thromboxane-b2 and Arteriosclerosis

Over the last 30 years, a growing body of evidence has documented the role of hyperhomocysteinemia (HHcy) as an independent vascular risk factor. However, the mechanisms through which elevated circulating levels of homocysteine (Hcy) cause vascular injury and promote thrombosis remain elusive. Most findings have been achieved in in vitro studies employing exceedingly high concentrations of Hcy, whereas only a few studies have been carried out in vivo in humans. In homocystinuric patients, homozygotes for mutations of the gene coding for the cystathionine beta-synthase enzyme, abnormalities of coagulation variables reflecting a hypercoagulable state, have been reported. In vitro studies provide a biochemical background for such a state. In homocystinuric patients, an in vivo platelet activation has also been reported. The latter abnormality is not corrected by the bolus infusion of concentrations of hirudin, which determines a long-lasting impairment of the conversion of fibrinogen to fibrin by thrombin; in contrast, it appears at least in part lowered by the administration of the antioxidant drug probucol. During the autooxidation of Hcy in plasma, reactive oxygen species are generated. The latter initiate lipid peroxidation in cell membranes (potentially responsible for endothelial dysfunction) and in circulating lipoproteins. Oxidized low-density lipoproteins (LDL) may trigger platelet activation as well as some of the hemostatic abnormalities reported in such patients. Thus the oxidative stress induced by Hcy may be a key process in the pathogenesis of thrombosis in HHcy. Accumulation of adenosylhomocysteine in cells (a consequence of high circulating levels of homocysteine) inhibits methyltransferase enzymes, in turn preventing repair of aged or damaged cells. This mechanism has been recently documented in patients with renal failure and HHcy and provides an additional direction to be followed to understand the tendency to thrombosis in moderate HHcy.

Topics: Adolescent; Adult; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Cellular Senescence; Child; Endothelium, Vascular; Female; Genetic Predisposition to Disease; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Lipid Peroxidation; Lipoproteins, LDL; Male; Methyltransferases; Oxidation-Reduction; Platelet Activation; Reactive Oxygen Species; Renal Insufficiency; Risk Factors; S-Adenosylhomocysteine; Thrombophilia; Thromboxane B2; Vitamin K

Topics: Animals; Arteries; Arteriosclerosis; Blood Platelets; Hemodynamics; Humans; Platelet Activation; Smoking; Thrombosis; Thromboxane B2

A number of experimental studies have reported that dietary fish oil can attenuate the development of atherosclerosis in cholesterol-fed rats, quails, rabbits, pigs, and monkeys. Epidemiologic studies suggest that dietary fish oil can reduce the development of cardiovascular disease in humans. Data are limited but suggest that laboratory animals, normal volunteers, and patients with hyperlipidemia show similar responses to the consumption of fish oil. The major effect of dietary fish oil on serum lipoproteins is a reduction in plasma triglyceride levels, with inconsistent effects on plasma cholesterol and HDL-cholesterol. Dietary fish oil induces a significant reduction of platelet aggregation associated with a prolonged bleeding time. This antithrombotic effect may be partially related to a decreased thromboxane A2 and to an increased prostacyclin level. Dietary fish oil may also have anti-inflammatory and anti-immunologic effects through an elevation of prostaglandins and a reduction in the level of leukotriene B4. Recent experimental data suggest that either fish oil or verapamil can bring on a regression in atherosclerosis in cholesterol-fed rabbits put on a normal diet; however, there was no additive effect of the combination of these agents. Overall, data suggest that fish oil may have a role in attenuating the development of atherosclerosis.

Topics: Animals; Anticoagulants; Arteriosclerosis; Blood Pressure; Dietary Fats, Unsaturated; Epoprostenol; Fish Oils; Humans; Immune System; Inflammation; Lipids; Radiography; Thromboxane B2; Verapamil

There is an abundance of information suggesting that prostaglandins are involved in the development and clinical expression of atherosclerosis. Many studies demonstrate a relationship between prostaglandins and the risk factors for peripheral and coronary artery disease. Thus, part of the mechanism by which hyperlipidemia, diabetes mellitus, smoking, hypertension, sex hormones, age, heredity, emotional stress and diet contribute to the development and progression of atherosclerosis may be through an imbalance between thromboxane A2 and prostaglandin I2. Recent studies show a temporal relationship between acute ischemic events (specifically, unstable angina) and a transcardiac increase in thromboxane B2, while others demonstrate a salutary effect of disaggregatory and vasodilatory prostaglandins in such patients. If prostaglandins and thromboxane prove important in ischemic vascular disease, attention will be directed at the correction of their pathologic imbalance. This may be accomplished by dietary manipulation as well as by the development of prostaglandin receptor antagonists or inhibitors of specific prostaglandin pathways.

Topics: Age Factors; Arteriosclerosis; Coronary Disease; Diabetes Mellitus; Diet; Epoprostenol; Gonadal Steroid Hormones; Humans; Hyperlipidemias; Hypertension; Prostaglandin Antagonists; Prostaglandins; Receptors, Prostaglandin; Risk; Smoking; Stress, Physiological; Thromboxane A2; Thromboxane B2

Topics: Animals; Arteriosclerosis; Aspirin; Bleeding Time; Blood Platelets; Chemical Phenomena; Chemistry; Cyclic AMP; Epoprostenol; Haplorhini; Humans; Male; Platelet Aggregation; Prostaglandins; Thromboxane A2; Thromboxane B2; Thromboxanes

This trial evaluated the effect of antioxidant supplementation on the urinary excretion of 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio, a marker of the pathogenesis of thrombosis and arteriosclerosis.. This study was a randomised, double-blind, placebo-controlled trial involving 186 presumably healthy volunteers. One hundred received a multi-antioxidant supplementation and 86 a placebo for two years. Blood zinc, selenium, beta-carotene, vitamin C and E and urinary excretion of 11-dehydro TXB(2) and 2,3 dinor 6 keto PGF(1alpha) were measured.. Baseline subject characteristics did not differ between the two groups. Blood zinc, selenium, and beta-carotene concentrations significantly increased between baseline and two years in the multi-antioxidant supplementation group supporting subject compliance (p < 0.05). At two years, the median urinary 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio was significantly lower in the multi-antioxidant supplementation group (3.4 versus 2.78, p = 0.015). Serum selenium concentration was the only antioxidant studied that was significantly related to the urinary 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio.. These results support the hypothesis that a low-dose multi-antioxidant supplementation may contributes to a reduction in platelet activation which is beneficial for cardiovascular function.

Topics: 6-Ketoprostaglandin F1 alpha; Antioxidants; Arteriosclerosis; beta Carotene; Biomarkers; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Patient Compliance; Platelet Activation; Prostaglandins I; Selenium; Thrombosis; Thromboxane B2; Thromboxanes; Trace Elements; Vitamins; Zinc

To investigate the effect of dietary saturated fat (SFA) from animal sources on the urine excretion 11-dehydro thromboxane B2 (TXB2) and 6-keto prostaglandin F 1alpha (PGF 1alpha) in 27 healthy free-living male subjects aged 30 to 55 years.. It was a randomized crossover design. Each volunteer was randomly assigned to one of the two diets (high fat and low fat) for a period of 4 weeks, after which each subject resumed his usual diet for 2 weeks as a 'wash-out period', before being assigned to the other diet for an additional 4 weeks.. Serum proportion of 20:4n-6 was 5% lower in the high fat (6.2% of total fatty acid) than in the low fat diet (6.5% of total fatty acid), which was associated with a significantly decreased ratio of the urinary excretion 11-dehydro TXB2 to 6-keto PGF 1alpha (P < 0.05). However, there was no significant fall in the absolute urinary excretion of 11-dehydro TXB2.. Diet rich in SFA from animal sources may influence TXA2 formation via effect on tissue proportion of 20:4n-6.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Cross-Over Studies; Dietary Fats; Fatty Acids; Humans; Male; Middle Aged; Thrombosis; Thromboxane B2

The formation of prostacyclin (PGI(2)), thromboxane (TX) A(2), and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis.. The study population consisted of 42 patients with atherosclerosis who were undergoing surgical revascularization. COX-2 mRNA was detected in areas of atherosclerosis but not in normal blood vessel walls, and there was evidence of COX-1 induction. The use of immunohistochemical studies localized the COX-2 to proliferating vascular smooth muscle cells and macrophages. Twenty-four patients who did not previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours before surgery and then for 3 days. Eighteen patients who were receiving aspirin were continued on a protocol of either aspirin alone or a combination of aspirin and nimesulide. Urinary levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha), metabolites of TXA(2) and PGI(2), respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211+/-533 versus 679+/-63 pg/mg creatinine, P<0.001; 594+/-156 versus 130+/-22 pg/mg creatinine, P<0.05, respectively), as was the level of the isoprostane 8-iso-PGF(2alpha). Nimesulide reduced 2, 3-dinor-6-keto-PGF(1alpha) excretion by 46+/-5% (378.3+/-103 to 167+/-37 pg/mg creatinine, P<0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB(2) before (2678+/-694 to 2110+/-282 pg/mg creatinine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the addition of nimesulide. None of the treatments influenced urinary 8-iso-PGF(2alpha) excretion.. Both COX-1 and -2 are expressed and contribute to the increase in PGI(2) in patients with atherosclerosis, whereas TXA(2) is generated by COX-1.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arteriosclerosis; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Epoprostenol; F2-Isoprostanes; Female; Humans; Isoenzymes; Macrophages; Male; Membrane Proteins; Microscopy, Fluorescence; Muscle, Smooth, Vascular; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Thromboxane A2; Thromboxane B2

A new formulation, low dose microencapsulated aspirin, permits slow absorption of aspirin and presystemic acetylation of platelet cyclo-oxygenase within the portal circulation, potentially avoiding deleterious effects on gastric and systemic prostaglandin synthesis. The objective of this study was to determine whether the administration of microencapsulated aspirin was as effective as enteric coated (EC) aspirin as an inhibitor of platelet function in patients with atherosclerosis.. One hundred and four patients were enrolled and randomised after a run in period of at least 14 days on aspirin EC 75 mg (day 0), to receive either microencapsulated aspirin 162.5 mg (n=34), aspirin EC 150 mg (n=36) or continue on aspirin EC 75 mg (n=34) for 28 days. Serum thromboxane B2 and collagen-induced platelet aggregation and release of 5-hydroxytryptamine (EC50 values) were measured on days 0 and 28. Aggregation/release EC50s were then repeated in the presence of a large dose of aspirin added in vitro to determine the EC50 at the maximum level of platelet inhibition.. Median thromboxane B2 levels were low after 14 days run-in therapy with aspirin EC 75 mg, but significant further reductions were seen on day 28 in patients randomised to microencapsulated aspirin 162.5 mg (P=0.0368) and aspirin EC 150 mg (P=0.0004) compared with those remaining on aspirin EC 75 mg. Median EC50 s on day 28 showed small but significant increases from baseline (day 0) in aggregation in patients randomised to microencapsulated aspirin 162.5 mg (0.62-0.85, P=0.0482) and in both aggregation and release in patients randomised to aspirin EC 150 mg (0.95-1.20, P=0.0002, 8.4-11.7, P<0. 0001, respectively) signifying enhanced antiplatelet activity. No changes were seen in patients continuing on aspirin EC 75 mg. Results following addition of high dose aspirin in vitro suggest that mechanisms other than thromboxane synthesis may be operative in the long term effects of microencapsulated aspirin 162.5 mg and aspirin EC 150 mg over aspirin EC 75 mg.. The results show good inhibition of thromboxane B2 synthesis and subsequent platelet activity by all preparations of aspirin, although both microencapsulated aspirin 162.5 mg and aspirin EC 150 mg are slightly more effective than aspirin EC 75 mg. A randomised trial is now required to determine whether microencapsulated aspirin is associated with fewer gastric side-effects.

Topics: Arteriosclerosis; Aspirin; Blood Platelets; Capsules; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Single-Blind Method; Thromboxane B2

Intravenous acetylsalicylic acid (ASA) and magnesium (Mg) both possess antiplatelet properties and are thus potential inhibitors of the formation of arterial thrombi. Their effect on the dynamic aspects of arterial thrombus formation was investigated following intravenous administration of both substances alone and in combination. A blinded, placebo-controlled, in-vivo study was performed in 71 rats. Thrombus formation was induced by a standardized arteriotomy in the right femoral artery with inversion of the vessel wall during subsequent closure. Thrombus formation was recorded on video tapes and analysed off-line for 30 min. Animals were randomly assigned to one of four groups: 20 mg bolus of ASA followed by 0.3 mmol/h Mg (ASA/Mg group); NaCl followed by 0.3 mmol/h Mg (Mg group); 20 mg bolus of ASA followed by NaCl (ASA group); or NaCl throughout the experiment (control group). In the ASA-treated groups, serum levels of thromboxane B2 were reduced significantly, and the Mg-treated groups reached a serum level of Mg just above 2.0 mmol/l. No significant differences were observed in initial or maximum thrombus area or in mean thrombus area during the study period. In the ASA/Mg group, a trend towards reduced thrombus formation was observed (P = 0.06). In the same group, seven of 22 animals developed an occlusive thrombus (P < 0.01), an unexpected adverse event possibly related to the combined administration of ASA and Mg.

