thromboxane-b2 and Hypercholesterolemia

We examined the time-dependent effects of atorvastatin and rosuvastatin on in vivo oxidative stress and platelet activation, to assess whether these phenomena are related to any pleiotropic effect of any statin or to their LDL-lowering effect. We also asked whether the presence of specific allele frequencies in carriers of the 3'UTR/lectin-like oxidized LDL receptor-1 (LOX-1) polymorphism may influence the effect of either statin.. We included 60 hypercholesterolemic subjects, previously screened for LOX-1 3'UTR polymorphism, randomized, according to genetic profile (15 T and 15 C carriers for each arm), to atorvastatin 20mg/day or rosuvastatin 10mg/day.. After 8 weeks, atorvastatin and rosuvastatin were associated with comparable, significant reductions in LDL cholesterol (40.8% and 43.6%, respectively), plasma hs-CRP (9.5% vs. 13.8%), urinary 11-dehydro-thromboxane (TX) B(2) (38.9% vs. 27.1%) and 8-iso-prostaglandin (PG) F(2α) (39.4% vs. 19.4%). The impact of rosuvastatin or atorvastatin on CRP, 8-iso-PGF(2α), and 11-dehydro-TXB(2) did not differ according to the LOX-1 haplotype. On multiple regression analyses, only CRP and LDL were independent predictors of 11-dehydro-TXB(2), and only LDL was a significant predictor of 8-iso-PGF(2α).. Both atorvastatin and rosuvastatin cause comparable reductions of thromboxane-dependent platelet activation, lipid peroxidation and inflammation. The presence of 3'UTR/LOX-1 polymorphism does not affect the changes induced by either statin.

Topics: 3' Untranslated Regions; Anticholesteremic Agents; Atorvastatin; Blood Platelets; Double-Blind Method; Female; Fluorobenzenes; Heptanoic Acids; Humans; Hypercholesterolemia; Lipids; Male; Middle Aged; Oxidative Stress; Platelet Activation; Polymorphism, Genetic; Prospective Studies; Prostaglandins A; Pyrimidines; Pyrroles; Regression Analysis; Rosuvastatin Calcium; Sulfonamides; Thromboxane B2

Laropiprant, an antagonist of the PGD(2) receptor, DP1, is effective in reducing the flushing symptoms associated with extended-release (ER) niacin and thereby improves the tolerability of niacin therapy for dyslipidemia. Because PGD(2) has been reported to inhibit platelet aggregation in vitro, it has been speculated that antagonism of DP1 may enhance platelet reactivity. Three clinical studies evaluated the potential effect of laropiprant, with or without coadministration of ER niacin, on in vivo platelet function in healthy subjects and hypercholesterolemic or diabetic subjects by measuring urinary levels of 11-dehydrothromboxane B(2) (11-dTxB(2)), a marker of in vivo platelet activation. Following 7 days of multiple-dose administration, coadministration of laropiprant with ER niacin did not increase urinary 11-dTxB(2) levels compared to ER niacin alone in healthy, hypercholesterolemic, or diabetic subjects. In hypercholesterolemic and diabetic subjects, laropiprant did not increase urinary 11-dTxB(2) levels compared to placebo. These results demonstrate that laropiprant does not enhance in vivo platelet reactivity, either alone or in combination with niacin.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Platelets; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus; Double-Blind Method; Epoprostenol; Female; Humans; Hypercholesterolemia; Indoles; Male; Middle Aged; Niacin; Platelet Activation; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Thromboxane B2; Young Adult

Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins.. We studied 80 hypercholesterolemic patients and 80 matched healthy subjects. Hypercholesterolemic subjects had enhanced levels of sCD40L, factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) compared with healthy subjects. sCD40L correlated with total cholesterol and LDL cholesterol. Moreover, sCD40L was positively associated with in vivo platelet activation, as reflected by plasma P-selectin and urinary 11-dehydro-thromboxane B2, and with procoagulant state, as reflected by FVIIa and F1+2. Inhibition of cholesterol biosynthesis by pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, FVIIa, and F1+2.. This study suggests that sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state and demonstrates that statin therapy may significantly reduce sCD40L and the prothrombotic state.

Topics: CD40 Ligand; Double-Blind Method; Factor VIIa; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Inflammation; Male; Middle Aged; P-Selectin; Peptide Fragments; Platelet Activation; Protein Precursors; Prothrombin; Thromboxane B2

The drugs in the group of the "statins" lower blood lipids, especially cholesterol, thereby reducing a risk factor for, and diminishing the incidence of, clinically important cerebrocardiovascular events. Cardiovascular events and stroke are significant causes of morbidity and mortality in China and the United States. Statins reduce platelet-mediated thrombus formation and atherosclerotic progression through mechanisms not completely elucidated. While important, the lipid-lowering action of statins does not completely explain their multifaceted benefits. Nonlipid related mechanisms are essential to such effects. The authors explore these nonlipid related mechanisms of action of pravastatin that may translate into clinically relevant benefits. This study was conducted in Guangzhou, China. Twenty-one hypercholesterolemic patients were treated with pravastatin--10-20 mg/day for 12 weeks. Blood for tests was obtained at baseline and after 8 and 12 weeks of pravastatin therapy. After 8- and 12-weeks of therapy, significant decreases were observed in the following: (1) total blood cholesterol and low density lipoprotein-C (P < 0.01), (2) ADP-induced maximum platelet aggregation (P < 0.01), (3) TXB2 or thromboxane B2 in platelets (P < 0.01), and (4) expression of GMP-140 or granule membrane protein-140 (P < 0.01). The therapeutic effects of the drug did not vary significantly with length of therapy. Pravastatin induces inhibition of platelet aggregation and expression of TXB2 and GMP-140, the likely causes of thrombus formation, atherosclerotic progression, and subsequently cardiovascular events. These potential beneficial events occur within 8 weeks of pravastatin therapy.

Topics: Analysis of Variance; Female; Humans; Hypercholesterolemia; Male; Middle Aged; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Pravastatin; Thromboxane B2

The purpose of this study was to observe the effects of dietary intervention, through the modification of dietary fatty acids composition and antioxidant vitamins, on plasma thromboxane B(2) (TXB(2)) levels in postmenopausal women with hypercholesterolemia. The subjects were treated for 12 weeks with one of three methods: hormone replacement therapy (HRT group, n=8), dietary intervention (DIET group, n=8), or HRT combined with dietary intervention (HRT +DIET group, n=8). Changes in serum phospholipid fatty acids composition, serum peroxides, and plasma TXB(2) levels were measured at weeks 0, 4 and 12. The P/S ratio increased and the n-6/ n-3 ratio decreased in the DIET and the HRT +DIET group at week 4 (p<0.05). The ratio of C20:5/C20:4 in serum phospholipid increased in the DIET (p<0.05) and the HRT +DIET groups (NS) at week 4. Plasma TXB(2) levels decreased in the DIET (-35%, p<0.05) and the HRT +DIET groups (-18.8%, NS) at week 4. Serum lipid peroxides levels significantly decreased by 10.5% and 15.2% in the DIET group at weeks 4 and 12, and by 10.8% in the HRT +DIET group only at week 12 (p<0.05). Dietary intervention may lower thrombotic risks in Korean postmenopausal women by changing the serum fatty acid composition, serum lipid peroxides levels and plasma thromboxane B(2) levels.

Topics: Antioxidants; Ascorbic Acid; Dietary Fats; Estrogen Replacement Therapy; Fatty Acids; Female; Humans; Hypercholesterolemia; Lipid Peroxidation; Middle Aged; Postmenopause; Thromboxane B2; Vitamin A; Vitamin E

A tocotrienol-rich fraction (TRF(25)) and novel tocotrienols (d-P(21)-T3 and d-P(25)-T3) of rice bran significantly lowered serum and low density lipoprotein cholesterol levels in chickens. The present study evaluated the effects of novel tocotrienols on lipid metabolism in swine expressing hereditary hypercholesterolemia. Fifteen 4-mo-old genetically hypercholesterolemic swine were divided into five groups (n = 3). Four groups were fed a corn-soybean control diet, supplemented with 50 microg of either TRF(25), gamma-tocotrienol, d-P(21)-T3 or d-P(25)-T3 per g for 6 wk. Group 5 was fed the control diet for 6 wk and served as a control. After 6 wk, serum total cholesterol was reduced 32-38%, low density lipoprotein cholesterol was reduced 35-43%, apolipoprotein B was reduced 20-28%, platelet factor 4 was reduced 12-24%, thromboxane B(2) was reduced 11-18%, glucose was reduced 22-25% (P<0.01), triglycerides were reduced 15-19% and glucagon was reduced 11-17% (P<0.05) in the treatment groups relative to the control. Insulin was 100% greater (P<0.01) in the treatment groups than in the control group. Preliminary data (n = 1) indicated that hepatic activity of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase was lower in the treatment groups, and cholesterol 7alpha-hydroxylase activity was unaffected. Cholesterol and fatty acid levels in various tissues were lower in the treatment groups than in control. After being fed the tocotrienol-supplemented diets, two swine in each group were transferred to the control diet for 10 wk. The lower concentrations of serum lipids in these four treatment groups persisted for 10 wk. This persistent effect may have resulted from the high tocotrienol levels in blood of the treatment groups, suggesting that the conversion of tocotrienols to tocopherols may not be as rapid as was reported in chickens and humans.

