Chronic effects of lovastatin and bezafibrate on cortical and medullary hemodynamics in deoxycorticosterone acetate-salt hypertensive mice.
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Cholesterol synthesis inhibitors and fibrates both exercise effects that could influence BP and renal function in hypertension. To test this issue, transit-time ultrasound flow probes, implanted optical fibers, and laser-Doppler flowmetry were used for measurements of total and regional renal blood flows in lovastatin (40 mg/kg body wt) and bezafibrate (50 mg/kg body wt) chronically treated deoxycorticosterone acetate (DOCA)-salt hypertensive mice. Total renal blood flow was well autoregulated between 70 and 150 mmHg (approximately 3.5 ml/min per g kidney weight in DOCA-salt mice). Both lovastatin and bezafibrate increased renal blood flow to a range between 4.7 and 5.5 ml/min per g kidney weight. In the renal perfusion pressure ranges investigated, renal vascular resistance increased in lovastin- and bezafibrate-treated DOCA-salt mice, but not as steeply as in vehicle-treated DOCA-salt mice. During a stepwise increase in renal perfusion pressure in lovastatin-treated DOCA-salt mice, medullary blood flow increased up to 130% of baseline values, which was not seen in vehicle- or bezafibrate-treated mice. After extracellular volume expansion with 1% saline, 1 ml over 1 min, total renal blood flow was also higher in lovastatin- or bezafibrate-treated DOCA-salt mice, whereas medullary blood flow increased more steeply in lovastatin-, compared with bezafibrate- or vehicle-treated mice. Systemic BP was significantly decreased in lovastatin-treated DOCA-salt mice compared with vehicle-treated mice. Lovastatin prevented histologic evidence for hemostasis in the medullary circulation of DOCA-salt mice. The results suggest that both lovastatin and bezafibrate diminished DOCA-salt-induced reductions in total renal blood flow. Lovastatin also abolished the perturbed medullary blood flow reactions to increased perfusion pressure or to volume expansion. Finally, lovastatin decreased systemic BP in DOCA-salt mice. These data suggest that cholesterol synthesis inhibition or fibrate treatment improve disturbed renal function in a mouse model of salt-dependent hypertension. (+info)
Combined effects of probucol and benzafibrate on lipoprotein metabolism and liver cholesteryl ester transfer protein mRNA in cholesterol-fed rabbits.
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Probucol decreases and bezafibrate increases plasma high density lipoprotein-cholesterol (HDL-C) levels in humans. This study was performed to determine whether the HDL-C-lowering effects of probucol could be reversed by treatment with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolipidemic Japanese White rabbits were divided into 5 groups [group 1: normal chow; group 2: 0.2% cholesterol (Ch) diet; group 3: 0.2% Ch and 1% probucol diet; group 4: 0.2% Ch and 1% bezafibrate diet; group 5: 0.2% Ch and 1% probucol plus 1% bezafibrate diet] and treated for 8 weeks. Plasma lipids, cholesteryl ester transfer protein (CETP) activity in the lipoprotein-deficient plasma fraction, CETP mRNA in liver tissue and plasma drug concentrations were investigated. Serum total cholesterol (TC) increased after the rabbits in groups 2, 3, 4 and 5 were fed Ch, but overall, no significant differences were observed in serum TC and triglyceride (TG) among these groups. Serum HDL-C levels increased (p<0.01) in the bezafibrate-treated group, but a significant (p<0.05) reduction in HDL-C was observed in both the Ch + probucol (group 3) and Ch + probucol plus bezafibrate (group 5) groups; no significant difference was observed between groups 3 and 5. Significant correlation (p<0.01) was found between serum low density lipoprotein cholesterol (LDL-C) levels and plasma probucol concentrations in groups 3 and 5, but no correlation was found between plasma concentrations of probucol/bezafibrate and serum HDL-C levels. CETP activity in the lipoprotein-deficient plasma fraction increased in the Ch-, Ch + probucol-, and Ch + probucol and bezafibrate-fed groups (groups 2, 3 and 5, respectively), whereas a significant reduction in this activity was observed in the Ch + bezafibrate-fed group (group 4). An analysis of covariance showed that the CETP activity responded more sensitively to drug treatment than did the serum HDL-C level. CETP mRNA in liver tissue was assessed by Northern blotting at 8 weeks, but no changes were observed among the 5 groups. Probucol decreased and bezafibrate increased serum HDL-C levels, through CETP activity without affecting liver CETP mRNA levels, and the decrease in HDL-C levels produced by probucol could not be reversed by bezafibrate. (+info)
Elevated serum triglyceride levels and long-term mortality in patients with coronary heart disease: the Bezafibrate Infarction Prevention (BIP) Registry.
