thromboxane-a2 and Arteriosclerosis

Topics: Arteriosclerosis; Aspirin; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Gastrointestinal Hemorrhage; Humans; Male; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk; Stroke; Thrombosis; Thromboxane A2

Topics: Arrhythmias, Cardiac; Arteriosclerosis; Biomarkers; Cholesterol, VLDL; Coronary Restenosis; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Hyperlipidemias; Hypertension; Liver; Reference Values; Thrombosis; Thromboxane A2

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arteriosclerosis; Arteriosclerosis Obliterans; Aspirin; Cell Division; Cells, Cultured; Clinical Trials as Topic; Eicosanoids; Eicosapentaenoic Acid; Epoprostenol; Fibrinolytic Agents; Growth Inhibitors; Hemostasis; Humans; Hypolipidemic Agents; Muscle, Smooth, Vascular; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Signal Transduction; Thrombophilia; Thrombosis; Thromboxane A2

Active smoking is a well known risk factor for the development of atherosclerosis and in particular coronary heart disease and peripheral vascular disease. The negative effects of active smoking demonstrated on platelet function, the eicosanoid system and platelet thromboxane A2 generation may contribute to the hemostatic imbalance reported. Recently, the problem of passive smoking as a health risk has been widely discussed. Detailed information on the role of passive smoking on hemostatic parameters, however, is still very limited. As far as present knowledge is concerned, platelet activation seems to be significantly involved in the deleterious vascular effects of passive smoking as well.

Topics: Arteriosclerosis; Blood Platelets; Coronary Artery Disease; Humans; Platelet Activation; Risk Factors; Smoking; Thromboxane A2; Tobacco Smoke Pollution

Topics: Animals; Arteriosclerosis; Blood Pressure; Blood Vessels; Cardiovascular Physiological Phenomena; Cardiovascular System; Epoprostenol; Fatty Acids, Omega-3; Female; Humans; Hypertension; Male; Thromboxane A2

Platelets and their interaction with the vessel wall play a role in atherogenesis and in the formation of the coronary thrombus. Supplementation of the diet with n-3 PUFA shifts the platelet-vessel wall interaction in anti-thrombotic direction in healthy persons and in patients with IHD. This is in part caused by an inhibition of Tx synthesis and also by an increased synthesis of PGI2 and PGI3 in the vessel wall. However, the clinical significance of these findings needs to be elucidated in clinical trials. Large, dense platelets are more reactive than small ones. Platelet size and density are determined at thrombopoiesis. Large, reactive platelets have in states with an increased platelet demand been shown to be produced from large, high-ploidy megakaryocytes. In patients with thrombopoiesis in steady-state an inverse relation between the bleeding time and both the DNA content and the size of the bone marrow megakaryocytes has been demonstrated. The bone marrow megakaryocytes in these patients were larger in men than in women, which may explain the sex difference in bleeding time observed by others. In experimental atherosclerosis changes in megakaryocyte size have been demonstrated. The significance of these changes are still unclear. In a single study stimulation of the platelet-megakaryocyte axis was associated with an acceleration of experimental atherosclerosis. This study suggests that large, high ploidy megakaryocytes may produce a large amount of atherogenic platelets that may be responsible for the increased formation of atheroma in this model. However, due to the complexity of the study design this hypothesis needs verification in other experimental and clinical studies. In patients suffering from an AMI the mean platelet volume is increased. The bleeding time is shortened at the time of infarction in these patients probably due to increased synthesis of TxA2, but an increased production of adrenaline may also be of importance. These large, reactive platelets present in AMI may be a reflection of an altered thrombopoiesis in these patients. It remains to be established whether these changes in platelet reactivity are present before the time of coronary thrombus formation.

Topics: Animals; Arteriosclerosis; Blood Platelets; Coronary Disease; Coronary Thrombosis; Endothelium, Vascular; Epoprostenol; Fatty Acids, Unsaturated; Humans; Megakaryocytes; Platelet Aggregation; Thromboxane A2

Arachidonic acid is metabolized in endothelial cells to antiaggregatory, vasodilatory prostacyclin (PGI2), and in platelets to aggregatory, vasoconstrictory thromboxane A2 (TxA2). The balance of these two prostanoids is supposed to be involved with thrombogenesis and atherogenesis. Acetylsalicylic acid (ASA) inhibits irreversibly the key enzyme of the synthesis of these prostanoids, i.e. cyclo-oxygenase. Platelets do not synthetize new protein, but endothelial cells do. Because of this, and certain pharmacokinetic characteristics of ASA, it should be possible to shift the balance between PGI2 and TxA2 to the dominance of the former with the proper dose of this drug. Altogether more than 50,000 subjects have volunteered for studies on the effect of ASA in the primary or secondary prevention of myocardial infarction or ischemic stroke. The results show that it is possible to reduce vascular attacks by ASA. Furthermore, ASA has also found to prevent pre-eclampsia. Conclusions on the effect of ASA on the PGI2/TxA2-balance are hampered by uncertainties concerning the measurement PGI2 and TxA2 productions in vivo. It is, however, evident that the doses of ASA used in most trials have been high enough to inhibit partly also the production of PGI2. Whether smaller doses or less frequent administration would be more efficient, remains to be studied.

Topics: Arteriosclerosis; Aspirin; Clinical Trials as Topic; Drug Administration Schedule; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2

Topics: Animals; Arteriosclerosis; Endothelium, Vascular; Epoprostenol; Humans; Lipoproteins, LDL; Thromboxane A2

Topics: Animals; Arteriosclerosis; Coronary Disease; Epoprostenol; Humans; Hypertension, Pulmonary; Thromboxane A2

Disturbances in the balance between the production of thromboxane A2 by the platelets and that of prostacyclin by the vessel wall may play a major role in disease and be a target for therapeutic agents. Acetylsalicylic acid, given in small doses, may inhibit the production of thromboxane A2 without affecting that of prostacyclin. Even if it reduces prostacyclin synthesis, the drug is beneficial as an antithrombotic agent, possibly because it has actions not related to inhibition of cyclooxygenase. Dazoxiben not only inhibits the production of thromboxane A2 by platelets, but also facilitates that of prostanoids, in part by diverting endoperoxides to the blood vessel wall and to leukocytes. Although reduced production of prostacyclin may contribute to the etiology of atherosclerosis, the blood vessel wall of hypercholesterolemic animals exhibits an increased production of prostacyclin. The latter has been given successfully in patients with accelerated turnover of platelets or with peripheral vascular disease. However, its very short t1/2 limits its practical use. The availability of stable prostacyclin derivates, such as ZK 36374, may bypass this problem.

Topics: Animals; Arteriosclerosis; Aspirin; Blood Platelets; Blood Vessels; Epoprostenol; Humans; Prostaglandins, Synthetic; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vascular Diseases

Injury to the endothelial lining of arteries is an important mechanism in both the early and late stages of the development of atherosclerosis. Platelets can contribute to the early lesions by releasing factors that cause smooth muscle cell migration and proliferation. In the later stages, the formation of large platelet-fibrin thrombi that become organized into the vessel wall contributes to the development of focal atherosclerotic narrowing of arteries. Injury to the vessel wall can also be a factor in causing spasm of coronary arteries, particularly at sites of stenosis. The spasm may cause ischemia, anginal pain, and, in some individuals, ventricular fibrillation and death. In other individuals, the spasm may not cause death but may persist long enough for an occlusive thrombus to form and cause myocardial infarction. The events leading to thrombosis involve not only the release of arachidonic acid and the formation of TXA2, but other pathways that are independent of the arachidonate pathway. In some circumstances thrombin (which causes platelet aggregation and release that are largely independent of the arachidonate pathway and TXA2 formation) is the primary stimulus causing the initiation and growth of the thrombus. The role of products of the arachidonate pathway in causing spasm is not understood. PGI2 produced by the vessel wall could be important in preventing or minimizing coronary artery spasm. The best way to prevent the development of atherosclerosis and its clinical complications is to prevent or minimize injury of the endothelium.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Cell Division; Coronary Vasospasm; Endothelium; Epoprostenol; Humans; Muscle, Smooth, Vascular; Platelet Aggregation; Thrombosis; Thromboxane A2; Vasoconstriction

Topics: Animals; Arteriosclerosis; Aspirin; Cell Survival; Disease; Epoprostenol; Extracorporeal Circulation; Freezing; Humans; Thromboxane A2; Thromboxane-A Synthase

There is abundant evidence that changes in diet and various types of vessel wall injury can independently induce the growth of arterial lesions in experimental animals. These lesions closely resemble those found in humans with atherosclerosis. Whether endothelial injury or accumulation of lipoprotein in the arterial intima is the initial event, the progression of the disease is characterized by changes in the neointima that favor the deposition of lipid. The metabolism of proteoglycans may be especially important in this process; this is relevant to diabetes because changes in proteoglycan metabolism are associated with this disease. Insulin and growth hormone may favor the proliferation of smooth muscle cells in the arteries of diabetic patients. Many agents, which are potentially injurious to the endothelium, accentuate the response of the vessel wall to injury. Modifications of the thrombotic process, such as increased production of thromboxane by platelets, decreased production of prostacyclin by the endothelium, and increased production of von Willebrand factor further enhance the thrombotic process and may be important in the initiation and subsequent progression of atherosclerosis in diabetics. Alterations in lipoprotein metabolism may also facilitate the development of endothelial injury.