Topics: Animals; Antioxidants; Blood Glucose; Cholesterol; Chromans; Hypercholesterolemia; Insulin; Lipid Metabolism; Liver; Oryza; Platelet Factor 4; Swine; Thromboxane B2; Vitamin E

Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase inhibitors reduces the incidence of atherosclerosis-related cardiovascular events. Adhesion molecules, regulating interactions between vascular and circulating cells, may play a central role in the pathogenesis of atherosclerosis and related complications. In the present report we examined the impact of the HMG-CoA reductase inhibitor fluvastatin on plasma levels of P-selectin and ICAM-1.. Plasma levels of P-selectin and ICAM-1 were determined using an enzyme immunoassay in 26 patients with type IIa hypercholesterolemia randomized to treatment with either fluvastatin (80 mg/d) or placebo in a double blind fashion for 12 weeks.. Fluvastatin administration reduced either P-selectin (118 +/- 63 vs 81 +/- 36 ng/mL [-31%], P = 0.0015) or ICAM-1 (264 +/- 75 vs 228 +/- 68 ng/mL [-13.7%], P = 0.0033) levels. Fluvastatin also lowered urinary 11-dehydro-TXB2 (1396 +/- 536 vs 1009 +/- 378 pg/mg creatinine [-27%], P = 0.0015) and von Willebrand Factor levels (1456 +/- 716 vs 1203 +/- 527 U/L [-17.4%], P = 0.0275), and a direct correlation was observed between P-selectin and 11-dehydro-TXB2 levels (r = 0.588, P = 0.0033). Patients treated with fluvastatin displayed an increase in nitric oxide (NO) generation, evaluated with measurements of serum NO2-/NO3-, (4.7 +/- 1 vs 8.9 +/- 3.1) mumol/L [98%], P = 0.0046). Moreover, an inverse correlation was observed between NO2-/NO3- and P-selectin (r = -0.420; P = 0.0343), 11-dehydro-TXB2 (r = -0.511; P = 0.0106), or LDL (r = -0.742; P = 0.0002) levels.. These results may provide novel biochemical basis for the beneficial clinical effects of HMG-CoA reductase inhibitors in hypercholesterolemia.

Topics: Adult; Aged; Creatinine; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Intercellular Adhesion Molecule-1; Male; Middle Aged; Nitric Oxide; Nitrogen Dioxide; P-Selectin; Thromboxane B2; von Willebrand Factor

Hypercholesterolemia is associated with platelet activation. Reduction of plasma cholesterol levels by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin has been found to improve certain aspects of platelet function in vitro and in vivo, but controlled trials are largely lacking. The present randomized, double-blind, crossover study was performed to evaluate whether 10- to 12-week treatment with simvastatin or placebo affects platelet function in vivo in 23 hypercholesterolemic men. Measurements were performed at rest and during mental stress. Simvastatin treatment reduced plasma total cholesterol levels by 18 +/- 2% and low density lipoprotein cholesterol levels by 26 +/- 2% (P < .001 for both), whereas high density lipoprotein cholesterol levels increased slightly (6 +/- 2%, P < .05). Platelet aggregability as assessed by filtragometry ex vivo was unaffected by simvastatin treatment both at rest and during mental stress. Plasma beta-thromboglobulin levels, which reflect platelet secretion, were also unaltered by simvastatin treatment both at rest (antilog of the mean: 20.2 versus 20.0 ng/mL during placebo) and during mental stress. Moreover, nocturnal excretion of 11-dehydrothromboxane B2 in urine did not differ between placebo and active treatment: 218 versus 216 ng/mmol creatinine, respectively. The corresponding values for urinary excretion of high-molecular-weight beta-thromboglobulin were 1.78 versus 1.92 ng/mmol creatinine. Thus, simvastatin treatment had no clear-cut effect on platelet function, as assessed by four different in vivo related platelet function variables, in hypercholesterolemic men.

Topics: Blood Platelets; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors; Humans; Hypercholesterolemia; Lipids; Lovastatin; Male; Platelet Aggregation; Rest; Simvastatin; Stress, Psychological; Thromboxane B2; Thyroglobulin

Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function.. We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB2, by radioimmunoassay. Urinary 11-dehydro-TXB2 was significantly (P = .0001) higher in patients with peripheral arterial disease (57 +/- 26 ng/h) than in control subjects (26 +/- 7 ng/h). Seventy percent of patients had metabolite excretion > 2 SD above the normal mean. However, 11-dehydro-TXB2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (P = .001) higher 11-dehydro-TXB2 excretion at baseline than patients who remained event free.. The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.

Topics: Adult; Aged; Aspirin; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Multivariate Analysis; Platelet Activation; Prospective Studies; Reproducibility of Results; Risk Factors; Smoking; Thromboxane A2; Thromboxane B2; Vascular Diseases

The aim of this study was to assess the effects of fluvastatin and pravastatin on lipid profiles and urinary thromboxane (TX) A2 metabolites (11-dehydro TXB2 and 2,3-dinor TXB2) in patients with type IIa hypercholesterolemia. A total of 20 patients (13 men, 7 women; mean age 53 +/- 9 years) with primary type IIa hypercholesterolemia (Fredrickson's classification) in a 4-week, double-blind, parallel-group study were randomized to fluvastatin or pravastatin, both at 40 mg once daily (at bedtime), after a single-blind, 4-week, placebo run-in period. Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides were measured after placebo (baseline) and after 4 weeks of double-blind treatment. Thromboxane metabolites were measured at the same time points, using an enzyme immunoassay kit, in 12 hr urine samples. At baseline, the mean +/- SD levels of total cholesterol, LDL-C, triglycerides, and HDL-C were: 292 +/- 23, 213 +/- 47, 186 +/- 119 and 41 +/- 17 mg/dL with fluvastatin; and 301 +/- 40, 212 +/- 40, 150 +/- 124 and 43 +/- 10 mg/dL with pravastatin, respectively. Baseline thromboxane-metabolite levels were positively and significantly (p < 0.04) correlated with levels of total cholesterol, but not LDL-C. Compared with baseline, total cholesterol and LDL-C were significantly (p < 0.01) decreased by 27% and 30% with fluvastatin, and by 23% and 31% with pravastatin, respectively. HDL-C increased from 41 +/- 17 to 59 +/- 25 mg/dL with fluvastatin, and from 43 +/- 10 to 46 +/- 12 mg/dL with pravastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anticholesteremic Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lipids; Male; Middle Aged; Placebos; Pravastatin; Single-Blind Method; Thromboxane A2; Thromboxane B2; Thromboxanes; Triglycerides

The effect of pravastatin on low density lipoprotein (LDL) cholesterol and platelet activation was studied in 16 patients with mild hypercholesterolaemia who had two or more additional cardiovascular risk factors. Patients were treated with either pravastatin (20-40 mg day-1) or placebo for 1 year. Plasma LDL and urinary excretion of 2,3-dinor-thromboxane B2 (an index of platelet activation in vivo) were determined at 0, 3, 6 and 12 months. There was a significant reduction in LDL at 6 and 12 months (2P less than 0.05) but this was not associated with any significant change in thromboxane metabolite excretion.

Topics: Aged; Anticholesteremic Agents; Cholesterol, LDL; Coronary Disease; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Male; Middle Aged; Naphthalenes; Platelet Activation; Pravastatin; Risk Factors; Thromboxane B2

A double-blind, crossover, 8-wk study was conducted to compare effects of the tocotrienol-enriched fraction of palm oil (200 mg palmvitee capsules/day) with those of 300 mg corn oil/d on serum lipids of hypercholesterolemic human subjects (serum cholesterol 6.21-8.02 mmol/L). Concentrations of serum total cholesterol (-15%), LDL cholesterol (-8%), Apo B (-10%), thromboxane (-25%), platelet factor 4 (-16%), and glucose (-12%) decreased significantly only in the 15 subjects given palmvitee during the initial 4 wk. The crossover confirmed these actions of palmvitee. There was a carry over effect of palmvitee. Serum cholesterol concentrations of seven hypercholesterolemic subjects (greater than 7.84 mmol/L) decreased 31% during a 4-wk period in which they were given 200 mg gamma-tocotrienol/d. This indicates that gamma-tocotrienol may be the most potent cholesterol inhibitor in palmvitee capsules. The results of this pilot study are very encouraging.