Topics: Animals; Arteriosclerosis; Aspirin; Blood Pressure; Double-Blind Method; Hemorrhage; Magnesium; Male; Rats; Rats, Wistar; Single-Blind Method; Thrombosis; Thromboxane B2

Our purpose was to investigate the effects of hormone replacement therapy on the reactivity of monocytes and platelets in whole blood, measured by tissue factor activity, tumor necrosis factor-alpha, and thromboxane B2.. Thirty-two women were randomized into either transdermal or oral combined hormone replacement therapy and underwent blood sampling before and after 3 and 12 months of treatment. The tissue factor activity in monocytes was measured both in unstimulated whole blood and after a weak lipopolysaccharide stimulation. Tumor necrosis factor-alpha and thromboxane B2 formation in plasma were measured after a weak lipopolysaccharide stimulation of whole blood.. After 12 months of hormone replacement therapy there were significant reductions of tissue factor activity in both unstimulated and lipopolysaccharide-stimulated monocytes (p < 0.001) and significant reductions in the formation of tumor necrosis factor-alpha (p < 0.03) and thromboxane B2 (p < 0.02). There were no differences in these parameters between the transdermal and the oral groups. No changes were observed after 3 months of therapy.. Twelve months of hormone replacement therapy reduces cellular activation of blood monocytes and platelets; these changes may account for some of the beneficial effects in reducing the risk of cardiovascular disease.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Arteriosclerosis; Blood Platelets; Estradiol; Estrogen Replacement Therapy; Female; Humans; Medroxyprogesterone; Middle Aged; Monocytes; Norethindrone; Thromboplastin; Thrombosis; Thromboxane B2; Tumor Necrosis Factor-alpha

Effects of a dietary intake of the polyunsaturated omega-6 essential fatty acids (EFAs) linoleic and gamma-linolenic acids (GLA) on blood lipids, platelet function, and vascular prostacyclin production were studied 12 hyperlipidemic patients (doses of 3 g/day) and 12 male Wistar rats (doses of 3 mg/kg/day) for 4 months. In humans, GLA supplementation decreased plasma triglyceride (TG) levels by 48% (p < 0.001) and increased HDL-cholesterol concentration by 22% (p < 0.01). Total cholesterol and LDL-cholesterol levels were significantly decreased by omega-6 EFAs. Platelet aggregation induced by low concentrations of adenosine diphosphate (ADP) and epinephrine, and serum thromboxane B2 decreased by 45% both in humans and animals after GLA supplementation. Bleeding time increased 40% (p , 0.01). In rats, vascular prostacyclin production measured by radioimmunoassay of 6-keto-PGF1 alpha was enhanced by GLA intake. These effects of omega-6 EFAs may contribute to cardiovascular protection and prevention of the atherosclerotic disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Arteriosclerosis; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Fats, Unsaturated; Epinephrine; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; gamma-Linolenic Acid; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thromboxane B2; Triglycerides

We studied 27 non-insulin-dependent diabetics without apparent atherosclerosis (AS) to investigate whether abnormal platelet function is related to asymptomatic atherosclerosis in diabetes mellitus. The degree of AS was quantitatively evaluated by determining the intimal plus medial thickness (IMT) of the carotid artery wall with ultrasound high-resolution B-mode imaging. Based on our previous finding that the upper threshold of the IMT was 1.1 mm in healthy subjects, the patients were divided into the AS-positive group with the IMT > 1.1 mm, (n = 17) and the AS-negative group with the IMT < 1.1 mm (n = 10). Among five variables measured as the factors concerned with thrombogenesis, only plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were significantly higher in the AS-positive group than in the AS-negative group. Chronic administration of pentoxifylline (300 mg/day) significantly reduced the abnormally high plasma levels of beta-TG and PF4 in 7 patients of the AS-positive group to normal levels, without lowering the normal plasma beta-TG and PF4 levels in the remaining 10 patients. Pentoxifylline treatment did not affect the plasma levels of the 3 other variables, von Willebrand factor, 6-keto prostaglandin F1 alpha and thromboxane B2. This study suggests that the progress of atherosclerosis in diabetes mellitus is associated with in vivo platelet activation and platelet activation does not occur in diabetics without carotid atherosclerosis. Pentoxifylline may impede the vicious cycle in which atherosclerosis is accelerated by platelet activation.

Topics: Aged; Arteriosclerosis; beta-Thromboglobulin; Blood Pressure; Carotid Arteries; Carotid Artery Diseases; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Pentoxifylline; Platelet Activation; Platelet Factor 4; Prostaglandins F; Thromboxane B2; Triglycerides; Ultrasonography; von Willebrand Factor

Although aspirin is an old drug, its optimal dose for the treatment of human atherosclerosis has not been finally proven. Various in-vitro and ex-vivo platelet function tests revealed a dose range from 1 to 3000 mg as being optimal. It was thus the goal to examine its in-vivo efficacy in human suffering from peripheral vascular disease in 7 different doses ranging from 1 mg to 1000 mg a day. All these patients have been treated for 3 months. Platelet half-life and platelet uptake ratio show an in part significant improvement being most pronounced at the daily doses of 20 and 1000 mg respectively. No change occurs in the placebo treated controls. These findings indicate, that 20 or 1000 mg aspirin taken daily per os, are superior to the other doses examined concerning the in-vivo platelet function (as measured by platelet half-life) and rendering the arterial surface less thrombogenic (as reflected by platelet uptake ratio-measurements).

Topics: Administration, Oral; Aged; Arteriosclerosis; Aspirin; Blood Platelets; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Middle Aged; Thromboxane B2; Time Factors

Although thromboxane A2 is a potent platelet agonist and vasoconstrictor in vitro, our knowledge of its pathophysiologic importance in human disease is limited. To facilitate the elucidation of its role in vivo, we sought to define a human syndrome in which pharmacologic interventions designed to inhibit the biosynthesis or biologic actions of thromboxane A2 might be appropriately assessed. Patients with severe peripheral vascular disease were selected on the basis of elevated plasma beta-thromboglobulin and circulating platelet aggregates and compared with healthy, age-matched control subjects. In addition to the platelet indexes, their bleeding time was shorter and excretion of 2,3-dinor-thromboxane B2, a noninvasive index of thromboxane formation in vivo, and 2,3-dinor-6-keto-prostaglandin F 1 alpha, the major urinary metabolite of prostacyclin, was markedly increased. A selective inhibitor of thromboxane synthase, imidazo (1,5-2) pyridine-5-hexanoic acid, was administered to these patients under randomized, double-blind, controlled conditions. Platelet aggregation ex vivo, the circulating platelet aggregate ratio, and the bleeding time were all unaltered, despite almost maximal inhibition of platelet thromboxane formation 1 hr after dosing. By contrast, pronounced inhibition of aggregation was observed when platelet cyclooxygenase was inhibited by aspirin. During long-term dosing with the synthetic inhibitor, inhibition of thromboxane biosynthesis was incomplete, which would permit continued thromboxane-dependent platelet aggregation to occur. However, the failure of enzyme blockade to influence platelet function at the time of maximal drug action, despite efficient inhibition of serum thromboxane B2, suggests that accumulation of proaggregatory endoperoxides is also likely to have contributed to the persistence of platelet activation. We have characterized a human preparation in which platelet activation coexists with increased thromboxane biosynthesis. In this setting, platelet activation persists despite long-term administration of a thromboxane synthase inhibitor in a dosing regimen representative of that employed in clinical trials. Prolongation of drug action and combination with antagonists of the shared endoperoxide/thromboxane A2 receptor may be necessary to assess the potential of selective inhibition of thromboxane synthase as a therapeutic strategy in man.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Arteriosclerosis; beta-Thromboglobulin; Epoprostenol; Female; Humans; Imidazoles; Male; Middle Aged; Platelet Aggregation; Platelet Factor 4; Pyridines; Thromboxane B2; Thromboxane-A Synthase

In a randomized pilot study we compared the antiplatelet effects of aspirin and BM 13.177 in two groups of 7 patients each undergoing PTCA. As compared with the pretreatment values template bleeding time was prolonged and collagen induced aggregation was inhibited in PRP and WB in all patients. In the course of angiography and PTCA a rise in platelet factor 4 and beta thromboglobulin was observed in both groups, followed by a decrease below the baseline levels. Thromboxane B2 in plasma and serum decreased in the aspirin group but remained unchanged during BM 13.177 treatment. In PRP and WB aggregation induced by U 46 619 was inhibited after ingestion of BM 13.177 but not following ASA. After three months a control coronary angiography was done. There was no difference in regard to the degree of restenosis between both groups. Medication was well tolerated, compliance was good and no side effects were noted.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angioplasty, Balloon; Arteriosclerosis; Aspirin; Bleeding Time; Blood Platelets; Clinical Trials as Topic; Collagen; Cyclooxygenase Inhibitors; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane B2; Thromboxanes

Vein graft failure within the first month after bypass surgery is largely because of thrombosis. However, systemic study of thrombus formation in vein grafts is still lacking, and few effective techniques are available to prevent this event. Herein, we analyzed the kinetics of thrombosis and tested the effectiveness of locally applied aspirin on prevention of the disease in a mouse model. En face analysis of vein grafts revealed that 67+/-12% and 54+/-17% of the surface areas were covered by microthrombi at 1 and 3 days, respectively. Thrombus generation was also identified by labeling of platelets and fibrin, which occurred in 35 grafts examined at 1 and 3 days and 1, 2, 4, and 8 weeks. In a fifth of grafts, the thrombus occluded the vessel lumen by > or =1/4. Furthermore, a significant loss of endothelial cells was evidenced by beta-gal staining for vein grafts in transgenic mice expressing LacZ gene controlled by TIE2-endothelial specific gene promoter. Following thrombosis, neointimal lesions were significantly increased by 4-fold 2 weeks after the operation. When vein grafts were treated locally with aspirin in pluronic gel-127, the thrombus area was significantly reduced (P<0.005) at 1, 4, and 8 weeks. Interestingly, neointimal lesions were markedly reduced in the local, but not oral, aspirin-treated group at 4 and 8 weeks by 50% to 70% (P<0.005). The mechanism of reduced lesions by locally applied aspirin involved the protection of vein graft endothelium. Thus, we provide strong evidence that thrombus formation occurs before the development of neointimal lesions in vein grafts and that local aspirin treatment successfully reduces vein graft arteriosclerosis through endothelial protection, resulting in reduction of thrombosis.

Topics: Animals; Arteriosclerosis; Aspirin; Blood Vessel Prosthesis Implantation; Carotid Arteries; Disease Models, Animal; Endothelium, Vascular; Fibrinolytic Agents; Graft Occlusion, Vascular; Hyperplasia; Mice; Mice, Knockout; Mice, Transgenic; Platelet Aggregation Inhibitors; Postoperative Complications; Receptor, TIE-2; Thrombosis; Thromboxane B2; Tunica Intima; Venae Cavae

To explore the interactive effect of low-dosage aspirin (ASA) combined with perindopril (PER), on prostacyclin (PGI2), thromboxone A2 (TXA2), and norepinephrine (NE) in the blood of arteriosclerosis rabbit models and the cardiac function.. Sixty adult New Zealand rabbits were randomly distributed into 5 groups with 12 rabbits in each group. One group was fed with standard fodder; the others were fed with high lipoid-diet (1% cholesterol content). Before and after 8 weeks' administration consecutively, LVEDP, LVSP, HR, +/- dp/dtmax, plasma PGI2 and TXA2, serum NE, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-ch), high-density lipoprotein cholesterol (HDL-ch) and triglycerides (TG) were evaluated.. TG, TC, LDL-ch and pathological results confirmed arteriosclerosis rabbit models successfully. ASA combined with PER led to a significant increase in PGI2/TXA2 (P < 0.01) together with a significant decrease in the NE levels (P < 0.01) in the rabbits' blood, and then improved the cardiac output, i.e. increased LVSP (P < 0.01), and decreased the heart rate (P < 0.01) and LVEDP (P < 0.01) to a greater extent in the arteriosclerosis rabbit models.. The ratio of PGI2 to TXA2 increased, and the NE levels decreased significantly; meanwhile, the heart rate decreased and the cardiac function improved during the administration of aspirin combined with perindopril in arteriosclerosis rabbit models. The results suggest that there is a synergism-action between low-dosage aspirin and ACE inhibitors due to increased PGI2/TXA2 and decreased NE levels.