Topics: Animals; Arteries; Arteriosclerosis; Blood Platelets; Diabetes Complications; Diabetes Mellitus; Glycosaminoglycans; Humans; Hyperlipoproteinemias; Lipoproteins; Rabbits; Thromboxane A2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Blood Platelets; Blood Vessels; Diet, Atherogenic; Epoprostenol; Hemodynamics; Humans; Lipid Peroxides; Lipoproteins, LDL; Lipoproteins, VLDL; Muscle, Smooth, Vascular; Platelet Aggregation; Rabbits; Risk; Stress, Physiological; Thrombosis; Thromboxane A2; Time Factors

Topics: Anticoagulants; Arteriosclerosis; beta-Thromboglobulin; Blood Platelets; Clinical Trials as Topic; Humans; Intermittent Claudication; Leg; Platelet Aggregation; Platelet Factor 4; Suloctidil; Thiophenes; Thrombosis; Thromboxane A2; Ticlopidine

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Coronary Disease; Diet, Atherogenic; Myocardial Contraction; Myocardial Infarction; Nucleotides, Cyclic; Prostaglandins; Rabbits; Thiophenes; Thromboxane A2; Ticlopidine

Tests of platelet behaviour in vitro, particularly aggregation and retention and in vivo tests such as measurement of platelet survival and plasma levels of beta-thromboglobulin are frequently abnormal in diabetic patients, particularly in those with vascular disease. The concept has therefore arisen that platelet hyper-reactivity is one factor responsible for diabetic microangiopathy. Whereas there is experimental and histological evidence for the mediation of platelets in the pathogenesis of atherosclerosis, direct evidence of platelet involvement in microangiopathy is scanty. Similar alterations in platelet behaviour have been observed in a variety of other conditions with vessel wall damage in common and evidence is presented which suggests that these platelet abnormalities may be secondary to vessel wall injury. In diabetic subjects, some changes in platelet behaviour are reversed by improved glycaemic control. Evidence that platelets are involved in the pathogenesis of diabetic microangiopathy therefore remains circumstantial, though current trials of anti-platelet agents may enable a more precise evaluation of their role.

Topics: Adenosine Diphosphate; Animals; Arteriosclerosis; beta-Thromboglobulin; Blood Glucose; Blood Platelets; Blood Vessels; Cell Survival; Diabetes Mellitus; Diabetic Angiopathies; Endothelium; Epoprostenol; Humans; Platelet Adhesiveness; Platelet Aggregation; Platelet Factor 4; Platelet Function Tests; Thromboxane A2

Atherosclerosis is a curious process of the intima of the vessel walls characterized by platelet aggregation, deposition of thrombotic material, lipid and fibrin which finally culminates in the intimal thickening, vascularization, and haemorrhage from the new vessels. The lipids demonstrated in the atherosclerotic plaque are mainly cholesterol, triglycerides, and phospholipids. Hyperlipidaemia initiates and maintains the atherosclerotic process and a diet rich in unsaturated essential fatty acids is known to be of benefit in arresting the process. Prostaglandins are formed from unsaturated essential fatty acids and are known to regulate platelet aggregation and thrombus formation. Thus atherosclerosis may be a disease of altered PG system and if so this would pave the way for new therapeutic strategies.

Topics: Alprostadil; Arteriosclerosis; Aspirin; Blood Vessels; Cell Membrane Permeability; Cell Survival; Cholesterol; Endothelium; Epoprostenol; Humans; Platelet Adhesiveness; Prostaglandins; Prostaglandins E; Thromboxane A2

Topics: Animals; Arteriosclerosis; Epoprostenol; Hemostasis; Humans; Platelet Aggregation; Thrombosis; Thromboxane A2; Thromboxanes

Topics: Animals; Arteriosclerosis; Cyclic AMP; Epoprostenol; Extracorporeal Circulation; Fibrinolytic Agents; Homeostasis; Humans; Platelet Adhesiveness; Platelet Aggregation; Prostaglandins; Prostaglandins E; Purpura, Thrombotic Thrombocytopenic; Rabbits; Thromboxane A2; Uremia

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Pressure; Cardiovascular Physiological Phenomena; Coronary Circulation; Epoprostenol; Humans; Hypertension; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandins; Thromboembolism; Thromboxane A2; Thromboxanes; Vascular Resistance

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; Chemical Phenomena; Chemistry; Epoprostenol; Hemostasis; Heparin; Humans; Prostaglandins; Prostaglandins G; Thrombosis; Thromboxane A2

Metabolism of arachidonic acid (AA) in blood platelets and in vascular endothelium does not lead to prostaglandins, but thromboxane A2 and prostacyclin are generated. These labile metabolites of AA antagonize each other: thromboxane A2 is a vasoconstrictor and proaggregatory agent, whereas prostacyclin dilates arteries, prevents platelets from aggregation, and dissipates the preformed platelet clumps. Prostacyclin is a powerful stimulator of adenylate cyclase in platelets and therefore its antiplatelet action is potentiated by phosphodiesterase inhibitors such as theophylline or dipyridamole. Cyclo-oxygenase of AA is inhibited by aspirin, thromboxane synthetase by analogues of prostaglandin endoperoxides, and prostacyclin synthetase by linear lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxydation in the body and the subsequent molecular damage to prostacyclin synthetase in the rheologically determined areas of arterial walls. Endothelium deprived of prostacyclin is the basis for microthrombi formation, and follows a sequence of events described by Rokitansky and later by Ross. Prostacyclin is also a circulating hormone which is generated by the lungs. Thereby a damage of this "endocrine gland" by respiratory disorders, air pollution, or tobacco smoking are likely to contribute to pathogenesis of atherosclerosis, myocardial infarction, and arterial thromboembolism. Pharmacological treatment and prevention of these diseases should logically include antioxydants, prostacyclin and its analogues, thromboxane synthetase inhibitors and perhaps cyclooxygenase inhibitors (aspirin ?). Prostacyclin was already infused intravenously to men and its powerful antiaggregatory and deaggregatory actions were demonstrated. These properties of prostacyclin along with its vasodilator and positive inotropic actions destine this hormone to be a new type of antithrombotic drug in acute myocardial infarction.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Aspirin; Blood Circulation; Blood Vessels; Carotid Artery Thrombosis; Cyclooxygenase Inhibitors; Dogs; Epoprostenol; Female; Humans; Infusions, Parenteral; Male; Mice; Myocardial Infarction; Platelet Aggregation; Prostaglandins; Rabbits; Rats; Structure-Activity Relationship; Thromboembolism; Thromboxane A2; Thromboxanes

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Diet; Epoprostenol; Humans; Platelet Aggregation; Prostaglandins; Thromboxane A2; Thromboxanes; Vascular Diseases

Topics: Arteries; Arteriosclerosis; Carbon Monoxide; Cholesterol Esters; Epoprostenol; Glycosaminoglycans; Humans; Hypoxia; Muscle, Smooth, Vascular; Platelet Aggregation; Thromboxane A2

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

Topics: Adenosine Diphosphate; Animals; Arachidonic Acids; Arteriosclerosis; Blood Coagulation; Blood Platelets; Calcium; Cyclic AMP; Hemostasis; Humans; Prostaglandins; Prostaglandins G; Prostaglandins H; Rats; Thrombosis; Thromboxane A2; Thromboxanes

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

So far pharmacological consequences of inhibition of thromboxane A2 (TXA2) synthase by imidazole derivatives (e.g., camonagrel or dazoxiben) were linked to suppression of platelet activity. Here we report that in patients with peripheral atherosclerosis or in cats with extracorporeal thrombogenesis treatment with camonagrel is associated with activation of fibrinolysis or thrombolysis. These phenomena seem to be related to the camonagrel-induced shift in metabolism of prostaglandin endoperoxides from TXA2 to prostacyclin (PGI2), although in an in vitro model the involvement of the L-arginine/nitric oxide pathway cannot be excluded. In cats camonagrel (10 mg/kg i.v.) produced not only a fall in TXB2 but also a rise in 6-keto-PGF1 alpha and no change in cyclic-GMP plasma levels. This points to PGI2 rather than to nitric oxide as an in vivo mediator of camonagrel-induced thrombolysis. The crucial role of endogenous PGI2 in the thrombolytic response to camonagrel in cats was evidenced by its blockade following pretreatment of animals with a megadose of aspirin (50 mg/kg i.v.) and lack of any effect on pretreatment with L-NAME (100 micrograms/kg/min, i.v.). Obviously TXA2 synthase inhibitors (e.g., camonagrel) and cyclo-oxygenase inhibitors (e.g., aspirin) antagonize each other in their anti-thrombotic actions and must not be administered at the same time. Furthermore, in patients camonagrel (800 mg orally) suppressed TXA2 generation by 99.5% and doubled the plasma level of 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arteriosclerosis; Blood Coagulation Tests; Cats; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Female; Fibrinolysis; Humans; Imidazoles; Male; Middle Aged; Platelet Aggregation; Thrombosis; Thromboxane A2; Thromboxane-A Synthase; Ultrasonography, Doppler

Topics: Anticoagulants; Arteriosclerosis; beta-Thromboglobulin; Blood Platelets; Clinical Trials as Topic; Humans; Intermittent Claudication; Leg; Platelet Aggregation; Platelet Factor 4; Suloctidil; Thiophenes; Thrombosis; Thromboxane A2; Ticlopidine

