thromboxane-a2 and Cardiovascular-Diseases

Atherothrombosis-related diseases are one of the world's leading causes of mortality, and thus the search for new therapeutic approaches in this area remains a very urgent task. Modern pharmacogenomic technologies make it possible to obtain valuable data on disease pathogenesis and optimal therapeutic approaches. One promising research direction is the study of the thromboxane A2 - thromboxane A synthase - thromboxane A2 receptor axis. This review summarizes the recent evidence and suggests that systematic works in this area are creating new and promising opportunities in the treatment of patients with cardiovascular diseases.

Topics: Animals; Cardiovascular Diseases; Drug Discovery; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Pharmacogenomic Testing; Platelet Aggregation; Polymorphism, Genetic; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction; Thromboxane A2; Thromboxane-A Synthase

Type 2 diabetes mellitus is characterised by persistent thromboxane (TX)-dependent platelet activation, regardless of disease duration. Low-dose aspirin, that induces a permanent inactivation of platelet cyclooxygenase (COX)-1, thus inhibiting TXA2 biosynthesis, should be theoretically considered the drug of choice. The most up-to-date meta-analysis of aspirin prophylaxis in this setting, which includes three trials conducted in patients with diabetes and six other trials in which such patients represent a subgroup within a broader population, reported that aspirin is associated with a non-significant decrease in the risk of vascular events, although the limited amount of available data precludes a precise estimate of the effect size. An increasing body of evidence supports the concept that less-than-expected response to aspirin may underlie mechanisms related to residual platelet hyper-reactivity despite anti-platelet treatment, at least in a fraction of patients. Among the proposed mechanisms, the variable turnover rate of the drug target (platelet COX-1) appears to represent the most convincing determinant of the inter-individual variability in aspirin response. This review intends to develop the idea that the understanding of the determinants of less-than-adequate response to aspirin in certain individuals, although not changing the paradigm of the indication to low-dose aspirin prescription in primary prevention, may help identifying, in terms of easily detectable clinical or biochemical characteristics, individuals who would attain inadequate protection from aspirin, and for whom different strategies should be challenged.

Topics: Animals; Aspirin; Biomarkers, Pharmacological; Blood Platelets; Cardiovascular Diseases; Cyclooxygenase 1; Diabetes Mellitus, Type 2; Humans; Platelet Activation; Precision Medicine; Risk Assessment; Thromboxane A2

Platelets play a central role in inflammation through their direct interaction with other cell types, such as leucocytes and endothelial cells, and by the release of many factors, that is, lipids [such as thromboxane (TX)A2 ] and proteins (a wide number of angiogenic and growth factors) stored in α-granules, and adenosine diphosphate (ADP), stored in dense granules. These platelet actions trigger autocrine and paracrine activation processes that lead to leucocyte recruitment into different tissues and phenotypic changes in stromal cells which contribute to the development of different disease states, such as atherosclerosis and atherothrombosis, intestinal inflammation and cancer. The signals induced by platelets may cause pro-inflammatory and malignant phenotypes in other cells through the persistent induction of aberrant expression of cyclooxygenase (COX)-2 and increased generation of prostanoids, mainly prostaglandin (PG)E2 . In addition to cardiovascular disease, enhanced platelet activation has been detected in inflammatory disease and intestinal tumourigenesis. Moreover, the results of clinical studies have shown that the antiplatelet drug aspirin reduces the incidence of vascular events and colorectal cancer. All these pieces of evidence support the notion that colorectal cancer and atherothrombosis may share a common mechanism of disease, that is, platelet activation in response to epithelial (in tumourigenesis) and endothelial (in tumourigenesis and atherothrombosis) injury. Extensive translational medicine research is necessary to obtain a definitive mechanistic demonstration of the platelet-mediated hypothesis of colon tumourigenesis. The results of these studies will be fundamental to support the clinical decision to recommend the use of low-dose aspirin, and possibly other antiplatelet agents, in primary prevention, that is, even for individuals at low cardiovascular risk.