Topics: Adult; Antioxidants; Apolipoproteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Chromans; Double-Blind Method; Female; Humans; Hypercholesterolemia; Lipoproteins, HDL; Male; Middle Aged; Platelet Aggregation; Platelet Factor 4; Thromboxane B2; Triglycerides; Vitamin E

The effects of the lipid-lowering drug gemfibrozil on platelet reactivity at rest and during submaximal exercise were investigated in 10 patients with serum cholesterol levels greater than 270 mg/dl. No significant changes were observed in platelet reactivity at rest after gemfibrozil treatment. However, a marked decrease in platelet reactivity was seen in almost all patients treated with gemfibrozil during exercise. The adrenaline concentration necessary to induce secondary aggregation increased in eight patients during exercise after gemfibrozil and in two after placebo treatment. When adenosine diphosphatase (2 to 4 mumol/L) was used to induce aggregation, 5-hydroxytryptamine (serotonin) and thromboxane B2 secretion by platelets decreased by 35% and 67%, respectively, during exercise in patients treated with gemfibrozil. The area under the aggregation curve decreased by 28% during exercise after gemfibrozil. No significant changes occurred in these variables during exercise after placebo. Thus, gemfibrozil seems to have antiplatelet effects that might have importance in the prevention of acute complications of atherosclerosis in patients with hypercholesterolemia.

Topics: Adult; Blood Platelets; Clinical Trials as Topic; Gemfibrozil; Humans; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Pentanoic Acids; Physical Exertion; Platelet Aggregation; Thromboxane B2; Valerates

Whether hypercholesterolemia is a risk factor for contrast-induced acute kidney injury (CI-AKI) remains unclear. In the present study, the effects of short- and long-term dietary hypercholesterolemia on contrast media-induced nephrotoxicity were evaluated.. Rats were fed either a normal rodent diet (N) or high-cholesterol diet (H). At the end of 2 and 8 weeks, 8 rats from each diet group were given a tail vein injection of either iohexol (group NC and group HC) or vehicle (group N and group H). Blood lipids, renal function and renal hemodynamics were evaluated 1 day after contrast media administration. Renal and urinary prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)) were detected by radioimmunoassay. Renal nitric oxide and malondialdehyde (MDA) were measured by the Griess reaction and thiobarbituric acid method, respectively.. Contrast media administration increased serum creatinine levels and induced severe renal tubular necrosis in rats fed the high-cholesterol diet for 8 weeks but not in rats fed the normal diet or high-cholesterol diet for 2 weeks. The renal and urinary PGE(2) and TXB(2) levels increased significantly in rats in group H and group HC at the end of 8 weeks. Renal nitric oxide production decreased, and MDA levels increased markedly in group HC and group H at the end of 8 weeks.. We conclude that long-term hypercholesterolemia appeared to be a risk factor for CI-AKI, which might be associated with disorders in intrarenal prostaglandins and abnormalities in renal nitric oxide system induced by lipid peroxidation.

Topics: Acute Kidney Injury; Animal Feed; Animals; Cholesterol; Contrast Media; Dinoprostone; Electrolytes; Hypercholesterolemia; Kidney; Male; Malondialdehyde; Nitric Oxide; Radioimmunoassay; Rats; Rats, Wistar; Risk Factors; Thromboxane B2

1. Human plasma contains unidentified components that inhibit arachidonic acid (AA) metabolism. In the present study, we investigated whether plasma from rabbits fed a normal or high-cholesterol diet for 16 weeks also inhibits AA metabolism. Specifically, we studied the effects of plasma on platelet aggregation and on the production of AA metabolites, tri-hydroxyeicosatrienoic acid, 12-hydroxyeicosatetraenoic acid and thromboxane B(2). 2. Haematological and lipid profiles were altered by a high-cholesterol diet. Platelets from hypercholesterolaemic rabbits showed enhanced aggregatory sensitivity to AA and platelet-activating factor. However, plasma from hypercholesterolaemic and control rabbits, when added to the incubation mixture, significantly inhibited platelet aggregation and eicosanoid production. 3. High- and low-density lipoprotein (HDL and LDL, respectively) concentrations increased several-fold in plasma with cholesterol feeding. When added directly to the incubation mixture, both HDL and LDL inhibited platelet aggregation, as well as AA metabolism. 4. Haptoglobin, albumin and Cohn's fraction IV, but not globulins, exhibited antiplatelet and anti-AA metabolism activities. Their concentrations in plasma were not affected by cholesterol feeding. 5. We conclude that LDL and HDL account for at least some of the inhibition of AA metabolism produced by plasma.

Topics: Animals; Arachidonic Acid; Cholesterol; Dietary Fats; Hypercholesterolemia; Lipoproteins; Male; Platelet Aggregation; Prostaglandins F; Rabbits; Thromboxane B2; Time Factors

The present paper compares the effects of two monounsaturated oils, extra virgin olive oil (EVOO) and high-oleic acid sunflower oil (HOSO), on serum and LDL peroxides, eicosanoid production and the thrombogenic ratio (thromboxane (TX) B2:6-keto-prostaglandin F1alpha) in fourteen non-obese post-menopausal women. The subjects, mean age 63 (SD 11) years, were assigned to two consecutive oleic acid-rich 28 d dietary periods. EVOO and HOSO represented 62 % of the total lipid intake and were used as the only culinary fat during the first and second dietary periods respectively. Serum peroxides, plasma alpha-tocopherol and TXB2 levels in stimulated platelet-rich plasma (PRP-TXB2) were significantly higher (P < 0.01, P < 0.001, and P < 0.05, respectively) after the HOSO diet than after the EVOO diet. The relationship between the serum cholesterol level (< 6.21 mmol/l or > or = 6.21 mmol/l) and the type of dietary oil on eicosanoids, peroxides and alpha-tocopherol were evaluated by two-way ANOVA. Dietary oil significantly affected (P < 0.05) the PRP-TXB2 level, whereas serum and LDL peroxides were significantly affected (P < 0.001 and P < 0.01, respectively) by the serum cholesterol level. The plasma alpha-tocopherol level was significantly affected by the serum cholesterol level and the type of dietary oil (both P < 0.001). No significant relationships were found between serum cholesterol levels, serum peroxide or LDL peroxide levels, plasma alpha-tocopherol concentrations or alpha-tocopherol intakes with eicosanoid production or the thrombogenic ratio due to dietary changes. However, in spite of their higher alpha-tocopherol levels, hypercholesterolaemic subjects showed increased peroxidation in serum and LDL in comparison with normocholesterolaemic subjects on the HOSO diet in comparison with the EVOO diet. These findings suggest that differences in the type of minor compounds, as well as in the concentration of linoleic acid, in both these monounsaturated oils may play an important role in modulating eicosanoid production and lipoprotein peroxidation when they constitute a large proportion of the diet of post-menopausal women.

Topics: Aged; Cholesterol; Cross-Over Studies; Diet; Dietary Fats, Unsaturated; Eicosanoids; Female; Humans; Hypercholesterolemia; Lipid Peroxidation; Middle Aged; Oleic Acid; Olive Oil; Peroxides; Plant Oils; Postmenopause; Prostaglandins F; Sunflower Oil; Thromboxane B2; Vitamin E

The efficacy of OPC-29030, a newly developed inhibitor of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) production, was evaluated on intimal hyperplasia of experimental autologous vein grafts in a distal poor-runoff model and a hyperlipidemic model in rabbits. First, rabbits were divided into two groups, the distal poor-runoff group (PR group) and the hyperlipidemic group (HL group). After 4 weeks preparing the PR model and the HL model, the femoral vein was implanted into the ipsilateral femoral artery. Then they were subdivided into two groups, depending on the diet provided; diet group with 0.1% OPC-29030 (OPC-29030 group) and normal diet group (control group). At 4 weeks, the grafts were harvested, and intimal hyperplasia of the graft was measured with an ocular cytometer. Intimal cell proliferation was determined by bromodeoxyuridine (BrdU) incorporation at 2 weeks after surgery. In addition, the effect of OPC-29030 on the proliferation or migration of rat aortic smooth muscle cells in culture was investigated. In the in vivo study in the PR group, the intimal hyperplasia and the plasma 12-HETE levels in the OPC-29030 group were significantly inhibited, compared with those of the control group. However, in the HL group, the intimal hyperplasia in both the OPC-29030 and control groups showed a remarkable degree of intimal hyperplasia. There was no significant difference between those two groups. Furthermore, there was no significant difference in the plasma 12-HETE levels in the HL group irrespective of the presence of OPC-29030. The BrdU labeling index at 2 weeks after grafting was significantly lower in the OPC-29030 group compared with that in the control group in the PR group. In the in vitro study, OPC-29030 did not inhibit smooth muscle cell proliferation; however, OPC-29030 inhibited the migration. These results demonstrate the efficacy of OPC-29030 in reducing the degree of intimal hyperplasia under PR conditions, but not under hyperlipidemic conditions. The mechanism of reducing the intimal hyperplasia may be that OPC-29030 inhibited 12-HETE production, which did not inhibit proliferation while inhibiting migration of the smooth muscle cell. These results suggested the possible involvement of 12-HETE with the intimal hyperplasia under PR conditions.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Cells, Cultured; Cholesterol; Femoral Vein; Graft Survival; Hypercholesterolemia; Hyperplasia; Imidazoles; Male; Muscle, Smooth, Vascular; Platelet Aggregation Inhibitors; Quinolones; Rabbits; Rats; Sulfur Compounds; Thromboxane B2; Tunica Intima

