol reduced its effect. There were no significant differences in the areas of the medial layers in these 3 groups. For the examination of the mechanism of the effect of probucol, rabbits were given chow containing 0.5% cholesterol with and without 0.5% probucol (7 rabbits each) and then the numbers of explants from their aortas showing outgrowth were compared. The plasma total cholesterol levels of these two groups were the same. The probucol concentrations in the plasma and aorta of the former group were 18.6 +/- 13.2 micrograms/ml and 7.3 +/- 5.4 micrograms/g wet tissue, respectively. The number of explants showing outgrowth on day 14 was suppressed by 34% in the probucol-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The effect of probucol on HDL-mediated sterol translocation and efflux from cells.

It has been suggested that the antioxidant drug probucol can prevent arterial cholesterol accumulation in part by promoting HDL-mediated cholesterol removal from cells. In this study, the effect of probucol in vitro on the interaction of HDL3 with cultured skin fibroblasts, bovine aortic endothelial cells and human monocyte-derived macrophages was tested. Treatment of cholesterol-loaded cells with up to 20 microM probucol had no effect on [3H]cholesterol efflux from plasma membranes. No effect of probucol on HDL3-mediated efflux of labeled sterol was seen after intracellular sterol was labeled either with the biosynthetic precursor [3H]mevalonolactone or after incubation with lipoprotein-associated [3H]cholesterol linoleate. Further, no effect of probucol on cell cholesterol mass efflux was observed. Thus these results demonstrate that probucol does not affect movement of sterol from different cellular radiolabeled sterol pools. Within the limitations of cell culture studies, it is suggested that the proposed antiatherogenic effect of probucol in vivo is not likely to be the result of modulation of major cellular pathways for removal of cholesterol.

Animals↗
PubMed1992

Probucol and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit--long-term antiatherogenic effect and effects on established plaques.

We performed two studies to investigate the effect of probucol on atherogenesis in vivo in the Watanabe heritable hyperlipidemic (WHHL) rabbit. In the first study (Study A), probucol was administered to 2-month-old WHHL rabbits, to evaluate its long-term effect. When killed at about 1.5 years of age, the percentage area of aorta covered with atherosclerotic plaque in probucol-treated rabbits was markedly less than that seen in non-treated rabbits (23.0 +/- 11.4% vs. 87.7 +/- 8.1%, M +/- S.D., P less than 0.001). In the second study (study B), administration of probucol was commenced with 8-month-old WHHL rabbits to investigate whether the drug was effective for limiting atherosclerosis in rabbits in which plaques had already developed. When killed after 6 months of treatment, the percentage area of aorta covered with plaque was 38.1 +/- 12.1% in treated rabbits and 82.7 +/- 22.6% in non-treated rabbits (P less than 0.02). Microscopic observations of lesions also supported the effect of probucol. Probucol treatment resulted in a change not only in the size but also the composition of lesions. Thus, probucol was effective in preventing atherosclerosis in long-term studies at both early and late stages.

Animals↗
PubMed1992

Non-macrophage-related accumulation of cholesterol during probucol treatment in familial hypercholesterolemia: report of two cases.

Two patients receiving long-term (3-4 years) treatment with probucol for familial hypercholesterolemia (FH) developed diffuse yellow lesions over the upper eyelids suggesting lipid storage in those tissues (diffuse lipid-storage lesions). Interestingly, each patient had shown a substantial reduction in their cholesterol levels together with a marked regression of their tendon xanthomas or typical xanthelasmas during treatment. To evaluate the role of probucol in this unusual finding we conducted histological and immunochemical evaluations of the lesions (removed surgically) and compared them with those of a non-probucol-treated subject with FH and typical audinal xanthelasma. In both probucol-treated patients the lesions were filled with foam cells and contained large amounts of cholesteryl ester. However, immunochemical analysis of the lesions of one patient using anti-monocyte monoclonal antibody (HAM56) demonstrated that they were not composed of macrophage-derived foam cells in contrast to those of the non-probucol-treated subject which stained clearly with anti-monocyte monoclonal antibody. In each case the foam cells did not react with muscle-actin-specific monoclonal antibody (HHF35). It appears that non-macrophage-related diffuse lipid-storage lesions may occur even during treatment with probucol despite the reduction in cholesterol levels and the regression of xanthomas, suggesting that probucol may alter the distribution of cholesterol from the macrophage to other cells.

