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PubMed2006

Probucol inhibits in-stent thrombosis and neointimal hyperplasia by promoting re-endothelialization.

BACKGROUND: Evidence suggests that delayed re-endothelialization is responsible for in-stent thrombosis. Probucol inhibits neointimal thickening in animals via enhanced re-endothelialization and is the only oral drug that consistently inhibits restenosis after coronary angioplasty in humans. Here, we examined the effects of probucol on re-endothelialization and neointimal formation in a stent model. METHODS AND RESULTS: New Zealand White rabbits were fed a hypercholesterolemic diet with probucol (1%) or without (control) (n=11 each) for 6 weeks. At 2 weeks, endothelial denudation and stenting of the iliac artery was performed. Iliac arteries were harvested at week 6, and stented segments sectioned and analyzed. Compared with control, probucol increased in-stent re-endothelialization (74+/-6% in controls versus 93+/-3% in probucol-treated; P=0.008), and decreased average luminal stenosis (58+/-27 versus 31+/-16%; P=0.01) and stent depth (619+/-310 versus 314+/-158 microm; P=0.009). Compared with control, probucol also decreased accumulation of macrophages in the neointima. Furthermore, none of the probucol-treated rabbits had in-stent thrombosis, whereas four of eleven control rabbits showed thrombosis (P=0.04). CONCLUSIONS: Probucol demonstrates anti-restenotic and appears to have anti-thrombotic properties that are likely related to its ability to promote in-stent re-endothelialization.

Animals↗
PubMed2005

Probucol attenuates oxidative stress and energy decline in isoproterenol-induced heart failure in rat.

In the present study, we examined whether the powerful antioxidant probucol (a clinically used lipid-lowering drug) would attenuate the oxidative stress and energy starvation in experimental model of heart failure (HF) using isoproterenol. Rats were injected subcutaneously with isoproterenol (2.4 mgkg-1) daily for 1 week, and then treated with probucol (61 mg/kg) daily for 2 weeks. Oxidative stress was assessed by measuring myocardial lipid peroxides level and antioxidant enzymes activities, glutathione peroxidase (GPx) and superoxide dismutase. In addition, cardiac metabolic damage was estimated by measuring myocardial ATP, ADP and AMP levels as well as ATP/ADP ratio. It was found that isoproterenol induced a significant increase in heart rate by approximately 30% as compared with the pre-value. These changes were significantly attenuated by post-treatment of rats with probucol. Also, isoproterenol induced several pathological changes including lymphocyte infiltration, myofibrillar hemorrhage and degeneration, and these changes were attenuated by probucol. In addition, animals treated with isoproterenol showed a significant increase in myocardial lipid peroxides level up to 163% and a significant decrease in myocardial GPx activity by 35% as compared with the control group. Probucol not only counteracted significantly the pronounced oxidative stress effect of isoproterenol but also it induced a significant increase in myocardial GPx as compared with the control group. The major new finding of the present study is that treatment with probucol induced a significant increase in myocardial ATP level (the source of energy) and ATP/ADP ratio. Moreover, there is a significant correlation between ATP/ADP ratio and myocardial probucol level. In conclusion, the cardioprotective effect of probucol in treatment of HF is a result of not only its antioxidant properties and an enhancement of endogenous antioxidant reserve (mainly GPx) but also an enhancement of myocardial energy state.

Animals↗
PubMed1998

Probucol treatment attenuates the aortic atherosclerosis in Watanabe heritable hyperlipidemic rabbits.

We examined the effect of probucol on the aortic atherosclerosis already developed in Watanabe heritable hyperlipidemic (WHHL) rabbits at the initiation of treatment. In WHHL rabbits treated with probucol for 5 months from 8 months old, the lesion area in the aorta was significantly (P < 0.05) reduced when compared with that in untreated animals as well as animals at age 8 months. In contrast, plasma cholesterol levels in the probucol-treated group and untreated group during the experiment were not significantly different. LDL prepared from rabbits receiving probucol for 5 months showed resistance to oxidation by copper ions. Plasma CETP activity was significantly (P < 0.05) increased by probucol treatment. An immunohistochemical study showed that macrophages were abundant in the atherosclerotic lesions of untreated rabbits whereas smooth muscle cells were predominant in lesions of probucol-treated rabbits. These results suggest that the atherosclerotic lesion in WHHL rabbits can regress when treated by probucol and that the attenuation of atherosclerosis in this animal involves effects of probucol other than a decrease in plasma cholesterol, for example anti-oxidant activity.