Topics: Animals; Arteriosclerosis; Aspirin; Drug Synergism; Epoprostenol; Female; Heart Function Tests; Heart Rate; Male; Norepinephrine; Perindopril; Rabbits; Random Allocation; Thromboxane A2; Thromboxane B2

The key role of platelets in the pathogenesis of atherosclerosis prompted considerable interest on the effect of physical exercise on platelets. Due to probable menstrual cycle variations, only a limited number of investigations have studied the effect of exercise on platelets in women. The study was undertaken to determine the effect of acute submaximal exercise on platelet aggregation and thromboxane A(2) (TxA(2)) formation in females during their late follicular and midluteal phases.. Twelve healthy, sedentary, female volunteers performed 15 min of cycling exercise at a workload that increased their heart rate to 75% of maximal in two phases of the menstrual cycle. The maximal rate of ADP and collagen-induced platelet aggregation was evaluated on citrated whole blood using the impedance technique. Thrombin-induced thromboxane A(2) formation was evaluated by the measurement of thromboxane B(2) (TxB(2)) level by enzyme-linked immunoassay.. No significant difference was found between maximal rates of platelet aggregation measured in the different phases of menstrual cycle. Collagen-induced platelet aggregation and platelet count increased significantly after the exercise in both late follicular and midluteal phases (p<0.05). ADP-induced platelet aggregation did not change due to the exercise during the two phases of menstrual cycle. The thromboxane B(2) level measured in the midluteal phase was significantly higher than that measured in late follicular phase at rest. It was significantly increased after the exercise in late follicular phase while no significant difference was found between pre-exercise and postexercise levels in the midluteal phase. The differences in thromboxane A(2) formation were pointed out in the changes in platelet reactivity status. The inhibitory systems for platelets need further investigations. Our findings support the idea that menstrual variations do not have pronounced and acute effects on both platelet aggregation and response of platelets to acute exercise.

Topics: Adenosine Diphosphate; Adult; Arteriosclerosis; Collagen; Estradiol; Exercise; Female; Follicular Phase; Humans; In Vitro Techniques; Luteal Phase; Platelet Aggregation; Progesterone; Thromboxane A2; Thromboxane B2

Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor-deficient (LDLR-/-) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice.. Treatment of male LDLR-/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1-mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF1alpha. Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2-/- --> LDLR-/- mice developed significantly less (33% to 39%) atherosclerosis than control COX-2+/+ --> LDLR-/- mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups.. The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis.

Topics: Animals; Arteriosclerosis; Blood Platelets; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Indomethacin; Isoenzymes; Kinetics; Lactones; Lipids; Liver Transplantation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Receptors, LDL; RNA, Messenger; Sulfones; Thromboxane B2

Peripheral artery angiography, a common diagnostic procedure, may cause early and late adverse reactions, such as anaphylaxis, thrombosis and possible progression of the underlying arterial disease. To test the hypothesis that radiographic contrast medium may contribute to these events by adversely affecting the endothelium, leucocytes and/or platelets, 19 subjects undergoing angiography for the investigation and/or treatment of lower limb atherosclerosis were recruited. Blood was obtained from the external iliac vein before, and at serial intervals after, the injection of radiographic contrast medium into the ipsilateral femoral artery for diagnostic use. Markers of endothelial cell injury (von Willebrand factor (vWf)), platelet activation (soluble P-selectin) and leucocyte activation (neutrophil elastase and soluble L-selectin) were measured in citrated plasma. Soluble intercellular adhesion molecule-1 (sICAM-1) and thromboxane B(2), which are non-specific markers of inflammation, were also measured. Compared with the sample prior to angiography, levels of soluble L-selectin and sICAM-1 were reduced (p<0.02) immediately after passage of the last bolus of contrast medium. 15 min later, levels returned to normal but the level of vWf had increased (p<0.02). After 30 min, only levels of thromboxane B(2) were increased (p<0.05). The following day both vWf (p<0.01) and soluble P-selectin (p<0.05) were increased. These data point to both early and late effects of contrast medium on markers of endothelial, platelet and leucocyte function.

Topics: Aged; Arteriosclerosis; Biomarkers; Blood Platelets; Contrast Media; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Iohexol; Leg; Leukocytes; Male; Middle Aged; P-Selectin; Pancreatic Elastase; Peripheral Vascular Diseases; Radiography; Thromboxane B2; von Willebrand Factor

Lipid peroxidation and platelet activation are thought to be important contributors to the pathogenesis of atherosclerosis. The relevance of their interaction in vivo, however, is unknown.. LDL receptor-deficient (LDLR(-/-)) mice on a high-fat diet developed extensive atherosclerosis and had increased urinary levels of 8,12-iso-isoprostane (iP) F(2alpha)-VI and 2,3-dinor-thromboxane (Tx) B(2), markers of in vivo lipid peroxidation and platelet activation, respectively. Vitamin E supplementation suppressed 8,12-iso-iPF(2alpha)-VI biosynthesis and reduced atherosclerosis (65%) without having a significant effect on lipid levels or TxB(2) biosynthesis. Addition of the platelet inhibitor indomethacin to vitamin E simultaneously suppressed 8,12-iso-iPF(2alpha)-VI and TxB(2), significantly reduced soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, and remarkably, further reduced atherosclerosis (80%).. These results indicate that in vivo lipid peroxidation and platelet activation coexist in murine atherosclerosis and that lipid peroxidation does not contribute to platelet activation and reflects the oxidant component of the inflammatory response. Our findings suggest that oxidant stress and platelet activation represent 2 distinct therapeutic targets in atherogenesis. We propose that a combination of antioxidants and platelet inhibitors might be rationally evaluated in the prevention of progression of human atherosclerosis.

Topics: Animals; Antioxidants; Aorta; Arteriosclerosis; Cyclooxygenase Inhibitors; Diet, Atherogenic; Dietary Supplements; Dinoprost; Disease Models, Animal; Disease Progression; Female; Immunohistochemistry; Indomethacin; Lipid Peroxidation; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet Activation; Receptors, LDL; Thromboxane A2; Thromboxane B2; Vitamin E

A comparative analysis of the content of the soluble form of cell adhesion protein P-selectin in the blood plasma of patients with acute myocardial infarction (AMI), massive atherosclerosis (MA) and primary pulmonary hypertension (PPH), investigation of the relationship between plasma content of P-selectin and known markers of platelets and endothelial cells activation, preliminary assessment of the prognostic value of P-selectin determination.. This study included 16 patients with AMI, 20 patients with MA, 21 patients with PPH and 18 healthy donors. The follow-up was 1-5 years. End-points in the group of patients with AMI were recurrent acute coronary syndrome and coronary artery by-pass operation, in the group with MA--thrombotic complications (acute coronary syndrome, ischemic stroke) and in the group with PPH--death. P-selectin was measured by ELISA and platelet factor 4 (PF4), thromboxane B2 (TXB2), endothelin-I and stable prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by means of commercial ELISA kits.. Mean level of P-selectin in blood plasma of patients with AMI (1 day) (361 +/- 18 ng/ml), MA (410 +/- 31 ng/ml) and PPH (627 +/- 83 ng/ml) was increased in comparison with the group of healthy donors (269 +/- 12 ng/ml) (everywhere p < 0.001). In AMI, P-selectin was increased on day 1 only, on days 2, 3 and 10-14 of the disease the level of P-selectin was significantly lower than on day 1 and did not differ from the control level in the group of donors. In patients with MA a significant correlation was detected between plasma content of P-selectin and platelet activation marker PF4 (r = 0.606, P = 0.007) and in patients with PPH between the content of P-selectin and another platelet activation marker TXB2 (r = 0.622, p = 0.013). However, no correlation was found in PPH patients between the content of P-selectin and markers of endothelial activation and/or damage (endothelin-1 and 6-keto-PGF1 alpha). Difference in the concentration of P-selectin in patients with or without end-points during the follow-up period was detected in patients with AMI (353 +/- 14 ng/ml and 451 +/- 24 ng/ml, p = 0.009) and PPH (477 +/- 58 ng/ml and 927 +/- 184 ng/ml, p = 0.017) but not with MA (426 +/- 37 ng/ml and 361 +/- 24 ng/ml, p = 0.295).. The level of P-selectin in plasma was increased in patients with acute thrombosis (AMI, 1 day) as well as in patients without clinical signs of thrombosis but with a massive injury of the vasculature (MA and PPH). The increase of P-selectin was, presumably, caused by its secretion from activated platelets since its concentration in plasma correlated with platelet concentration but not endothelial activation markers. Preliminary data indicate that blood plasma soluble P-selectin may be considered as a potential prognostic marker in AMI and PPH.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arteriosclerosis; Biomarkers; Blood Coagulation; Blood Vessels; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Infarction; P-Selectin; Platelet Activation; Platelet Factor 4; Prognosis; Solubility; Thromboxane B2

Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A(2). The actions of TxA(2) as well as of other arachidonic acid products, such as prostaglandin (PG) H(2), PGF(2alpha), hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this study was to determine the role of platelet-derived TxA(2) in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist S18886. The effect of 11 weeks of treatment with aspirin (30 mg. kg(-1). d(-1)) or S18886 (5 mg. kg(-1). d(-1)) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA(2) metabolite TxB(2) was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB(2) levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA(2). S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA(2) synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels. The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA(2), perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA(2).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Aspirin; Body Weight; Cell Adhesion; Cholesterol; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Naphthalenes; Platelet Aggregation Inhibitors; Propionates; Receptors, Thromboxane; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; U937 Cells; Umbilical Veins; Vasoconstrictor Agents

This study investigates how strenuous arm exercise affects oxidized-low density lipoprotein (O(X)-LDL) mediated-platelet activation in patients with SCI. Ten patients with SCI and ten age- and sex-matched healthy subjects exercised strenuously using an arm crank ergometer. The following measurements were taken both when the subjects were at rest, and immediately after exercise: plasma lipid profile, O(X)-LDL mediated platelet aggregability and [Ca(2+)]i, urinary 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and 8-iso-prostaglandin F(2alpha), (8-iso-PG F(2alpha)) contents, and plasma NO metabolite (nitrite plus nitrate) level. Based on these measurements, the major findings of this study can be summarized as follows: 1) the SCI group had higher urinary 8-iso-PGF(2alpha) and 11-dehydro-TXB2 contents, but a lower plasma nitrite plus nitrate level than the control group; 2) at rest, the SCI group had a higher platelet aggregability and [Ca(2+)]i, and O(X)-LDL-potentiated platelet activation than the control group; 3) O(X)-LDL-potentiated platelet aggregation was enhanced by strenuous arm exercise in both groups, but the effect of exercise was more pronounced in the SCI group than in the control group; 4) treating the platelet with L-arginine inhibited O(X)-LDL-potentiated platelet activation in both groups. The study concludes that individuals with SCI had more extensive resting and exercise-enhanced O(X)-LDL-potentiated platelet activation and greater amounts of preformed lipid peroxides than those without SCI. Therefore, supplementation therapy with antioxidants may be needed for patients with SCI, especially in a strenuous arm exercise period.

Topics: Adult; Arm; Arteriosclerosis; Calcium; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Dinoprost; Exercise Test; F2-Isoprostanes; Female; Humans; Lipid Peroxidation; Lipoproteins, LDL; Male; Nitrates; Nitric Oxide; Nitrites; Oxidative Stress; Platelet Activation; Platelet Aggregation; Platelet Count; Risk Factors; Spinal Cord Injuries; Thromboxane B2

Thromboxane A(2) is a potent vasoconstrictor and platelet agonist; prostacyclin is a potent platelet inhibitor and vasodilator. Altered biosynthesis of these eicosanoids is a feature of human hypercholesterolemia and atherosclerosis. This study examined whether in 2 murine models of atherosclerosis their levels are increased and correlated with the evolution of the disease. Urinary 2,3-dinor thromboxane B(2) and 2,3-dinor-6-keto prostaglandin F(1 alpha), metabolites of thromboxane and prostacyclin, respectively, were assayed in apoliprotein E (apoE)-deficient mice on chow and low-density lipoprotein receptor (LDLR)-deficient mice on chow and a Western-type diet. Atherosclerosis lesion area was measured by en face method. Both eicosanoids increased in apoE-deficient mice on chow and in LDLR-deficient mice on a high-fat diet, but not in LDLR-deficient mice on chow by the end of the study. Aspirin suppressed ex vivo platelet aggregation, serum thromboxane B(2), and 2,3-dinor thromboxane B(2), and significantly reduced the excretion of 2,3-dinor-6-keto prostaglandin F(1 alpha) in these animals. This study demonstrates that thromboxane as well as prostacyclin biosynthesis is increased in 2 murine models of atherogenesis and is secondary to increased in vivo platelet activation. Assessment of their generation in these models may afford the basis for future studies on the functional role of these eicosanoids in the evolution and progression of atherosclerosis. (Blood. 2000;96:3823-3826)

Topics: Age Factors; Animals; Aorta; Arteriosclerosis; Aspirin; Diet, Atherogenic; Disease Models, Animal; Eicosanoids; Epoprostenol; Female; Hominidae; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins F; Receptors, LDL; Thromboxane A2; Thromboxane B2