Dihomo-gamma-linolenic acid ( DHLA ), a precursor of monoenoic anti-aggregatory prostaglandins (PGE1, PGD2), was administered for 4 weeks in a daily dose of 1.0 g into 33 patients with atherosclerosis on a basis of a double-blind trial. Comparison of treatment and placebo groups revealed elevation of DHLA in red cell lipids in DHLA -treated subjects. No differences, however, between the two groups could be observed in platelet aggregability, thromboxane A2 generation by platelets, serum cholesterol, PGE1 and PGE2 levels, and in inhibitory activity of low-density lipoproteins against prostacyclin synthetizing system in arteries. The dietary supplementation used did not lead to distinct antithrombotic effects.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Aged; Arteriosclerosis; Blood Glucose; Cholesterol; Dinoprostone; Epoprostenol; Fatty Acids, Unsaturated; Humans; Lipids; Lipoproteins, LDL; Male; Middle Aged; Platelet Aggregation; Prostaglandins E; Thromboxane A2

Antagonism or deletion of the receptor (the TP) for the cyclooxygenase (COX) product thromboxane (Tx)A2, retards atherogenesis in apolipoprotein E knockout (ApoE KO) mice. Although inhibition or deletion of COX-1 retards atherogenesis in ApoE and LDL receptor (LDLR) KOs, the role of COX-2 in atherogenesis remains controversial. Other products of COX-2, such as prostaglandin (PG) I2 and PGE2, may both promote inflammation and restrain the effects of TxA2. Thus, combination with a TP antagonist might reveal an antiinflammatory effect of a COX-2 inhibitor in this disease. We addressed this issue and the role of TxA2 in the promotion and regression of diffuse, established atherosclerosis in Apobec-1/LDLR double KOs (DKOs).. TP antagonism with S18886, but not combined inhibition of COX-1 and COX-2 with indomethacin or selective inhibition of COX-2 with Merck Frosst (MF) tricyclic, retards significantly atherogenesis in DKOs. Although indomethacin depressed urinary excretion of major metabolites of both TxA2, 2,3-dinor TxB2 (Tx-M), and PGI2, 2,3-dinor 6-keto PGF(1alpha) (PGI-M), only PGI-M was depressed by the COX-2 inhibitor. None of the treatments modified significantly the increase in lipid peroxidation during atherogenesis, reflected by urinary 8,12-iso-iPF(2alpha)-VI. Combination with the COX-2 inhibitor failed to augment the impact of TP antagonism alone on lesion area. Rather, analysis of plaque morphology reflected changes consistent with destabilization of the lesion coincident with augmented formation of TxA2. Despite a marked effect on disease progression, TP antagonism failed to induce regression of established atherosclerotic disease in this model.. TP antagonism is more effective than combined inhibition of COX-1 and COX-2 in retarding atherogenesis in Apobec-1/LDLR DKO mice, which perhaps reflects activation of the receptor by multiple ligands during disease initiation and early progression. Despite early intervention, selective inhibition of COX-2, alone or in combination with a TP antagonist, failed to modify disease progression but may undermine plaque stability when combined with the antagonist. TP antagonism failed to induce regression of established atherosclerotic disease. TP ligands, including COX-1 (but not COX-2)-derived TxA2, promote initiation and early progression of atherogenesis in Apobec-1/LDLR DKOs but appear unimportant in the maintenance of established disease.

Topics: Animals; Aorta; Arteriosclerosis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dietary Fats; Drug Interactions; Furans; Membrane Proteins; Mice; Naphthalenes; Propionates; Prostaglandin-Endoperoxide Synthases; Receptors, Thromboxane; Thromboxane A2

Production of thromboxane (TX) A2 and PG I2/prostacyclin (PGI2) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE-/-TP-/- mice exhibited a significant delay in atherogenesis, and apoE-/-IP-/- mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE-/-IP-/- mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE-/-TP-/- mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE-/-IP-/- and apoE-/-TP-/- mice, respectively, than in those of apoE-/- mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE-/-IP-/- mice than in either apoE-/-TP-/- or apoE-/- mice. We conclude that TXA2 promotes and PGI2 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Epoprostenol; Intercellular Adhesion Molecule-1; Macrophages; Mice; Mice, Knockout; Platelet Aggregation; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Epoprostenol; Receptors, Thromboxane; Thromboxane A2

We compared the impact of hypercholesterolaemia and mixed dyslipidaemia on vascular function, vascular structure and fibrinolytic balance in rabbits. To this end, vascular reactivity was studied in aortic rings from rabbits fed a control diet, a diet containing 0.5% cholesterol+14% coconut oil (mixed dyslipidaemia) or a diet containing 1% cholesterol (hypercholesterolaemia) for 12-14 weeks. Morphometric analysis of aorta was also performed and plasminogen activator inhibitor-1 (PAI-1) as well as tissue-type plasminogen activator (t-PA) plasma activities were measured. Both diets induced a similar increase in cholesterol plasma levels, although triacylglycerols (triglycerides) were increased in animals with mixed dyslipidaemia. Hypercholesterolaemia was associated with intimal thickening, reduction in acetylcholine-induced relaxation ( P <0.05) and increased vasoconstriction induced by acetylcholine+ N (G)-nitro-L-arginine methyl ester (L-NAME) when compared with controls ( P <0.05). These effects were more marked ( P <0.05) in animals with mixed dyslipidaemia. Incubation with ifetroban, a thromboxane A(2)/prostaglandin H(2) receptor antagonist, increased acetylcholine-induced relaxation ( P <0.05) and reduced acetylcholine+L-NAME contraction ( P <0.05) in both diet groups. In contrast, the presence of PD 145, an endothelin (ET)(A)/ET(B) receptor antagonist, exerted these effects only in rabbits with mixed dyslipidaemia. Both hypercholesterolaemia and mixed dyslipidaemia induced a similar increase in PAI-1 and a similar decrease in t-PA plasma activities. These data suggest that hypertriglyceridaemia can increase the deleterious effects of hypercholesterolaemia on endothelial function and vascular structure. This additional harmful effect exerted by triacylglycerols on endothelial function could, in part, be mediated by ET.

Topics: Acetylcholine; Animals; Aorta; Arteriosclerosis; Bridged Bicyclo Compounds, Heterocyclic; Diet; Endothelium, Vascular; Enzyme Inhibitors; Fibrinolysis; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; In Vitro Techniques; Male; Models, Animal; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxazoles; Plasminogen Activator Inhibitor 1; Rabbits; Thromboxane A2; Tissue Plasminogen Activator; Vasoconstrictor Agents

Epidemiological studies link acute infection of the respiratory tract to a transient increased risk of acute myocardial infarction. The underlying mechanisms remain unknown. We hypothesized that vasoactive mediators produced by inflammatory cells in the lungs and drained in the coronary circulation may trigger acute myocardial ischemia. To test this hypothesis we used an experimental model in the rabbit. Injection of the bacterial-derived peptide N-formyl-Met-Leu-Phe (or N-formyl-Methionyl-Leucyl-Phenylalanine)(fMLP) in the jugular vein induced massive recruitment of both polymorphonuclear leukocytes (PMN) and platelets in the microcirculation of the lungs, accompanied by rapid and marked increase of leukotriene B4, cysteinyl leukotrienes and thromboxane (Tx) A2 in the aortic blood. In all animals, fMLP evoked ischemic electrocardiographic changes: within the first minute of infusion a profound depression of the ST segment and inversion of the T wave were observed. Mean aortic pressure and heart rate fell to 64.0 +/- 6.9 and 83.5 +/- 3.1% of the basal levels at 3 and 10 min, respectively. All these alterations were transient. Aspirin, prevented electrocardiographic ischemic changes, reverted bradycardia and hypotension but did not significantly modify either PMN or platelet recruitment nor leukotriene synthesis. Ridogrel, a Tx-synthase and receptor inhibitor, prevented ECG alterations and bradycardia, but did not prevent and even worsened hypotension; it blocked platelet, but not PMN, sequestration. Pretreatment of animals with intravenous high dose of aspirin prevented ridogrel-dependent hypotension and platelet inhibition, suggesting that PGI2 contributes to the effects of Tx-synthase and receptor inhibitor. In hypercholesterolemic rabbits, ECG alterations persisted longer than in normal controls. In summary, our results indicate that acute activation of PMN and platelets in the lungs provokes transient myocardial ischemia, in normal animals that is exacerbated in hypercholesterolemic rabbits. TxA2 appears to be the major mediator of this phenomenon. Moreover the data suggest that a balance between TxA2 and PGI2 plays a pivotal role in platelet activation and recruitment in our model.