Actins↗
PubMed1997

Decrease in oral bioavailability of cyclosporin A by coadministration of probucol in rats.

To assess the pharmacokinetic interaction of cyclosporin A with probucol, we administered cyclosporin A (10 mg/kg body weight) to rats orally or intravenously with or without pretreatment of probucol (10 mg/animal, daily for 8 days). The whole blood cyclosporin A concentration-time curves after oral administration showed a 34% reduction in peak concentration and a 30% decrease in area under the blood concentration-time curve (AUC) by administration of probucol. No apparent change in elimination half-life or volume of the central compartment was observed with the treatment of probucol. After intravenous administration of cyclosporin A, the blood levels could be described by a two-compartment open model. No differences were observed in the AUC, elimination half-life or total clearance of cyclosporin A by the pretreatment of probucol. Calculated bioavailability following oral administration of cyclosporin A decreased by 33% with the treatment of probucol. These results suggest that probucol may not profoundly influence the disposition of cyclosporin A. Coadministration of probucol could decrease the fraction of absorbed cyclosporin A after oral administration.

Administration, Oral↗
PubMed1997

The effect of probucol on intimal thickening of autologous vein grafts in hyperlipidemic rabbit.

Probucol is used to treat hypercholesterolemia and also has an anti-atherogenic effect. The effects of probucol on intimal thickening of autologous vein graft in hyperlipidemic rabbits with poor distal run-off were investigated. A poor distal run-off model was prepared in the right hindlimb of 18 rabbits allocated to four groups depending on diet: normolipidemic commercial diet, (NL group, n = 5); hyperlipidemic diet (HL group, n = 5); commercial diet with 1% probucol (NP group, n = 4); and hyperlipidemic diet with 1% probucol (HP group, n = 4). After 4 weeks the femoral vein grafts were implanted into normal (n = 18) or poor (n = 18) runoff limbs. Vein grafts were harvested 4 weeks after implantation. Intimal thickening of the graft was measured and macrophages therein examined immunohistochemically. The serum cholesterol level was not reduced by probucol treatment. The mean flow rate of the graft was significantly reduced in the poor run-off limb. On histological examination intimal thickening in the poor run-off limb was significantly greater than that of controls, while intimal thickening in the HL and HP groups was enhanced compared with that in the NL and NP groups, respectively. Mean intimal thickening in each limb in HP group rabbits was significantly lower than that in HL rabbits (microm): control (HL/HP): 99.4(7.4)/58.8(0.7) (P < 0.05); poor run-off (HL/HP): 155.3(9.6)/130.3(7.3) (P < 0.O5). There was no difference between NL and NP (microm): control (NL/NP): 44.6(24.7)/31.5(12.8); poor run-off (HL/HP): 115.3(13.8)/97.5(34.0). In addition, enhanced intimal thickening due to poor distal run-off was not suppressed. Immunohistochemical staining showed intimal macrophage infiltration in the HL and HP groups; however, macrophage infiltration in grafts in the HP group was less than in the HL group. In conclusion, under hyperlipidemic conditions, probucol decreased intimal thickening enhancement of the vein graft, and suppressed intimal macrophage infiltration. These findings were similar to the anti-atherogenic effect of probucol in the native artery. Hence, probucol administration after vascular reconstruction with vein grafts in patients with hyperlipidemia may be beneficial.

Animals↗
PubMed1989

Effect of probucol on the physical properties of low-density lipoproteins oxidized by copper.