Olive oil is the main source of dietary fatty acids in the Mediterranean region. The objective of this study was to evaluate the effect of dietary supplementation with virgin olive oil in an experimental model with rabbits fed an atherogenic diet (saturated fat 48% of total fat). Four different groups of 10 animals each were studied: (1) normolipemic diet (NLD), (2) atherogenic diet or saturated fatty acid-enriched diet (SFAED), (3) NLD with 15% olive oil (NLD+OLIV), and (4) SFAED with 15% virgin olive oil (SFAED+OLIV). The animals were fed the experimental diets for 6 weeks, after which we determined serum lipid profile (total cholesterol, HDL-cholesterol, and triglycerides), platelet aggregation, platelet thromboxane B(2), aortic prostacyclin, and platelet and vascular lipid peroxidation. Scanning electron microscopic images of the vascular endothelium were studied, as were morphometric parameters in the arterial wall and thrombogenicity of the subendothelium (annular perfusion chamber). Animals fed the SFAED showed platelet hyperactivity and increased subendothelial thrombogenicity. Animals fed the SFAED+OLIV showed, compared with the SFAED group, an improved lipid profile with decreased platelet hyperactivity and subendothelial thrombogenicity and less severe morphological lesions of the endothelium and vascular wall. We conclude that supplementation of the SFAED with 15% olive oil reduced vascular thrombogenicity and platelet activation in rabbits. Although the percentage of olive oil in the diet was higher than the amount in the human diet, these results may be helpful in determining the effect of olive oil in the human thrombogenic system.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Cholesterol; Diet, Atherogenic; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelium, Vascular; Fatty Acids; Fatty Acids, Unsaturated; Fibrinolytic Agents; Hyperlipidemias; Lipids; Male; Malondialdehyde; Microscopy, Electron, Scanning; Olive Oil; Plant Oils; Platelet Aggregation; Rabbits; Stress, Mechanical; Thrombosis; Thromboxane B2

In this paper, three compounds were isolated and identified from the leaves of Salix matsudana. They are apigenin-7-0-beta-D-glucopyranside(I), luteolin-7-0-beta-D-glucopyranside(II), compound III. Compound I and II are isolated firstly from Salix spp., compound III is found firstly in the world. Furthermore, study on effect of arachidonic acid metabolisin in rat platelets by them with radio-chromatography found that they can significantly inhibit the production of 12-HETE(12-hydroxy-5,8, 10,14-eicosatetraenoic acid), which can induce allergy and arteriosclerosis. The production of apigenin-7-0-beta-D-glucopyranside being hydrolyzed was apigenin, it can inhibit TXB2(thromoxane B2) which can induce platelet aggregation.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Apigenin; Arachidonic Acid; Arteriosclerosis; Blood Platelets; Drugs, Chinese Herbal; Fibrinolytic Agents; Glucosides; Luteolin; Plant Leaves; Platelet Aggregation; Rats; Salix; Thromboxane B2

Ciprofibrate is one of the basic drugs used to lower risk values of lipid parameters and fibrinogen in atherosclerosis patients. Since antiaggregation treatment with acetylsalicylic acid is a complex part of obligatory therapy of these patients, the authors studied the influence of ciprofibrate on chosen lipid parameters, fibrinogen and thromboxane in monotherapy, and also in combination with acetylsalicylic acid (ASA) in patients with advanced atherosclerosis and hyperlipoproteinemia. In the first group of patients (A-C, n = 12) after one month of low-lipid diet acetylsalicylic acid in a dose of 100 mg was administered daily during a period of 2 months followed by addition of 100 mg of ciprofabrate daily during the next 2 months. In the second group of patients (C-A, n = 11) after one month of low-lipid diet the same drugs were administered but in opposite order. Ciprofibrate was most effective in lowering the levels of triacylglycerids (-41%) and VLDL-cholesterol (-34%), but effectively lowered also the values of total cholesterol and LDL-cholesterol. In both studied groups it led to mild increase of HDL-cholesterol levels. Simultaneous administration of ASA did not significantly influence its hypolipemic activity. Ciprofibrate also significantly lowered the level of fibrinogen (-17%). Increase of the total number of platelets by about 10% was not accompanied by changes of the values and production of thromboxane. Simultaneous administration of ASA caused more than 90% inhibition of thromboxane production in monotherapy and in combination with ciprofibrate. Ciprofibrate is an effective hypolipidemic agent, also lowering the level of fibrinogen. Its combination with ASA is adequate, safe and without negative interaction influencing treatment. (Tab. 6, Fig. 1, Ref. 16.)

Topics: Aged; Arteriosclerosis; Aspirin; Clofibric Acid; Drug Therapy, Combination; Female; Fibric Acids; Fibrinogen; Humans; Hyperlipoproteinemias; Hypolipidemic Agents; Lipids; Male; Middle Aged; Platelet Aggregation Inhibitors; Thromboxane B2

Myocardial ischemia plays a central role in the development of right ventricular failure after acute pulmonary embolism. This study investigates whether pulmonary mediators act specifically on coronary tone and cardiac contractile function in acute pulmonary microembolization and whether such effects are altered in the case of early systemic atherosclerosis. We employ a novel model of serial perfusion in which an isolated rabbit heart is perfused with the effluent of the same animal's isolated lung.. Controlled experiment using isolated organs.. Experimental laboratory.. Male New Zealand White rabbits (controls). Age-matched, male Watanabe rabbits (hypercholesterolemic, development of accelerated atherosclerosis).. Seven isolated control and seven isolated Watanabe hearts were perfused with the saline effluent of the same animal's isolated lung. After the assessment of the baseline data, the lungs were gradually embolized with glass beads measuring 100 microm in diameter to induce an increase in mean pulmonary arterial pressure from 6 to 8 mm Hg, at baseline, up to 25 mm Hg.. Pulmonary embolization to 25 mm Hg evoked a coronary constriction, measured as coronary flow decrease to 89 +/- 7% of the baseline value in controls. In the Watanabe group, coronary constriction was significantly enhanced, compared with controls, with coronary flow decreasing to 76 +/- 6% of the baseline value. In both groups, coronary constriction was followed by a deterioration in cardiac contractile performance. This cardiodepression was significantly deeper in Watanabe hearts with respect to both maximum ventricular pressures and maximum rates of pressure development and decline. Coronary constriction and cardiodepression were prevented by coronary infusion of the nonselective endothelin antagonist PD-145065, the endothelinA antagonists A-127722 and BQ-123, and the endothelin-converting enzyme inhibitor phosphoramidon. Concentration of big endothelin in pulmonary effluent increased from 5.6 +/- 0.3 pmol/L in controls and 5.6 +/- 0.2 pmol/L in the Watanabe group, at baseline, to 8.8 +/- 0.4 pmol/L in controls and 8.9 +/- 0.4 pmol/L in the Watanabe group, at 25 mm Hg pulmonary arterial pressure. Endothelin was not detectable at any time during the experiment in pulmonary effluent. The coronary gradient, calculated as a difference in concentration between coronary and pulmonary effluent, was negative for big endothelin and positive for endothelin in both groups.. We have demonstrated that an increase in pulmonary release of big endothelin occurs during lung embolism, which, in turn, results in coronary constriction and consequent cardiodepression. This action of big endothelin is based on its local coronary conversion into endothelin. In addition, coronary endothelial dysfunction, attributed to early systemic atherosclerosis, was shown to represent a specific risk factor in these events.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Aspartic Acid Endopeptidases; Atrasentan; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Glycopeptides; In Vitro Techniques; Male; Metalloendopeptidases; Myocardial Contraction; Oligopeptides; Peptides, Cyclic; Protein Precursors; Pulmonary Embolism; Pyrrolidines; Rabbits; Thromboxane B2; Vasoconstriction

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

Disorders in arterial production of PGI2 and NO occur in atherosclerosis. Exogenous PGI2 and NO are capable of interacting pharmacologically. We claim that no such direct interactions occur between endogenous endothelial PGI2 and NO. Studying mechanisms of cardiac reactive hyperemia in guinea pigs and of thrombolysis in cats, we surmise that in vivo vascular intima releases PGI2 intraluminally while NO is secreted abluminally and thus these two ephemeral mediators do not see each other. Hence, in any disease, the disturbances in endothelial generation of PGI2 or NO have to be scrutinized separately. It may well be that endogenous PGI2 maintains endothelial thromboresistance while NO controls arterial myocytes and tissues in which microcirculation is embedded. These responsibilities remain unshared. Interactions between PGI2 and NO are confined to pharmacological domains.

Topics: Animals; Arteriosclerosis; Blood Pressure; Cats; Coronary Disease; Cyclic GMP; Epoprostenol; Guinea Pigs; Hyperemia; In Vitro Techniques; Male; Myocardium; Nitric Oxide; Thrombosis; Thromboxane B2

27 Japanese white male rabbits were divided into 3 groups for evaluation of Tongmai Jiangzhi Oral Liquor (TMJZ) in reducing the serum cholesterol, the level of plasma lipid peroxidation (LPO), the plasma TXB2 and suppressing of atherosclerotic plaque formation in atherogenesis. The results indicated that TMJZ not only decreased significantly the levels of serum cholesterol, triglyceride, LPO and TXB2, but also increased markedly blood glutathion peroxidase (GSH-Px) activity and regulated the balance of TXB2/6-keto-PGF1 alpha. The area of atherosclerotic plaque coverage in aorta and the thickness of plaque after oral TMJZ were much smaller than those of high cholesterol-fed rabbits. It is suggested that the effect of TMJZ on above-mentioned indexes might be important mechanism of its anti-atherosclerotic effect.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Cholesterol; Drugs, Chinese Herbal; Glutathione Peroxidase; Hypolipidemic Agents; Male; Malondialdehyde; Rabbits; Thromboxane B2

Angioplasty of stenotic iliac artery was performed in 23 Japanese white rabbits. Angiography and histopathology examinations were performed one day (6 rabbits), 3 days (5 rabbits), one week (5 rabbits) and one month (7 rabbits) after dilation. TXB/PGF in blood was analyzed with radio-immunologic method. TXB/6-K-PGF increased at 1st day, began to reduce at 3rd day, became almost normal after one week and returned to normal level week after one month. Restenosis occurred in all animals. Platelet aggregation and mural thrombi were observed at 1st and 3rd day. New endothelial cells covered the surface of denuded endothelium at 3rd day. At 7th day, repairing of endothelium was completed and proliferation of smooth muscle cells were prominent in new intimia. Stenosis of lumen occurred again after 1 month. The results suggested that intimia injury during the procedure initiates the process of restenosis and aggregation of platelets, imbalance of between TXA and PGI is and proliferation of smooth muscle cells play important roles in the formation of restenosis.

Topics: 6-Ketoprostaglandin F1 alpha; Angioplasty, Balloon, Coronary; Animals; Arteriosclerosis; Endothelium, Vascular; Iliac Artery; Platelet Aggregation; Rabbits; Recurrence; 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

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

The hypothesis that n-3 fatty acid incorporation into low-density lipoprotein (LDL) particles renders them more susceptible to oxidative modification and possibly more atherogenic was tested using two groups of female Yucatan miniature swine (10 animals per group) fed an atherogenic diet for 8 months. As a supplement to the atherogenic diet, the first group received a daily oral dose of the fish oil (FO) concentrate MaxEPA, rich in n-3 fatty acids, while the second group received the same dosage of a control oil (CO) low in n-3 fatty acids but with the same ratio of polyunsaturated to monounsaturated to saturated fatty acids as MaxEPA. At 8 months, the animals were killed and perfusion fixed, and all major vessels were removed for morphological assessment of atherosclerotic lesion area. Before fixation, blood samples were collected from all 20 pigs, and LDL (d = 1.019 to 1.063 g/mL) was separated from the plasma by ultracentrifugation. A series of in vitro oxidative modification reactions were carried out by incubating the LDL with a copper sulfate solution. The susceptibility of each LDL preparation to oxidation was determined by measuring both the formation of conjugated dienes and the relative mobility of each sample in an agarose gel. The incorporation of n-3 fatty acids into LDL particles decreased the lag phase by 30%, resulting in an increased mobility of FO-LDL (compared with CO-LDL) when incubated for 0.5 to 12 hours, but at longer incubation times (18 to 24 hours), the extent of modification between the two groups became equal.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arteriosclerosis; Dietary Fats, Unsaturated; Fatty Acids; Fatty Acids, Omega-3; Female; Fish Oils; Lipoproteins, LDL; Oxidation-Reduction; Swine; Swine, Miniature; Thromboxane B2; Triglycerides

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

To evaluate the effect of angioplasty on the production of prostanoids in atherosclerotic vessels in rabbits.. Open study.. 38 Rabbits.. Rabbits in group A (n = 12) were given a cholesterol rich diet (2%) for 10 weeks, and then treated with angioplasty. Rabbits in group B (n = 11) were given a cholesterol rich diet for 10 weeks, and then returned to a normal diet until the serum cholesterol concentration returned to the reference range (a further 12 weeks). Rabbits in group C (n = 15) were anaesthetised, and a 3 mm balloon was introduced into the right femoral artery, fed 20 cm proximally, inflated, and pulled twice along the aorta; the animals were then given a cholesterol rich diet (2%) for eight weeks, and treated with angioplasty.. Serum cholesterol concentrations were measured once a week. Prostacyclin and thromboxane were measured as 6-keto prostaglandin F1 alpha and thromboxane B2 in both treated and control segments of aorta.. 15 Rabbits died while atherosclerosis was being induced, leaving 23 for analysis. Angioplasty reduced the amounts of prostanoids released in animals in which the atherosclerosis had been induced by diet alone. When endothelial injury and diet were used together, there was no difference between the treated and control segments in the amounts of prostanoids released.. These findings could be of use in the comparison of methods used to induce atherosclerosis, and in the study of the mechanisms of thrombosis after transluminal angioplasty.