L-arginine exerts anti-atherosclerotic effects in hypercholesterolaemic rabbits via modulating endogenous NO production. We investigated whether L-arginine inhibits thromboxane formation in vivo and platelet aggregation ex vivo in this animal model.. The urinary excretion rates of 2,3-dinor-6-keto-PGF1 alpha (major urinary metabolite of PGI2) and 2,3-dinor-TXB2 (major urinary metabolite of thromboxane A2) were used as indicators of platelet-endothelial cell interactions in vivo. Rabbits were fed 1% cholesterol (Cholesterol group, N = 8), 1% cholesterol plus 2.25% L-arginine (Cholesterol + L-arginine, N = 8), or normal rabbit chow (Control, N = 4) for 12 weeks. Urine samples were collected in weekly intervals. At the end of the study period platelet aggregation ex vivo and endothelium-dependent and -independent vascular function of isolated aortic rings in vitro was assessed.. Urinary 2,3-dinor-TXB2 excretion significantly increased in the cholesterol group (p < 0.05), and endogenous NO formation (measured as urinary nitrate excretion) decreased (p < 0.05). Both parameters were significantly correlated with each other (R = 0.48, p < 0.01). L-arginine partly restored urinary nitrate excretion and significantly reduced TXA2 production to values even below those in the control group (p < 0.001). Urinary 2,3-dinor-6-keto-PGF1 alpha excretion increased in early hypercholesterolaemia and returned to control values in the second half of the study period. The early increase in urinary 2,3-dinor-6-keto-PGF1 alpha excretion was attenuated by L-arginine. Platelet aggregation was significantly enhanced in cholesterol-fed rabbits and attenuated by dietary L-arginine. L-arginine also improved the impaired endothelium-dependent relaxations to ADP, and normalized the vasoconstrictor effects of 5-HT in isolated aortic rings.. Cholesterol-feeding enhances platelet aggregation and TXA2 formation, and stimulates platelet-endothelial cell interaction in rabbits. These effects are probably due to impaired NO elaboration, as indicated by decreased urinary nitrate excretion. Chronic dietary supplementation with L-arginine elevates systemic NO elaboration and significantly increases the PGI2/TXA2 ratio. It thus beneficially influences the homeostasis between vasodilator and vasoconstrictor prostanoids in vivo.

Topics: Adenosine Diphosphate; Animals; Aorta; Arginine; Biomarkers; Creatinine; Diet; Endothelium, Vascular; Epoprostenol; Gas Chromatography-Mass Spectrometry; Hypercholesterolemia; In Vitro Techniques; Male; Nitrates; Nitroprusside; Platelet Aggregation; Rabbits; Thromboxane A2; Thromboxane B2; Vasodilator Agents

The effects of vitamin E supplementation in a dose of 450 mg/1000 g chow on the myointimal proliferation of the abdominal aorta after balloon injury were studied in 4 groups of rabbits (24 each). The animals were fed regular diet, regular diet plus vitamin E, 1% cholesterol-enriched diet, and 1% cholesterol-enriched diet plus vitamin E. Each animal underwent a balloon injury of the abdominal aorta and left common iliac artery after 2 weeks of feeding. The animals remained on their respective diets thereafter. In 8 balloon-injured and 8 sham-operated animals of each group, the abdominal aortas were harvested 3 days after the procedure for the analysis of prostacyclin and thromboxane A2 synthesis, thiobarbituric acid reactive substances (TBARS) levels, enzyme activities of glutathione reductase (GR) and glutathione peroxidase (GP) as well as reduced (GSH) and oxidized (GSSG) glutathione levels, 3H-thymidine uptake, cholesterol as well as vitamin E contents. In the other 8 balloon-injured rabbits of each group, the tissue was harvested 3 weeks later for the morphometric study. In dependent of high cholesterol feeding, the vitamin E-treated rabbits had lower aortic production of thromboxane B2, higher 6-keto-PGF1 alpha and higher 6-keto-PGF1 alpha/thromboxane B2 ratios in both procedures. The aortic TBARS levels of the rabbits treated high cholesterol alone were significantly higher than the other three groups in both procedures. Balloon injury had a trend to increase TBARS levels and had significantly higher 3H-thymidine uptake (each p < 0.001) than sham operation in each group. Vitamin E supplement to high cholesterol diet or regular chow reduced aortic TBARS levels (p < 0.005 and 0.01, respectively) and 3H-thymidine uptake (p < 0.05 and 0.01, respectively), as well as attenuated myointimal proliferation of the abdominal aorta and left common iliac artery after balloon injury; but only supplement to high cholesterol diet reached statistical significances (both p < 0.05 compared to rabbits fed high cholesterol alone). These results suggest that vitamin E supplement changes prostanoid metabolism to a favorable pattern and reduces lipid peroxidation of the abdominal aortic wall, thus attenuates myointimal proliferation after balloon injury; these presentations are particularly obvious in diet-induced hypercholesterolemic rabbits.

Topics: 6-Ketoprostaglandin F1 alpha; Angioplasty, Balloon; Animals; Antioxidants; Aorta, Abdominal; Cell Division; Cholesterol, Dietary; Diet; Hypercholesterolemia; Lipid Metabolism; Lipid Peroxidation; Lipids; Male; Rabbits; Thiobarbituric Acid Reactive Substances; Thromboxane B2; Thymidine; Tunica Intima; Vitamin E

After the rapid extracorporal reduction of plasma low-density lipoprotein (LDL) by LDL apheresis, the percentages of arachidonic acid (AA)-containing species of phosphatidylcholine (PC) were lowered in the plasma of patients with hypercholesterolemia. The same PC species with AA were also decreased in the patient's platelets. Thus the supply of phospholipid-bound AA from LDL to the platelets was probably diminished after the apheresis. We therefore analyzed the concentration dependence of the transfer of phospholipid-bound AA from LDL to the platelets under in vitro conditions. The amount of [14C]AA-PC transferred to platelets strongly increased upon elevation of LDL from 0.1 to 1 mg protein/ml, with a less marked elevation being noted at higher LDL concentrations. After stimulation with thrombin (0.5 U/ml), 7.1% ([14C]AA-PC) and 10.6% ([14C]AA-phosphatidylethanolamine) of the 14C transferred from LDL to the platelets were recovered in the eicosanoids [14C]thromboxane B2 (TxB2) plus 12-[14C]hydroxyeicosatetraenoic acid. Experimental increases and reductions of the [14C]AA-PC import were associated with comparable modifications in the [14C]TxB2 production of the platelets. Accordingly, the import of phospholipid-bound [14C]AA is a necessary prerequisite for the formation of 14C-labeled eicosanoids. In summary, the transfer of phospholipids from LDL to the platelets markedly varies within the physiological range of lipoprotein concentrations. LDL contributes to platelet eicosanoid formation by supplying platelets with phospholipid-bound AA.

Topics: Arachidonic Acids; Blood Platelets; Carbon Radioisotopes; Eicosanoids; Humans; Hydroxyeicosatetraenoic Acids; Hypercholesterolemia; In Vitro Techniques; Kinetics; Lipoproteins, LDL; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Radioisotope Dilution Technique; Reference Values; Thromboxane B2; Tritium

F2-isoprostanes are bioactive prostaglandin (PG)-like compounds that are produced from arachidonic acid through a nonenzymatic process of lipid peroxidation catalyzed by oxygen free-radicals. 8-Epi-PGF2 alpha may amplify the platelet response to agonists, circulates in plasma, and is excreted in urine. We examined the hypothesis that the formation of 8-epi-PGF2 alpha is altered in patients with hypercholesterolemia and contributes to platelet activation in this setting. Urine samples were obtained from 40 hypercholesterolemic patients and 40 age- and sex-matched control subjects for measurement of immunoreactive 8-epi-PGF2 alpha. Urinary excretion of 11-dehydro-thromboxane (TX) B2, a major metabolite of TXA2, was measured as an in vivo index of platelet activation. Low-dose aspirin, indobufen, and vitamin E were used to investigate the mechanism of formation and effects of 8-epi-PGF2 alpha on platelet activation. Urinary 8-epi-PGF2 alpha was significantly (P = .0001) higher in hypercholesterolemic patients than in control subjects: 473 +/- 305 versus 205 +/- 95 pg/mg creatinine. Its rate of excretion was inversely related to the vitamin E content of LDL and showed a positive correlation with urinary 11-dehydro-TXB2. Urinary 8-epi-PGF2 alpha was unchanged after 2-week dosing with aspirin and indobufen despite complete suppression of TX metabolite excretion. Vitamin E supplementation was associated with dose-dependent reductions in both urinary 8-epi-PGF2 alpha and 11-dehydro-TXB2 by 34% to 36% and 47% to 58% at 100 and 600 mg daily, respectively. We conclude that the in vivo formation of the F2-isoprostane 8-epi-PGF2 alpha is enhanced in the vast majority of patients with hypercholesterolemia. This provides an aspirin-insensitive mechanism possibly linking lipid peroxidation to amplification of platelet activation in the setting of hypercholesterolemia. Dose-dependent suppression of enhanced 8-epi-PGF2 alpha formation by vitamin E supplementation may contribute to the beneficial effects of antioxidant treatment.