Topics: Animals; Aspirin; Blood Platelets; Cardiovascular Diseases; Colorectal Neoplasms; Cyclooxygenase 2; Disease Models, Animal; Endothelial Cells; Humans; Inflammation; Leukocytes; Neoplasms; Platelet Activation; Platelet Aggregation Inhibitors; Stromal Cells; Thromboxane A2; Up-Regulation

Isoprostanes are free radical-catalysed PG-like products of unsaturated fatty acids, such as arachidonic acid, which are widely recognized as reliable markers of systemic lipid peroxidation and oxidative stress in vivo. Moreover, activation of enzymes, such as COX-2, may contribute to isoprostane formation. Indeed, formation of isoprostanes is considerably increased in various diseases which have been linked to oxidative stress, such as cardiovascular disease (CVD), and may predict the atherosclerotic burden and the risk of cardiovascular complications in the latter patients. In addition, several isoprostanes may directly contribute to the functional consequences of oxidant stress via activation of the TxA2 prostanoid receptor (TP), for example, by affecting endothelial cell function and regeneration, vascular tone, haemostasis and ischaemia/reperfusion injury. In this context, experimental and clinical data suggest that selected isoprostanes may represent important alternative activators of the TP receptor when endogenous TxA2 levels are low, for example, in aspirin-treated individuals with CVD. In this review, we will summarize the current understanding of isoprostane formation, biochemistry and (patho) physiology in the cardiovascular context.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Free Radicals; Humans; Isoprostanes; Lipid Peroxidation; Oxidative Stress; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

The roles of prostanoids in the pathogenesis of cardiovascular diseases and in the development of pathological conditions have been examined using mice lacking the individual, specific prostanoid receptor. Prostaglandin (PG) I2 protected the heart from ischemia-reperfusion injury in a model of acute myocardial infarction. In addition, PGI2 suppressed the development of pressure overload-induced cardiac hypertrophy. Aside from its potent vasodilatory action, PGI2 contributed critically to the development of renovascular hypertension via the activation of the renin-angiotensin-aldosterone system. Thromboxane (TX) A2 and PGF2alpha were found to be the mediators of inflammatory tachycardia under a systemic inflammatory condition induced by lipopolysaccharide. Under a septic condition leading to a vascular hypo-responsive state, TXA2 worked to maintain vascular tone by inhibiting the induction of inducible nitric oxide synthase in vascular smooth muscle cells. Mice lacking the PGE2 receptor subtype EP3 had a bleeding tendency and were resistant to thromboembolism, due to a defective activation of platelets. From these studies, the important and novel roles of prostanoids in the pathogenesis of cardiovascular diseases have been clarified.

Topics: Animals; Blood Platelets; Cardiomegaly; Cardiovascular Diseases; Dinoprost; Epoprostenol; Hemodynamics; Humans; Hypertension, Renovascular; Inflammation Mediators; Mice; Mice, Knockout; Myocardial Reperfusion Injury; Prostaglandins; Receptors, Prostaglandin; Sepsis; Signal Transduction; Tachycardia; Thromboxane A2

Platelets are major players in arterial thrombosis, and antiplatelet therapy has a clear clinical benefit in the treatment and prevention of cardiovascular events. In particular, aspirin and clopidogrel have become cornerstones in the treatment of patients with atherothrombosis. However, despite the proven efficacy of antiplatelet drugs, cardiovascular events remain an important cause of morbidity and mortality in these patients. Furthermore, a considerable variability in platelet reactivity during treatment with established oral antiplatelet therapy has prompted the search for novel drugs against platelet-dependent thrombosis. Possible benefits of upcoming drugs include a more efficient platelet inhibition and a reversible effect on platelet function. Aspirin, clopidogrel, prasugrel, ticagrelor, terutroban, E5555, SCH 530348 and cilostazol are discussed. This review highlights the rationale for important oral antiplatelet drugs in development and provides clinical perspectives on their pharmacological advantages and challenges.

