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PubMedDate not supplied

Effects of probucol on vascular remodeling after coronary angioplasty. Multivitamins and Protocol Study Group.

BACKGROUND: We have shown that probucol reduces restenosis after balloon angioplasty. Whether probucol acted via prevention of neointimal formation or improvement in vascular remodeling could not be addressed by angiography and required the use of intravascular ultrasound (IVUS). METHODS AND RESULTS: Beginning 30 days before angioplasty, 317 patients were randomly assigned to receive probucol, multivitamins, combined treatment, or placebo. Patients were then treated for 6 months after angioplasty. IVUS examination was performed immediately after angioplasty and at follow-up in 94 patients (111 segments). The cross section selected for serial analysis was the one at the angioplasty site with the smallest lumen area at follow-up. In the placebo group, lumen area decreased by -1. 21+/-1.88 mm2 at follow-up, and wall area and external elastic membrane (EEM) area increased by 1.50+/-2.50 and 0.29+/-2.93 mm2, respectively. Change in lumen area, however, correlated more strongly with the change in EEM area (r=0.53, P=0.002) than with the change in wall area (r=-0.13, P=0.49). Lumen loss was -1.21+/-1.88 mm2 for placebo, -0.83+/-1.22 mm2 for vitamins, -0.25+/-1.17 mm2 for combined treatment, and -0.15+/-1.70 mm2 for probucol alone (P=0.002 for probucol, P=0.84 for vitamins). Change in wall area was similar for all groups. EEM area increased by 0.29+/-2.93 mm2 for placebo, 0. 09+/-2.33 mm2 for vitamins only, 1.17+/-1.61 mm2 for combined treatment, and 1.74+/-1.80 mm2 for probucol only (P=0.005 for probucol). CONCLUSIONS: Lumen loss after balloon angioplasty is due to inadequate vessel remodeling in response to neointimal formation. Probucol exerts its antirestenotic effects by improving vascular remodeling after angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1986

Mode of action of probucol in reducing serum cholesterol in mice.

The mode of action of probucol in reducing serum cholesterol was studied in normal and cholesterol-fed mice. Probucol did not affect intestinal absorption of radioactive cholesterol in normal and cholesterol-fed mice. In normal mice, probucol treatment resulted in inhibition of incorporation of [14C]-acetate into cholesterol in the liver, while it stimulated the incorporation in the small intestines. Incorporation of [14C]-mevalonate into cholesterol was not affected by the treatment. These results were consistent with the finding that the HMG-CoA reductase activity was decreased in the liver, but increased in the intestinal tissues of the treated mice. In cholesterol-fed mice, probucol treatment had no effect on cholesterol synthesis in the liver, while it increased the intestinal cholesterol synthesis. The over-all effect of this drug on cholesterol synthesis was not significant, although it tended to be inhibitory in normal mice and stimulatory in cholesterol-fed mice. On the other hand, probucol treatment resulted in acceleration of the clearance of [14C]-cholesterol-derived radioactivity from the circulation and resulted also in a significant increase in fecal excretion of the radioactivity, cholesterol and bile acids without changes in lipid composition of the bile. Cholesterol content in and radioactivity distribution among the tissues were not affected by probucol. Hepatic cholesterol 7 alpha-hydroxylase activity was increased by probucol. These findings indicate that probucol lowers serum cholesterol mainly by increasing catabolic excretion of cholesterol into bile.

Animals↗
PubMed2002

Effects of plaque composition on vascular remodelling after angioplasty in the MultiVitamins and Probucol (MVP) trial.