Topics: Acute Disease; Animals; Arteriosclerosis; Disease Models, Animal; Electrocardiography; Epoprostenol; Inflammation Mediators; Male; Myocardial Ischemia; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activation; Pneumonia; Rabbits; Thromboxane A2

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

Current consensus suggests that lysophosphatidylcholine is the major detrimental factor in oxidized low-density lipoprotein that may contribute to the alterations of vasomotor responses associated with atherosclerosis. This study investigated the influences of lysophosphatidylcholine and major lipid components in oxidized low-density lipoprotein on vascular relaxation. We also determine if there was any interaction between these phospholipid components on relaxation. Porcine coronary artery rings were incubated with lysophosphatidylcholine, phosphatidylcholine or sphingomyelin. After contraction by the thromboxane A2 mimetic U46619, rings were relaxed with bradykinin and calcium ionophore A23187. Lysophosphatidylcholine with a higher proportion of stearoyl-lysophosphatidylcholine to palmitoyl-lysophosphatidylcholine ratio caused greater reduction of relaxational responses. While phosphatidylcholine and sphingomyelin had no effect on vascular relaxation, they reduced the ability of lysophosphatidylcholine to impair vascular relaxation. Our results thus suggested that the effectiveness of oxidized low-density lipoprotein at inhibiting vasodilatory responses may be determined by the relative proportion of different types of lysophosphatidylcholine as well as the amount of other phospholipid components: phosphatidylcholine and sphingomyelin.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arteriosclerosis; Bradykinin; Calcimycin; Calcium; Cattle; Coronary Vessels; Dose-Response Relationship, Drug; Endothelium, Vascular; Ionophores; Lipoproteins, LDL; Liver; Lysophosphatidylcholines; Oxygen; Phosphatidylcholines; Phospholipids; Sphingomyelins; Swine; Thromboxane A2; Vasoconstrictor Agents

We examined the mechanism of action of lysophosphatidylcholine (lyso-PC), which is suggested to be involved in the pathogenesis of atherosclerosis and inflamatory disorders, and its interaction with well-known vasoactive compounds such as hydrogen peroxide (H2O2), thromboxane A2 (TX-A2), serotonin (5-HT), angiotensin II (Ang-II), endothelin-1 (ET-1), or urotensin II (U-II) on VSMC proliferation. Growth-arrested rabbit VSMCs were incubated with given concentrations of lyso-PC with H202, TX-A2, 5-HT, Ang-II, ET-1, or U-II. [3H]Thymidine incorporation into DNA was measured as an index of VSMC proliferation. Lyso-PC induced a maximal effect on [3H]thymidine incorporation at a concentration of 15 microM (156%), and its effect was significantly inhibited by the phospholipase C inhibitor U73122 (10 microM), the intracellular antioxidant NAC (400 microM), and the NADPH oxidase inhibitor diphenylene iodonium (1 microM), but not by the MAPK kinase inhibitor (10 microM). H2O2, TX-A2, 5-HT, Ang-II, ET-1, or U-II also stimulated [3H]thymidine incorporation in a dose-dependent manner. A non-mitogenic concentration of lyso-PC (5 microM) significantly potentiated the effect of low concentrations of H2O2 (0.1 microM, 110 to 222%), TX-A2 (5 microM, 120 to 202%), 5-HT (5 microM, 182 to 259%), Ang-II (0.5 microM, 167 to 304%), ET-1 (0.01 microM, 139 to 297%), or U-II (0.025 microM, 120 to 332%) on [3H]thymidine incorporation. The results suggest that lyso-PC acts synergistically with the vasoactive compounds H2O2, TX-A2, 5-HT, Ang-II, ET-1, or U-II in inducing VSMC proliferation, which may play an important role in the progression of atherosclerosis.

Topics: Angiotensin II; Animals; Aorta; Arteriosclerosis; Cells, Cultured; DNA; Drug Synergism; Endothelin-1; Hydrogen Peroxide; Lysophosphatidylcholines; Mitogens; Muscle, Smooth, Vascular; Rabbits; Serotonin; Thromboxane A2; Thymidine; Type C Phospholipases; Urotensins; Vasoconstrictor Agents

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 is the main lesion in allografts undergoing chronic rejection. We investigated the effect of OP-2507 (prostaglandin I2 analogue) and OKY-046 (thromboxane A2 synthetase inhibitor) on graft atherosclerosis morphologically and the production of eicosanoids in grafts in a rat aortic allograft model.. Abdominal aortic allografts of Lewis (RT-1(l)) rats were transplanted orthotopically into fully major histocompatibility complex mismatched Wistar King A/Qdj (RT-1(u)) rats that were subcutaneously administered OP-2507 (0.1 mg/kg/d) or OKY-046 (125 mg/kg/d), or both, with an osmotic pump. Four, 8, or 12 weeks later, the grafts were harvested and examined histologically, and the concentration of eicosanoids in the grafts were analyzed.. Lewis aortic allografts in Wistar King A recipients with no treatment displayed atherosclerosis, which involved gradual intimal thickening and medial thinning with continuous inflammation in adventitia. Neither OP-2507 nor OKY-046 treatment affected the intensity of adventitial inflammation. Although inhibition of medial thinning or a decrease in medial nuclear density was not observed, OKY-046 administration alone significantly inhibited an increase in intimal thickness. OP-2507 administration alone significantly inhibited a decrease in medial nuclear density and intimal thickening. Combined treatment with OP-2507 and OKY-046 further decreased the alteration of media and intima. The ratio of thromboxane B2 and 6-keto-prostaglandin F(1alpha) in the grafts was significantly reduced by OKY-046 but not by OP-2507 alone.. We have demonstrated that atherosclerosis in aortic allografts is inhibited by the continuous administration of either OP-2507 or OKY-046, and a combination of both agents strongly increases this inhibitory effect. Amelioration of balance in eicosanoid production in the grafts by the use of thromboxane A2 synthetase inhibitor and the simultaneous usage of stable prostaglandin I2 analogue may be a strategy for preventing atherosclerosis that results from chronic rejection.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Cell Nucleus; Drug Therapy, Combination; Enzyme Inhibitors; Epoprostenol; Kinetics; Male; Methacrylates; Rats; Rats, Inbred Lew; Rats, Wistar; Superoxides; Thromboxane A2; Thromboxane-A Synthase; Transplantation, Homologous

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

Thromboxane A(2) (TXA(2)) synthesis and expression of procoagulant activity (PCA) were investigated in mononuclear cells and monocytes prepared from a control and a Type 2 diabetic group. Monocytes from the diabetic group produced 2.10+/-0.81 ng of TXB(2)/5 x 10(5) monocytes compared to 1.26+/-0.43 ng/5 x 10(5) monocytes by the control group (P<0.01, n=11) when incubated in autologous plasma containing arachidonic acid (200 microg/ml). When monocytes were incubated in buffer containing arachidonic acid (20 microg/ml), cells from the diabetic group produced 1.65+/-0.68 ng of TXB(2)/5 x 10(5) monocytes compared to 1.07+/-0.31 ng/5 x 10(5) monocytes by the control group (P<0.02, n=12). Expression of PCA was examined in mononuclear cell preparations. Basal and maximally stimulated PCA with lipopolysaccharide (4.2 microg/ml) were not different between control and diabetic groups. However, arachidonic acid induced a four-fold (P<0.001) increase in PCA in the diabetic group. This activity was characterized as tissue factor. Increased synthesis of TXA(2) and expression of PCA may potentiate thrombosis and increase fibrin deposition, events that play primary roles in the development of vascular disease.

Topics: Arachidonic Acid; Arteriosclerosis; Blood Coagulation Factors; Cells, Cultured; Culture Media, Serum-Free; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Female; Humans; Kinetics; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Middle Aged; Monocytes; Thrombosis; Thromboxane A2

To determine the preventive effect of the oil from the seed of Torreya grandis cv. merrillii (OTM) on experimental atherosclerosis in rats.. The concentration of blood lipids, plasma thromboxane (TXA2), prostacyclin (PGI2), the ratio of TXA2/PGI2 and endothelin (ET) were investigated in male Wistar rats fed high-fat feed (HFF) containing OTM(2%) for 12 weeks.. OTM could reduce the level of serum total cholesterol (TC), triglyceride (TG) and the atherosclerosic index (AI), and increase the level of serum high-density-lipoprotein cholesterol (HDL-C). The plasma concentration of TXA2, ET and the ratio of TXA2/PGI2 in group supplemented with OTM were lower than those in HFF group. Moreover, the level of plasma PGI2, was higher than that in HFF group.. OTM is beneficial in preventing atherosclerosis.

Topics: Animals; Arteriosclerosis; Cholesterol, HDL; Epoprostenol; Lipids; Male; Plant Oils; Rats; Rats, Wistar; Seeds; Taxaceae; Thromboxane A2; Triglycerides

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

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

The authors present the evidence of atherogenic properties of VLDL and LDL potentiation on the model of endothelial cells-human umbilical vein endothelial cells, by preferable stimulation of the endothelial cell to thromboxane A1 production at in vitro conditions by atherogenic lipoproteins. The vasoconstrictive, thrombogenic and atherogenic effects of TXA2 are exerted on the vessel in this way. The ratio prostacycline/thromboxane, decisive for the maintenance of vascular homeostasis, is less than 1, this means the beneficial effect of prostacycline can not be applied. Protective, antiatherogenic effect of HDL and its subfractions HDL2 and HDL3/predominantly through their function in the reverse cholesterol transport from the periphery to the liver, antioxidative influence on LDL, as far as antiaggregation and fibrinolytic effects of HDL/is multiplied by the fact that HDL preferably stimulates the secretion of prostacycline by the endothelial cell. The ratio prostacycline/thromboxane A2 is higher than 1, that means beneficial vasodilative, antiaggregation and antiatherogenic effect of prostacycline on the vessel wall predominate. Quantitative evaluation of antiatherogenic effects of HDL subfractions (HDL2 and HDL3) revealed more significant antiatherogenic effect in HDL2 subfraction-in the sense of prostacycline secretion stimulation and exertion of its beneficial effects on the vessel. (Fig. 5, Ref. 33.)