Adult↗
PubMed1995

Inhibitory effect of a single local probucol administration on neointimal formation in balloon-injured rat carotid artery.

The aim of this study was to determine whether a single local probucol administration could suppress neointimal formation in balloon-injured rat carotid artery. Rats were divided into four groups; (i) rats receiving no probucol (control group); (ii) rats receiving topical application of 50 mg probucol at the time of ballooning (p-top group); (iii) rats fed chow containing 1% probucol (p-fed group; (iv) rats receiving both topical application of 50 mg probucol and chow containing 1% probucol (p-top/fed group). Although serum total cholesterol levels did not significantly differ between the control and the p-top groups at two weeks after balloon injury, the p-top group had a smaller intimal/medial ratio or intimal area than the control group (0.97 +/- 0.11 vs. 0.53 +/- 0.08 or 0.15 +/- 0.02 mm2 vs. 0.08 +/- 0.02 mm2 respectively, P < 0.01). Neointimal formation was suppressed to a similar extent in the p-fed group, in which serum total cholesterol level was approximately 40% lower than that in the control group. Thus, a single local delivery of probucol can suppress neointimal formation in balloon-injured rat carotid artery without altering serum lipid level.

Administration, Topical↗
PubMed1991

Probucol attenuated hyperglycemia in multiple low-dose streptozotocin-induced diabetic mice.

The present studies were undertaken to examine the effects of probucol on the protection against pancreatic beta-cell damage by multiple low-dose streptozotocin (STZ: 40 mg/kg, ip). The degree of hyperglycemia at 7, 14 and 17 days after STZ injection was attenuated by probucol. Serum immunoreactive insulin (IRI) levels were increased in the rats fed probucol containing diet at Day 14 and 17. Serum IRI levels after intraperitoneal injection of 2.0 g/kg glucose was reduced in STZ mice and the reduction of serum IRI levels was attenuated in the rats fed probucol, accompanied with a significant reduction of the degree of hyperglycemia after bolus of glucose. Probucol attenuated the reduction of pancreatic IRI content by STZ. The percentage of Thy 1.2-positive splenocytes was increased by STZ and probucol reduced the percentage of Thy 1.2-positive splenocytes, although there were no differences in the populations of splenocytes, positive with Lyt 2 or L3/T4. These data suggest that probucol has a protective action against pancreatic insulitis by multiple low-dose STZ administration.

Administration, Oral↗
PubMed1996

Effects of probucol on hypercholesterolemia-induced changes in antioxidant enzymes.

Effects of high cholesterol diet (0.5% and 1%) on the activity of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px)] in the aortic tissue of rabbits were investigated in the absence or presence of probucol (0.5 gm/kg daily, orally). Five groups of ten rabbits each were studied. Group I, regular rabbit chow diet; Group II, chow + 0.5% cholesterol; Group III, chow + 0.5% cholesterol+probucol; Group IV, chow + 1% cholesterol and Group V, chow + 1% cholesterol+probucol. The aorta was removed at the end of 4 months for measurement of the antioxidant enzymes. An increase in activity of aortic antioxidant enzymes was noted in cholesterol-fed rabbits (Groups II and IV), being similar for SOD and catalase but higher for GSH-Px in Group IV as compared to Group II. Probucol was ineffective in altering this cholesterol-induced increase in enzyme activity except in Group III where it increased the activity of GSH-Px. These results suggest that aortic antioxidant enzymes are affected in hypercholesterolemia and that probucol is ineffective in altering the aortic antioxidant enzyme activity except GSH-Px activity which increased in 0.5% cholesterol-fed rabbits. The protective effects of probucol against hypercholesterolemic atherosclerosis may be partly due to an increase in the GSH-Px activity at low levels of hypercholesterolemia. At higher levels of hypercholesterolemia, the protective effects of probucol could be due to its antioxidant activity.

Animals↗
PubMed2006

Role of probucol in inhibiting intimal hyperplasia after coronary stent implantation: a randomized study.