BACKGROUND: The antioxidant probucol reduced coronary restenosis in the MultiVitamins and Probucol (MVP) trial by improving vascular remodelling. Whether calcification limits the extent of adaptive vessel enlargement is not known. OBJECTIVE: To determine whether plaque composition at the dilated site affects probucol-induced vascular remodelling after angioplasty. PATIENTS AND METHODS: Beginning 30 days before percutaneous transluminal coronary angioplasty (PTCA), 317 patients received either probucol, vitamins, probucol and vitamins, or placebo. Patients were then treated for six months after PTCA. Intravascular ultrasound (IVUS) was performed post-PTCA and at follow-up in 94 patients (111 segments). The cross-section for serial analysis was the one at the angioplasty site with the smallest lumen area at follow-up. Quantitative analysis consisted of measurements of lumen area and external elastic membrane (EEM) area. The selected cross-section was also divided into five regions according to the type of plaque present (calcific, fibrotic, hypoechoic, fibrohypoechoic or normal). Plaque characterization scores (PCS) (PCS for arc, area, inner perimeter and outer perimeter) were calculated using weighting factors. RESULTS: There were no interactions between potential PCS covariates and probucol main effect on changes in lumenal, EEM and wall area. There were no significant PCS covariates in the model for change in EEM as they were all removed using a backward stepwise procedure. The last potential covariate (area PCS) had a significance level of P=0.48. In contrast, probucol significantly influenced the change in EEM over time (P=0.003). CONCLUSION: Plaque composition at the dilated site does not appear to influence probucol-induced vascular remodelling after angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1992

Effects of probucol in renal function and structure in rats with subtotal kidney ablation.

Probucol is a bisphenolic compound that lowers serum cholesterol and also has potent antioxidant properties. The present studies examined the effects of probucol administration on renal function and structure in a rat model of subtotal renal ablation. After subtotal nephrectomy, rats were fed an isocaloric rat chow diet containing 22.8% protein with or without the addition of 1% probucol. After 4 weeks, clearance studies were performed for determination of glomerular filtration rate (inulin clearance) and effective renal plasma flow (paraaminohippurate clearance). After completion of clearance studies and measurements of arterial blood pressure, the animals were exsanguinated and renal tissue was obtained for histologic evaluation. There were no differences in body weight, hematocrit, and blood pressure between the two groups of rats 4 weeks after subtotal nephrectomy. Rats with a remnant kidney given probucol had a significantly lower serum cholesterol level (47.4 +/- 5.3 mg/dl vs 87.2 +/- 10.4 mg/dl) and urea nitrogen level (40.7 +/- 3.2 mg/dl vs 63.6 +/- 8.1 mg/dl) than the control group. Rats given probucol also had significantly greater values for inulin clearance and clearance of paraaminohippurate and significantly less proteinuria than control rats. Also, rats with a remnant kidney given probucol had a significantly greater number of normal glomeruli (6.2% +/- 2.1% vs 1.1% +/- 0.9%) and a lesser number of severely affected glomeruli, grades III and IV (26.0% +/- 5.9% vs 50.9% +/- 9.1%) than rats with a remnant kidney not given probucol. Tubulointerstitial changes also were significantly less in rats with a remnant kidney given probucol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

In vitro studies on the distribution of probucol among human plasma lipoproteins.

The role of human plasma lipoproteins as carriers in the blood transport of the cholesterol-lowering and water-insoluble drug, probucol, was investigated in in vitro studies. [14C]Probucol was incubated in whole human blood, a serum pool, individual diluted sera, and isolated protein and lipoprotein fractions. In whole blood, about 90% partitioned in plasma. Following ultracentrifugal fractionation of the serum, it was found that less than 5% distributed in the d greater than 1.20 protein fraction (albumin-rich fraction) and more than 95% in the lipoprotein fractions. The distribution of probucol in the lipoprotein fractions correlated with the lipoprotein total lipid volume under saturation conditions (incubation of isolated lipoprotein fractions) as well as nonsaturation conditions (fractionation of serum exposed to [14C]probucol). Incubation of the albumin-rich fraction and of apolipoproteins originating from the isolated lipoprotein fractions showed that they account for a negligible part in the interaction of probucol with blood components. The probucol uptake of individual sera was shown to be correlated to the lipid content of the serum. When probucol was incubated in erythrocyte suspensions containing variable amounts of lipoproteins, probucol partitioned less in erythrocytes as the lipoprotein concentration increased in the suspension.