Topics: Arteriosclerosis; Cells, Cultured; Endothelium, Vascular; Epoprostenol; Humans; Lipoproteins, LDL; Lipoproteins, VLDL; Prostaglandins; Thromboxane A2

Topics: Arteriosclerosis; Epoprostenol; History, 19th Century; History, 20th Century; Platelet Aggregation Inhibitors; Poland; Thromboxane A2

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

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arteriosclerosis; Calcium; Calcium Channel Blockers; Diet, Atherogenic; Estradiol; Magnesium; Male; Myocardial Contraction; Prostaglandin Endoperoxides, Synthetic; Rabbits; Rats; Rats, Wistar; Swine; Thromboxane A2; Verapamil

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

Cultured bovine aortic endothelial cells (BAEC) were incubated for 5 days with 10(-5) 4-hydroxynonenal (HN). HN treated BAEC and controls were either (i) further incubated with 125I-polymyxin B (IPxB) or with radioiodinated, inactivated coagulation factor Xa (IFXai) as markers of membrane phospholipid perturbation, or (ii) assayed for the synthesis of prostacyclin (PGI2) and thromboxane A2 (TXA2). Rabbit blood mononuclear cells enriched in monocytes (MC) were isolated and assayed for chemotactic response to HN. The results showed six - fold increases of IPxB and IFXai binding to BAEC treated with HN, as compared to untreated controls. We also found in HN treated cells a marked inhibition of PGI2 synthesis, but an unmodified TXA2 production. In addition, HN in the 10(-5)-10(-10) M range induced oriented migration of MC.

Topics: Aldehydes; Animals; Arteriosclerosis; Cattle; Cells, Cultured; Chemotaxis, Leukocyte; Endothelium, Vascular; Epoprostenol; Female; In Vitro Techniques; Lipid Peroxidation; Membrane Lipids; Monocytes; Pregnancy; Thromboxane A2

Topics: Animals; Arteriosclerosis; Blood Platelets; Endothelium, Vascular; Humans; Platelet Aggregation Inhibitors; Platelet-Derived Growth Factor; Thromboxane A2

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

Activated leukocytes release a variety of substances which have been shown in vitro to modulate vascular tone. The chemotactic peptide complement C5a is a physiological activator of leukocytes. We injected human recombinant complement C5a (10 and 100 micrograms) into the blood-perfused hind limb of normal and atherosclerotic cynomolgus monkeys and examined vascular responses. In both normal and atherosclerotic monkeys, the high dose of C5a produced about 65% decrease in leukocyte cell count in venous blood drainage from the hind limb. Injection of C5a produced a pronounced increase in resistance of large arteries (segment from iliac artery to dorsal pedal artery) in atherosclerotic, but not in normal monkeys. The constrictor effect of C5a in atherosclerotic monkeys was abolished by the thromboxane A2 receptor antagonist SQ 29,548 (2 mg/kg i.v.). The platelet-activating factor antagonist WEB 2086 (5 mg/kg, i.v.) did not alter vascular responses to C5a. We conclude that activation of leukocytes produces constriction of large arteries in atherosclerotic, but not normal, monkeys in vivo. This response may be mediated in part by release of thromboxane A2.

Topics: Animals; Arteries; Arteriosclerosis; Azepines; Bridged Bicyclo Compounds, Heterocyclic; Complement C5a; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Leukocytes; Lipids; Macaca fascicularis; Male; Platelet Activating Factor; Prostaglandins; Thromboxane A2; Triazoles; Vasoconstriction

Epidemiological studies performed in Greenland Eskimos and Japanese indicated that ingestion of fish meat rich in omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), reduces the incidence of cerebro- and cardiovascular thrombotic diseases. Therefore, the effect of administration of purified EPA, derived from sardine oil, on hemorrheological properties and serum lipids in patients with thrombotic disorders was studied. Dietary supplementation of EPA resulted in decrease in platelet aggregability with reduction of TXA2 production, prolongation of bleeding time, decrease of platelet adhesiveness, increase of red cell deformability, and improvement of serum lipid concentration. Decrease in platelet TXA2 production may be ascribed to the decrease in arachidonate (AA) content of platelet membrane, inhibition of AA release from platelet membrane and competitive inhibition of AA metabolism at the level of cyclo-oxygenase, by EPA. Administration of EPA increased PGI2 production in the rat thoracic aorta and co-culture of rat aorta smooth muscle cell with EPA also increased PGI2 production, but suppressed smooth muscle cell proliferation. This may be explained by a EPA-derived peroxide stimulation of cyclo-oxygenase activity. Administration of EPA decreased platelet-derived growth factor (PDGF) production in rat peritoneal macrophages. In EPA-rich peritoneal macrophages from rat given EPA, incorporation of acetyl LDL and accumulation of cholesterol in macrophages decreased. This may indicate that dietary supplementation of EPA suppress foam cell formation. An interesting finding is that EPA-rich LDL obtained from rabbits given EPA is less susceptible to Cu(2+)-catalyzed oxidative modification. This seems to indicate that EPA may also suppress lipid peroxidation of lipoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arachidonic Acid; Arteriosclerosis; Eicosapentaenoic Acid; Epoprostenol; Fibrinolytic Agents; Humans; Lipid Peroxidation; Lipids; Platelet Aggregation Inhibitors; Thrombosis; Thromboxane A2

Topics: Arachidonic Acid; Arteriosclerosis; Blood Platelets; Cell Membrane; Humans; Hyperlipidemias; Membrane Lipids; Platelet Aggregation; Prostaglandins; Thromboxane A2

Through an unknown mechanism, dimethyl sulfoxide (DMSO) retards atherogenesis in cholesterol-fed rabbits (CFR). We studied the effects on the development of lesions and prostacyclin (PGI2) production in the thoracic aorta and total serum lipid and cholesterol content of the abdominal aortic serum thromboxane (TXB2) and plasma fibrinogen levels in rabbits fed control versus atherogenic diets, with and without DMSO. Without DMSO, PGI2 production was significantly higher in CFR versus control animals (8.65 +/- 1.0 vs 6.38 +/- 0.3 ng/15 min [p less than 0.02]). DMSO did not influence PGI2 production in any of the groups but significantly reduced the number of atheromatous lesions in CFR (78% +/- 9% vs 8% +/- 4% [p less than 0.001]). With DMSO, CFR had a significant reduction in total lipid levels (422 +/- 5 vs 300 +/- 21 mg/gm dry wt [p less than 0.01]) and cholesterol levels (74 +/- 12.8 vs 31.8 +/- 6.4 mg/gm dry wt [p less than 0.01]) compared with control animals. Fibrinogen levels were significantly lower in CFR versus control animals (0.83 +/- 0.07 vs 2.42 +/- 0.13 mg/ml [p less than 0.01]). TXB2 was lower in DMSO plus control versus control animals alone. In conclusion, DMSO does not appear to act through changes in PGI2 or fibrinogen activity. Its effect in lowering TXB2 in CFR suggests an action on platelet function.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Dimethyl Sulfoxide; Drinking; Epoprostenol; Fibrinogen; Male; Rabbits; Thromboxane A2; Triglycerides; Weight Gain

Topics: Arteriosclerosis; Blood Platelets; Chromatography, Affinity; Chromatography, High Pressure Liquid; Diabetes Mellitus; Diabetic Angiopathies; Humans; Lipoproteins; Radioimmunoassay; Thromboxane A2

Differential inhibition of thromboxane A2 (TxA2) and prostacyclin (PGI2) biosynthesis has an antithrombotic potential, since it may change the TxA2/PGI2 formation ratio in a favourable direction. Very low doses of acetylsalicylic acid (ASA) have been demonstrated to elicit differential inhibition of TxA2 and PGI2 formation in healthy subjects; whether a similar effect can be obtained in patients with atherosclerosis is still an open question. We addressed this by analyzing the urinary excretion of the 2,3-dinor-metabolites of TxA2 (Tx-M) and PGI2 (PGI-M) in 10 patients with severe atherosclerosis during 10 consecutive days. The first three days were a basal period, under which no treatment was given. During the subsequent seven days a daily 50 mg oral dose of ASA was administered. In the basal state urinary Tx-M did not differ from that of PGI-M, the median excretion rates of the two eicosanoid metabolites being 526 (range 68-1490) and 562 (range 93-1970) pg/mg creatinine, respectively. During ASA treatment urinary Tx-M fell to a lower (p less than 0.001) level than PGI-M. Thus, during the last 5 days of ASA treatment the median excretion of Tx-M was depressed (p less than 0.001) to 148 (range 48-428) pg/mg creatinine, while that of PGI-M was decreased (p less than 0.01) to 313 (range 42-2658) pg/mg creatinine. These data indicate that a daily 50 mg dose of ASA inhibits cardiovascular formation of eicosanoids in patients with severe atherosclerosis and increased platelet TxA2 formation. Furthermore, this dose of ASA inhibits the formation of TxA2 more than that of PGI2.

Topics: Aged; Aged, 80 and over; Arteriosclerosis; Aspirin; Cyclooxygenase Inhibitors; Epoprostenol; Female; Humans; Male; Thromboxane A2

Total saponins of Panax notoginseng (PNS) were given orally 100 mg/(kg.d) to rabbit for 8 wk. Aortic atherosclerotic plaque formation was restrained as compared to the control group. Radioimmunoassay was used to investigate the effects of PNS on the contents of prostacyclin in carotid artery and thromboxane A2 in blood platelets of rat. Oral administration of PNS 25,50,100 mg/(kg.d) for 10 d, the caused an increase of prostacyclin in carotid artery and a decrease of thromboxane A2 in blood platelets as compared to the control group. These results show that the anti-atherosclerotic action of PNS may be a result of the correction of the unbalance between prostacyclin and thromboxane A2.