BACKGROUND: Oxygen-free radicals can stimulate smooth muscle cell proliferation and may therefore be involved in the genesis of in-stent restenosis. Thus, treatment with probucol, a potent antioxidant agent that has been shown to reduce restenosis after balloon angioplasty, may be an effective strategy to prevent intimal hyperplasia after stenting. METHODS: In a prospective double-blind study, 59 patients submitted to coronary stent implantation were randomly assigned to treatment with either probucol (1 g/d) or placebo, starting two weeks before the procedure and continued for 6 months. The primary end point was the intimal hyperplasia volume at 6 months measured by intravascular ultrasound (IVUS) imaging. RESULTS: Of the 59 randomized patients, 54 underwent successful stent implantation, completed the follow-up period, and underwent repeat angiography, 6.1 +/- 1.1 months after the procedure. Volumetric IVUS analysis revealed similar intimal hyperplasia volumes (403 +/- 26.7 mm3 for probucol vs 44.8 +/- 28.3 mm3 for placebo) and percent volume obstruction of the lumen (30.4% +/- 14.5% for probucol versus 30.7% +/- 17.2% for placebo) in both groups. In addition, quantitative coronary angiography showed no differences in late loss (1.0 +/- 0.8 mm vs 1.1 +/- 0.8 mm), loss index (0.5 +/- 0.4 for both groups), or angiographic restenosis rates (19.4% vs 18.5%) between the probucol and placebo groups, despite the observation of significant changes in the lipid profile and in the plasma antioxidant defenses in patients receiving probucol. CONCLUSIONS: Treatment with the antioxidant probucol failed to reduce neointimal formation after coronary stent implantation as assessed by IVUS volumetric analysis.

Aged↗
PubMed1996

Probucol-associated tachyarrhythmic events and QT prolongation: importance of gender.

From published articles and adverse reactions reports filed with the FDA (available through the Freedom of Information Act), we analyzed occurrences of tachyarrhythmias and the magnitude of QTc prolongation associated with probucol therapy. Of 16 cases of tachyarrhythmic events reported in association with probucol, 15 (94%) occurred in women (p < 0.01 vs expected value of 58%). Tachyarrhythmias were specifically described as TdP in 11 (63%) cases, all women; additional potential contributory QT-prolonging factors (besides probucol) were not identifiable in 2 of the 11 cases. We also analyzed QTc responses in 359 probucol-treated patients, all having baseline QTc < or = 0.44 sec1/2. At doses of 500 to 1000 mg/day, probucol-associated prolongation of QTc to values > or = 0.45 sec1/2 was observed in 22% of women versus 7% of men (p < 0.001) and to values > or = 0.47 sec1/2 in 8% of women versus 2% of men (p < 0.03). Multivariate analysis identified baseline QTc (p < 0.0001) and female gender (p < 0.03), but neither age nor dose, as significant independent predictors of QTc prolongation to > or = 0.45 sec1/2 with probucol. These findings have relevance to the clinical use of probucol, provide further evidence that women have a relatively greater predisposition to development of acquired long QT syndrome, and carry implications for the design of trials involving QT-prolonging drugs.

Adult↗
PubMed1988

Increased levels of messenger ribonucleic acid for apolipoprotein E in the spleen of probucol-treated rabbits.

To study the organ-specific effect of probucol, a potent cholesterol-lowering drug, on apolipoprotein(apo)E synthesis, rabbit apoE complementary deoxyribonucleic acid (cDNA) clones were isolated and apoE messenger ribonucleic acid (mRNA) levels were determined in various tissues isolated from probucol-treated rabbits. A 0.54 kb apoE cDNA was cloned from a rabbit liver cDNA library using a synthetic oligonucleotide probe. The amino acid sequence deduced from an apoE coding region indicated 78% homology for human apoE and 63% homology for rat apoE. RNA blot analysis showed that apoE mRNA was most abundant in the liver, then in the brain and spleen. The relative amounts of apoE mRNA were determined in tissues of rabbits fed a normal diet, or high-cholesterol (1%) diet with or without probucol (1%). ApoE mRNA levels increased 2- to 4-fold in the spleen and brain after cholesterol feeding for 4 weeks and were higher by 52 to 70% in the spleen of probucol-treated rabbits than in nontreated rabbits. This induction of apoE mRNA occurs within 7 days after the initiation of probucol treatment. However, apoE mRNA levels in the liver, a major apoE-synthesizing organ, were not enhanced after probucol treatment. These results indicate that probucol induces apoE mRNA expression specifically in the spleen and may affect apoE-mediated lipoprotein metabolism, the so-called reverse cholesterol transport.