Apolipoproteins↗
PubMedDate not supplied

Interaction between probucol and cyclosporine in renal transplant patients.

OBJECTIVE: To investigate a possible interaction between probucol and cyclosporine during coadministration. DESIGN: Before/after trial of 15 weeks' duration. SETTING: Clinical pharmacokinetics laboratory of a teritiary care center. PATIENTS: Ten renal transplant patients who were immunosuppressed with cyclosporine therapy for at least six months and who had been receiving probucol for more than eight weeks. METHODS: Patients continued to receive probucol during the first five weeks of the trial (phase A). Probucol then was discontinued until the end of the trial (phase B). Blood samples from each patient were collected at weekly intervals during phase A and again during the last five weeks of phase B. Samples were assayed by fluorescence polarization immunoassay (TDx) to determine trough concentrations of the cyclosporine parent compound in whole blood, and of cyclosporine and metabolites in whole blood and in plasma. Comparison of the data was performed using a paired t-test. RESULTS: An increase in trough concentrations of cyclosporine was observed in phase B (without probucol) with respect to phase A (with probucol). These differences were statistically significant for the cyclosporine parent compound in whole blood (p = 0.02), and for cyclosporine and metabolites in whole blood (p = 0.02) and in plasma (p = 0.001). CONCLUSIONS: When cyclosporine and probucol are coadministered in transplant patients, a close monitoring of cyclosporine concentrations is advised because probucol can induce a decrease in trough concentrations of cyclosporine.

Adult↗
PubMed1996

The effect of probucol on low density lipoprotein oxidation and femoral atherosclerosis.

The Probucol Quantitative Regression Swedish Trial (PQRST) investigated the effect of the lipid lowering and antioxidant drug probucol on the development of atherosclerosis in humans. 303 hypercholesterolemic patients were randomized to receive either probucol or placebo, in combination with dietary advice and cholestyramine for a three-year period. Probucol was not found to effect progression regression of femoral atherosclerosis significantly as assessed by quantitative arteriography. To evaluate the effectiveness of probucol as an antioxidant during the study period, detailed analyses were performed on 42 of the randomized patients. During the trial, probucol-treated patients (n = 26) had 15% lower total cholesterol (P < 0.01) and 35% lower high density lipoprotein (HDL) cholesterol (P < 0.0001) compared with controls (n = 16). Low density lipoprotein (LDL) from probucol treated individuals was more resistant to oxidation by Cu2+ as determined by the lag phase for the formation of conjugated dienes (220 +/- 8 vs. 82 +/- 7 min (mean +/- S.E)), showed a 13 times lower formation of lipid peroxides, a 97% reduction in macrophage degradation and close to 90% less decrease in LDL receptor binding following oxidation as compared with controls (P < 0.001 for all differences). The results demonstrate that although probucol provided a significant protection against Cu(2+)-induced oxidative modification of LDL, it lacked effect on the development of femoral atherosclerosis. The relevance of these observations for the proposed role of lipid oxidation in atherosclerosis is discussed.

Adult↗
PubMed1999

Sustained Intramural Retention and Regional Redistribution Following Local Vascular Delivery of Polylactic-Coglycolic Acid and Liposomal Nanoparticulate Formulations Containing Probucol.