Topics: Antioxidants; Aspirin; Cardiovascular Diseases; Cross-Sectional Studies; Cyclooxygenase Inhibitors; Dinoprost; Female; Humans; Hypercholesterolemia; Isoindoles; Lipid Peroxidation; Lipoproteins, LDL; Male; Middle Aged; Phenylbutyrates; Platelet Activation; Platelet Aggregation Inhibitors; Reactive Oxygen Species; Thromboxane B2; Vitamin E

Cortisol is the most important hormone secreted in response to acute and chronic stress. Thromboxane A2 (TxA2) is a potent eicosanoid with vasoconstricting and proaggregatory actions. Our earlier finding of a close correlation between plasma levels of TxB2, the stable metabolite of TxA2, and cortisol in subjects with major depression but without frank hypercortisolism prompted us to investigate a possible association between TxA2 and cortisol production in nondepressed subjects. The 24-hour urinary excretion values of 2,3-dinor-TxB2 (the urinary catabolite of TxA2) and cortisol were measured by radioimmunoassay in 50 subjects divided into three groups matched for age, sex distribution, and body mass index. Group 1 consisted of 19 healthy subjects; group 2 consisted of 15 patients with type IIa hypercholesterolemia, a condition associated with a high atherothrombotic risk, but without history of atherosclerosis or evidence of this disorder documented clinically or in noninvasive diagnostic tests; and group 3 consisted of 16 patients with regional atherosclerosis (8 with cerebrovascular disease, 6 with coronary artery disease, and 2 with peripheral vascular disease). Although the three groups had similar cortisol and 2,3-dinor-TxB2 urinary values, a significant direct correlation emerged between the two catabolites in the whole study sample (r = 0.63; p < 0.0001) and the three groups (r1 = 0.62, p < 0.01; r2 = 0.78, p < 0.0001; r3 = 0.63, p < 0.01). The close association between cortisol and thromboxane A2 biosynthesis thus appears to be a general phenomenon. These findings may be important in interpreting the well-described causative link between stress and atherothrombotic cardiovascular disease.

Topics: Aged; Anxiety; Arteriosclerosis; Cholesterol, HDL; Cholesterol, LDL; Circadian Rhythm; Female; Humans; Hydrocortisone; Hypercholesterolemia; Male; Middle Aged; Radioimmunoassay; Reference Values; Thromboxane A2; Thromboxane B2; Triglycerides

The effects of supplementing with fish oil on the myointimal proliferation of the abdominal aorta after balloon injury were studied in control and in rabbits fed a 1% cholesterol-enriched diet, with and without 10% fish oil supplementation. Twenty-one animals in each group underwent a balloon injury of the abdominal aorta and left common iliac artery after 2 weeks of feeding. The animals remained on their respective diets thereafter. In 7 balloon-injured and 7 sham-operated animals of each group, the abdominal aorta was harvested 3 days later for the analysis of prostanoids, malondialdehyde, superoxide dismutase activity, [3H]thymidine uptake, and cholesterol levels. In the other 7 balloon-injured rabbits of each group, the tissue was harvested 3 weeks later for morphometric study. The fish oil-treated rabbits had the lowest aortic production of thromboxane B2 levels and the highest 6-keto-PGF1 alpha/thromboxane B2 ratios among the three groups after balloon injury. The aortic malondialdehyde levels of the cholesterol-fed rabbits were significantly higher than the other two groups (each P < 0.001) independent of balloon injury. The myointimal proliferation of the abdominal aorta and left common iliac artery in the fish oil-treated rabbits was less severe than in the cholesterol-fed animals (both P < 0.001) and was comparable with the controls. These results suggest that a fish oil supplement changes prostanoid metabolism to a favorable pattern and reduces lipid peroxidation on the abdominal aortic wall, thus attenuating myointimal proliferation after balloon injury in diet-induced hypercholesterolemic rabbits.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antioxidants; Aorta, Abdominal; Catheterization; Cell Division; Cholesterol, Dietary; Dietary Fats, Unsaturated; DNA; Fish Oils; Hypercholesterolemia; Iliac Artery; Lipid Peroxidation; Lipids; Male; Rabbits; Thromboxane B2

This study determines the antiplatelet effects of oral ticlopidine (100 mg/kg x day) in experimental hypercholesterolemia. Rabbits were fed either a standard diet or a cholesterol-enriched diet (0.5% for 3 months, 1% for 1 month). In normocholesterolemic controls ADP-, but not collagen-induced platelet aggregation was inhibited by ticlopidine treatment. This was accompanied by a significantly enhanced inhibition of ADP-induced platelet aggregation and stimulation of cyclic AMP accumulation by iloprost. Hypercholesterolemia considerably attenuated the inhibition of ADP-induced aggregation by ticlopidine but did not change its effect on the iloprost-induced inhibition of platelet function and cyclic AMP formation. ADP-induced platelet-derived thromboxane formation was considerably greater in hypercholesterolemic rabbits and not reduced by ticlopidine. Ticlopidine did also not significantly influence the extent and severity of atherosclerotic plaque formation although a tendency for improvement was observed in a subgroup of animals. The data suggest that hypercholesterolemia attenuates the inhibitory effect of ticlopidine on ADP-induced platelet aggregation. This might be related to the stimulation of thromboxane formation by ADP in hypercholesterolemia. The maintained protection from ADP-induced inhibition of cAMP accumulation suggests a minor role of this mechanism in the progression of hypercholesterolemia-induced vessel disease in this model.

Topics: Adenosine Diphosphate; Animals; Aortic Diseases; Arteriosclerosis; Biotransformation; Cholesterol, Dietary; Collagen; Cyclic AMP; Hypercholesterolemia; Iloprost; Indomethacin; Liver; Male; Platelet Aggregation; Rabbits; Signal Transduction; Thromboxane B2; Ticlopidine

Topics: Humans; Hypercholesterolemia; Nephrotic Syndrome; Platelet Aggregation; Pravastatin; Serum Albumin; Thromboxane B2

Plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 levels were determined to evaluate their role as predictive indicators for the development and progression of coronary atherosclerosis in young hypercholesterolemic swine. 32 young swine were randomly assigned to the control or atherogenic diet group for 10, 30, 90, or 180 days. Lipid profiles were obtained at the onset and repeated throughout the study. Radioimmunoassays of plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 were recorded at 10 day intervals in the 10 and 30 day subjects and at 30 day intervals in the 90 and 180 day subjects. Sections from the proximal left anterior descending coronary artery were classified based on their histological evidence of atherosclerosis by light microscopy. Hypercholesterolemia was positively correlated with development of coronary atherosclerosis (r = 0.704). However, plasma 6-keto-prostaglandin F1 alpha, thromboxane B2, and the thromboxane B2:6-keto-prostaglandin F1 alpha ratio were not found to be predictive indicators (p > 0.05) for the development or early progression of coronary atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Body Weight; Diet, Atherogenic; Disease Models, Animal; Epoprostenol; Female; Hematocrit; Hypercholesterolemia; Lipids; Male; Random Allocation; Risk Factors; Swine; Thromboxane A2; Thromboxane B2

To investigate the effect on platelet function of the interaction between dietary cholesterol and moderate, chronic doses of ethanol, hypercholesterolemia was induced in rabbits by 8 weeks of administration of a chow diet with added (0.25% wt/wt) cholesterol; during the eighth week, a moderate amount of ethanol (6% in drinking water) was given. Blood alcohol levels were not detectable in ethanol-treated rabbits at the time of exsanguination. Ethanol did not affect plasma cholesterol levels or the cholesterol to phospholipid molar ratio in platelets. Platelet membrane fluidity, which decreased with cholesterol feeding, was not altered further by administration of ethanol. The overall fatty acid composition of platelet phospholipids was not affected by either cholesterol feeding or chronic ethanol intake. Responses of washed platelets stimulated with either ADP or thrombin were studied to determine whether ethanol administration modified platelet functions in hypercholesterolemia. Primary ADP-induced aggregation was not affected by cholesterol feeding or chronic ethanol intake, but thrombin-induced aggregation and secretion of [14C]serotonin from prelabeled platelets, which were enhanced by cholesterol feeding, were diminished by administration of ethanol to hypercholesterolemic rabbits. This reduction in thrombin-induced responses was also observed with aspirin-treated platelets, which cannot form thromboxane A2. Thus, chronic short-term administration of a moderate amount of ethanol inhibited the enhanced responses of platelets from rabbits with diet-induced hypercholesterolemia, via a thrombin-induced, thromboxane A2-independent pathway.