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BACKGROUND: The association between elevated blood triglyceride levels and subsequent mortality risk in patients with established coronary heart disease (CHD) has been investigated rarely. The aim of the present study was to investigate this association. METHODS AND RESULTS: We evaluated mortality over a mean follow-up time of 5. 1 years among 9033 male and 2499 female CHD patients who were screened for participation in the Bezafibrate Infarction Prevention (BIP) Study. A stepwise increase in mortality with increasing serum triglyceride levels was observed in patients with desirable or elevated serum total cholesterol levels and in patients with either desirable or abnormally low HDL cholesterol levels. Multivariate adjustment for factors other than HDL cholesterol yielded a slightly increased adjusted mortality risk with a 1-natural-log-unit elevation of triglyceride levels in men (hazard ratio [HR] 1.14, 95% CI 1.00 to 1.30) and women (HR 1.37, 95% CI 1.04 to 1.88). Excess covariate-adjusted risk was noted among patients with elevated total and LDL cholesterol and in women with HDL cholesterol levels >45 mg/dL. After additional adjustment for HDL cholesterol, the risk of mortality with a 1-natural-log-unit elevation of triglycerides declined in men (HR 1.09, 95% CI 0.94 to 1.26) and in women (HR 1.10, 95% CI 0.80 to 1.50). A trend for increased mortality risk remained in patients with elevated total and LDL cholesterol and in women with HDL cholesterol >45 mg/dL. CONCLUSIONS: Elevated triglyceride levels were associated with a small, independent increased mortality risk in CHD patients. This risk may be increased among subgroups of patients with elevated total cholesterol and LDL cholesterol levels. (+info)
Bezafibrate as differentiating factor of human myeloid leukemia cells.
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Bezafibrate belongs to the class of fibric acid derivatives usually used as antihyperlipidemia agents. From the biochemical point of view, these drugs show intriguing properties which leads one to think they may promote a differentiation process in tumour cells. This new pharmacological activity of fibrates could partially depend on the induction of an oxidative stress. To test this hypothesis, the effect of bezafibrate, as well as of clofibric acid and gemfibrozil, on growth, functional and cytochemical characteristics of human leukaemia-derived cell lines HL-60, U-937 and K-562 has been studied in some details. The results show that bezafibrate, gemfibrozil and clofibric acid, do induce differentiation in human myeloid leukaemia cell lines as indicated by several differentiation markers. Moreover fibrates, in dose dependent manner, significantly alter the cell cycle distributions, mainly leading to G0/G1 phase increment and G2/M phase reduction. The differentiating activity of fibrates could have significant implications both for the pharmacotoxicological profile of this class of compounds and for the pathophysiology of neoplastic disease. (+info)
Peroxisome proliferator-activated receptor beta regulates acyl-CoA synthetase 2 in reaggregated rat brain cell cultures.
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Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate the expression of many genes involved in lipid metabolism. The biological roles of PPARalpha and PPARgamma are relatively well understood, but little is known about the function of PPARbeta. To address this question, and because PPARbeta is expressed to a high level in the developing brain, we used reaggregated brain cell cultures prepared from dissociated fetal rat telencephalon as experimental model. In these primary cultures, the fetal cells initially form random aggregates, which progressively acquire a tissue-specific pattern resembling that of the brain. PPARs are differentially expressed in these aggregates, with PPARbeta being the prevalent isotype. PPARalpha is present at a very low level, and PPARgamma is absent. Cell type-specific expression analyses revealed that PPARbeta is ubiquitous and most abundant in some neurons, whereas PPARalpha is predominantly astrocytic. We chose acyl-CoA synthetases (ACSs) 1, 2, and 3 as potential target genes of PPARbeta and first analyzed their temporal and cell type-specific pattern. This analysis indicated that ACS2 and PPARbeta mRNAs have overlapping expression patterns, thus designating the ACS2 gene as a putative target of PPARbeta. Using a selective PPARbeta activator, we found that the ACS2 gene is transcriptionally regulated by PPARbeta, demonstrating a role for PPARbeta in brain lipid metabolism. (+info)
Serum insulin-like growth factor-I level is independently associated with coronary artery disease progression in young male survivors of myocardial infarction: beneficial effects of bezafibrate treatment.