BACKGROUND: Probucol reduces restenosis after angioplasty, provided oral administration is begun 1 month before the procedure. Local vascular delivery of a nonoparticulate formulation of probucol may obviate the need for drug loading by acutely raising arterial intramural concentration while providing sustained intramural retention. To test this hypothesis, we compared the retention and redistribution of (35)S-probucol encapsulated in either liposomal or polylactic-coglycolic acid (PLGA) nanoparticles after local vascular delivery. METHODS: Nanoparticles were delivered using a Crescendo microporous infusion catheter (Cordis, Warren, NJ) after balloon angioplasty of rabbit iliac arteries (n = 12-18 arteries per formulation per time point). Animals were euthanized on day 0, 3, or 7 after delivery. Iliac arteries, perivascular fat, and downstream tissues were harvested and the radioactivity disintegrations per minute was measured. Autoradiographic and confocal microscopic analyses of tissue sections were performed to evaluate intramural distribution of probucol. RESULTS: Immediately after delivery, radioactivity in the iliac arteries (log[dpm/mg], mean +/- SEM) was greater with PLGA (2.72 +/- 0.08) than with liposomal encapsulation (2.10 +/- 0.08, P = 0.001). Intramural retention of probucol was 23% at 7 days using liposomes and 10% using PLGA, corresponding to a probucol concentration of 0.1 ng/mg tissue for both formulations. By the third day after delivery, radioactivity in peri-iliac fat, femoral arteries, and hindlimb muscle increased by 88%, 29%, and 154%, respectively. Thereafter, radioactivity decreased to 56%, 43%, and 134% of initial dpm respectively, by day 7. CONCLUSIONS: although delivery efficiency was superior with PLGA encapsulation, intramural probucol concentrations were similar on day 7 using both formulations. Radial and axial redistribution of probucol was observed, indicating that this technique can be exploited to increase adjacent tissue delivery.

Journal Article↗
PubMed1984

Electrocardiographic effects of probucol. A controlled prospective clinical trial.

Probucol is known to prolong QT intervals in some patients and to produce fatal arrhythmias in selected animal species. To assess the prevalence and clinical relevance of this effect in a controlled manner, we analyzed electrocardiograms (ECGs) and medical events in patients during a placebo-controlled crossover trial comparing single or combined administration of probucol and colestipol. Forty-two Type II hyperlipoproteinemic patients were studied for eighteen to twenty-four months. Two cardiologists independently read the tracings which were previously arranged randomly without names or dates. There were no statistical differences between the reports of the ECG parameters by the two cardiologists. The mean QTc interval of the entire patient population was lengthened after probucol administration without reaching statistical significance when compared to placebos or colestipol treatments. Forty-eight % of the patients showed lengthening of the QTc interval during probucol treatment by 11 to 70 msec increment over baseline placebo. The remaining had either no change or shortening of the interval. There were no statistically significant differences in means of R-R, PR, QRS, QTc or QoT intervals among placebo, probucol., colestipol and probucol plus colestipol treatments. It is concluded that probucol prolonged QT intervals in the electrocardiograms of about one half of patients receiving the drug with no other clinical or statistically significant evidence of cardiotoxicity or electrocardiographic effects.

Adult↗
PubMed1984

Prolongation of the QT interval induced by probucol: demonstration of a method for determining QT interval change induced by a drug.

Sudden death has occurred in monkeys fed large doses of probucol, a cholesterol-lowering drug, given in combination with an atherogenic diet. These monkeys develop prolonged QT intervals and high serum levels of probucol. We investigated the effect of probucol on QT interval and the incidence of ventricular ectopy during a double-blind placebo-controlled study in 16 patients with less than 600 premature ventricular complexes (PVCs) per day and a corrected QT interval of less than 0.44 second. Seven patients received probucol and nine patients received placebo. Three 24-hour continuous ECG recordings were obtained prior to entry into the study and three additional recordings were obtained after 6 months of drug or placebo therapy. A 15-second ECG tracing was sampled from the continuous ECG recording every 30 minutes and, for the group, 15,000 QT intervals were measured permitting construction of QT versus R-R regression lines for each patient before and during therapy. Comparison of the regression lines revealed that the measured QT interval prolonged 20 +/- 18 msec during the awake state and 24 +/- 20 msec during sleep (mean + standard deviation) at matched heart rates in the seven patients receiving probucol (p less than 0.01). Using Bazett's formula to correct for rate, corrected QT interval prolonged 22 +/- 23 msec in the awake state and 20 +/- 18 msec in the asleep state (p less than 0.01). In probucol treated patients QT interval prolongation was directly related to increasing probucol plasma levels (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Studies on the mechanism of action of probucol.