Topics: Adenosine Diphosphate; Alcoholism; Animal Feed; Animals; Blood Platelets; Carbon Radioisotopes; Cholesterol, Dietary; Hypercholesterolemia; Male; Platelet Aggregation; Rabbits; Serotonin; Thrombin; Thromboxane B2; Time Factors

Thromboxane A2 biosynthesis was studied in healthy subjects, in patients in whom the extent of carotid atherosclerosis was determined, and in patients receiving chronic aspirin treatment, to determine what factors activate platelets to develop carotid atherosclerosis. Urinary 11-dehydrothromboxane B2, a major metabolite of thromboxane A2, was measured by radioimmunoassay after purification by reverse-phase HPLC. The extent of carotid atherosclerosis was determined by real-time B-mode ultrasonography. The severity of carotid atherosclerosis in each subject was evaluated by plaque score, which was computed by summing the maximum thickness of plaque measured in millimeters. Urinary excretion of 11-dehydrothromboxane B2 in healthy subjects was higher (P < 0.01) in cigarette smokers (1063 +/- 244 ng/g creatinine) than in non-smokers (815 +/- 183 ng/g creatinine). Aspirin significantly suppressed 11-dehydrothromboxane B2 excretion (266 +/- 114 ng/g creatinine). In the 24 patients in whom the plaque score was measured, multivariate analysis indicated a significant positive correlation between urinary excretion of 11-dehydrothromboxane B2 and plaque score, age, smoking and hypercholesteremia. Our results indicate that risk factors such as age, hypercholesteremia, atherosclerosis and smoking activate platelets in vivo to develop carotid atherosclerosis.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Arteriosclerosis; Aspirin; Carotid Artery Diseases; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Multivariate Analysis; Platelet Activation; Risk Factors; Smoking; Thromboxane B2

The study was performed to investigate the influence of lipoproteins (LP) on the thromboxane (TX) A2 formation capacity of platelets in clotting whole blood in vitro. The different lipoprotein fractions VLDL, LDL, HDL2 and HDL3 were isolated from blood of normo- or dyslipidemic volunteers by ultracentrifugation. These lipoproteins were incubated in blood with different levels of serum total cholesterol (TC) taken from normolipidemics (TC < 200 mg/dl), moderate hypercholesterolemics (TC: 200-250 mg/dl) or subjects with high cholesterol level (TC > 250 mg/dl), respectively. The amount of serum TXA2 formed within 60 min at 37 degrees C was measured by enzyme immunoassay. The results obtained show that the efficacy of separate LP fractions to influence the TXA2 production depends not only on the type of LP fraction but also on the source of plasma used for isolation of LP and on the cholesterol level in the blood for incubation: LDL taken from normolipidemics or moderate hyperlipidemics inhibited the TXA2 formation in blood from normolipidemics (P < 0.02, respectively), but enhanced it in blood from persons with moderate hypercholesterolemia (P < 0.05). LDL from hyperlipidemics enhanced TXA2 production in blood from hyperlipidemics (P < 0.05). The HDL2 fractions inhibited the TXA2 formation in blood from normo- and hypercholesterolemics (P < 0.02, resp.), but there was no effect of HDL2 in clotting blood from persons with moderate hypercholesterolemia. All HDL3 fractions tested inhibited the TXA2 formation in all types of blood used for clotting (P < 0.02, resp.), probably due to their great cholesterol accepting capacity.

Topics: Blood Coagulation; Blood Platelets; Humans; Hypercholesterolemia; Hyperlipidemias; In Vitro Techniques; Lipoproteins; Thromboxane A2; Thromboxane B2

We studied the changes in myocardial and aortic concentrations of prostacyclin and thromboxane A2 during acute coronary occlusion with or without reperfusion in rabbits fed with a cholesterol-enriched diet with or without fish oil supplementation for a short (5 days) or long period (6 weeks). New Zealand white male rabbits were divided into 5 groups: Group I, 15 control rabbits fed with a laboratory standard rabbit chow. In addition to the standard chow, the 4 study groups were treated with cholesterol or fish oil. Group II, 17 rabbits fed with a 1% high cholesterol diet for 5 days. Group III, 16 rabbits fed with a diet containing 1% cholesterol and 10% fish oil for 5 days. Group IV, 17 rabbits fed with the same diet as group II for 6 weeks. Group V, 18 rabbits fed with the same diet as group III for 6 weeks. Each group of rabbits was randomly divided into the coronary occlusion or occlusion-reperfusion mode of experiment. Acute coronary occlusion was induced by ligating the marginal branch of the left circumflex coronary artery for 1 h. Subsequent reperfusion for 4 h was performed in the occlusion-reperfusion rabbits. The aortic tissue above the aortic valve and the ischemic and normal (nonischemic) areas of the left ventricle were excised for the measurement of 6-keto-PGF1 alpha and thromboxane B2 levels by radioimmunoassay. Both during coronary occlusion and occlusion-reperfusion, rabbits showed higher myocardial concentrations of 6-keto-PGF1 alpha and thromboxane B2 in the ischemic area than in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta; Cholesterol, Dietary; Coronary Disease; Disease Models, Animal; Evaluation Studies as Topic; Fish Oils; Hypercholesterolemia; Lipoproteins; Male; Myocardial Reperfusion; Myocardium; Prostaglandins; Prostaglandins F; Rabbits; Radioimmunoassay; Thromboxane B2; Triglycerides

The plasma cholesterol, plasma malonaldehyde (MDA), platelet thromboxane A2 (TXA2) and vascular prostacyclin (PGI2) were measured in male Sprague-Dawley rats fed diets supplemented with cholesterol (1%) and cholic acid (0.5%). For comparisons, measurements were made in rats fed normal diets. The concentration of cholesterol in the plasma of rats had reached a maximum in 1 week of feeding experimental diets. TXA2 production from collagen and thrombin stimulated platelets was significantly decreased in animals fed experimental diets for 1 week. The production of MDA in the plasma of animals fed experimental diets for 8 weeks was significantly lower compared to the animals fed normal diets. There was a small but significant reduction in the formation of PGI2 in rats fed experimental diets for 8 weeks. These data suggest that feeding cholesterol rich diets to rats alters the platelet membrane properties differently from human and rabbit. Furthermore, cholesterol feeding to rats had some damaging effect on the arterial PGI2 synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Collagen; Epoprostenol; Hypercholesterolemia; Lipid Peroxidation; Male; Platelet Activation; Rats; Rats, Inbred Strains; Thrombin; Thromboxane A2; Thromboxane B2

We evaluated the effects of heparan-sulphate administration on clotting times, thromboelastographic parameters and serum thromboxane B2 levels in hypercholesterolemic rabbits with aortic atherosclerotic lesions (sudanophilic areas). 24 New Zealand male rabbits were divided into three groups of 8 animals each. Group A and B were fed a rabbit chow diet containing 0.7% of cholesterol whereas Group C was fed a standard rabbit diet without cholesterol. Group A was treated by subcutaneous route with 6 mg/kg/day of heparan sulphate. At the beginning of the study and after 3 and 6 months of treatment, serum cholesterol and thromboxane B2 levels were tested. Furthermore, at the end of the experiment, we evaluated plasma fibrinogen, aPTT, PT and TT values. The administration of heparan-sulphate in cholesterol fed rabbits produced: a reduction of plasma fibrinogen levels, without modifying aPTT and TT; a protective effect vs the lengthening in PT values, likely induced by cholesterol rich diet; a reduction of plasma thrombophilic activities and of aortic atheromasic involvement induced by dietetic cholesterol intake. However, increased serum thromboxane B2 levels, likely through a proaggregant activity were observed. We suggest that heparan-sulphate administration, in cholesterol fed rabbits, has a favourable effect on clotting parameters, while contrasting effects were found on platelet activity.