Topics: Animals; Arteriosclerosis; Blood Platelets; Carotid Arteries; Epoprostenol; Male; Panax; Plants, Medicinal; Rabbits; Rats; Rats, Inbred Strains; Saponins; Thromboxane A2

The lipoprotein (LP) fractions VLDL, LDL, HDL2 and HDL3 were prepared by ultracentrifugation of plasma from healthy volunteers and from patients with coronary heart disease (CHD). We investigated the capacity of platelets from healthy volunteers and patients with atherosclerosis to generate thromboxane A2 (TXA2) during spontaneous clotting of whole blood under the influence of the lipoprotein fractions. In our experiments the serum concentration of TXB2, reflecting the capacity of platelets to generate TXA2 during clotting, depends on several factors: the type of LP fraction used, the blood used for generation of TXA2, and for the same LP fraction whether it was taken from plasma of healthy volunteers or patients with CHD. VLDL prepared from plasma of healthy volunteers inhibited but VLDL prepared from plasma of patients with CHD enhanced the TXA2 formation of platelets from healthy volunteers (p less than 0.05, resp.). LDL from CHD patients inhibited the TXA2 formation of platelets from atherosclerotic patients (p less than 0.01). The HDL subfractions HDL2 and HDL3 from healthy volunteers inhibited TXA2 formation by platelets from healthy volunteers as well as those from atherosclerotic patients (p less than 0.05; p less than 0.01, respectively). HDL2 from patients with CHD inhibited only the TXA2 formation of platelets from healthy volunteers (p less than 0.01), whereas HDL3 from CHD patients inhibited only the TXA2 formation of platelets from atherosclerotic patients (p less than 0.01).

Topics: Adult; Aged; Arteriosclerosis; Blood Platelets; Cholesterol; Coronary Disease; Humans; Lipoproteins; Middle Aged; Thromboxane A2; Triglycerides

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

The demonstration that lipid peroxidation (enzymatic or non enzymatic oxidation of polyunsaturated fatty acids) is involved and plays a pathophysiological role (in relation to the metabolic pathways of prostaglandins, leukotrienes and to others inflammation-related events) in the initiation of arteriosclerotic plaques is a breakthrough in the pathogenesis of atheroma. Macrophages play a central role in this mechanism. Indeed foam cells are macrophages loaded with oxidized low density lipoproteins (LDL). These oxidized LDL are preferentially recognized by macrophages thanks to their scavenger receptor. The role of such foam cells in the initiation and development of atheroma is well known. The formation of arteriosclerotic plaques results in important endothelial alterations, and endothelial cells lose their protective ability to prevent platelet aggregation and related thrombotic events. Inflammation and thrombosis are overlapping phenomena which are mediated by common cells (platelets, polymorphonuclear leucocytes, monocytes, macrophages, endothelial cells). During the activation of such inflammatory cells a number of eicosanoids are produced, and the profile of such metabolites is largely controlled by cellular interactions. In addition these inflammatory cells have the ability to produce oxygen free radicals, and initiate non enzymatic lipid peroxidation.

Topics: Arteriosclerosis; Endothelium, Vascular; Humans; Lipid Peroxidation; Lipoproteins, LDL; Macrophages; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2

In monkeys with early and advanced atherosclerosis, we examined responses to the three major vasoactive agonists that are released when platelets aggregate. Measurements were obtained in normal cynomolgus monkeys and in monkeys fed an atherogenic diet for 4 +/- 1, 9 +/- 1, and 19 +/- 1 months (mean +/- SEM). Morphometry of femoral and iliac arteries indicated that 4 months of atherogenic diet produced only slight intimal thickening, 9 months produced early lesions, and 19 months produced approximately 5-10 fold greater intimal proliferation than did 9 months of atherogenic diet. Serotonin and adenosine 5'-diphosphate (ADP), which are endothelium-dependent agonists, and adenosine and phenylephrine, which are endothelium-independent agonists, were injected intra-arterially into the perfused hind limb. Thromboxane A2 analogue U46619 also was studied. Vasoconstrictor responses to serotonin were potentiated, and vasodilator responses to ADP were impaired by early and advanced atherosclerosis. In contrast, vasoconstrictor responses to phenylephrine and vasodilator responses to adenosine were similar in all groups. Vasoconstrictor responses to U46619 were potentiated by advanced atherosclerosis. Thus, vascular responses to serotonin, ADP, and thromboxane A2 are altered by atherosclerosis in a direction that would favor vasoconstriction when platelets aggregate. Furthermore, because responses to endothelium-dependent agonists are altered, these data suggest that endothelium is dysfunctional in early atherosclerosis. These findings may explain, in part, the propensity for exaggerated vasoconstriction even in arteries with minimal atherosclerotic lesions.

Topics: Adenosine Diphosphate; Animals; Arteriosclerosis; Blood Vessels; Diet, Atherogenic; Macaca fascicularis; Male; Serotonin; Thromboxane A2; Vasoconstriction

The effect of drugs on eicosanoid production and on the development of atherogenic index was investigated in canine myocardial ischemia. Iloprost, verapamil, the trapidil derivative AR 12463 or 0.9% NaCl solution were administered 60 min after coronary artery ligation in anaesthetized dogs. Both iloprost and AR 12463 reduced the thromboxane A2/prostacyclin (TXA2/PGI2) ratio in coronary sinus plasma in comparison to controls. The atherogenic index was significantly decreased in the iloprost as well as in the AR 12463-treated group in comparison to the control group. Verapamil had no influence on the investigated parameters.

Topics: Animals; Antihypertensive Agents; Arteriosclerosis; Biomarkers; Coronary Disease; Dogs; Epoprostenol; Female; Iloprost; Male; Pyrimidines; Reference Values; Thromboxane A2; Trapidil

Topics: Animals; Arteriosclerosis; Blood Platelets; Drugs, Chinese Herbal; Epoprostenol; Male; Membrane Fluidity; Rabbits; Thromboxane A2

Topics: Animals; Arteriosclerosis; Blood Platelets; Diet; Epoprostenol; Humans; Platelet Aggregation; Thromboxane A2

It has been proposed that atherosclerotic arteries produce less prostacyclin (PGI2) than nonatherosclerotic arteries do, thereby predisposing arteries to vasospasm and thrombosis in vivo. We reexamined this concept by measuring spontaneous as well as arachidonate-induced PGI2 biosynthesis in aortic segments from nonatherosclerotic and cholesterol-fed atherosclerotic New Zealand White rabbits. Thromboxane A2 (TXA2) generation was also measured. Formation of PGI2, as well as TXA2, as measured by radioimmunoassay (RIA) of their metabolites, was increased in atherosclerotic aortic segments relative to nonatherosclerotic segments (P less than or equal to 0.05) at 0, 5, 10, 15, and 30 min of incubation with arachidonate. Pretreatment of arterial segments with indomethacin inhibited PGI2 as well as TXA2 formation, whereas pretreatment with the selective TXA2 inhibitor OKY-046 inhibited only TXA2 release, thus confirming the identity of icosanoids. To confirm the RIA data, aortic segments were incubated with [14C]arachidonate prior to stimulation with unlabeled arachidonate. The uptake of arachidonate was similar, but the release of incorporated [14C]arachidonate was significantly (P less than or equal to 0.05) greater in atherosclerotic segments than in nonatherosclerotic ones. Conversions of released [14C]arachidonate to 6-keto[14C]prostaglandin F1 alpha and [14C]thromboxane B2 were similar in the two types of aortic segments. Thus, synthesis of PGI2 as well as TXA2 is increased in atherosclerosis, and this alteration in arachidonate metabolism is related to increased release of arachidonate.

Topics: Animals; Aorta, Abdominal; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Diet, Atherogenic; Epoprostenol; In Vitro Techniques; Indomethacin; Kinetics; Male; Rabbits; Reference Values; Thromboxane A2

The effect of dietary fish oil (rich in n-3 polyunsaturated fatty acids (PUFA], corn oil (rich in n-6 PUFA) and coconut oil (low in n-3 and n-6 PUFA) on the induction of atherosclerosis by serum sickness in rabbits was investigated over a 12-month period. Dietary fish oil led to a significant increase in the level of eicosapentaenoic acid (EPA) in all platelet phospholipid fractions and to a significant reduction in the level of platelet phosphatidylethanolamine arachidonic acid (AA). In aortic total phospholipids, rabbits given fish oil showed a significant reduction in AA and a significant increase in EPA. Rabbits given fish oil showed significantly lower collagen-induced platelet thromboxane A2 release and aortic production of 6-keto-PGF1 alpha. Serum total immune complex levels and anti-horse serum IgG levels were not influenced by diet. There was a significant reduction in total aortic atherosclerosis in fish oil-fed animals compared with coconut oil fed animals.