Earlier clinical studies suggested that probucol lowers plasma levels of low density lipoprotein (LDL) by increasing the rate of its removal. The drug has been shown to be effective in patients lacking the LDL receptor and, more recently, in LDL receptor-deficient rabbits. These latter studies showed that probucol increased the fractional catabolic rate of LDL by 40% to 50%. This finding in a receptor-deficient model implies that probucol can enhance the removal of LDL cholesterol by alternative pathways. Because the same enhanced removal was seen when LDL from probucol-treated rabbits was injected into untreated rabbits, it appears that the drug somehow alters the metabolic properties of the LDL itself rather than the metabolic behavior of the tissues of treated animals. Whether or not this mechanism explains the action of probucol in man remains to be determined. It has been postulated that the oxidative modification of LDL might contribute to atherogenesis by facilitating lipid accumulation in macrophages (foam cells) and by inhibiting macrophage motility. LDL resists oxidative modification, however, when probucol is added to in vitro incubations or when the LDL itself is isolated from probucol-treated patients. These findings lay the groundwork for evaluating the possible in vivo significance of LDL oxidation.

Animals↗
PubMed1986

Effects of probucol on xanthomata regression in familial hypercholesterolemia.

Fifty-one patients with familial hypercholesterolemia were treated for 2 to 4 years with probucol, cholestyramine, clofibrate and compactin in various combinations. Mean baseline serum cholesterol was 359 +/- 10 mg/dl in the heterozygote, and 582 +/- 52 mg/dl in the homozygote patients. We found that a combination of probucol, cholestyramine and compactin decreased serum cholesterol to normal or near normal in most of the heterozygote patients. In 3 severely affected heterozygote and all 8 homozygote patients, adequate cholesterol reduction was only possible with plasmapheresis plus a hypolipidemic agent. Measurement of the Achilles tendon after 12 to 16 months of treatment showed that reductions in thickness occurred in all patients taking probucol, even in a single-drug regimen, in those undergoing plasmapheresis, especially if probucol was used and in those receiving a combination of cholestyramine and compactin. Probucol was most effective in patients who experienced the greatest decreases in high density lipoprotein (HDL) levels, whereas the cholestyramine-compactin combination worked without decreasing HDL concentrations. Combined clofibrate-cholestyramine therapy, by contrast, led to increased tendon thickness in all but 1 patient. It is believed that probucol exerts its positive effect on xanthomata regression by reducing the size of HDL particles, as was shown in this study. It has already been reported that smaller HDL particles are more active in reverse cholesterol transport. The direct peripheral action of probucol may have aided regression as well.

Achilles Tendon↗
PubMed1985

Sterol synthesis in vitro in freshly isolated blood mononuclear leukocytes from familial hypercholesterolemic patients treated with probucol.

Sterol synthesis rates were measured in freshly isolated blood mononuclear leukocytes obtained from familial hypercholesterolemic patients undergoing treatment with either probucol alone or probucol plus cholestyramine. Subjects with heterozygous familial hypercholesterolemia on probucol had a significant 31% reduction in mononuclear cell sterol synthesis rates as compared to control patients; sterol synthesis in cells from homozygous familial hypercholesterolemic patients on probucol did not differ from that in control subjects. Addition of cholestyramine to probucol therapy in heterozygous familial hypercholesterolemic patients caused an increase in sterol synthesis rates equal to but not greater than control values, thus negating the decreased mononuclear leukocyte sterol synthesis associated with probucol administration alone. Probucol treatment effectively decreased plasma cholesterol levels in both homozygous and heterozygous familial hypercholesterolemic subjects; however, the data suggest that the drug may exert different effects on sterol synthesis in peripheral tissues depending upon the presence or absence of cellular receptors for low-density lipoproteins.