Amino Acid Sequence↗
PubMed2002

Comparison of antioxidant effects of naringin and probucol in cholesterol-fed rabbits.

BACKGROUND: Due to the strong evidence on the involvement of active oxygen species in a variety of disorders, the role of antioxidants against oxidative stress has recently received increased attention. METHODS: Twenty male rabbits were served a high-cholesterol (HC, 5 g/kg diet) diet or high-cholesterol diet supplemented with naringin (0.5 g/kg diet) or probucol (0.5 g/kg diet) for 8 weeks to compare the antioxidative effects of the citrus bioflavonoid (naringin) and antioxidative cholesterol-lowering drug (probucol). RESULTS: The plasma thiobarbituric acid-reactive substances (TBARS) concentration was not significantly different between the groups, whereas the hepatic TBARS concentration was significantly lower in the probucol group than in both normal and HC control or naringin group. Probucol and naringin supplementation led to an increase in the hepatic superoxide dismutase (SOD) and catalase (CAT) activities, and a decrease in the hepatic mitochondrial hydrogen peroxide (H(2)O(2)) content compared to the HC-control group. However, there was no difference in the cytosolic H(2)O(2) content or cytosolic glutathion peroxidase (GSH-Px) activity in the liver between the groups. Both naringin and probucol supplements significantly increased the plasma vitamin E concentration compared to the HC-control group. As regards the antioxidant enzyme gene expressions, naringin significantly increased the expression of three antioxidant enzyme mRNAs compared to the HC-control group, whereas probucol significantly increased the only SOD mRNA expression. CONCLUSIONS: The probucol supplement was very potent in the antioxidative defense system, whereas naringin exhibited a comparable antioxidant capacity based on increasing the gene expressions in the antioxidant enzymes, while also increasing the hepatic SOD and CAT activities, sparing plasma vitamin E, and decreasing the hepatic mitochondrial H(2)O(2) content.

Animals↗
PubMed1998

Effect of probucol on serum lipids, atherosclerosis and toxicology in fat-fed LDL receptor deficient mice.

Although numerous transgenic mouse models for atherosclerosis have been developed recently, little is known about their response to hypolipidaemic or anti-atherosclerotic agents. We investigated the effect of the known hypocholesterolaemic and anti-atherosclerotic drug probucol on serum lipids, lipoproteins and atherosclerosis in fat-fed low density lipoprotein (LDL) receptor deficient mice. Probucol at doses of 0.2 and 1% in the diet which are similar to those used in the mouse by other investigators reduced serum cholesterol by 26 and 37%, respectively. Probucol also reduced serum triglyceride levels by 33 and 47% at doses of 0.2 and 1%, respectively. The decrease in serum cholesterol and triglycerides was mainly due to a decrease of these lipids in VLDL and or chylomicrons. Despite these potentially beneficial changes in serum lipids atherosclerotic lesion areas in the aortic root were unchanged in the probucol treated mice. After 12 weeks treatment most of the mice receiving probucol had swollen feet and tails due to oedema. Histological examination of the base of the hearts from the probucol treated mice revealed lipid droplets within the reticuloendothelial and other interstitial cells. There was also an interstitial subacute inflammatory cell infiltration associated with the lipid deposition. The oedema induced by probucol could be the result of cardiac insufficiency due to interstitial lipidosis and inflammation in the base of the heart together with the extensive atherosclerotic lesions in the aortic sinus.

Animals↗
PubMed1999

Opposite effects on serum cholesteryl ester transfer protein levels between long-term treatments with pravastatin and probucol in patients with primary hypercholesterolemia and xanthoma.