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OBJECTIVES: We investigated whether the effect of bezafibrate on progression of coronary atherosclerosis in the BEzafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) was related to insulin-like growth factor (IGF)-I and glucose-insulin homeostasis. BACKGROUND: BECAIT, the first double-blind, placebo-controlled, randomized, serial angiographic trial of a fibrate compound, demonstrated that progression of focal coronary atherosclerosis in young patients after infarction could be retarded by bezafibrate treatment. METHODS: The treatment effects on serum concentrations of IGF-I and insulin-like growth factor binding protein (IGFBP)-1, as well as on basal and postload glucose and insulin levels, were examined, and on-trial determinations were related to the angiographic outcome measurements. RESULTS: Bezafibrate treatment resulted in a significant reduction of serum IGF-I levels, both at two and five years, and on-trial serum IGF-I levels were directly related to changes in both minimal lumen diameter (r = 0.25, p < 0.05) and mean segment diameter (r = 0.29, p < 0.05). In contrast, none of the available indexes of insulin resistance (homeostasis model assessment estimate, basal and postload plasma insulin concentrations and serum IGFBP-1 levels) were related to the angiographic changes, nor were they significantly affected by bezafibrate treatment. Multiple stepwise regression analysis showed that the relation between on-trial serum IGF-I level and coronary artery disease (CAD) progression was independent of baseline angiographic score, age, body mass index, serum lipoprotein and plasma fibrinogen concentrations and measures of glucose-insulin homeostasis. CONCLUSIONS: IGF-I could be implicated in the progression of premature CAD, and a reduction of serum IGF-I concentration could account partly for the effect of bezafibrate on progression of focal coronary atherosclerosis. (+info)
Differences in the formation of PPARalpha-RXR/acoPPRE complexes between responsive and nonresponsive species upon fibrate administration.
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Peroxisome proliferator-activated receptor-alpha (PPARalpha) is responsible for the hypolipidemic, peroxisome proliferation and carcinogenic effects of fibrates. Rats and mice are responsive, but guinea pigs and primates are resistant to the proliferative and carcinogenic effects of these drugs, but the hypolipidemic effect is still manifest. It is not yet clear whether humans should be considered unresponsive, and there is concern about the long-term safety of fibrates. We present molecular evidence for the reported resistance of human cells to peroxisome proliferation by describing a deficient interaction of nuclear extracts from human cells with an acyl-CoA oxidase (ACO)-peroxisome proliferator response element probe upon fibrate addition. Electrophoretic mobility shift assay analysis showed that ciprofibrate elicited a concentration-dependent increase in the binding of nuclear extracts from cells of rat (Morris) and human (HepG2) origin to an ACO-peroxisome proliferator response element probe, although in HepG2 cells the increase was of marginal statistical significance. In Morris cells, the increase was more marked than in HepG2 cells (4-fold versus 1.5-fold at 0.2 mM ciprofibrate), and maximal binding was achieved earlier in Morris (30 min) than in HepG2 cells (3 h). Morris cells responded to the addition of ciprofibrate by increasing the levels of ACO mRNA, whereas HepG2 did not. The ratio between PPARbeta/PPARalpha mRNAs was higher in HepG2 cells than in Morris cells (3.2 versus 1.9), pointing to an antagonizing effect of PPARbeta on PPARalpha activity. These results were obtained in untransfected cells expressing their own basal set of receptors. We also provide evidence of the translocation of PPARalpha from the cytosol to the nucleus upon activation by ciprofibrate. (+info)
Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease.
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BACKGROUND: Coronary heart disease patients with low high-density lipoprotein cholesterol (HDL-C) levels, high triglyceride levels, or both are at an increased risk of cardiovascular events, but the clinical impact of raising HDL-C or decreasing triglycerides remains to be confirmed. METHODS AND RESULTS: In a double-blind trial, 3090 patients with a previous myocardial infarction or stable angina, total cholesterol of 180 to 250 mg/dL, HDL-C < or =45 mg/dL, triglycerides < or =300 mg/dL, and low-density lipoprotein cholesterol < or =180 mg/dL were randomized to receive either 400 mg of bezafibrate per day or a placebo; they were followed for a mean of 6.2 years. The primary end point was fatal or nonfatal myocardial infarction or sudden death. Bezafibrate increased HDL-C by 18% and reduced triglycerides by 21%. The frequency of the primary end point was 13. 6% on bezafibrate versus 15.0% on placebo (P=0.26). After 6.2 years, the reduction in the cumulative probability of the primary end point was 7.3%, (P=0.24). In a post hoc analysis in the subgroup with high baseline triglycerides (> or =200 mg/dL), the reduction in the cumulative probability of the primary end point by bezafibrate was 39.5% (P=0.02). Total and noncardiac mortality rates were similar, and adverse events and cancer were equally distributed. CONCLUSIONS: Bezafibrate was safe and effective in elevating HDL-C levels and lowering triglycerides. An overall trend in a reduction of the incidence of primary end points was observed. The reduction in the primary end point in patients with high baseline triglycerides (> or =200 mg/dL) requires further confirmation. (+info)