Cholesterol↗
PubMed1988

Probucol reduces the rate of association of apolipoprotein C-III with dimyristoylphosphatidylcholine.

The effect of low concentrations of probucol and cholesterol on the association of dimyristoylphosphatidylcholine with human plasma apolipoprotein C-III was studied. Liposomes of dimyristoylphosphatidylcholine with or without probucol or cholesterol were prepared by swelling the lipids in buffer at 37 degrees C. The association of apolipoprotein C-III with the liposomes was determined at 24 degrees C by measuring the rate of clearing of turbidity at 400 nm following addition of protein. At a weight ratio of probucol/dimyristoylphosphatidylcholine of 1:25 (5 mol% probucol), the rate of clearing of liposomes was decreased by 60%; 5 mol% cholesterol had no effect on the clearing rate. Liposomes were then added to the preformed apolipoprotein C-III/lipid micelles. In the absence of probucol, the added liposomes cleared rapidly regardless of the presence or absence of cholesterol. With 5 mol% probucol, almost no decrease in absorbance was noted on addition of liposomes to the micelles. These data show that probucol reduces the rate of association of an apolipoprotein with lipid and suggests that the interaction of probucol with lipid may modify the assembly and/or metabolism of lipoproteins.

Apolipoprotein C-III↗
PubMed1993

The effects of probucol on the levels, structure, composition and metabolism of plasma lipoprotein in rats.

The effects of probucol administration on the levels, structure, composition and metabolism of plasma lipoproteins were determined in male rats. Probucol caused a 25% decrease of plasma cholesterol and a 20% decrease of plasma triacylglycerols. The effect was more pronounced on lipoproteins of density less than 1.063 g/ml (-35%) than on density greater than 1.063 g/ml (-21%). The density of LDL, HDL-1 and HDL-2 separated by ultracentrifugation on a zonal rotor was shifted towards a higher density. The content of cholesteryl esters increased in VLDL and LDL and decreased in HDL-1 and HDL-2. LDL, HDL-1 and HDL-2 were relatively enriched with proteins. The intravascular metabolism of 125I-labeled apo A-I was identical in control and probucol-treated rats with a circulating half-lifetime of 9.5 h. The circulating half-lifetime of LDL labeled biosynthetically with [3H]cholesteryl esters was also identical, 6.5 h. The circulating half-lifetime of [3H]cholesteryl esters in HDL-2, in contrast, was 9.5 h in control rats and 7.5 h in probucol-treated animals. Plasma cholesterol ester transfer activity was almost undetectable in either control or probucol treated animals. The investigation demonstrates a pronounced effect of probucol on plasma lipid and lipoprotein levels in rats, on cholesterol ester distribution between lipoproteins and on lipoprotein transport rates in the plasma. These effects may contribute to the anti-atherogenetic action of probucol.

Animals↗
PubMed1981

Effect of probucol on serum lipoprotein levels in normal and dyslipoproteinemic mice.