Topics: Adenosine; Administration, Oral; Cardiovascular Diseases; Cilostazol; Coronary Artery Disease; Coronary Thrombosis; Drug Resistance; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Tetrazoles; Thiophenes; Thromboxane A2; Ticagrelor

The present review focuses on the roles of thromboxane A2 (TxA2) in arterial thrombosis, atherogenesis, vascular stent-related ischemic events and renal proteinuria. Particular emphasis is laid on therapeutic interventions targeting the TxA2 (TP) receptors and TxA2 synthase (TS), including dual TP-receptor antagonists and TS inhibitors. Their significant inhibitory efficacies on arterial thrombogenesis, atherogenesis, restenosis after stent placement, vasoconstriction and proteinuria indicate novel and improved treatments for cardiovascular and selected renal diseases. New therapeutic interventions of the TxA2 pathway may also be beneficial for patients with poor biological antiplatelet drug response, for example, to aspirin and/or clopidogrel. These new TP/TS agents offer novel improved treatments to efficiently and simultaneously interfere with thrombogenesis and atherogenesis, and to enlarge the existing panel of platelet inhibitors for efficient prophylaxis and treatment of arterial thrombosis and renal proteinuria.

Topics: Aspirin; Cardiovascular Diseases; Clopidogrel; Coronary Artery Disease; Coronary Restenosis; Humans; Kidney Diseases; Platelet Aggregation Inhibitors; Proteinuria; Receptors, Thrombin; Thrombosis; Thromboxane A2; Thromboxane-A Synthase; Ticlopidine

Via its antiplatelet effect, aspirin reduces the odds of an arterial thrombotic event in high-risk patients by approximately 25%. However, 10% to 20% of patients with an arterial thrombotic event who are treated with aspirin have a recurrent arterial thrombotic event during long-term follow-up. Nevertheless, the effectiveness of aspirin has been questioned by the emergence of the concept of aspirin resistance, which has been introduced as an explanation of the fact that a considerable proportion of patients treated with aspirin exhibit normal platelet function.. We systematically reviewed all available evidence till March 2008 on prevalence of aspirin resistance and its association with clinical outcome. We also collected articles showing the possible way of treatment.. Analyzing the data of different laboratory methods aspirin resistance seems to be associated with poor clinical outcome, although currently no standardized or widely accepted definition of aspirin resistance exists. The widely used laboratory methods might not be comparable with each other; therefore, specific treatment recommendations for patients who exhibit high platelet reactivity during aspirin therapy or who have poor platelet inhibition by aspirin are not established.

Topics: Aspirin; Bleeding Time; Cardiovascular Diseases; Drug Resistance; Evidence-Based Medicine; Humans; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Predictive Value of Tests; Reproducibility of Results; Terminology as Topic; Thromboxane A2; Treatment Outcome

Historically, the vasodilatory prostanoids, especially prostacyclin and prostaglandin E(2), are believed to contribute significantly to the regulation of normal vascular tone and blood pressure (BP), primarily by counteracting the prevailing effects of the systemic vasoconstrictor systems, including angiotensin II, the catecholamines, and vasopressin. In contrast, the primary vasoconstrictor prostanoid thromboxane A(2) (TxA(2)) is produced in far smaller quantities in the normal state. While TxA(2) is believed to play a significant role in a variety of cardiovascular diseases, such as myocardial infarction, cerebral vasospasm, hypertension, preeclampsia, and various thrombotic disorders, its role in the regulation of vascular tone and BP in the normal physiological state is, at best, uncertain. Numerous studies have firmly established the dogma that TxA(2), while important in pathophysiological states in males, plays little or no role in the regulation of vascular tone or BP in females, except in the pulmonary vasculature. However, this concept is largely based on the predominant and preferential use of males in animal and human studies. Recent studies from our laboratory and others challenge this dogma and reveal that the TxA(2) pathway in the systemic vascular wall is an estrogen-dependent mechanism that appears to play an important role in the regulation of vascular tone and BP in females, in both normal and pathophysiological states. It is proposed that the potent vasoconstrictor action of TxA(2) is beneficial in the female in the normal state by acting as a local counterregulatory mechanism to increase vascular tone and BP and defend against hypotension that could result from the multiple estrogen-sensitive local vasodilator mechanisms present in the female vascular wall. Validation of this proposal must await further studies at the systemic, tissue, and molecular levels.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Endothelium, Vascular; Estrogens; Female; History, 20th Century; Homeostasis; Humans; Male; Muscle, Smooth, Vascular; Sex Factors; Signal Transduction; Thromboxane A2; Vasoconstriction