Human plasma low-density lipoproteins (LDL) were incubated with 10 microM probucol for 1 h at 37 degrees C. Probucol incorporation into the LDL was complete as judged by filtration through a 0.2-micron filter, ultracentrifugation, and gel filtration. LDL with and without probucol were incubated for up to 24 h with 5 microM Cu2+ at 37 degrees C. Copper oxidation increased the content of random structure in the LDL protein from 30% to 36% at the expense of beta-structure (which decreased from 22% to 16%) without a change in alpha-helical content as measured by circular dichroism spectroscopy. This loss of beta-structure was prevented by the presence of probucol in the LDL during the copper incubation. Probucol reduced the rate of increase of fluorescence during copper oxidation at 37 degrees C. After 6 h, the fluorescence intensity at 360-nm excitation and 430-nm emission was 30% less in probucol-containing samples. Probucol had no effect on the circular dichroic spectrum of LDL and only minimal effects (less than 5%) on the fluorescence emission spectrum at wavelengths below 500 nm. Two fluorescence peaks, with emission at 420 nm and excitation at 340 and 360 nm, are resolved in three-dimensional fluorescence spectra of oxidized LDL. Probucol reduces the intensity of both peaks equally. The binding of a highly reactive heparin (HRH) fraction to LDL was measured by titration of LDL with HRH in the presence of fluoresceinamine-labeled HRH. The decrease in fluorescence anisotropy of the labeled HRH is proportional to the concentration of bound HRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed2002

Evaluation of pharmacokinetic interaction between cyclosporin A and probucol in rats.

PURPOSE: The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. METHODS: The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. RESULTS: The area under the blood concentration-time curve (AUC) after the administration of Sandimmun (corn oil) and Neoral (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral (saline), it was unchanged. The terminal elimination rate constant was not affected by probucol in any type of cyclosporin A solution. The solubility of cyclosporin A or tacrolimus in water dropped to 49% or 16% of the respective control in the presence of probucol. CONCLUSION: The interaction between cyclosporin A and probucol is caused by the decreased absorption of cyclosporin A partly based on the lowered solubility in the presence of probucol.

Animals↗
PubMed2001

Effects of probucol on atherosclerosis of apoE-deficient or LDL receptor-deficient mice.

The effect of probucol on atheroma formation was evaluated using mouse models for atherosclerosis with different diet protocols. Dietary administration of probucol (0.5 %, wt/wt) for 12 weeks reduced total plasma cholesterol levels in both apolipoprotein E (apoE)-deficient mice fed a western diet and in low-density lipoprotein receptor (LDLR)-deficient mice fed a Paigen diet by 60 % and 30 % to 60 %, respectively. Probucol treatment also significantly reduced high-density lipoprotein (HDL) levels in apoE-deficient mice, but not in LDLR-deficient mice. Atherosclerotic plaques in the aortic sinus of probucol-treated apoE-deficient mice were two-fold larger than those in untreated apoE-deficient mice, while the lesions in probucol-treated LDLR-deficient mice were similar to those in untreated LDLR-deficient mice. A strong negative correlation between HDL cholesterol levels and lesion sizes at the aortic sinus was observed in apoE-deficient mice, but not in LDLR-deficient mice. Thus, in contrast to LDLR-deficient mice, probucol had a strong proatherogenic effect in the aortic sinus of apoE-deficient mice associated with the reduction of HDL levels in spite of the reduction of total plasma cholesterol levels. The varying effects of probucol on atherogenesis depend upon the portion of aorta and which animal model is evaluated, implicating that complex cellular events are involved in the effect of probucol.

Animals↗
PubMed1992

Effect of probucol on recovery from streptozotocin diabetes in rats.

The present study was conducted to see the effect of probucol on streptozotocin diabetes in rats. After 2 weeks of a 1% probucol diet, 35 or 50 mg/kg of streptozotocin were intravenously injected into male Wistar rats. All the rats became diabetic 2 days after treatment. Thereafter, in order to see the effect of probucol on spontaneous recovery from streptozotocin diabetes, 25 mg/kg of streptozotocin was injected into rats after two weeks of probucol diet and the diet was continued for additional two weeks. All the rats with a standard diet (group CS, n = 13) and 12 of 13 rats with probucol diet (group PS) became diabetic 2 days after streptozotocin injection. One rate from group PS did not develop diabetes. Two weeks after injection, only 4 of 13 rats in groups CS showed recovery, while 11 of 12 rats in group PS showed recovery from streptozotocin diabetes (p less than 0.05). The average blood glucose levels in group PS were significantly lower than group CS (10.5 +/- 4.6 vs 18.5 +/- 0.6 mM, p less than 0.05). In addition, the pancreatic insulin content of group PS was 8 times greater than that of group CS (0.75 +/- 0.24 vs 0.09 +/- 0.03 mmol/pancreas, p less than 0.01). Thus, the in vivo diabetogenic action of streptozotocin could not be reduced by pretreatment with probucol. However, recovery from streptozotocin diabetes was induced by subsequent treatment with probucol. The precise mechanisms for this phenomenon were not known; but the present findings suggest the protective effect of probucol on beta-cell damage induced by small dose of streptozotocin.