Topics: Animals; Arteriosclerosis; Blood Coagulation; Cholesterol, Dietary; Drug Evaluation, Preclinical; Heparitin Sulfate; Hypercholesterolemia; Male; Rabbits; Thromboxane B2; Time Factors

The effect of purified eicosapentanoic acid on intimal fibrous hyperplasia in expanded polytetrafluoroethylene grafts was examined in 18 rabbits undergoing infrarenal aorta reconstruction. Six rabbits received commercial rabbit chow (control group), six a regular diet supplemented with 1% cholesterol (cholesterol group), and six the cholesterol diet with 91.1% pure eicosapentanoic acid 500 mg/day (eicosapentanoic acid group). Grafts were harvested 3 months after surgery for histologic examination. The platelet count and serum beta-thromboglobulin and platelet factor 4 concentrations were not significantly different between groups. Serum arachidonic acid level in the cholesterol group was significantly higher than in the control group, and serum eicosapentanoic acid levels in the eicosapentanoic acid group were significantly higher than in the remaining two groups. Intergroup differences in serum 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations were not significant. Intimal thickness at midgraft was 5.2 +/- 6.2 microns in the control group, 67.6 +/- 46.9 microns in the cholesterol group, and 19.2 +/- 18.4 microns in the eicosapntanoic acid group. intimal thickness in the cholesterol group was greater than in either the control or licosapentanoic acid group (p less than 0.01 and p less than 0.05, respectively). These data suggest that eicosapentanoic acid reduces intimal fibrous proliferation in expanded polytetrafluoroethylene grafting as a result of hypercholesterolemia and that this effect is independent of the platelet count, activated platelet factors, and the prostacyclin/thromboxane A2 ratio.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Abdominal; Arachidonic Acid; Arachidonic Acids; beta-Thromboglobulin; Blood Vessel Prosthesis; Cholesterol, Dietary; Eicosapentaenoic Acid; Elastic Tissue; Endothelium, Vascular; Hypercholesterolemia; Hyperplasia; Male; Platelet Count; Platelet Factor 4; Polytetrafluoroethylene; Rabbits; Radiography; Thromboxane B2; Wound Healing

Hypercholesterolemia (mean plasma cholesterol: 15 mM) was induced in rabbits by the feeding of a chow diet enriched with a low amount (0.25%, w/w) of cholesterol only. Platelet size and protein content decreased significantly, but the whole blood platelet count did not change. The platelets became enriched in cholesterol, as indicated by a significant increase in the cholesterol:phospholipid molar (C/P) ratio. Specific responses of washed platelets stimulated with various agonists were studied to determine the effects of hypercholesterolemia on the various pathways of platelet aggregation in the absence of plasma components. In platelets from hypercholesterolemic rabbits compared with controls: aggregation induced by ADP was not altered; collagen-induced responses (aggregation, secretion of [14C]serotonin from prelabelled platelets, thromboxane A2 (TXA2) formation, mobilization of [3H]arachidonate from prelabelled platelets) were enhanced; with aspirin-treated platelets, aggregation induced by the TXA2 mimetic U46619 was enhanced: and thrombin-induced responses of both untreated platelets (aggregation, secretion of granule contents, TXA2 formation) and aspirin-treated platelets (aggregation) were enhanced. Thus, platelets from cholesterol-fed rabbits not only form more TXA2, but they aggregate more extensively when stimulated by its mimetic. In addition, it has not been previously recognized that these platelets are also hypersensitive to thrombin-induced aggregation that is independent of TXA2.

Topics: Adenosine Diphosphate; Animals; Aspirin; Blood Platelets; Cholesterol; Collagen; Hypercholesterolemia; Male; Platelet Aggregation; Platelet Count; Prostaglandin Endoperoxides, Synthetic; Rabbits; Serotonin; Thrombin; Thromboxane A2; Thromboxane B2

Normolipemic and genetically hypercholesterolemic pigs of defined lipoprotein genotype were fed a standard diet supplemented with 50 micrograms/g tocotrienol-rich fraction (TRF) isolated from palm oil. Hypercholesterolemic pigs fed the TRF supplement showed a 44% decrease in total serum cholesterol, a 60% decrease in low-density-lipoprotein (LDL)-cholesterol, and significant decreases in levels of apolipoprotein B (26%), thromboxane-B2 (41%), and platelet factor 4 (PF4; 29%). The declines in thromboxane B2 and PF4 suggest that TRF has a marked protective effect on the endothelium and platelet aggregation. The effect of the lipid-lowering diet persisted only in the hypercholesterolemic swine after 8 wk feeding of the control diet. These results support observations from previous studies on lowering plasma cholesterol in animals by tocotrienols, which are naturally occurring compounds in grain and palm oils and may have some effect on lowering plasma cholesterol in humans.

Topics: Animals; Antioxidants; Apolipoproteins B; Cholesterol; Female; Hypercholesterolemia; Male; Platelet Factor 4; Swine; Thromboxane B2; Vitamin E

The production of thromboxane A2 (TXA2) and prostacyclin (PGI2) is altered in hypercholesterolaemia. The purpose of this study was to investigate the effect of an acute rise in arterial pressure produced by pressor agents on the release of TXA2 and PGI2 in hypercholesterolaemic rabbits. Hypercholesterolaemia was induced in rabbits by feeding pellet food containing 1% cholesterol for 3 months. Administration of pressor agents (ergonovine 0.5-2.0 mg.kg-1, noradrenaline 5.0-20.0 micrograms.kg-1 and angiotensin-II 0.5-2.0 micrograms.kg-1) increased arterial pressure dose dependently, accompanied by a pressure dependent increase in the plasma concentrations of both TXB2 and 6-keto-PGF1 alpha (stable metabolites of TXA2 and PGI2) in control rabbits, but only of TXB2 in hypercholesterolaemic rabbits. In control rabbits the maximum increase in TXB2 was 51% with ergonovine, 73% with noradrenaline, and 51% with angiotensin-II; and the maximum increase in 6-keto-PGF1 alpha was 48% with ergonovine, 76% with noradrenaline, and 198% with angiotensin-II. In hypercholesterolaemic rabbits the maximum increase in TXB2 was 130% with ergonovine, 144% with noradrenaline, and 128% with angiotensin-II. The pressor induced increase in TXB2 was suppressed when the increase in arterial pressure was counteracted by the concomitant administration of vasodilators (glyceryl trinitrate 40 micrograms.kg-1.min-1 and verapamil 20 micrograms.kg-1.min-1) in both control and hypercholesterolaemic rabbits. Neither TXB2 biosynthesis nor phospholipase A2 activity in platelets was affected by ergonovine, noradrenaline or angiotensin-II in vitro. These results suggested that the acute rise in arterial pressure caused by these pressor agents increased TXA2 release in vivo and that the increase was greater in hypercholesterolaemic than in control rabbits.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Blood Pressure; Dose-Response Relationship, Drug; Epoprostenol; Ergonovine; Hypercholesterolemia; Nitroglycerin; Norepinephrine; Rabbits; Thromboxane A2; Thromboxane B2; Verapamil

The effects of alimentary hypercholesterolemia and nephrotic hyperlipidemia, alone and in combination, on rat peritoneal macrophage phagocytosis, basal eicosanoid production, and glomerular macrophage number during peak PA nephrosis were evaluated in rats fed four different diets: 1) normal/standard chow; 2) PA/standard chow; 3) normal/cholesterol-supplemented diet; and 4) PA/cholesterol-supplemented diet. Both PA/standard chow and normal/cholesterol-supplemented rodent groups manifested significantly greater peritoneal macrophage phagocytosis and glomerular macrophage number when compared with normal/standard chow animals. However, the combination of the nephrotic state with superimposed alimentary hypercholesterolemia (PA/cholesterol-supplemented group) produced the greatest rise in these parameters, a rise that was significantly greater than was produced in the three other groups. Regarding basal eicosanoid production by macrophages, there was a numerical trend toward increased production of thromboxane B2 in the PA/standard chow animals and normal/cholesterol-supplemented rats when compared with normal/standard chow. Again, the combination of nephrosis and alimentary hypercholesterolemia in the PA/cholesterol-supplemented group was associated with a significantly greater amount of thromboxane B2 generated when compared with the other three groups. Regarding PGE2 production, there were no significant differences among the groups, despite marked differences in fasting serum lipid levels. This data suggest that there is a synergistic effect between alimentary hypercholesterolemia and the secondary hyperlipidemia of nephrosis in producing these macrophage functional alterations. Because fasting triglyceride values between the two nephrotic groups were indifferent, one can further speculate that it is the elevation of the serum cholesterol value that predominantly evokes these changes in macrophage function.

Topics: Animals; Cell Count; Cholesterol; Dinoprostone; Eicosanoids; Hypercholesterolemia; Hyperlipidemias; Kidney Glomerulus; Macrophages; Male; Nephrosis; Nucleosides; Peritoneal Cavity; Phagocytosis; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane B2; Triglycerides

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Angina Pectoris; Animals; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Pre-Eclampsia; Pregnancy; Rabbits; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2

In rabbits receiving a normal laboratory diet the platelet half-life was 40.4 +/- 2.5h (mean +/- S.D., n = 35). In animals fed the cholesterol-enriched diet for 12 weeks the platelet half-life was reduced to 31.6 +/- 3.6h (mean +/- S.D., n = 35). Treatment of cholesterol-fed animals with a single daily dose of CGS 12970 (a long acting inhibitor of thromboxane synthase) normalised the platelet half-life. Single daily doses of the relatively shorter acting thromboxane synthase inhibitors (CGS 13080 and dazoxiben) failed to correct the reduced platelet survival. However, twice daily dosing with dazoxiben was effective. The cyclooxygenase inhibitors, aspirin and sulphinpyrazone, failed to correct the reduced platelet survival.