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Cardiovascular Diseases; Drug Resistance; Humans; Platelet Aggregation; Thromboxane A2

Topics: Adenosine Diphosphate; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atherosclerosis; Biomarkers; Biotransformation; Blood Coagulation Tests; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Hemorrhage; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Thrombosis; Thromboxane A2; Thromboxane B2; Ticlopidine; Treatment Failure

Historically, anti-inflammatory drugs had their origins in the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., this enabled these compounds to be synthesized and from this, acetyl-salicylic acid or Aspirin was developed. Likewise, the chemical advances of the 19th-20th centuries lead to development of the non-steroidal anti-inflammatory drugs (NSAIDs), most of which were initially organic acids, but later non-acidic compounds were discovered. There were two periods of NSAID drug discovery post-World War 2, the period up to the 1970's which was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in the drug-discovery process. Those drugs developed up to the 1980-late 90's were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities in laboratory animal models. Some were successfully developed that showed low incidence of gastro-intestinal (GI) side effects (the principal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GI reactions being detected and screened out in animal assays. In the 1990's an important discovery was made from elegant molecular and cellular biological studies that there are two cyclo-oxygenase (COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2)]; COX-1 that produces PGs and TxA2 that regulate gastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990's for the discovery and development of drugs to selectively control COX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor in development of adverse reactions, including those in the GI tract. At the turn of this century, there was enormous commercial development following the introduction of two new highly selective COX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) which were claimed to have low GI side effects. While found to have fulfilled these aims in part, an alarming turn of events took place in the late 2004 period when rofecox

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; Digestive System Diseases; Disease Models, Animal; Drug Delivery Systems; Drug Design; Fever; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Inflammation; Isoenzymes; Neoplasms; Neurodegenerative Diseases; Pain; Prostaglandins; Signal Transduction; Stroke; Thromboxane A2

Increased platelet aggregation plays a significant role in the aetiology of cardiovascular disease, and is complex involving multiple mechanisms. On platelet activation, there is a transient increase in free cytoplasmic calcium (Ca(2+)), thromboxane A2 generation, and the activation of the fibrinogen receptor GPIIb/IIIa. Other modulators are also involved in platelet aggregation and include lipoxygenase metabolites, protein kinase C, cyclic adenosine monophosphate (cAMP), cyclic guanine monophosphate (cGMP) and nitric oxide (NO). Garlic is reported to prevent cardiovascular disease by multiple effects, one of which is the inhibition of platelet aggregation and its ability to do this has been extensively investigated in vitro, however, in vivo studies are limited. In vitro studies indicate that garlic prevents inhibition of platelet aggregation by inhibiting cyclooxygenase activity and thus thromboxane A2 formation, by suppressing mobilization of intraplatelet Ca2+, and by increasing levels of cAMP and cGMP. Garlic also displays strong antioxidant properties and activates nitric oxide synthase (NOS), leading to an increase in platelet-derived NO. It can also interact directly with the GPIIb/IIIa receptors, thus reducing the ability of platelets to bind to fibrinogen. It is concluded that garlic inhibits platelet aggregation by multiple mechanisms and may have a role in preventing cardiovascular disease.

Topics: Blood Platelets; Cardiovascular Diseases; Cyclooxygenase Inhibitors; Garlic; Humans; Phytotherapy; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane A2

Since the discovery of COX-2, a second subtype of cyclooxygenase, selective inhibitors or "coxibs" were developed with the idea that this isoform was inducible at the site of inflammation whereas COX-1 was expressed constitutively in several tissues including gastric epithelium. This new class of non steroidal anti-inflammatory agents was though to be safer for ulcerations of the gastroinstestinal mucosa observed with non selective COX-2 inhibitors. Nevertheless, at the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. This decision raised serious concerns about safety of selective COX-2 inhibitors which are actively marketed today, and the ones currently under development. The mechanism of this cardiovascular toxicity could lie in the inhibition of COX-2 itself, and thus be a class effect. On the other hand, these cardiovascular side effects could be limited on rofecoxib and be dependent on its chemical and/or pharmacological own properties. This hypothesis is undermined by the unexpected findings of one colon cancer study which has shown that celecoxib might also increase the chance of heart attack and stroke in some patients. In this review, we compared the different coxibs marketed to date on the basis of their clinical, pharmacological and chemical properties with the aim of providing some clues in the understanding of their potential or revealed "cardiovascular effects".