Animals↗
PubMed2006

Pretreatment with probucol attenuates cardiomyocyte apoptosis in a rabbit model of ischemia/reperfusion.

OBJECTIVE: Apoptosis plays an important role in ischemic reperfusion injury. Probucol is a hypolipidemic agent and has antioxidant activity, which may inhibit the oxidative modification of low-density lipoprotein cholesterol. Studies have demonstrated that probucol improves left ventricular function, prevents left ventricular dilatation, and reduces cardiac fibrosis. However, the exact mechanism of probucol on the cardioprotective effect is not known. The objective of the present study was to examine the effect of probucol on ischemia/reperfusion-induced cardiomyocyte apoptosis. MATERIAL AND METHODS: Thirty male New Zealand White rabbits were randomly divided into sham, control, and treated groups, each group comprising 10 rabbits. Before establishment of the ischemia/reperfusion model, animals in the treated group were additionally fed daily with probucol (1000 mg per day) for 4 weeks. In the sham group, the heart was exposed after the chest had been opened, but the coronary artery was not ligated. The animals were killed 150 min after the procedure. In the other two groups, the rabbits were subjected to 30-min of coronary occlusion followed by a 2-h reperfusion. A blood sample was drawn from the right atrium before the animal was killed. The apoptotic myocytes were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Expression of caspase-3 and mitochondrial cytochrome c release was detected by immunohistochemical analysis and Western blot analysis. The level of serum superoxide dismutase (SOD) was tested using the xanthine oxidase method, and the content of serum malondialdehyde (MDA) was measured by colorimetry. RESULTS: As compared with the sham group, the control group had a significantly higher apoptotic index ((32.48 +/- 4.56) % versus (0.56 +/- 0.18) %, p < 0.01) and serum MDA concentration (2.70 +/- 0.64 versus 1.06 +/- 0.46 micromol/L, p < 0.01), and a significantly lower serum SOD level (144.27 +/- 21.69 versus 204.64 +/- 16.67 microU/L, p < 0.01). Probucol pretreatment apparently caused a decrease in the apoptotic index ((21.64 +/- 3.08) %, p < 0.01 versus the sham or control group) and serum MDA concentration (1.95 +/- 0.51 micromol/L, p < 0.01 versus the sham or control group), and increased the levels of serum SOD (162.61 +/- 16.13 microU/L, p < 0.01 versus the sham group; p < 0.05 versus the control group). The caspase-3 activation and mitochondrial cytochrome c release in the control group were also higher than those in the treated group (p < 0.01). CONCLUSIONS: The present study shows that probucol attenuates ischemia/reperfusion-induced cardiomyocyte apoptosis. The protective effect of probucol on the myocardium may be partly due to its antioxidant activity.

Animals↗
PubMed1993

Preservation of endothelium-dependent relaxation in atherosclerotic rabbit aorta by probucol.

Oxidized low-density lipoproteins (LDL), which may play an important role in atherogenesis, inhibit endothelium-dependent relaxations of normal arteries in vitro. The effects of probucol, an inhibitor of LDL oxidation, on endothelium-dependent relaxations in thoracic aorta of rabbits that received a cholesterol-rich (0.5%) or standard diet for 10 weeks were determined. In some rabbits in each group, the diet was supplemented with probucol (1%) for the last 6 weeks. The cholesterol-rich diet markedly increased plasma cholesterol and resulted in increased plasma lipid peroxides. Probucol prevented the increase in lipid peroxides, but had no effect on plasma cholesterol. Rings of aorta were mounted in organ chambers for measurement of isometric tension and contracted with phenylephrine. Endothelium-dependent relaxations to acetylcholine and A23187 were significantly impaired in aortic rings from cholesterol-fed rabbits. Aortic rings from rabbits fed cholesterol and treated with probucol relaxed normally to both vasodilators. Relaxations to acetylcholine and A23187 were not significantly changed in rings from rabbits that received probucol-supplemented standard diet. Endothelium-independent relaxations to sodium nitroprusside (SNP) were not influenced by the cholesterol diet or probucol. Thus, probucol preserves endothelium-dependent relaxations of hypercholesterolemic rabbit aorta without reducing plasma cholesterol. As demonstrated by the reduction in plasma lipid peroxides, the effect of probucol may be related to its antioxidant properties and may imply that oxidized lipids have a role in endothelial cell dysfunction of atherosclerotic arteries in vivo.