Topics: 6-Ketoprostaglandin F1 alpha; Angioplasty, Balloon; Animals; Aorta; Arachidonic Acids; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Epoprostenol; Rabbits; Thromboxane B2; Thromboxanes

Thirty male N-Z white rabbits were randomized into 3 groups (10 each). Normal control group (C) were fed regular chow. Atherosclerotic control group (CAS) were fed a chow containing 1% cholesterol. Nifedipine group (N) were fed 1% cholesterol chow and nifedipine 40 mg/animal/day. The experiment lasted for 12 weeks. Blood total cholesterol, HDL-C, MDA, 6-keto-PGF1 alpha and TXB2 were measured. After the sacrifice of the animals, electron probe microanalysis was employed to cryo-ultrathin sections of the aorta for measuring cytoplasmic calcium content in situ in the medial smooth muscle cells. The area of atherosclerotic plaques of the aortae was planimetried with computer. The results showed that MDA and TXB2 in group CAS were markedly higher than those in groups C and N (P < 0.01 or 0.05). The cytoplasmic calcium in group CAS was significantly higher than that in groups C and N (P < 0.01). The difference between groups C and N was not significant. The area of atherosclerotic lesions in group CAS was 44 +/- 8%, markedly larger than that in group N (13 +/- 5%, P < 0.01). The antiatherosclerotic effects of nifedipine may be mainly by a mechanism of inhibiting intracellular calcium overload.

Topics: Animals; Aorta; Arteriosclerosis; Calcium; Cholesterol, Dietary; Cytoplasm; Male; Malondialdehyde; Muscle, Smooth, Vascular; Nifedipine; Rabbits; Thromboxane B2

Topics: Animals; Aorta; Arteriosclerosis; Biphenyl Compounds; Cell Division; Cells, Cultured; Eicosanoids; Fatty Acids, Monounsaturated; Graft Rejection; Heptanoic Acids; In Vitro Techniques; Muscle, Smooth, Vascular; Pyridines; Rats; Rats, Inbred Strains; Rats, Inbred WF; Thromboxane B2; Transplantation, Homologous; Transplantation, Isogeneic

The aim of our study was to examine the release of various lipid and peptide contracting autacoids by aortae of normal and atherosclerotic rabbits. Leukotriene (LT) E4, an enzymatic derivative of LTC4, thromboxane (Tx) B2, and endothelin-1 (ET-1) were measured by radioimmunoassay techniques in aortic preparations of normal and cholesterol-fed rabbits. Intact aortae of normal rabbits incubated with the calcium ionophore A23187 for 1 h at 37 degrees C released LTE4 and TxB2 (22 +/- 3.5 and 14.8 +/- 2 pg/mg of tissue, respectively, mean +/- SEM, n = 33). Removal of aortic endothelium was associated with a significant reduction in LTE4 (44%) and TxB2 (58%) release. In aortic preparations from cholesterol-fed rabbits, the release of LTE4 was significantly enhanced (41 +/- 8 pg/mg of tissue, mean +/- SEM, n = 27) whereas TxB2 was not significantly altered. No detectable amounts of ET-1 were measured after 1 h of incubation. However, at 4 h, an endothelium-dependent release of ET-1 from normal aortae was demonstrated. In atherosclerotic aortae, ET-1 release was significantly higher than in controls (10 +/- 1.3 vs. 5 +/- 0.5 pg/cm2, mean +/- SEM, n = 16). We conclude that enhanced formation of vasoconstrictor autacoids may contribute to altered vasomotion of atherosclerotic blood vessels.

Topics: Animals; Aorta; Arteriosclerosis; Calcimycin; Cholesterol, Dietary; Endothelins; Indoles; Indomethacin; Leukotriene Antagonists; Leukotriene E4; Male; Rabbits; SRS-A; Thromboxane B2

Thromboxane A2 (TXA2) biosynthesis was studied in healthy subjects, patients with chronic cerebral infarction, patients under chronic aspirin treatment and patients with atrial fibrillation. Urinary 11-dehydro-TXB2, as a major metabolite of TXA2, was measured by radioimmunoassay. The extent of carotid atherosclerosis was determined by B-mode ultrasonography. The mean +/- SD urinary excretion in patients with cerebral infarction and distinct carotid-atherosclerotic lesions (1,725 +/- 239 ng/g creatinine, n = 6) was significantly higher (p less than 0.01) than in healthy subjects (911 +/- 239 ng/g creatinine, n = 44) and patients with cerebral infarction who had no distinct carotid lesion (1,050 +/- 191 ng/g creatinine, n = 6). The urinary excretion of healthy subjects was higher (p less than 0.01) in smokers (1,063 +/- 244 ng/g creatinine, n = 17) than in non-smokers (815 +/- 183 ng/g creatinine, n = 27). Aspirin largely suppressed 11-dehydro-TXB2 excretion (266 +/- 114 ng/g creatinine, n = 7). Three of 5 patients with atrial fibrillation showed very high values. Our results indicated that platelet activation occurs in the atherosclerotic lesions, and that urinary 11-dehydro-TXB2 is the appropriate analytic target for detecting platelet activation.

Topics: Adult; Aged; Arteriosclerosis; Aspirin; Atrial Fibrillation; Carotid Artery Diseases; Cerebral Infarction; Female; Humans; Male; Middle Aged; Platelet Activation; Thromboxane A2; Thromboxane B2

This paper reports the treatment with Yiqi Huoxue and Shugan Liqi agents in atherosclerosis of rabbit. The results suggested: 1. Both decoctions could reduce the cholesterol of hypercholesterolemia and improve the atherosclerosis, but the former was better than the latter. 2. Both decoctions could alter the components of bile lipids, but on the contrary, the latter was better than the former in reducing the formation of gallstones. 3. Both decoctions could decrease the plasma concentration of LPO and ratio of TXB2/6-K-PGF1 alpha, while increase the ratio of cAMP/cGMP in plasma. So, the different prescriptions of TCM affecting the same link of pathogenesis might play the role of "Different Treatments in Same Disease".

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Cholelithiasis; Drugs, Chinese Herbal; Lipid Peroxides; Rabbits; 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

Apparently healthy adults were examined for their lipid and thromboxane parameters. The correlation between the levels of total cholesterol in serum and thromboxane B2/TXB2/ in plasma was strong mainly in men (p less than 0.01). However, the association between atherogenic index /AI/ and TXB2 levels tended to be higher in women. The authors suggest that, in healthy adults, elevated cholesterol levels coexist with abnormalities in thromboxane metabolism.

Topics: Adult; Aged; Arteriosclerosis; Cholesterol; Female; Humans; Hungary; Male; Middle Aged; Reference Values; Thromboxane B2

We have studied the relationship between levels of lipids and prostacyclin in 3- to 14-year-old children with a family history of ischaemic heart disease. The total levels of cholesterol in the serum of these children increased, while levels of the HDL-fraction and prostacyclin (measured as 6-keto-prostaglandin F1a) decreased significantly. Levels of thromboxane B2 in the plasma were unchanged. It is suggested that, in childhood, abnormalities of lipid metabolism co-exist with decreased levels of prostacyclin. The latter may be a new important indicator of early atherosclerotic disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Arteriosclerosis; Child; Child, Preschool; Cholesterol; Cholesterol, HDL; Coronary Disease; Female; Humans; Male; Risk Factors; Thromboxane B2

In 12 patients (8 males, 4 females; 59.4 +/- 6.2 years) with clinically manifest atherosclerosis (peripheral vascular disease stage II according to Fontaine and coronary heart disease) without any risk factor and 6 controls (4 males, 2 females; 58.5 +/- 7.06 years) autologous platelets were labelled using 100 microCi 111-In-oxine. In parallel, serum- and plasma-thromboxane (TX) B2 and conversion of exogenous radiolabelled arachidonic acid towards TXB2 were determined. No difference in labelling efficiency and recovery was noted. Platelet half-life was significantly (p less than 0.01) shortened in the atherosclerotics. Gamma-camera images were obtained during the first 64 minutes after reinjection as well as 2, 6, 18, 24 and daily up to 1 week after reinjection of autologous radiolabelled platelets. No difference between the patients suffering from atherosclerosis--having either visible atherosclerotic lesions or not--could be discovered. Serum-TXB2 was comparable, whereas plasma-TXB2 showed a trend towards an increase and the conversion from exogenous 14C-AA to 14C-TXB2 was increased in atherosclerosis.

Topics: Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; beta-Thromboglobulin; Blood Platelets; Cell Survival; Female; Half-Life; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Platelet Factor 4; Radionuclide Imaging; Thromboxane B2

Examination of the effect of calcium antagonists on the functional activity of monocytes revealed the possibility of using these cells as an object for testing antiatherosclerotic agents. The functional activity of monocytes was evaluated by their capacity of producing thromboxane B2 and by the cellular content of cyclic AMP. It is suggested that calcium antagonists verapamil and niphedipin, in particular, are potential antiatherosclerotic agents.

Topics: Angina Pectoris; Arteriosclerosis; Calcium Channel Blockers; Cells, Cultured; Cyclic AMP; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Monocytes; Physical Exertion; Thromboxane B2

The effects of edible black tree fungus (BFF) compared with aspirin on serum lipid level and experimental atherosclerosis and thrombosis in rabbits were studied. The results showed that total serum cholesterol and B-lipoprotein of the BTF group were significantly decreased (P less than 0.01) than the aspirin group and the group with neither BTF nor aspirin. There were less aortic atherosclerotic plaque and intramyocardial arterial lumen stenosis in the BTF group. The development of thrombus and platelet aggregation and thromboxane TXB2 level were inhibited both in the BTF and aspirin group (P less than 0.01). These findings indicate BTF may be used as a healthy food in preventing atherosclerosis and coronary heart disease, but its mechanism requires further investigation.

Topics: Animals; Arteriosclerosis; Basidiomycota; Cholesterol; Cholesterol, HDL; Food; Male; Platelet Aggregation; Rabbits; Thromboxane B2

Generation of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a greater than 90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PGF1 alpha levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples. We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Arteriosclerosis; Aspirin; Bleeding Time; Blood Platelets; Drug Administration Schedule; Endothelium, Vascular; Epoprostenol; Female; Humans; Male; Microcirculation; Middle Aged; Thromboxane A2; Thromboxane B2

In young patients with borderline arterial hypertension and, to a greater extent, with Stage 1 hypertensive disease (HD), changes were found in the proatherogenic plasma lipid and apoprotein composition, which were manifested as higher levels of total cholesterol, triglycerides, low and very low density lipoprotein cholesterols along with increased apolipoprotein B and apolipoprotein B:apolipoprotein AI ratio. The prostacyclin-thromboxane system in borderline arterial hypertension was in an activated state by retaining the physiological ratio of its components. The patients with Stage I HD exhibited a considerable increase in thromboxane activity, which determined the system's imbalance towards its predominance. In Stage I HD, the thrombocytic link of hemostasis was characterized by enhanced platelet aggregability mediated by the imbalance of the prostacyclin-thromboxane system in the direction of thromboxane.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Epoprostenol; Female; Humans; Hyperlipidemias; Hypertension; Lipids; Male; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Time Factors

Since Lou Fu-qing et al first reported that tea had effect on the prevention of atherosclerosis (AS) in the 1960s, we have conducted experimental and clinical studies, and found that tea-pigment (TP) could reduce blood coagulability, increase fibrinolysis, prevent platelet adhesion and aggregation, and decrease cholesterol content in aortic walls in vivo (P less than 0.01). In addition, TP was shown to inhibit the proliferation of cultured human aortic smooth muscle cells in normal and elevated LDL circumstance in vitro (P less than 0.01), and decreased the level of T x B2 in platelet-rich plasma and remote myocardial infarction patients (P less than 0.01). TP can be used in the prevention of AS.

Topics: Animals; Anticoagulants; Arteriosclerosis; Blood Coagulation; Catechin; Male; Muscle, Smooth, Vascular; Pigments, Biological; Platelet Aggregation Inhibitors; Rabbits; Tea; Thromboxane B2

Data in the literature suggest that cases of hypoalphalipoproteinemia involve an increase in thromboxane B2 (TXB2) together with an increased risk of atherosclerosis. A recent detailed examination of a 32-year-old man revealed clinical and biochemical features strongly indicative of that pathology. The case presented several unusual features: marked infiltration of the skin and mesenteric lymph nodes by histiocytic lipids with sufficient hyperplasia to induce acute intestinal occlusion combined with an in vivo TXB2 generation curve, subsequently inhibited by aspirin, that was comparable to the curves of the control subjects. Furthermore there were no signs of early atherosclerotic damage so that it was possible to postulate the hypothesis that despite the 50% drop in alpha-lipoprotein levels, they were still sufficient to ensure normal turnover of the other lipoproteins so that, however complex the clinical condition, it was an incomplete expression of a phenotype.