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2 Inhibitors; Epoprostenol; Humans; Isoxazoles; Lactones; Pyrazoles; Structure-Activity Relationship; Sulfonamides; Sulfones; Thromboxane A2

Topics: Angiotensin II Type 1 Receptor Blockers; Cardiovascular Diseases; Humans; Hypertension; Platelet Aggregation Inhibitors; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

Even though non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for a long time, the search continues for anti-inflammatory drugs with few side-effects. COX-2 inhibitors are currently most debated, because they have less gastrointestinal side effects but have been linked to increased cardiovascular morbidity and mortality, presumably related to thrombotic events. This has brought about the withdrawal of rofecoxib and other COX-2 inhibitors from the market. Although the results of several large studies with prospective, randomized design and meta-analysis of different trials have led to the demise of many popular COX-2 inhibitors, yet the conclusion seems to be rather simplistic. This review presents evidence from basic biology and clinical studies with the expectation that a balanced position, particularly in relation to increase in cardiovascular events, may be elucidated.

Topics: Animals; Blood Platelets; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Diclofenac; Drug Labeling; Endothelium, Vascular; Epoprostenol; Humans; Lactones; Platelet Aggregation; Product Surveillance, Postmarketing; Pyrazoles; Randomized Controlled Trials as Topic; Risk Assessment; Sulfonamides; Sulfones; Thromboxane A2

Selective inhibitors of cyclooxygenase (COX)-2 were developed to improve the safety of anti-inflammatory therapy in patients at elevated risk for gastrointestinal complications which are thought to be caused primarily by depression of COX-1 derived mucosal prostanoids. They were not expected to be more efficacious analgesics than compounds acting on both cyclooxygenases, the traditional (t) non-steroidal antiinflammatory drugs (NSAIDs). While these predictions were generally supported by clinical evidence, an elevated rate of severe cardiovascular complications was observed in randomized controlled trials of three chemically distinct COX-2 selective compounds. The cardiovascular hazard is plausibly explained by the depression of COX-2 dependent prostanoids formed in vasculature and kidney; vascular prostacyclin (PGI2) constrains the effect of prothrombotic and atherogenic stimuli, and renal medullary prostacyclin and prostaglandin (PG) E(2) formed by COX-2 contribute to arterial pressure homeostasis. A drug development strategy more closely linking research into the biology of the drug target with clinical drug development may have allowed earlier recognition of these mechanisms and the cardiovascular risk of COX-2 inhibition. Open questions are i) whether the gastrointestinal benefit of COX-2 selective compounds drugs can be conserved by identifying individuals at risk and excluding them from treatment; ii) whether the risk extends to tNSAIDs; iii) and whether alternative strategies to anti-inflammatory therapy with a more advantageous risk-benefit profile can be developed.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Endothelium, Vascular; Epoprostenol; Gastrointestinal Hemorrhage; Humans; Renal Circulation; Renin-Angiotensin System; Signal Transduction; Thromboxane A2

Aspirin is the mainstay antiplatelet treatment in patients with high risk of cardiovascular atherothrombotic events, and its beneficial effect is documented in several clinical trials. Nevertheless, the effectiveness of aspirin has been questioned by the emergence of the concept of 'aspirin resistance' (AR). This phenomenon, although lacking a precise definition, covers the fact that some patients do not exhibit the expected platelet inhibition by use of various techniques for measuring platelet function. In this critical review, we evaluate the methods used for measuring AR. We will discuss the available data regarding the prevalence and the clinical importance of the phenomenon. Finally, the potential mechanisms underlying AR are considered.