Acetylcholine↗
PubMed2006

Probucol up-regulates paraoxonase 1 expression in hepatocytes of hypercholesterolemic rabbits.

Paraoxonase 1 (PON1), an HDL-associated enzyme, has anti-oxidative property. Probucol, a hydrophobic antioxidant drug, inhibits progression of atherosclerosis and post-angioplasty restenosis. However, the mechanism by which probucol affects atherosclerosis is not completely understood. Sixteen rabbits fed with high cholesterol diet for 8 weeks were randomly divided into two groups: (1) starch group (n = 8): maintained high cholesterol diet plus starch (500 mg/kg/d) for 6 weeks; (2) probucol group (n = 8): the same cholesterol diet plus probucol (500 mg/kg/d) for 6 weeks. Control group (n = 8) was fed with normal diet for 14 weeks. The classic in-situ two-step perfusion of the liver with collagenase IV was used to isolate the parenchymal hepatocytes. The total activity of superoxide dismutase (SOD) and malondialdehyde (MDA) and PON1 concentrations in serum were measured after 0, 8, and 14 weeks of feeding. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the mRNA expression of PON1. Compared with control group, rabbits fed with high cholesterol diet showed higher levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), all of which were significantly reduced by probucol. Probucol significantly decreased the MDA concentration but was ineffective on SOD activity. High cholesterol diet decreased serum PON1 concentration and down-regulated PON1 mRNA expression in hepatocytes. Probucol significantly increased serum PON1 level and up-regulated the mRNA expression of PON1 as compared with starch group (0.65 +/- 0.06 versus 0.46 +/- 0.05, P = 0.001). The PON1 concentration is negatively associated with MDA concentration (r = -0.86, P = 0.003) but not with the level of HDL-C. In conclusion, probucol decreased MDA concentration, and increased PON1 serum level as well as mRNA expression in hepatocytes, which may help us to understand its antioxidant and anti-atherogenic effects.

Animals↗
PubMed1996

Action of probucol in arteries from normal and hypercholesterolaemic rabbits.

1. The effect of probucol on the vascular reactivity of different arteries isolated from rabbits was studied as well as its effects on the development of atherosclerosis in a cholesterol-fed rabbit model. 2. Probucol 10(-6)-5 x 10(-4)M produced a concentration-dependent inhibition of the contractile responses induced by KCI (80 mM), the sequence for the IC50 was: mesenteric artery (5th branch, 4.8 +/- 2.6 x 10(-5) M) > aorta (8.2 +/- 2.3 x 10(-5) M) > femoral artery (> 5 x 10(-4) M). The response to noradrenaline was: mesenteric artery (5th branch, 4.2 +/- 1.3 x 10(-5) M) > aorta (3.2 +/- 3.0 x 10(-4) M) > femoral (> 5 x 10(-4) M). 3. In the aorta, probucol (10(-5)-10(-4) M) shifted the concentration-response curves to Ca2+ downward and to the right. 4. Probucol at 5 x 10(-5) M and 5 x 10(-4) M showed a reduction in the 45Ca2+ uptake in resting, non-stimulated aortic rings as well as the uptake induced by both noradrenaline 10(-6) M and KCI 80 mM. 5. In experiments in vivo, probucol did not affect lipid profiles; however, drug-treatment significantly decreased the cholesterol content of aortic tissue and the extent of intimal surface covered with atherosclerotic lesions. 6. The vascular reactivity was recovered in femoral arteries from rabbits on the atherogenic diet plus probucol. 7. It is concluded that the effect of probucol in vascular smooth muscle can be attributed to an inhibition of Ca2+ entry through both potential- and receptor-operated pathways. Moreover our findings suggest that the effects of probucol on movement of calcium in vascular smooth muscle may play an important role in the mechanism of antiatherogenic properties of this drug.