Long-term effects of pravastatin and probucol on serum cholesteryl ester transfer protein (CETP) and xanthoma/xanthelasma size were compared. Twenty-three patients with primary hypercholesterolemia and xanthoma/xanthelasma, including 11 patients with heterozygous familial hypercholesterolemia, were treated with pravastatin (20 mg/day) or probucol (1000 mg/day) for 24 months. Serum CETP levels were measured by sandwich ELISA. In 11 patients (six men and five women, 55 +/- 2 [SE] yr) treated with pravastatin, serum cholesterol levels decreased from 262 +/- 13 to 229 +/- 13 mg/dl during the 24-month treatment period (P = 0.05). Serum HDL cholesterol levels were not changed. Serum CETP levels decreased from 2.5 +/- 0.2 to 2.0 +/- 0.2 microg/ml (-21%, P = 0.002). By contrast, in 12 patients (four men and eight women, 57 +/- 4 year) treated with probucol, serum cholesterol levels did not significantly decrease from 236 +/- 11 to 207 +/- 13 mg/dl. Serum HDL cholesterol levels decreased from 44 +/- 2 to 30 +/- 2 mg/dl (P = 0.009). Serum CETP levels increased from 2.3 +/- 0.1 to 2.8 +/- 0.2 microg/ml (+23%, P = 0.02). Xanthelasma regression was found in two of four patients (50%) each treated with pravastatin and probucol, respectively. In contrast, Achilles' tendon xanthoma regressed in four of five patients (80%) treated with pravastatin, but only in two of five patients (40%) treated with probucol. Patients with xanthoma/xanthelasma regression after 2 years treatment had higher baseline levels of serum CETP than those without regression (2.7 +/- 0.2 microg/ml [n = 9] versus 2.1 +/- 0.2 microg/ml [n = 7], P = 0.05). Serial changes in serum CETP levels during treatment with pravastatin and probucol were discordant, but not related to the degree of xanthoma regression. However, higher level of serum HDL3 cholesterol was an independent factor in the smaller size of Achilles' tendon xanthoma at baseline. In addition, higher levels of serum HDL3 triglyceride on lipid-lowering therapy (6 months) appear to be a common predictor of regression of Achilles' tendon xanthoma in the treatment with either pravastatin or probucol.

Achilles Tendon↗
PubMed2000

Probucol promotes reverse cholesterol transport in heterozygous familial hypercholesterolemia. Effects on apolipoprotein AI-containing lipoprotein particles.

In order to investigate the effect of Probucol therapy on reverse cholesterol transport, apo AI-containing lipoprotein particles were isolated and characterized, and their cholesterol effluxing capacity and LCAT activity were assayed in four familial hypercholesterolemia patients before and after 12 weeks of Probucol therapy. Four major subpopulations of apo A-containing lipoprotein particles are separated before and after drug treatment; LpAI, LpAI:AII, LpAIV, LpAI:AIV:AII. Probucol reduces both total plasma and LDL-cholesterol (-17 and -14%, respectively). Apo B decreases slightly (-7.6%). Plasma HDL-cholesterol and apo AI decrease by 36.6 and 34.7%. LpA-I showed a marked decrease (-46%). Moreover, plasma LCAT and CETP activities were markedly increased under Probucol treatment. Analysis of lipoprotein particles showed that Probucol induces a decrease of protein content and an increase of cholesterol and triglycerides contents. Interestingly, Probucol induces an enhancement of LCAT activity in LpAI (4.5-fold). This drug induces a trend toward greater cholesterol efflux from cholesterol-preloaded adipose cells promoted by Lp AI and Lp AIV but not by Lp AI:AII. This study confirms the hypothesis, in addition to the lowering LDL-cholesterol levels and antioxidant effects of Probucol, that HDL reduction was not an atherogenic change in HDL system but may cause an antiatherogenic action by accelerating cholesterol transport through HDL system, promoting reverse cholesterol transport from peripheral tissues.

Adipocytes↗
PubMed2003

The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: implications for Alzheimer's disease.