Topics: Adult; Arteriosclerosis; Aspirin; Chronic Disease; Histiocytes; Humans; Hypolipoproteinemias; Lipoproteins, HDL; Lymph Nodes; Male; Skin; Thromboxane B2

1. Aggregation of diluted whole blood (impedance method) and thromboxane B2 production during aggregation were measured in cigarette smokers and non-smokers, aged 41-68 years, with (n = 14) and without (n = 15) major symptomatic peripheral vascular disease. The plasma level of the lyso derivative of platelet activating factor (lyso-PAF) was also measured using a bioassay with 14C-serotonin labelled rabbit platelets, after extraction and acetylation to active PAF. 2. Aggregation to ADP and collagen was significantly less in non-smokers without vascular disease (n = 8) than in the other three groups (P less than 0.01; ANOVA). Thromboxane B2 production was not significantly different between the groups. There was no significant difference in plasma lyso-PAF between groups. No change was found in any variable after smokers smoked two cigarettes. 3. In these older age subjects, both vascular disease and the smoking habit were associated with greater whole blood aggregation. However, current smoking and the smoking of two cigarettes did not affect aggregation in subjects with vascular disease and plasma lyso-PAF levels were not consistently related to either smoking or vascular disease.

Topics: Adenosine Diphosphate; Adult; Aged; Arteriosclerosis; Cell Aggregation; Collagen; Humans; Male; Middle Aged; Platelet Activating Factor; Smoking; Thromboxane B2; Vascular Diseases

A remarkable variation in monocyte activation among individuals was observed when blood from different people was incubated with lipopolysaccharides. To elucidate this phenomenon, we studied intracellular signals associated with monocyte activation. This was done by measuring induced thromboplastin synthesis. An inhibitor of phospholipase A2 blocked the lipopolysaccharide induced synthesis of thromboplastin. Thus, release of arachidonic acid (20: 4) seemed to be necessary to activate the monocytes. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, had no effect on the monocyte activation in subjects with a low response to lipopolysaccharides (low responders); this contrasted with nearly 80% inhibition in individuals with very sensitive cells (high responders). Taking aspirin raised monocyte activation by an average of 50%, this was caused by the effect of aspirin on the platelets. Platelets enhanced the lipopolysaccharide activation of monocytes 2-3 fold. The high response phenomenon was partially due to platelets. When platelets in the blood of high responders were substituted with platelets from low responders, the monocyte activation fell by up to 70%. Fatty acids seemed to play a central role in the activation of monocytes. Intake of cod liver resulted in significant reduction of induced thromboplastin synthesis. It is suggested that those who are high responders may be more susceptible to developing atherosclerosis.

Topics: Arteriosclerosis; Blood Platelets; Dietary Fats; Fatty Acids; Humans; Monocytes; Thromboplastin; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Angiography; Arteriosclerosis; Cyclic AMP; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Physical Exertion; Polydeoxyribonucleotides; Thromboangiitis Obliterans; Thromboxane B2

The mechanism by which atherosclerotic disease is induced by cigarette smoking has not yet been identified unequivocally. Chronic cigarette smoking and the generation of vasoactive prostanoids and the size of carotid atherosclerotic plaques were studied in nine pairs of identical male twins discordant for smoking for over 20 years. The urinary excretion of 2,3-dinor-thromboxane B2 (thromboxane B2 metabolite) of the smoking twin was significantly higher (on average 1.8 times higher) in every pair and that of 2,3-dinor-6-keto-prostaglandin F1 alpha (prostacyclin metabolite) was significantly higher (on average 1.3 times higher) in eight of the nine pairs. The ratio of excretion of these metabolites was significantly higher, being 4.0 (95% confidence interval 2.7 to 5.4) among the smokers compared with 2.9 (2.1 to 3.8) among the non-smokers, thus favouring a mechanism of vasoconstriction. Excretion of the thromboxane B2 metabolite was related to the urinary concentrations of nicotine metabolites. Atherosclerotic plaques detected by ultrasonography in the carotid arteries were significantly larger among smokers but did not correlate with the urinary excretion of prostacyclin and thromboxane B2 metabolites or intensity of smoking. Smoking was concluded to induce activation of platelets by an effect mediated by nicotine. The increased prostacyclin production, on the other hand, suggested a compensatory mechanism for the general vasoconstrictive properties of cigarette smoking.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Carotid Artery Diseases; Cotinine; Diseases in Twins; Humans; Male; Middle Aged; Smoking; Thromboxane B2; Twins; Twins, Monozygotic; Ultrasonography

We have investigated the effects of a low-dose aspirin regimen (120 mg orally, then 20 mg twice daily) on the in vivo synthesis of prostacyclin, thromboxane and prostaglandin E in man by measurement of their urinary metabolites (PGI2-M, TxB2-M, PGE-M) using gas chromatography-mass spectrometry. A comparison was made between the selectivity of low-dose aspirin for thromboxane vs prostacyclin synthesis in patients with atherosclerosis, age-matched controls without vascular disease, and young healthy volunteers. After one week of treatment, aspirin reduced TxB2-M synthesis to a similar extent in the three groups (mean declines of 86, 84 and 78% respectively), while there was an unexpected difference in effect on PGI2-M, with only a 27% fall in the young volunteers but 53% and 54% declines in the patients with vascular disease and their age-matched controls. Serum TxB2 was reduced greater than 98% in all groups while PGE-M excretion was unchanged. These results indicate that bioselectivity for inhibition of Tx synthesis by aspirin is more difficult to achieve in older subjects than in the young volunteers previously studied and that very low, frequent dosing, or a sustained-release preparation of aspirin would be needed to achieve bioselectivity for Tx inhibition in patients with vascular disease.

Topics: Adult; Age Factors; Arteriosclerosis; Aspirin; Epoprostenol; Humans; Male; Middle Aged; Prostaglandins E; Thromboxane B2

To evaluate the effects of dietary fish oil on cholesterol-induced atherosclerosis, 36 New Zealand rabbits in four groups were fed a 0.3% cholesterol diet for 10 weeks. One group served as control, whereas groups I, II and III received 1, 2 and 3 ml/day, respectively, of fish oil (Protochol, eicosapentaenoic acid, 180 mg, and docosahexaenoic acid [DHA], 120 mg/ml). The percent of aortic and pulmonary atherosclerosis was measured by planimetry of sudanophilic lesions. The percent of aortic lesions in the control group was 59 +/- 22%. The two higher dose fish oil groups showed a significant reduction in aortic lesions: group I (40 +/- 26%, p = NS), group II (18 +/- 11%, p less than 0.01) and group III (36 +/- 22%, p less than 0.05). Area of pulmonary artery lesions was significantly higher in the control group (48 +/- 22%) as compared with group I (15 +/- 13%, p less than 0.01), group II (4 +/- 3%, p less than 0.01) and group III (8 +/- 9%, p less than 0.01). The high cholesterol diet in the control group decreased bleeding time from 82 +/- 17 to 59 +/- 22 s (p less than 0.05). Groups II and III showed an increased bleeding time (62 +/- 15 to 84 +/- 17 s and 66 +/- 22 to 95 +/- 27 s; p less than 0.05, respectively). Fish oil did not significantly alter total serum cholesterol and high density lipoprotein (HDL) cholesterol. In group II triglyceride decreased from 128 +/- 22 to 64 +/- 25 mg/dl (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta; Arteriosclerosis; Bleeding Time; Cholesterol; Cholesterol, Dietary; Fish Oils; Pulmonary Artery; Rabbits; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Arteriosclerosis; Blood Platelets; Epoprostenol; Humans; Leg; Physical Exertion; Thromboxane B2

Thromboxane and prostacyclin metabolite determinations (radioimmunoassay) were performed in obliterative atherosclerosis and in diabetes mellitus with microangiopathy. The shift of these metabolites to the thromboxane side could have been documented in both diseases. This phenomenon calls attention to an increased platelet activation and endothelial cell damage. In a third group patients received aspirin (500 mg on alternative days) which caused a marked inhibition of both thromboxane and prostacyclin production, measured this way. The possible role of altered balance of these two prostanoids in atherogenesis and diabetic angiopathy is discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Aspirin; Diabetes Mellitus; Epoprostenol; Female; Humans; Male; Middle Aged; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Thromboxane B2

The newly developed method, based on the quantitation of changes in electrical impedance, to determine platelet aggregation in whole blood was applied to the evaluation of the effects of Indobufen, a well known inhibitor of platelet rich plasma aggregation. The platelet antiaggregatory activity of the drug after single (200 or 400 mg) and repeated doses (200 mg or 200 mg b.i.d. for 1 week) was determined on whole blood aggregation and thromboxane B2 formation by platelet rich plasma of 16 patients with high risk of atherosclerosis. At 2 hr after the single dose treatments, Indobufen significantly reduced the whole blood aggregation induced by 0.5-2 micrograms/ml collagen. At 24 hr from the intake of the drug the aggregation was significantly inhibited in patients who ingested the 400 mg dose only. As far as the repeated administrations are concerned, it appears that the inhibition of whole blood aggregation and thromboxane B2 formation by platelets reached 12 hr after the last drug administration was comparable to the degree of inhibition achieved 2 hr after Indobufen intake. It is concluded that Indobufen orally administered to patients with high risk of atherosclerosis is a potent inhibitor of whole blood aggregation.

Topics: Adult; Aged; Arteriosclerosis; Blood Coagulation; Dose-Response Relationship, Drug; Female; Humans; Isoindoles; Male; Middle Aged; Phenylbutyrates; Platelet Aggregation Inhibitors; Risk Factors; Thromboxane B2

It is of great importance to clarify the role of thromboxane and prostacyclin in the process of atherosclerosis. In order to study this we induced atherosclerosis in rabbits through cholesterol feeding (1% w/w) for three to 12 weeks. After sacrifice the aorta was quickly removed and incubated. The in vitro thromboxane production measured as immunoreactive thromboxane B2 increased by 86 per cent in atherosclerotic vessels compared to control vessels (p less than 0.0005). The in vitro production of prostacyclin measured as immunoreactive 6-keto-prostaglandin F1 alpha showed a tendency to higher values in the atherosclerotic vessels compared to the control vessels (31%, p less than 0.025). This suggests that an increased thromboxane production rather than a decreased prostacyclin production might be important for the progression of atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Cholesterol, Dietary; Male; Rabbits; Thromboxane B2

11-Dehydro-TxB2 and 2,3-dinor-TxB2 are products of the two major pathways of thromboxane metabolism in man. In this study we compared urinary excretion of 2,3-dinor-TxB2 and 11-dehydro-TxB2 as indices of Tx biosynthesis in vivo. We performed three studies to assess i) the relative abundance of these two metabolites in the urine of healthy subjects, ii) their cellular origin under physiological conditions and iii) their relative formation during platelet activation. In healthy normal volunteers urinary 11-dehydro-TxB2 is more abundant than 2,3-dinor-TxB2 (792 +/- 119 pg/mg creatinine vs 106 +/- 21 pg/mg creatinine). Administration of a dose of aspirin selective for platelet cyclooxygenase (20 mg/day for 10 days) caused substantial and comparable suppression of both 11-dehydro-TxB2 (mean 82 +/- 4.9%) and 2,3-dinor-TxB2 (mean 79 +/- 6.9%). recovery of excretion of both metabolites after a nonselective aspirin regimen (325 mg BID for 3 days) corresponded to platelet life-span. Furthermore, excretion of both metabolites was increased in patients with severe atherosclerosis consistent with the known increase in platelet activation in this setting. Quantitative analysis of both urinary 11-dehydro-TxB2 and 2,3-dinor-TxB2 by GC-MS established that, in contrast to previous assumptions, 11-dehydro-TxB2 is the most abundant urinary metabolite of TxB2. The aspirin study demonstrates that platelets are the major source of both metabolites in urine, consistent with their increased excretion in severe atherosclerosis. Combined analysis of both metabolites will distinguish altered metabolism from increased biosynthesis of thromboxane A2.