Animals↗
PubMed1991

The lowering effect of probucol on plasma lipoprotein and proteinuria in puromycin aminonucleoside-induced nephrotic rats.

Hyperlipidemia associated with nephrotic syndrome was treated with probucol and the changes in plasma lipoprotein lipid concentration and urinary protein excretion were examined in puromycin aminonucleoside-induced nephrotic rats. Rats made nephrotic exhibited severe hyperlipidemia with increases in all major lipoprotein fractions. Probucol treatment of nephrotic rats significantly lowered plasma triglyceride (TG), cholesterol (Ch) phospholipid (PL) and apoprotein B associated with very-low-density and low-density lipoprotein and Ch and PL in high-density lipoprotein (HDL). Malondialdehyde (MDA) associated with the lipoproteins was significantly elevated in nephrotic rats and probucol treatment also lowered MDA concentration in all major lipoproteins. In control rats probucol moderately, but significantly, reduced plasma TG and HDL-Ch concentrations. Proteinuria associated with nephrosis was decreased significantly by treatment with probucol. Probucol treatment did not affect blood urea nitrogen and plasma creatinine levels. A significant positive correlation existed between the amount of protein excreted in urine and the plasma lipid concentrations in all nephrotic rats, suggesting that the hypolipidemic effect of probucol may attenuate proteinuria associated with nephrosis. These results suggest that probucol may be a favorable treatment for hyperlipidemia associated with nephrotic syndrome.

Animals↗
PubMed1996

Probucol downregulates E-selectin expression on cultured human vascular endothelial cells.

Probucol, which inhibits monocyte adhesion, is a potent antioxidant to vascular endothelium in the cholesterol-fed rabbit. The accumulation of macrophages in the lesion is influenced by increased expression of specific adhesion molecules on vascular endothelial cells. We investigated the effect of probucol on the expression of cell adhesion molecules in cultured human umbilical vein endothelial cells (HUVECs). HUVECs were treated with lipopolysaccharide in the presence or absence of probucol (0 to 5 mumol/L) and assayed for the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin by cell-enzyme-linked immunosorbent assay. Probucol significantly downregulated the expression of E-selectin on HUVECs in a dose-dependent manner. In contrast, the expression of ICAM-1 was not affected. E-selectin but not ICAM-1 mRNA expression on HUVECs was also significantly inhibited by probucol in a dose-dependent manner. We also examined whether probucol affects cellular binding between the human monocytic cell line U937 and lipopolysaccharide-stimulated HUVECs by using an in vitro binding assay and found that probucol significantly suppressed their mutual binding in a dose-dependent manner. These data indicate a novel mechanism of action for probucol to reduce the development of atherosclerotic lesions in hyperlipidemic states.

Animals↗
PubMed1997

Long-term probucol treatment reverses the severity of myocardial injury in watanabe heritable hyperlipidemic rabbits.

We previously reported that administration of NO donors ameliorates the severity of myocardial injury in cholesterol-fed rabbits. We now evaluated the effects of probucol, a lipid-lowering antioxidant that can preserve endothelium-dependent relaxation (EDR), in the aortas of cholesterol-fed rabbits. We examined the effects of short-term (7 days) or long-term (24 weeks) administration of 1% probucol on the size of infarcts resulting from 30 minutes of coronary occlusion followed by reperfusion (for 48 hours) in Watanabe heritable hyperlipidemic (WHHL) rabbits. Infarcts in untreated WHHL rabbits were significantly larger than those in the rabbits receiving the long-term but not the short-term treatment with probucol (72.2 +/- 5.4%, 37.6 +/- 6.4%, and 66.7 +/- 3.5%, respectively). Long-term probucol treatment also significantly reduced myeloperoxidase activity in both ischemic and nonischemic myocardium and suppressed P-selectin expression in the coronary vasculature. No significant differences were observed in hemodynamic parameters during myocardial ischemia/reperfusion. Long-term probucol treatment significantly reduced the surface area of atherosclerotic plaque lesions in the aorta (24.4 +/- 3.8% vs 46.3 +/- 6.3, P < .05). Moreover, long-term probucol treatment restored acetylcholine-induced EDR in aortic rings but did not affect sodium nitroprusside-induced relaxation. Finally, long-term probucol treatment resulted in significantly elevated cGMP levels in the aorta. These results indicate that long-term probucol treatment significantly ameliorates myocardial injury in heritable atherosclerotic rabbits, perhaps by reducing the accumulation of leukocytes in the myocardium and atherosclerotic vascular lesions. Thus, long-term administration appears to suppress the progression of atherosclerotic vascular disease in this animal model.