Several recent epidemiological studies have proposed that cholesterol-lowering drug Statin may provide protection against Alzheimer's disease (AD). Probucol is a non-Statin cholesterol-lowering drug and a potent inducer of apolipoprotein E (apoE) production in peripheral circulation. A recent clinical study using Probucol in elderly AD subjects revealed a concomitant stabilisation of cognitive symptoms and significant increases in apoE levels in the cerebral spinal fluid in these patients. To gain insight into the mechanisms underlying these effects, we treated a cohort of aged male rats (26-month-old) with oral dose of Probucol for 30 days. Specifically, we examined the effects of Probucol on apoE production and its receptors (low density lipoprotein receptor [LDLr] and low density lipoprotein receptor-related protein [LRP]), astroglial marker of cell damage (glial fibrillary acidic protein [GFAP]), markers of neuronal synaptic plasticity and integrity (synaptosomal associated protein of 25 kDa [SNAP-25] and synaptophysin) as well as cholesterol biosynthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase [HMGCoAr]) in the hippocampus. We report that Probucol induces the production of apoE and one of its main receptors, LRP, increases HMGCoAr (rate-limiting enzyme in cholesterol synthesis), substantially attenuates age-related increases in glial activation, and induces production of synaptic marker SNAP-25, a molecule commonly associated with synaptogenesis and dendritic remodeling. These findings suggest that Probucol could promote neural and synaptic plasticity to counteract the synaptic deterioration associated with brain aging through an apoE/LRP-mediated system. Consistent with the beneficial effects of other cholesterol-lowering drugs such as the Statin, Probucol could also offers additional benefits based on apoE neurobiology.

Aging↗
PubMed2002

Improved post-myocardial infarction survival with probucol in rats: effects on left ventricular function, morphology, cardiac oxidative stress and cytokine expression.

OBJECTIVES: The goal of this study was to evaluate whether reducing the potentially deleterious effects of oxidative stress with the potent anti-oxidant probucol improves prognosis after myocardial infarction (MI) in rats. BACKGROUND: Oxidative stress has been documented in patients early and late after MI, particularly when it is associated with congestive heart failure. METHODS: Rats surviving acute MIs for 24 h (n = 247) were assigned to vehicle or probucol (61 mg/kg, daily) for four weeks, at which time cardiac hemodynamic, morphologic and molecular measurements were done. RESULTS: In rats with large MIs, probucol improved survival (87.9%) when compared with vehicle (50.6%) (p < 0.001). Probucol also partially preserved left ventricular (LV) systolic but not diastolic function. Probucol increased scar thickness and decreased cardiac fibrosis but did not modify LV hypertrophy or dilation. Finally, probucol decreased cardiac oxidative stress, as assessed by measuring cardiac malondialdehydes, and decreased the cardiac expression of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-6 but did not modify fetal gene re-expression in rats with large MIs. CONCLUSIONS: This study indicates that the anti-oxidant probucol markedly improves post-MI survival in rats despite few demonstrable effects on cardiac remodeling or hemodynamics. Its beneficial effects may, however, be associated with reduced cardiac fibrosis, oxidative stress and expression of pro-inflammatory cytokines.

Animals↗
PubMed1998

Effect of probucol on smooth muscle cell proliferation and dedifferentiation after vascular injury in rabbits: possible role of PDGF.

We previously reported a clinical study in which probucol reduced the restenosis rate. The mechanism of this effect is unclear. Restenosis is characterized by neointimal hyperplasia caused by proliferation of smooth muscle cells (SMCs), which increases the expression of Platelet-derived growth factor (PDGF)-A and SMemb. SMemb, a non-muscle-type myosin heavy chain most predominantly expressed in embryonic smooth muscle, can be used as a good molecular marker for dedifferentiated SMC. The aim of this study was to analyze the effect of probucol on neointimal proliferation and the level of expression of PDGF-A and SMemb after balloon injury in rabbits. Probucol was given orally 1.3 g/d from 2 weeks prior to carotid balloon injury to the time of killing (2 or 4 weeks after balloon injury). Intimal area was determined histologically using a computerized morphometry program. For quantification of SMC proliferation, alpha-actin-positive cells and proliferating cell nuclear antigen (PCNA)-labeled cells were counted. The expression of PDGF-A and SMemb mRNA was analyzed by the RNase protection assay. SMemb expression was also examined by immunohistochemistry. Probucol remarkably decreased intimal area by 70% and the number of SMC and PCNA-labeled cells in the intima. The expression of PDGF-A mRNA was significantly increased after balloon injury in untreated rabbits, whereas it was markedly suppressed with probucol treatment. The expression of SMemb was significantly increased in injured arteries at mRNA and protein levels. However, probucol did not suppress SMemb expression. Probucol is effective in preventing SMC proliferation, which is possibly due to a decrease in the expression of PDGF.

Angioplasty, Balloon↗