Topics: Animals; Aspirin; Blood Platelets; Cell Survival; Cholesterol, Dietary; Cyclooxygenase Inhibitors; Hypercholesterolemia; Imidazoles; Pyridines; Rabbits; Sulfinpyrazone; Thromboxane B2; Thromboxane-A Synthase

Rabbits were fed with 1% cholesterol-containing standard diet for 1 to 3 months. The arachidonic acid (AA)-induced aggregation of the platelet-rich plasma (PRP) of the control rabbits was accelerated by substitution of hypercholesterolemic plasma. The incorporation of 14C-AA into thromboxane B2 in platelets was increased approximately 1.6 times with PRP and 1.2 times with the washed platelet suspension (WPS) in hypercholesterolemic rabbits as compared with those of the control. Analysis of the fatty acid compositions of phospholipids and total lipids of hypercholesterolemic rabbits revealed an increase in AA of platelets and plasma, and a decrease in docosahexaenoic acid (DHA) in plasma. The AA/DHA ratio of plasma increased dependently on the period of feeding with the high cholesterol diet, and the increase in the ratio was parallel with the acceleration of platelet aggregation by AA in PRP.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Unsaturated; Hypercholesterolemia; Lipids; Male; Plasma; Platelet Aggregation; Rabbits; Thromboxane B2

Thromboxane B2 biosynthesis from arachidonic acid was increased in platelets from hypercholesterolemic rabbits. The enzymic activity of phospholipase A2 which releases arachidonic acid, the precursor for the biosynthesis of thromboxane B2, showed hardly any change in hypercholesterolemic platelets. Phospholipase C and diglyceride lipase activities also were not changed in platelets from hypercholesterolemic rabbits. Furthermore, phospholipid concentration in platelets were not increased in this state. Thus, I conclude that the supply of precursor for thromboxane B2 biosynthesis was not increased in platelets from hypercholesterolemic rabbits as compared to controls. I have clarified this mechanism for the increased thromboxane synthesis. The biosynthesis of prostaglandin H2 and thromboxane B2 were unaffected by superoxide dismutase, xanthine, xanthine oxidase, mannitol, or benzoate in the experiments designed to study the possible involvement of reactive oxygen species. The effect of glutathione, glutathione peroxidase and H2O2 on cyclooxygenase and thromboxane synthetase were studied by using partially purified enzymes and platelet microsomes. Glutathione and glutathione peroxidase inhibited the activity of the cyclooxygenase but did not inhibit that of thromboxane synthetase. H2O2 caused the inactivation of cyclooxygenase, but the addition of H2O2 did not inhibit the formation of thromboxane B2 from prostaglandin H2. An examination of glutathione concentration and glutathione peroxidase activity in platelets from normal and experimentally hypercholesterolemic rabbits demonstrated that both were decreased in platelets from latter group. The observed alterations in glutathione levels and glutathione peroxidase activity are large enough to cause increased thromboxane B2 synthesis in platelets but the possibility that other unidentified factors may also contribute cannot be excluded.

Topics: Animals; Blood Platelets; Fatty Acids; Glutathione Peroxidase; Hypercholesterolemia; Metals; Microsomes; Phospholipases; Phospholipids; Prostaglandins; Rabbits; Sterol Esterase; Thromboxane B2; Thromboxanes

Induction of atherosclerosis in rabbits by feeding a cholesterol enriched diet reduced the platelet half-life in male rabbits from 37.0 +/- 4.1 hr to 30.1 +/- 3.9 hr (mean +/- S.D. p less than or equal to 0.01). Platelets from these animals exhibited increased sensitivity to arachidonic acid but decreased sensitivity to ADP. No significant change was found in aggregation to collagen or thrombin, or in the production of thomboxane B2 induced by collagen. The reduced platelet survival was dependent upon the recipient animal and not the platelet donor. Platelets from cholesterol-fed animals survived normally in normal animals, whereas platelets from normal animals in cholesterol-fed animals had a reduced platelet survival even compared to platelets from cholesterol-fed animals. This might suggest that some functional change had occurred in the cholesterol platelet in response to its altered environment. Anagrelide (1 mg/kg/day) normalised shortened platelet survival in both male and female rabbits fed the high cholesterol diet.

Topics: Animals; Arteriosclerosis; Blood Platelets; Cell Survival; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Diet, Atherogenic; Female; Half-Life; Hypercholesterolemia; Lipoproteins, HDL; Male; Platelet Aggregation; Quinazolines; Rabbits; Thromboxane B2; Triglycerides

The synthesis of thromboxane B2 is increased in platelets from rabbits with experimental hypercholesterolemia, but the increase is not due to increased phospholipids hydrolysis. We have clarified the mechanism for the increased thromboxane synthesis. The biosyntheses of prostaglandin H2 and thromboxane B2 were unaffected by superoxide dismutase, xanthine oxidase, mannitol, or benzoate in other experiments designed to study the possible involvement of reactive oxygen species. These results suggest that O2.- and OH were not likely to be involved as intermediates in the synthesis of prostaglandin H2 and thromboxane B2 in platelets. The rate of prostaglandin H2 biosynthesis was promoted in deuterium oxide, and this deuterium oxide enhancement effect was reversed by 2,5-diphenylfuran, suggesting that singlet oxygen may be involved in prostaglandin H2 biosynthesis. The biosynthesis of prostaglandin H2 was promoted by ADP-Fe3+ but inhibited by EDTA and EDTA-Fe3+. The effect of ADP-Fe3+ could not be replaced by EDTA-Fe3+. The effects of glutathione, glutathione peroxidase and H2O2 on cyclooxygenase and thromboxane synthetase were studied by using partially purified enzymes and platelet microsomes. Glutathione and glutathione peroxidase inhibited the activity of cyclooxygenase but did not inhibit that of thromboxane synthetase. H2O2 caused the inactivation of cyclooxygenase, but the addition of H2O2 did not inhibit the formation of thromboxane B2 from prostaglandin H2. An examination of glutathione concentration and glutathione peroxidase activity in platelets from normal and experimentally hypercholesterolemic rabbits demonstrated that both were decreased in platelets from later group. The observed alterations in glutathione levels and glutathione peroxidase activity are large enough to cause increased thromboxane B2 synthesis in platelets but the possibility that other unidentified factors may also contribute cannot be excluded.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Catalase; Ferric Compounds; Glutathione Peroxidase; Hypercholesterolemia; Kinetics; Microsomes; NADPH-Ferrihemoprotein Reductase; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Rabbits; Superoxide Dismutase; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Aorta, Thoracic; Blood Platelets; Blood Vessels; Cholesterol; Chromonar; Coumarins; Epoprostenol; Hypercholesterolemia; In Vitro Techniques; Male; Platelet Aggregation; Rabbits; Thromboxane B2

The effects of Metformin treatment on platelet responsiveness to aggregating agents was studied in cholesterol-fed rabbits. Three groups of animals were fed, for one month, either a normal (N), or a hypercholesterolemic (HC), or a hypercholesterolemic + 0.5% Metformin diet (HC + Met), Platelets from the HC rabbits required significantly lower collagen and arachidonic acid concentrations to aggregate, as compared to platelets from N rabbits. The platelet response from the HC + Met rabbits was not significantly different from that of normals. The cholesterol/phospholipid ratio in platelets was increased in both dietary groups (HC, HC + Met). The serum thromboxane B2 concentrations did not show any significant difference between the groups. Plasma exchange experiments failed to indicate a specific effect of the plasma environment on platelet behaviour. In view of the inactivity of metformin on the platelet cyclo-oxygenase pathway, the reported results suggest that metformin may act by an as yet unexplored mechanism.

Topics: Animals; Blood Platelet Disorders; Blood Platelets; Cholesterol, Dietary; Collagen; Hypercholesterolemia; Hypersensitivity; Lipids; Male; Metformin; Plasma Exchange; Platelet Aggregation; Rabbits; Thromboxane B2

Thromboxane B2 biosynthesis from arachidonic acid was increased in platelets from hypercholesterolemic rabbits. The enzymic activity of phospholipase A2 which releases arachidonic acid, the precursor for the biosynthesis of thromboxane B2, showed hardly any change in hypercholesterolemic platelets. Phospholipase C and diglyceride lipase activities also were not changed in platelets from hypercholesterolemic rabbits. Furthermore, phospholipid concentration in platelets were not increased in this state. Thus, we conclude that the supply of precursor for thromboxane B2 biosynthesis was not increased in platelets from hypercholesterolemic rabbits as compared to controls. These results suggest that the enzyme activity of thromboxane B2 biosynthesis may be enhanced in platelets from hypercholesterolemic rabbits.

Topics: Animals; Blood Platelets; Cholesterol, Dietary; Fatty Acids; Hydrolysis; Hypercholesterolemia; Lipoprotein Lipase; Phospholipases A; Phospholipases A2; Phospholipids; Rabbits; Sterol Esterase; Thromboxane B2; Thromboxanes; Type C Phospholipases

Topics: Arachidonic Acids; Blood Platelets; Humans; Hypercholesterolemia; Platelet Aggregation; Thromboembolism; Thromboxane B2; Thromboxanes