Administration, Oral↗
PubMed2001

Effect of probucol in lecithin-cholesterol acyltransferase-deficient mice: inhibition of 2 independent cellular cholesterol-releasing pathways in vivo.

Cellular cholesterol release takes place by at least 2 distinct mechanisms: the lecithin-cholesterol acyltransferase (LCAT)-driven net efflux by cholesterol diffusion and the generation of high density lipoprotein (HDL) with cellular cholesterol and phospholipid on the cell-apolipoprotein interaction. Therefore, LCAT deficiency impairs the former pathway, and the latter can be inhibited by probucol, which interferes with the apolipoprotein-cell interaction. Hence, probucol was given to the LCAT-deficient mice in the attempt to suppress both of these pathways. The mice were fed low (0.2%) and high (1.2%) cholesterol diets containing 0.5% probucol for 2 weeks. LCAT deficiency and probucol markedly decreased plasma HDL, and the effects were synergistic. Tissue cholesterol content was lower in the adrenal glands and ovaries in the LCAT-deficient mice and in the probucol-treated mice, suggesting that HDL is a main cholesterol provider for these organs. It was also moderately decreased in the spleen of the low cholesterol-fed female mice and in the thyroid gland of the low cholesterol-fed male mice. On the other hand, the esterified cholesterol content in the liver was substantially increased by the probucol treatment with a high cholesterol diet in the LCAT-deficient mice but not in the wild-type mice. Among the groups, there was no significant difference in the tissue cholesterol levels in other organs, such as the liver, spleen, thymus, brain, erythrocytes, thyroid gland, testis, and aorta, resulting from either LCAT deficiency or probucol. Thus, the apolipoprotein-mediated mechanism plays a significant role in the export of cellular cholesterol in the liver, indicating that the liver is a major site of the HDL assembly. Otherwise, tissue cholesterol homeostasis can largely be maintained in mice even when the assembly of new HDL is inhibited by probucol in the absence of LCAT. Nonspecific diffusion of cholesterol perhaps adequately maintains the homeostasis in the experimental condition.

Animals↗
PubMed2004

Probucol protects against smooth muscle cell proliferation by upregulating heme oxygenase-1.

BACKGROUND: Evidence suggests that induction of heme oxygenase-1 (HO-1) inhibits proliferation of vascular smooth muscle cells and intimal thickening after arterial injury, and therapeutic molecules induce HO-1. Probucol is the only oral drug that inhibits restenosis in humans and intimal thickening in animals, although its underlying mechanism remains unclear. METHODS AND RESULTS: Aortas were harvested from New Zealand White rabbits fed normal or 0.75% (wt/wt) probucol-fortified chow, with or without endothelial denudation of the abdominal aorta on day 21, and analyzed for heme oxygenase and apoptosis. Uninjured aortas were harvested on day 21 and balloon-injured aortas on days 22 and 25. Probucol significantly increased mRNA of HO-1 assessed by real-time PCR and HO activity in aortas at all time points. Probucol also enhanced apoptosis of medial cells in the injured aorta, as evidenced by the TUNEL assay. Furthermore, probucol (100 micromol/L) increased HO-1 mRNA and HO activity when added to rabbit aortic smooth muscle cells (RASMCs) cultured in serum-free medium for 24 hours. Induction of HO-1 mRNA was inhibited by actinomycin D and was associated with inhibition of RASMC proliferation. This probucol-induced increase in HO-1 mRNA and inhibition of RASMC proliferation was prevented by the HO inhibitor Sn(IV) protoporphyrin or transfection with small interference RNA (siRNA) to knockdown HO-1, but not by inactive Cu(II) protoporphyrin or scrambled siRNA. CONCLUSIONS: Probucol induces HO-1, and this contributes to the inhibition of vascular SMC proliferation. This novel finding may explain how probucol inhibits restenosis and highlights HO-1 as a target for therapeutic intervention against occlusive vascular disease.

Animals↗