Topics: Adult; Arteriosclerosis; Blood Platelets; Female; Humans; Male; Reference Values; Thromboxane B2

Molecular markers of hemostatic activation provide a reliable measure of the endogenous pathophysiologic state in atherosclerosis. Measurement of these markers before and after exercise provides a diagnostic probe for cellular-vascular interactions in patients with atherosclerosis. Molecular markers may possibly identify very early stages of atherosclerosis due to their inherent sensitivity. A high-risk cardiovascular population can be easily recognized by profiling molecular markers of hemostatic activation. Newly developed immunoassays can be used to quantitate these markers in routine laboratories. Additional clinical studies are needed to establish the diagnostic role of these molecular markers in patients with atherosclerosis and related disorders.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arteriosclerosis; beta-Thromboglobulin; Exercise Test; Fibrinopeptide A; Hemostasis; Humans; Middle Aged; Platelet Aggregation; Platelet Factor 4; Thromboxane B2; Tissue Plasminogen Activator

Topics: Arteriosclerosis; beta-Thromboglobulin; Blood Platelets; Half-Life; Humans; Hyperlipoproteinemias; Platelet Aggregation; Platelet Factor 4; Thromboxane B2

Populations that consume a diet rich in marine lipids may have a lower risk of atherosclerotic disease. Fish oil contains the N-3 polyunsaturated fatty acid eicosapentaenoate, and the biosynthesis of thromboxanes and prostacyclins from eicosapentaenoate (thromboxane A3 and prostaglandin I3), rather than from the usual precursor arachidonate (thromboxane A2 and prostaglandin I2), may help to reduce the risk. To examine this hypothesis, we studied the effect of eicosapentaenoate supplementation (10 g per day) for one month on the synthesis of thromboxanes and prostacyclins, as assessed by urinary metabolite excretion, in six patients with peripheral vascular disease and seven normal controls. Supplementation markedly increased the eicosapentaenoate content of phospholipids from red cells and platelets. Synthesis of the platelet agonist thromboxane A2, which was elevated in the patients at base line, declined by 58 percent during supplementation but did not reach normal values. The decline in thromboxane A2, which is synthesized from arachidonate, coincided with the formation of the inactive thromboxane A3, which is synthesized from eicosapentaenoate. A lower dose of eicosapentaenoate (1 g per day) was not sufficient to maintain the changes in thromboxane A2 synthesis. Platelet function was only moderately inhibited during eicosapentaenoate supplementation, consistent with incomplete suppression of thromboxane A2 synthesis. These studies show that a high dose of eicosapentaenoate alters the pattern of synthesis of thromboxanes and prostacyclins. However, effects comparable to those of aspirin require long-term administration in high doses. Whether other properties of fish oil might render it a more attractive antithrombotic therapy remains to be determined.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arteriosclerosis; beta-Thromboglobulin; Bleeding Time; Blood Platelets; Dietary Fats; Eicosapentaenoic Acid; Epoprostenol; Erythrocytes; Fatty Acids; Fish Oils; Humans; Male; Middle Aged; Phospholipids; Platelet Count; Platelet Factor 4; Thromboxane A2; Thromboxane B2; Thromboxanes

Patients were treated with defibrotide (3 X 200 mg/day) for 7 days. Plasma PGI2 and TXB2 levels were measured by RIA using EDTA-aspisol as anticoagulant and cyclooxygenase inhibitor. Isolated platelet c-AMP levels were also determined by RIA, using EDTA-dipyridamole as anticoagulant and phosphodiesterase inhibitor. Blood PGI2 levels were found to increase significantly upon treatment while the increase in TXB2 levels was not significant. Blood PGI2/TXB2 ratio increased 51%, 30 min after intravenous injection and it remained 28% higher during therapy than the predrug blood level. Significantly higher platelet c-AMP levels were also obtained after the injection of drug (0.02 less than p less than 0.05).

Topics: 6-Ketoprostaglandin F1 alpha; Arteriosclerosis; Blood Platelets; Cyclic AMP; Fibrinolytic Agents; Humans; Malondialdehyde; Platelet Aggregation; Polydeoxyribonucleotides; Prostaglandins; Thromboxane B2; Time Factors

The formation of the major metabolic products of endogenous arachidonic acid (AA) via cyclooxygenase and lipoxygenase pathways in platelets from normal and type IIA hypercholesterolemic subjects was evaluated. 12-Hydroxyeicosatetraenoic acid (12-HETE) and thromboxane B2(TXB2) were determined by selected ion monitoring (SIM) after extraction and purification of collagen stimulated platelet-rich plasma (PRP). The levels of both arachidonic acid metabolites in the non-stimulated PRP of control and type IIA subjects were below the detection limit of the method, rising significantly after collagen stimulation. Both 12-HETE and TXB2 levels in collagen-stimulated PRP samples from the patients were significantly higher than levels in controls (P less than 0.001). In view of the key role of 12-HETE in mediating smooth muscle cell migration and proliferation and in stimulating macrophage activity, these data may provide information for the understanding of the elevated incidence of thrombosis and atheromatous lesion in patients with type IIA hypercholesterolemia.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Female; Humans; Hydroxyeicosatetraenoic Acids; Hyperlipoproteinemia Type II; Male; Middle Aged; Platelet Aggregation; Thromboxane B2

Feeding a cholesterol rich diet (0.3%) to rabbits for up to 10 weeks resulted in morphological changes of the vascular wall. Microscopic evaluation of the aorta revealed a lipid infiltration and an intimal thickening containing foam cells, which both became more pronounced as the cholesterol feeding was more prolonged. The intimal prostacyclin production showed a transient increase after 2 weeks, but was significantly decreased after 6 weeks of diet and remained at this low level during the rest of the experiment. No significant changes in formation of thromboxane B2 by the platelets could be observed, whereas the production of 12-HETE was enhanced.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Epoprostenol; Male; Microscopy, Electron; Rabbits; Thromboxane B2; Triglycerides

Platelets play an important role in the development of atherosclerosis. The arachidonic acid, whose oxygenated metabolites are potent regulators of the platelet-vessel wall interactions, is released from membrane phospholipids by the phospholipase (s) system (s). These membrane-linked phenomena are strongly modulated by the membrane physical properties. The present study was carried out to investigate the relationship between membrane fluidity and arachidonic acid metabolism in platelets from atherosclerotic patients. Twenty-one patients with peripheral vascular disease and twelve controls were studied. Platelets from patients showed an increase in membrane fluidity and enhanced thrombin-stimulated thromboxane synthesis. No alterations were found, however, in total phospholipid fatty acid composition. A significant decrease in the cholesterol/phospholipid ratio could account for the alterations in the membrane physical properties described in the platelets from patients.

Topics: Aged; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Chromatography, High Pressure Liquid; Fluorescence Polarization; Humans; Lipids; Male; Membrane Fluidity; Middle Aged; Thrombin; Thromboxane A2; Thromboxane B2; Thromboxanes; Tritium

In a review the possible relevance of the eicosanoid system for arteriosclerosis is outlined. Particularly the interdependence between prostacyclin and thromboxane regarding the development of arteriosclerosis is discussed. Own findings show the influence of lipoproteins on the synthesis of prostacyclin or thromboxane in different biological material. On the one hand, HDL stimulates the synthesis of prostacyclin, whereas LDL inhibits it; both of them were sampled from human volunteers. On the other hand, the synthesis of thromboxane is inhibited by HDL and stimulated by LDL. The results indicate the close relationship between the lipoprotein and the eicosanoid hypotheses of arteriosclerosis.

Topics: Animals; Arteries; Arteriosclerosis; Blood Platelets; Eicosanoic Acids; Epoprostenol; Humans; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Thromboxane A2; Thromboxane B2

We studied platelet half-life (T/2), plasma thromboxane B2-levels (TXB2) and circulating endothelial cells in 107 patients with a mean age of 63 +/- 6.8 years and angiographically proven peripheral vascular disease (PVD). Patients were divided into 4 groups according to Fontaine but also according to additional clinical manifestations of atherosclerosis like coronary heart disease (CHD) and cerebrovascular disease (CVD). Furthermore, the influence of sex and smoking was investigated. Compared to patients without atherosclerotic manifestations we could detect an enhanced platelet consumption measured as shortened platelet half-life time (79.2 +/- 9.1 vs 100.9 +/- 5.6 hours, p less than 0.001 and an increased platelet activity measured as increased TXB2-plasma levels (51.6 +/- 20.9 vs 23.2 +/- 11.2 ng/ml, p less than 0.001). Correspondingly, the amount of circulating endothelial cells was increased 45.2 +/- 25.7 vs 20.3 +/- 23.4, p less than 0.001). Patients with PVD who smoked had the shortest actual platelet half-life, the highest TXB2 plasma levels and the greatest amount of circulating endothelial cells compared to non-smoking patients and controls. Patients with clinical stage IV according to Fontaine had the shortest platelet half-life, the highest TXB2 plasma levels and the greatest amount of circulating endothelial cells compared to the other clinical stages. Analyzing the influence of additional clinical manifestations of atherosclerosis we could detect only in patients with PVD and CHD significant differences compared to the other groups.

Topics: Adult; Arteriosclerosis; Blood Platelets; Endothelium; Female; Half-Life; Humans; Leg; Male; Middle Aged; Thromboxane B2

The phospholipid platelet-activating factor (PAF) stimulates platelet aggregation and coronary vasoconstriction. In this study we determined whether PAF alters coronary flow patterns in vivo in a canine preparation with concentric coronary artery stenosis. This preparation is characterized by cyclic flow variations in coronary blood flow associated with transient platelet aggregation at the site of the coronary constriction. Thirty-nine male mongrel dogs were used in three protocols. In protocol 1, PAF (10(-9) or 10(-8) mol/min) was infused into the coronary artery proximal to the stenosis to determine (1) whether PAF induces cyclic flow variations and (2) whether PAF has an effect on systemic hemodynamics. Cyclic flow variations were induced in three of six dogs; in these animals, mean arterial pressure decreased by 5.5% and 42.1% 10 min after infusion of the lower and higher dose of PAF. In protocol 2, cyclic flow variations were abolished with either the thromboxane synthetase inhibitor UK38485 (mean dose 2.2 mg/kg iv), the serotonin antagonist ketanserin (0.5 mg/kg iv), or the alpha 2-adrenergic antagonist yohimbine (2 mg/kg iv). Subsequent administration of PAF restored the frequency of cyclic flow variations to the preantagonist levels. Thromboxane (Tx) B2 and 6-keto-PGF1 alpha, the stable metabolites of TxA2 and prostacyclin, respectively, were measured in blood obtained distal to the coronary stenosis. TxB2 levels increased substantially during cyclic flow variations and were returned to control values with the thromboxane synthetase inhibitor UK38485. Infusion of PAF subsequently restored cyclic flow variations without altering coronary arterial coronary arterial TxB2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic alpha-Antagonists; Animals; Arteriosclerosis; Coronary Circulation; Coronary Disease; Dogs; Hemodynamics; Imidazoles; Male; Platelet Activating Factor; Platelet Aggregation; Serotonin Antagonists; Thromboxane B2

Plasma levels of thromboxane B2 (TXB2) and 6-keto PGF1 alpha in the blood samples taken at the coronary sinus and ascending aorta from twenty-one Japanese patients with variant angina and twenty with effort angina were measured by radioimmunoassay, the objective being to search for the contribution of prostanoids in coronary spasm. The data were compared with data on thirteen subjects free from coronary artery diseases. In coronary sinus blood, plasma TXB2 in patients with effort angina exhibited statistically significant high levels, as compared with data in the controls. These with variant angina also had high levels, albeit without a statistically significant difference. Eight patients with variant angina and for whom the coronary angiogram showed more than 50% of narrowing had statistically significant high levels of TXB2, and the other thirteen with variant angina and normal coronaries or less than 50% of narrowing had the same plasma levels of TXB2 as the controls. In contrast to TXB2, the plasma levels of 6-keto PGF1 alpha in both coronary sinus and aortic blood of patients with variant angina were very low, as compared with normal controls. Statistically significant low levels of 6-keto PGF1 alpha were noted in the coronary sinus blood of patients with variant angina with normal coronaries and in the aortic blood of those with variant angina, as compared with data on the normal controls. Neither ergonovine test nor spontaneous attacks in patients with variant angina revealed characteristic changes in levels of TXB2 and 6-keto PGF1 alpha in the coronary sinus. These data suggest that high levels of TXB2 in patients with atherosclerotic coronaries may be one factor leading to spasm, while low levels of PGI2 may be a contributing factor.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Angina Pectoris, Variant; Arteriosclerosis; Coronary Vessels; Ergonovine; Exercise Test; Female; Humans; Male; Middle Aged; Thromboxane B2

The metabolism of [1-14C]arachidonic acid [( 1-14C]AA) by washed platelets from macaques and human subjects was investigated. The results were as follows: At substrate levels of 1 microM, similar amounts of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), and thromboxane A2 (TXA2), measured as thromboxane B2 (TXB2), were produced from [1-14C]AA by platelets from rhesus, Celebes black, and cynomolgus macaques and humans. An increase in the AA concentration from 1 microM to 20 microM decreased the TXB2: PGD2 ratio (aggregator: antiaggregator) from greater than 5 to less than 2 in all series. In the human series, the ratio decrease was due to an increase in PGD2 production; in the macaque series, PGD2 production increased and TXB2 production decreased. Under basal conditions and at 1 microM AA concentrations, the amounts of prostaglandins and thromboxanes produced by platelets from male and female rhesus macaques were the same. An increase in substrate concentration from 1 microM to 20 microM AA decreased TXB2 production and increased PGD2 production to the same extent in platelets from male and female rhesus macaques. Imidazole increased prostaglandin production and decreased TXB2 production by platelets from both male and female rhesus macaques. The TXB2: PGD2 ratios were reduced below 1.5; there was no difference between the ratios in the two series. In the presence of 1 mM imidazole, greater amounts of prostaglandins and thromboxanes were produced in the male than in the female series. These data indicate that macaque's platelets are a suitable model for the study of AA metabolism in human platelets.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Chromatography, Thin Layer; Dinoprost; Dinoprostone; Female; Humans; Macaca; Male; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins D; Prostaglandins E; Prostaglandins F; Sex Factors; Thromboxane B2

Thrombin-induced thromboxane (TX) A2 production in whole blood, as reflected by serum TXB2 measurements, has proven to be a simple and reproducible capacity-related index of platelet TXA2 production ex vivo. In the present study we have determined the influence of a number of physiologic variables on serum TXB2 measurements performed by radioimmunoassay in a group of 177 subjects undergoing evaluation for atherosclerosis risk factors. Serum TXB2 averaged 300 +/- 108 ng/ml in the whole group, with a normal distribution. No statistically significant correlation was found between serum TXB2 and the continuous variables examined (age, BMI, blood pressure, cigarettes, serum cholesterol, triglyceride, glucose and wine consumption) except for the number of platelets. Platelet TXB2 production did not differ between men and women (296 +/- 119 vs 302 +/- 100 ng/ml). We conclude that, within the limits of the examined variables, serum TXB2 is an easily measurable and highly reproducible capacity index primarily related to platelet cyclooxygenase and TX-synthase activity, which can be used for monitoring drug- or disease-induced changes of these enzyme activities.