The effect of probucol was studied on serum lipoprotein levels in normal and cholesterol-fed, hypercholesterolemic mice. In normal mice, probucol caused a significant reduction in LDL + VLDL cholesterol at daily doses above 25-50 mg/kg and also in HDL cholesterol at higher doses. In cholesterol-fed mice, probucol treatment decreased LDL + VLDL cholesterol at daily doses exceeding 200 mg/kg and also HDL cholesterol at a daily dose of 800 mg/kg. The ratio of LDL + VLDL cholesterol to HDL cholesterol was significantly reduced by treatment at 25-100 mg/kg in normal mice and at 200 mg/kg in hypercholesterolemic mice. The ratio was not reduced at doses above these ranges. These dose-effect relationships were not modified by duration of probucol treatment. These findings suggest that there is an optimum dosage of probucol to lower LDL + VLDL cholesterol and the atherogenic index, and that the actual optimum dosage for the beneficial effect depends on blood lipid levels or types of hyperlipidemia. This may be important in the clinical application of this drug, because a negative correlation has been demonstrated between HDL cholesterol levels and ischemic heart disease. Clofibrate treatment did not affect serum lipid levels significantly in either normal or cholesterol-fed mice. Probucol was again effective in lowering LDL cholesterol values in cholesterol-fed mice which had previously been treated with clofibrate for 2 weeks without any beneficial effect. In an additional experiment, it was found that the probucol-induced reduction in cholesterol returned to the pre-treatment levels gradually over several days, depending on the dose and without rebound elevation after withdrawal of the drug.

Animals↗
PubMed1986

Probucol prevents lipid storage in macrophages.

Effects of probucol on lipid storage in macrophages in vitro in the presence of acetylated low density lipoprotein (acetyl-LDL) were observed using macrophage-like cells (UE-12) established from a human histiocytic lymphoma cell line (U-937). Under ordinary light microscopy as well as under electron microscopy we found that probucol added to the medium, either in ethanolic solution or bound to LDL, markedly prevented the development of macrophages into foam cells. Microscale enzymatic assay of cholesterol also showed that the intracellular accumulation of esterified cholesterol caused by acetyl-LDL was markedly decreased by the addition of probucol. The concentration of probucol added to the medium was almost comparable to the plasma concentration of the drug usually obtained in patients under treatment with probucol. The possibility that probucol interferes with the binding of acetyl-LDL to the receptors on the cell surface was suggested. The results of the present investigation coincide with the clinical findings that probucol causes a more marked regression of xanthomas than would be expected from the extent of lowering of LDL cholesterol.

Cell Line↗
PubMed1989

Lack of effect of probucol on atheroma formation in cholesterol-fed rabbits kept at comparable plasma cholesterol levels.

Rabbits were fed cholesterol for 14 weeks to study the effect of probucol on atheroma formation. Three groups of animals were investigated: group CHOL was fed 1% cholesterol and served as control for group P + CHOL. fed 1% cholesterol and 1% probucol from the onset till the end of the experiment: group CHOL + P received 1% cholesterol throughout the experiment and 1% probucol during the last 4 weeks only. Plasma cholesterol concentrations were monitored at frequent intervals and were modulated by dietary perturbations so that the areas under the curve expressing plasma cholesterol changes with time, were similar in probucol and non-treated rabbits. The efficacy of long-term probucol treatment was evidenced by a significant reduction in plasma apolipoprotein A-I throughout the experiment and lower plasma TBARs during the first 6 weeks, when the hypocholesterolemic effect of probucol was also seen. Two weeks prior to the termination of the experiment, the rabbits were injected with rabbit plasma labeled with [3H]cholesteryl linoleyl ether [( 3H]CLE). Aortic atheromatosis was quantified by determination of total and cholesteryl ester (CE). The aortic cholesterol content was related to the arch, thoracic and abdominal segments, to the surface area of each segment or its dry defatted weight. Total and esterified cholesterol were highest in the aortic arch in all 3 groups when related to any of the above mentioned parameters. No statistically significant difference in aortic total cholesterol and CE content was seen among the three groups studied. The [3H]CLE recovered in the aortic segment correlated with the CE content and the [3H]CLE (dpm)/mg CE in all segments was similar. No statistically significant difference in the [3H]CLE recovered in the aortic segments among the 3 groups was seen. We conclude that in cholesterol-fed rabbits, in which the plasma cholesterol levels were maintained at comparable levels, probucol treatment did not affect plasma CE influx into the aorta and did not attenuate development of aortic atherosclerosis.

Animals↗