Topics: Animals; Antigen-Antibody Complex; Aorta; Arteriosclerosis; Blood Platelets; Cholesterol; Collagen; Dietary Fats, Unsaturated; Fatty Acids; Lipid Metabolism; Lipids; Muscle, Smooth, Vascular; Phospholipids; Prostaglandins; Rabbits; Thromboxane A2

Marine lipids containing omega-3 fatty acids (chiefly, eicosapentanoic acid [EPA] and docosahexanoic acid [DHA]) may inhibit the development of atherosclerotic vascular disease, but the mechanisms responsible for this putative beneficial effect are unknown. We investigated the effects of EPA and DHA in a canine model of accelerated vein graft arteriosclerosis during a 3-month period. Twenty-five dogs were divided into three dietary groups: group I (control), group II (2.5% cholesterol), and group III (2.5% cholesterol plus 2 gm EPA/day [as MaxEPA]). The effects of EPA on vein graft intimal thickening, platelet and vascular prostaglandin metabolism, lipid and lipoprotein receptor metabolism, and hematologic parameters were assessed. Cholesterol feeding caused a significant 54% increase in graft intimal thickness compared with control animals (124.9 +/- 50.4 vs 81.2 +/- 32.4 micron; p = 0.013), which was prevented by supplementation with EPA in group III (56.9 +/- 30.0 micron; p = 0.001 vs group II). Intimal thickness in group III was not significantly different from that of control. EPA supplementation was also associated with a 38% decline in serum thromboxane levels from 457.0 +/- 129.3 pg/0.1 ml in group II to 283.5 +/- 96.9 pg/0.1 ml in group III (p = 0.007). The alterations in lipoprotein metabolism associated with cholesterol feeding were not affected by EPA: in both groups II and III, serum cholesterol and high-density lipoproteins and liver cholesterol content were elevated and hepatic low-density lipoproteins (LDL) receptor content was reduced. There were no differences between the three groups in terms of vein graft or native vessel prostacyclin production, hematocrit, platelet count, or coagulation parameters. In this canine model, dietary supplementation with marine omega-3 fatty acids reduced the extent and magnitude of accelerated vein graft intimal thickening induced by hypercholesterolemia; moreover, this beneficial effect was associated with lower serum thromboxane production and appeared to be independent of alterations in lipoprotein metabolism or LDL receptor density.

Topics: Animals; Arteriosclerosis; Blood Vessel Prosthesis; Cholesterol, Dietary; Docosahexaenoic Acids; Dogs; Drug Combinations; Eicosapentaenoic Acid; Endothelium, Vascular; Fatty Acids, Unsaturated; Female; Fish Oils; Lipoproteins; Liver; Male; Receptors, LDL; Thromboxane A2

Effects of dietary supplementation with highly purified EPA (1.8-2.7 g/day) for 16 weeks on platelet and red blood cell function and serum lipids concentration were investigated in patients with various thrombotic diseases. Decreases in platelet aggregation, thromboxane formation in platelets, platelet retention and whole blood viscosity, increased red blood cell deformation and prolongation of bleeding time were observed in the present study. In addition a reduction in serum cholesterol and triglyceride concentrations was noted in patients with hyperlipidemia after EPA ingestion. Some clinical improvements such as improvement of diabetic gangrene or peripheral vascular occlusive disease were observed. These results indicate that dietary supplementation of purified EPA may be beneficial for prevention and treatment of cerebro- and cardiovascular diseases.

Topics: Arteriosclerosis; Bleeding Time; Blood Viscosity; Capsules; Drug Evaluation; Eicosapentaenoic Acid; Erythrocyte Deformability; Female; Humans; Lipids; Male; Middle Aged; Platelet Aggregation; Thrombosis; Thromboxane A2

Topics: Animals; Arteriosclerosis; Drugs, Chinese Herbal; Epoprostenol; Hyperlipidemias; Lipid Peroxides; Male; Rabbits; Thromboxane A2

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

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

Evidence is presented that arachidonic acid metabolites are involved to an important extent in platelet-arterial wall interaction. The perspectives opened up by these results are the possible prevention and therapy of atherosclerosis by a fish-diet containing eicosapentaenoic acid, the use of prostaglandins, releasers of endogenous PGI2 and thromboxane synthetase inhibitors.

Topics: Arachidonic Acids; Arteriosclerosis; Blood Platelets; Cyclic AMP; Eicosapentaenoic Acid; Epoprostenol; Fatty Acids; Humans; Lipid Peroxides; Lipids; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandin-Endoperoxide Synthases; Thromboxane A2

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

Topics: Adult; Arteriosclerosis; Diabetic Angiopathies; Epoprostenol; Female; Humans; Male; Middle Aged; Thrombocytopenia; Thromboxane A2

We have studied generation of eicosanoids in blood vessels and platelets of rabbits in relation to platelet aggregation and plasma fibrinolytic activity at early stages of experimental atherosclerosis. A level of lipid peroxides in plasma augmented progressively from the 2-nd to 12-th week of atherogenic diet. In parallel, platelets generated more TXA2 and 12-HETE while in blood vessels a gradual reduction of prostacyclin formation was observed. Reduction in generation of PGI2 was accompanied by steady formation of PGE2. In the second week of the diet a slight decrease appeared of aggregatory response while later aggregability of platelets was increased. At first, plasma fibrinolytic activity was decreased, but it significantly augmented after 12 weeks of the diet. The above data indicate that changes of arachidonic acid metabolism in platelets and blood vessels appear at a very early stage of atherosclerosis and they influence platelet function and plasma fibrinolytic activity.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Aorta; Arteriosclerosis; Blood Platelets; Blood Vessels; Diet, Atherogenic; Dinoprostone; Eicosanoic Acids; Epoprostenol; Fibrinolysis; Hydroxyeicosatetraenoic Acids; Lipid Peroxides; Mesenteric Arteries; Platelet Aggregation; Prostaglandins E; Rabbits; Thromboxane A2

Elevated oestradiol (E2) levels may be a risk factor for ischaemic heart disease in men, although the mechanisms for the elevation of oestrogen and for its adverse effects remain unclear. We have studied 100 Caucasian males undergoing elective coronary angiography for ischaemic chest pain and measured serum oestradiol, a profile of haemostatic tests, extent of coronary artery disease and evidence of previous myocardial infarction in order to assess any relationships which could explain the effect of elevated serum oestradiol levels. Levels were significantly higher in men with a history of myocardial infarction compared to those without (p less than 0.01), but were unrelated to the extent of coronary disease or to the haemostatic tests. These results suggest that the association of oestradiol with coronary events relates to myocardial infarction, not to atherogenesis, and is not due to any currently measurable alterations of haemostasis. Current beta-adrenoceptor blocker treatment was associated with lower oestradiol and thromboxane B2 concentrations (both, p = 0.06). These incidental findings suggest that further studies of the effects of beta-blockade on oestradiol and thromboxane metabolism are indicated.

Topics: Adrenergic beta-Antagonists; Arteriosclerosis; Coronary Disease; Estradiol; Hemostasis; Humans; Male; Middle Aged; Myocardial Infarction; Risk; Thromboxane A2

Topics: Animals; Arteriosclerosis; Coronary Vasospasm; Disease Models, Animal; Epoprostenol; Histamine; Indomethacin; Swine; Swine, Miniature; Thromboxane A2

Icosanoides (prostaglandins, leukotrienes) seem to play an essential part in cardiovascular pathology. A range of experimental data obtained both in vitro and in vivo has resulted in a rapid progression of our understanding of their biochemical and functional properties and has opened up new fields of pharmacological research. However, a clear cut demonstration of their clinical relevance remains difficult. Improved methodology will no doubt provide more information about the importance of these compounds. For the present, we recommend reexamination of previously reported results.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Blood Vessels; Cells, Cultured; Endothelium; Humans; Leukotriene B4; Muscle, Smooth, Vascular; Prostaglandins; Rabbits; SRS-A; Thromboxane A2

Topics: Arteriosclerosis; Epoprostenol; Humans; Lipid Peroxides; Platelet Adhesiveness; Thromboxane A2

The role of prostanoids in a swine model of coronary artery spasm was examined. Eighteen miniature pigs underwent endothelial denudation of the left coronary artery (left circumflex branch in 14 pigs and left anterior descending branch in 4 pigs) followed by high cholesterol feeding. Three months after the denudation, when coronary artery spasm was repeatedly provoked along the denuded portion of the coronary artery by histamine, the vasoconstrictive effect of thromboxane A2 and the preventive effects of indomethacin and prostacyclin against histamine-induced coronary artery spasm were examined. Intracoronary administration of thiothromboxane A2, 200 micrograms, a stable thromboxane A2 analog, failed to provoke coronary artery spasm (seven of seven cases) but nonselectively constricted the coronary artery by 33%. Intravenous administration of indomethacin, 2 mg/kg, or continuous intravenous infusion of prostacyclin, 50 ng/kg per min, failed to prevent histamine-induced coronary artery spasm (four of four and eight of eight cases, respectively), yet the spasm was all but prevented by intravenous pretreatment with diphenhydramine at a dose of 1 mg/kg. Thus, in this swine model, prostanoids may not play a primary role in the occurrence of coronary artery spasm.

Topics: Animals; Arteriosclerosis; Body Weight; Cholesterol; Coronary Vasospasm; Disease Models, Animal; Epoprostenol; Histamine; Indomethacin; Male; Prostaglandins; Swine; Swine, Miniature; Thromboxane A2

Topics: Arteriosclerosis; Dietary Fats; Eicosanoic Acids; Endothelium; Epoprostenol; Fatty Acids, Unsaturated; Fibromuscular Dysplasia; Humans; Platelet Aggregation; Thromboxane A2

Topics: Animals; Arteriosclerosis; Blood Platelets; Humans; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2

Topics: Arteriosclerosis; Cardiovascular Diseases; Coronary Disease; Fibrinolytic Agents; Humans; Platelet Adhesiveness; Platelet Aggregation; Prostaglandins; Risk; Thromboxane A2

Topics: Alprostadil; Angioplasty, Balloon; Anti-Bacterial Agents; Anticoagulants; Arterial Occlusive Diseases; Arteriosclerosis; Aspirin; Dipyridamole; Endarterectomy; Exercise Therapy; Fibrinolysis; Humans; Hyperlipidemias; Hypertension; Infusions, Intra-Arterial; Intermittent Claudication; Prostaglandins E; Serotonin Antagonists; Sympathectomy; Thromboxane A2

We studied the ability of a single oral dose of aspirin to inhibit prostacyclin synthesis by human arterial and venous tissue and to inhibit thromboxane A2 synthesis by platelets in 70 patients who were undergoing aortocoronary bypass. A dose of 40, 80, or 325 mg of aspirin was administered 12 to 16 hours before surgery. The generation of thromboxane in serum--which provides an estimate of platelet thromboxane production--was reduced from the control value by 77, 95, and 99 per cent after single doses of 40, 80, and 325 mg of aspirin, respectively. By contrast, prostacyclin production in aortic tissue that was removed at operation was reduced by only 35, 38, and 75 per cent, respectively, in response to these doses. Production of prostacyclin in saphenous-vein tissue (not tested after 40 mg of aspirin) fell only slightly and not significantly after 80 mg but was reduced by 85 per cent after 325 mg. These findings indicate that a low dose of aspirin (40 to 80 mg) can largely inhibit platelet aggregation and thromboxane synthesis but has much less effect on prostacyclin production in arterial and venous endothelium.