Topics: Adolescent; Adult; Aged; Alcohol Drinking; Arteriosclerosis; Blood Platelets; Child; Female; Humans; Lipids; Male; Middle Aged; Thromboxane B2; Thromboxanes

Seven males with atherosclerotic disease received daily 1.6 g of the thromboxane antagonist BM 13.177 in two separate oral dosages over a period of four days. The drug significantly reduced elevated plasma levels of thromboxane B2, beta-thromboglobulin and platelet factor 4, whereas thromboxane B2 generation was only slightly depressed. BM 13.177 inhibited platelet aggregation by collagen, and to a minor degree the second wave of ADP induced aggregation. Platelet sensitivity to prostacyclin and aggregation by ristocetin were not altered. Bleeding time was prolonged. All effects disappeared within 24 hours after the last application of the drug. No side effects were noted. Thus BM 13.177 appears to be a safe and effective new antiplatelet drug.

Topics: Arteriosclerosis; beta-Thromboglobulin; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; Male; Metabolic Clearance Rate; Middle Aged; Platelet Aggregation; Platelet Factor 4; Sulfonamides; Thromboxane B2

Topics: Animals; Arteriosclerosis; Blood Platelets; Diet, Atherogenic; Dietary Fats; Disease Models, Animal; Epoprostenol; Fatty Acids; Liver; Phospholipids; Prostaglandins; Rabbits; Rats; Thrombosis; Thromboxane B2; Thromboxanes

Plasma levels of thromboxane B2, and 6-Keto-PGF1 alpha, stable metabolites of thromboxane and of prostacyclin were determined by radioimmunoassay in 17 patients with arterial disease and 10 control subjects. The production of prostacyclin from incubates of aortic microsomal fractions of patients was also studied. There was a significant elevation of thromboxane B2 in the peripheral venous blood of patients with arterial lesions (142 +/- 152 pg/ml vs 22 +/- 2 pg/ml, p less than 0.005); levels of 6-KetoPGF1 alpha were equally low in controls and patients. Rate of production of prostacyclin, which was 450 +/- 24 pmol/50 mg of proteins in 10 minutes in controls, was reduced to 97 +/- 86 pmol/50 mg prot. 10 min (p less than 0.01) in patients. Co-existence of raised plasma thromboxane levels and a reduced capacity for prostacyclin synthesis in the same patients is supportive evidence of the thrombogenic theory of arterial disease.

Topics: 6-Ketoprostaglandin F1 alpha; Aorta; Arteriosclerosis; Epoprostenol; Humans; Leg; Male; Middle Aged; Thromboxane B2; Thromboxanes

We evaluated the effect of four weeks treatment with 90 mg and 1500 mg of acetylsalicylic acid (ASA), 990 mg of ASA together with 225 mg of dipyridamole and 225 mg of dipyridamole daily on the production of thromboxane A2 (TxA2) by platelets of atherosclerotic subjects. All doses of ASA studied inhibited 99% or more of TxA2 production from the third day to the end of the treatment, whereas dipyridamole did not have any effect. After the treatment, TxA2 production recovered in two weeks. Our results argue against the clinical relevance of the recent suggestions that salicylate accumulating during prolonged treatment with ASA could reduce the effect of the parent drug on the synthesis of TxA2 by platelets. Our data also dispute the inhibition of TxA2 synthesis as an antithrombotic mechanism of dipyridamole.

Topics: Aged; Arteriosclerosis; Aspirin; Blood Platelets; Dipyridamole; Female; Humans; Kinetics; Male; Thromboxane A2; 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 effect of an atherogenic diet on the endothelium of the central artery of the rabbit ear was studied by scanning and transmission electron microscopy. Examination of the inner surface of the artery after only 5 weeks on the diet revealed morphological changes including irregularly shaped cells, breaks at intercellular junctions, swelling of the membrane over the central part of the cells, and occasional holes in the cells. By 9 weeks more severe damage was seen including lifting off of cells and some holes. In addition, arrays of dark spots were seen by scanning electron microscopy in some cells in arteries of rabbits fed the diet for 5 to 9 weeks. The dark spots may correspond to abnormally large vacuoles seen inside endothelial cells by transmission electron microscopy. The central ear artery and aorta of some rabbits were tested for their ability to convert arachidonic acid into prostacyclin and thromboxane A2 by radioimmunoassay of the stable metabolites 6-keto-prostaglandin F1 alpha and thromboxane B2. The vessels from rabbits fed the atherogenic diet did not differ from vessels of rabbits on the control diet in their production of either metabolite.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Arteries; Arteriosclerosis; Cell Membrane; Diet, Atherogenic; Ear; Endothelium; Male; Microscopy, Electron; Rabbits; Thromboxane B2; Vacuoles

Topics: Animals; Arteriosclerosis; Blood Platelets; Cholesterol, Dietary; Coronary Vessels; Dinoprost; Electrocardiography; Heart Rate; Male; Microsomes; Prostaglandins F; Rabbits; Thromboxane A2; Thromboxane B2; Thromboxanes

The role of thromboxane in human, rabbit, dog, pig and sheep platelet aggregation has been studied. Each of these species showed a concentration-dependent relationship between collagen concentrations and the thromboxane B2 (TXB2) released from aggregating platelets, however sheep platelets produced only 17.5% of the amount of TXB2 released from human platelets under the same collagen stimulus. Indomethacin did not inhibit sheep platelet aggregation in the concentration range 0.114 mM - 0.114 muM, yet proved to be a potent inhibitor of human platelet aggregation. The prostaglandin endoperoxide analogue, U.46619, induced human platelet aggregation at a dose of 100 ng, however the analogue, at doses as high as 500 micrograms was much less active on sheep platelets when compared to human platelets. Thus we have demonstrated that there are differences in the extent of thromboxane involvement in platelet aggregation between different species, which must be considered with other criteria, before choosing an animal model for studying human atherosclerosis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arteriosclerosis; Blood Platelets; Collagen; Dogs; Humans; Indomethacin; Prostaglandin Endoperoxides, Synthetic; Rabbits; Sheep; Species Specificity; Swine; Thromboxane B2; Thromboxanes

In our ongoing studies of the interrelationship between platelets and the vascular wall we found that an accurate estimate could be made of the clinical condition and more effective therapy prescribed when we monitored alterations in the plasma levels of TXB2. For this purpose we devised a radioimmunoassay with I125-TXB2-Tyramide. Patients with ischemic heart disorders, cerebral apoplexy, diabetes mellitus, Buerger's disease, Takayasu disease etc., all had statistically high levels of TXB2 as compared with healthy controls. In particular, patients with myocardial infarction, cerebral thrombosis and/or hemorrhage all revealed increases in levels of TXB2 and these levels increased in parallel with a worsening of the clinical condition, and there was always a re-increase in TXB2 level before a recurrence of an attack. As plasma TXB2 levels clearly reflect thrombogenic disorders, the assessment of these levels on a routine basis, enables a more accurate diagnosis, an indication of possible recurrences, and more effective chemotherapy and rehabilitation.

Topics: Adolescent; Adult; Arteriosclerosis; Arteriosclerosis Obliterans; Child; Chromatography, Gel; Circadian Rhythm; Coronary Disease; Diabetes Mellitus; Dinoprost; Female; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Prostaglandins F; Takayasu Arteritis; Thromboangiitis Obliterans; Thromboxane B2; Thromboxanes

Topics: Arteriosclerosis; Aspirin; Coronary Circulation; Coronary Disease; Coronary Vessels; Dipyridamole; Humans; Platelet Aggregation; Propranolol; Tachycardia; Thromboxane B2; Thromboxanes

Prostacyclin is a potent but unstable vasodilator, and inhibitor of platelet aggregation, which is produced by blood vessel walls. Platelet aggregability may be constantly conditioned in vivo by local or circulating prostacyclin. Prostacyclin is important in the maintenance of vascular homeostasis and may be implicated in certain disease states. The use of prostacyclin in antithrombotic therapy appears logical, considering its action in increasing platelet cyclic AMP and reducing aggregation; its potential in antithrombotic therapy is presently being explored.

Topics: Arteriosclerosis; Blood Coagulation; Epoprostenol; Extracorporeal Circulation; Heparin; Humans; Lipid Peroxides; Platelet Aggregation; Prostaglandins; Thrombosis; Thromboxane B2

OKY-1581 is an effective inhibitor of thromboxane synthesis in vivo and in vitro. The generation of thromboxane B2 (TxB2), prostaglandin E (PGE) and prostaglandin F (PGF) was measured following clotting and during platelet aggregation induced by collagen. The presence of OKY 1581 either in vivo or in vitro caused a reduction in TxB2 generation during clotting and platelet aggregation with a concomitant increase in PGE and PGF. The effect could be observed two hours after oral or subcutaneous administration of 5 to 100 mg per rabbit and lasted for 24 to 48 hours. The reduction in TxB2 was not accompanied by an inhibition of clotting or platelet aggregation. OKY-1581 appears to be a suitable agent for studying the role of TxB2 in atherosclerosis.

Topics: Acrylates; Animals; Arteriosclerosis; Blood Platelets; In Vitro Techniques; Male; Methacrylates; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Rabbits; Thromboxane B2; Thromboxanes

A model system has been developed which employs the central artery of the rabbit ear, and allows for the study of 1) ultra-structural changes in the arterial endothelium and 2) formation and release of prostacyclin and thromboxane from the arteries in situ. Use of the model should be helpful in evaluating the initial events in atherosclerosis. Both prostacyclin and thromboxane (detected by radioimmunoassay) were formed by arteries in situ in response to infusion of sodium arachidonate.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Disease Models, Animal; Ear; Endothelium; Epoprostenol; Male; Rabbits; Thromboxane B2

Comparison of thrombocyte aggregation in response to arachidonic acid and synthesis of prostaglandins from C14-arachidonic acid by thrombocytes was made between atherosclerosis-susceptible White Carneau and atherosclerosis-resistant Show Racer Pigeons. Contrary to the expectations, thrombocytes from atherosclerosis-susceptible pigeons were a) less sensitive to arachidonic acid induced aggregation and b) synthesized less thromboxane B2 (stable product of proaggregatory thromboxane A2) from C14-arachidonic acid. Analysis of fatty acid composition of thrombocyte phospholipids indicated a higher concentration of arachidonic acid in White Carneau Pigeons. These results suggest that thrombocytes from atherosclerosis-susceptible pigeons are altered early and as a defense mechanism display less responsiveness towards aggregation.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Cholesterol; Columbidae; Phospholipids; Platelet Aggregation; Prostaglandins; Species Specificity; Thromboxane B2; Thromboxanes

Intact platelets from atherosclerotic rabbits release more thromboxane B2 (TXB2) and 12-hydroxyeicosatetraenoic acid (HETE) than platelets from normal rabbits following incubation with [14C]arachidonic acid (AA). In contrast, no difference is found between homogenates of platelets from normal and atherosclerotic animals. PGI2 stimulates cAMP accumulation and inhibits TXB2 formation more potently in intact platelets from atherosclerotic than from normal rabbits, but has no effect on AA metabolism in homogenised platelets.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Cyclic AMP; Epoprostenol; Male; Prostaglandins; Rabbits; Thromboxane B2; Thromboxanes

Groups of New Zealand white male rabbits were fed atherogenic diets containing 1% cholesterol. The diets of experimental groups were supplemented additionally with either aspirin, phenylbutazone, mefenamic acid, flufenamic acid, oxyphenylbutazone or aminopyrine. Blood cholesterol and phospholipids were measured at 3--4 week intervals. After 12 weeks the animals were sacrificed and the severity of atherosclerosis in the thoracic aorta was measured. In separate experiments, rabbit platelets were incubated with each of the drugs individually and conversion of [14C]arachidonic acid to thromboxanes and related compounds was assayed. Inhibition of collagen and arachidonic acid-induced platelet aggregation by each drug was also measured. All drugs inhibited thromboxane synthesis and platelet aggregation in varying degrees with flufenamate and aspirin being most and aminopyrine least effective. The pattern of metabolite formation from [14C]arachidonate was consistent with a block in the cyclooxygenase reaction. Phenylbutazone, flufenamic acid and oxyphenylbutazone produced significant reductions in atherosclerotic plaque formation without major changes in blood cholesterol levels or blood cholesterol--phospholipid ratios. Aspirin and aminopyrine were ineffective. The results indicate that the effectiveness of anti-inflammatory drugs as inhibitors of thromboxane synthesis and platelet aggregation in vitro does not afford a sufficient predictive index of their anti-atherogenicity in vivo. The significance of these findings is discussed in terms of the possible involvement of cyclooxygenase derivatives in atherogenesis.

Topics: Aminopyrine; Animals; Anti-Inflammatory Agents; Arteriosclerosis; Aspirin; Drug Evaluation; Flufenamic Acid; In Vitro Techniques; Male; Mefenamic Acid; Phenylbutazone; Platelet Aggregation; Rabbits; Thromboxane B2