Topics: Administration, Oral; Aged; Arteries; Arteriosclerosis; Aspirin; Blood Platelets; Blood Vessels; Culture Techniques; Epoprostenol; Female; Humans; Male; Middle Aged; Platelet Aggregation; Prostaglandins; Thromboxane A2; Veins

Topics: Arteriosclerosis; Blood Platelets; Coronary Disease; Dietary Fats; Epoprostenol; Humans; Myocardial Infarction; Prostaglandins; Thrombosis; Thromboxane A2

Vascular surgeons have not paid enough attention to all of the host factors responsible for the pathogenesis of atherosclerosis. With a clearer understanding of the role of platelets and endothelial cells, improved results and better long-term palliation can be realized by combining newer pharmacologic approaches with well-established surgical procedures. Prostaglandin chemistry research may provide promising therapeutic adjuncts to current techniques for managing atherosclerosis.

Topics: Animals; Arteriosclerosis; Blood Platelets; Epoprostenol; Humans; Platelet Aggregation; Risk; Thrombosis; Thromboxane A2

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

The level of arterial blood pressure is set by complete interactions of several mechanisms which influence both blood flow in and resistance of the vascular system. An imbalance favouring elevation of vascular resistance or extracellular volume will result in hypertension. Such alterations may include increased activity of the sympathetic nervous system, of the renin-angiotensin system, or excessive secretion of mineralocorticoids. Of equal importance may be a reduced activity of blood pressure-lowering factors such as prostaglandins and the kallikrein-kinin system. This paper describes the possible significance of prostaglandins in the pathophysiology of hypertension and in degenerative vascular disease, based on their involvement in the control of vascular resistance, renal regulation of extracellular volume and platelet-vessel wall interactions. An abnormality in the biosyn-thesis of certain prostaglandin endoperoxide metabolites may lead to hypertension even without an increase in the activity of the classic blood-pressure-elevating systems. The contribution of prostaglandins for the development of hypertension and degenerative vascular disease may be based on an inherent abnormality of the prostaglandin system, as well as on the effects of major risk factors such as dietary intake of sodium and fat on prostaglandin synthesis. Specific blockade or stimulation of distinct biosynthetic pathways leading to antagonistically acting prostaglandins and nutritional manipulation of precursor fatty acids should lead to a better understanding of the pathomechanisms involved and may offer new strategies for therapy or prevention of these cardiovascular disorders.

Topics: Arachidonic Acids; Arteriosclerosis; Aspirin; Dinoprostone; Humans; Hypertension; Platelet Adhesiveness; Prostaglandins; Prostaglandins E; Thromboxane A2

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

Topics: Arteriosclerosis; Aspirin; Blood Platelets; Coronary Disease; Dipyridamole; Epoprostenol; Hemostasis; Humans; Propranolol; Prostaglandin Antagonists; Risk; Sulfinpyrazone; Thromboxane A2

Topics: Arteriosclerosis; Aspirin; Epoprostenol; Hemostasis; Platelet Aggregation; Prostaglandin Antagonists; Prostaglandins; Thrombosis; Thromboxane A2; Thromboxanes

Topics: Animals; Arteriosclerosis; Blood Platelets; Cell Survival; Epoprostenol; Humans; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2

Topics: Arteriosclerosis; Epoprostenol; Humans; Prostaglandins; Thrombosis; Thromboxane A2; Thromboxanes

Topics: Animals; Arteriosclerosis; Aspirin; Blood Coagulation; Blood Platelets; Epoprostenol; Humans; Lipid Peroxides; Platelet Aggregation; Prostaglandins; Thromboxane A2

Prostacyclin is a very unstable prostaglandin, which is continuously synthetized and released by blood vessels. It fulfills 2 main functions, namely strong inhibition of platelet aggregation and vasodilation. Thus it acts as an important defense mechanism of the vascular wall, which is directed against overwhelming platelet aggregation and against the development of atherosclerosis. Besides endogenous prostacyclin is an important antihypertensive factor. In several diseases, as diabetes mellitus, obliterative arteriopathy and haemolytic-uraemic syndrome, the reduced prostacyclin-synthesis is thought to be a key mechanism for the development of vascular lesions. On the other hand the haemorrhagic diathesis of uraemics is seen in connection with an increased vascular prostacyclin release. Synthetic prostacyclin is now under trial for therapy in peripheral obliterative arteriopathy and extracorporeal circulation, as haemodialysis and cardiopulmonary bypass.

Topics: Arteriosclerosis; Diabetic Angiopathies; Epoprostenol; Female; Hemolytic-Uremic Syndrome; Humans; Intermittent Claudication; Muscle, Smooth, Vascular; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Prostaglandins; Purpura, Thrombotic Thrombocytopenic; Thromboxane A2; Vasodilation

Topics: Aorta; Apoproteins; Arteriosclerosis; Egypt; Germany; History, Ancient; History, Medieval; History, Modern 1601-; Humans; Italy; Lipid Metabolism; Liver; Platelet Aggregation; Smoking; Thromboxane A2

Unlike arachidonic acid (eicosatetraenoic acid, C20:4omega-6, A.A.), eicosapentaenoic acid (C20:5omega-3, E.P.A.) does not induce platelet aggregation in human platelet-rich plasma (P.R.P.), probably because of the formation of thromboxane A3 (T.X.A3) which does not have platelet aggregating properties. Moreover, E.P.A., like A.A., can be utilised by the vessel wall to make an anti-aggregating substance, probably a delta17-prostacyclin (P.G.I3). This finding suggests that, in vivo, high levels of E.P.A. and low levels of A.A. could lead to an antithrombotic state in which an active P.G.I3 and a non-active T.X.A3 are formed. Eskimos have high levels of E.P.A. and low levels of A.A. and they also have a low incidence of myocardial infarction and a tendency to bleed. It is possible that dietary enrichment with E.P.A. will protect against thrombosis.

Topics: Arachidonic Acids; Arteriosclerosis; Blood Vessels; Denmark; Epoprostenol; Fatty Acids, Unsaturated; Greenland; Humans; Inuit; Models, Chemical; Myocardial Infarction; Platelet Aggregation; Thrombosis; Thromboxane A2

Topics: Animals; Aorta, Thoracic; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Diet, Atherogenic; Epoprostenol; Male; Mesenteric Arteries; Myocardium; Platelet Aggregation; Prostaglandins; Rabbits; Thromboxane A2; Thromboxanes

Recently two local hormones, thromboxane A2 (TXA2) and prostacyclin (PGI2) have been discovered. These hormones are labile metabolites of arachidonic acid. TXA2 is generated by blood platelets, while PGI2 is produced by vascular endothelium. TXA2 is a potent vasoconstrictor. It also initiates the release reaction, followed by platelet aggregation. PGI2 is a vasodilator, especially potent in coronary circulation. It also inhibits platelet aggregation by virtue of stimulation of platelet adenyl cyclase. Common precursors for both hormones are cyclic endoperoxides PGG2 and PGH2, being formed by cyclooxygenation of arachidonic acid. This last enzymic reaction is more efficient in platelets than in vascular endothelium, and therefore the generation of PGI2 by vasuclar wall is accelerated by an interaction between platelets and endothelial cells. During this interaction platelets supply the endothelial PGI2 synthetase with their cyclic endoperoxides. The newly formed PGI2 repels the platelets from the intima. When PGI2 synthetase is irreversibly inactivated by low concentration of lipid peroxides, then the platelets are not rejected but stick to the endothelium, generate TXA2 and mature thrombi are formed. A balance between formation and release of PGI2, TXA2 and/or cyclic endoperoxides in circulation is of utmost importance for the control of intra-arterial thrombi formation and possibly plays a role in the pathogenesis of atherosclerosis.

Topics: Adenylyl Cyclases; Animals; Aorta; Arachidonic Acids; Arteriosclerosis; Blood Circulation; Blood Platelets; Epoprostenol; Heart; Platelet Aggregation; Prostaglandins; Rabbits; Thromboxane A2; Thromboxanes

Experimental atherosclerosis in rabbits was associated with increased aggregation of their platelets to arachidonic acid, and with increased generation of thromboxane A2 by their platelet-rich plasma. A heightened susceptibility of platelets to the anti-aggregatory action of prostacyclin against the ADP-induced aggregation was also observed. It is concluded that in advance atherosclerosis the platelet system is hypersensitive to biologically active metabolites of arachidonic acid.

Topics: Adenosine Diphosphate; Animals; Arachidonic Acids; Arteriosclerosis; Epoprostenol; Platelet Aggregation; Prostaglandins; Rabbits; Thromboxane A2; Thromboxanes