Topics: Aspirin; Atherosclerosis; Cardiovascular Diseases; Drug Resistance; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Thrombosis; Thromboxane A2; Thromboxane B2

Topics: Asthma; Biomarkers; Cardiovascular Diseases; Humans; Immunoenzyme Techniques; Ischemia; Kidney Failure, Chronic; Radioimmunoassay; Reference Values; Specimen Handling; Thrombosis; Thromboxane A2; Thromboxane B2

Aspirin protects many though not all patients from acute cardiovascular events. It is generally accepted that such prophylactic effect depends mainly on the antithrombotic action involving inhibition of thromboxane A(2) production and platelet aggregation. In many patients aspirin failure to protect against cardiovascular event is obvious, as their symptoms simply cannot be controlled by the administration of a single drug. Others do not adhere properly to the treatment regimen. There is, however, a group of subjects, in which aspirin fails to inhibit platelet function (measured by various in vitro tests) and thromboxane A(2)(TxA(2)) formation (measured either in whole blood or as urinary TXA(2) metabolite excretion). There is evidence that such impairment of biochemical aspirin effect may be of importance in predicting future cardiovascular events. Several factors can influence antiplatelet effectiveness of aspirin; among them: hypercholesterolemia, increased expression of the isoform 2 of cyclooxygenase, genetic factors (polymorphisms of beta(3) integrin, and factor XIII A-subunit), use of other nonsteroidal anti-inflammatory use, and possibly others. Still, several questions remain unanswered. While biochemical aspirin resistance can predict major cardiovascular events we are still lacking a reliable test to predict such a risk in an individual patient. In addition, we do not know whether any alteration in therapy may improve clinical outcome in a subject identified as aspirin-resistant.

Topics: Aspirin; Cardiovascular Diseases; Drug Resistance; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Risk Factors; Thromboxane A2; Treatment Outcome

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Epoprostenol; Humans; Lactones; Pyrazoles; Sulfonamides; Sulfones; Thromboxane A2

Topics: Aspirin; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Follow-Up Studies; Genetic Variation; Humans; Patient Compliance; Platelet Aggregation; Platelet Aggregation Inhibitors; Risk; Thromboxane A2; Thromboxane B2; Treatment Failure

Moderate alcohol consumption has convincingly been associated with decreased cardiovascular mortality in epidemiological studies and metaanalyses. This decreased mortality has been attributed to changes in lipid profiles, decreased coagulation, increased fibrinolysis, inhibition of platelets, increased nitric oxide, and antioxidant capacities of alcoholic beverages. Most of these laboratory and animal studies, as well as small intervention trials in human volunteers, have revealed many interesting mechanisms that contribute to the cardioprotective effects of alcohol, red wine, or red wine polyphenolic compounds. An update on putative mechanisms is presented in this review.

Topics: Alcohol Drinking; Antioxidants; Cardiovascular Diseases; Cholesterol, HDL; Ethanol; Fibrinolysis; Flavonoids; Humans; Lipids; Nitric Oxide; Phenols; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Polyphenols; Thromboxane A2; Wine

Prostanoids, consisting of the prostaglandins (PGs) and thromboxanes (TXs), exert various actions through activation of their specific receptors. They include the DP, EP, FP, IP, and TP receptors for PGD2, PGE2, PGF2alpha, PGI2, and TXA2, respectively. Moreover, EP receptors are classified into four subtypes, the EP1, EP2, EP3 and EP4 receptors. Using mice lacking prostanoid receptors, we intended to clarify in vivo roles of prostanoids under pathophysiological conditions of the cardiovascular system, which include ischemia-induced cardiac injury, pressure overload-induced cardiac hypertrophy, renovascular hypertension, tachycardia during systemic inflammation and thromboembolism. The results demonstrated that 1) PGI2 plays an important role in attenuating the ischemic injury and the pressure overload-induced hypertrophy of the hearts, and also contributes to the development of renovascular hypertension; 2) PGE2 plays a cardioprotective role against the ischemic injury via both the EP3 and EP4, and also participates in acute thromboembolism via the EP3; and 3) both PGF2alpha and TXA2, which have been produced during systemic inflammation, are responsible for tachycardia.

Topics: Cardiovascular Diseases; Dinoprost; Dinoprostone; Epoprostenol; Humans; Prostaglandins; Thromboxane A2

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the western world. These disorders share a common pathophysiology -- atherosclerosis, which affects various arterial beds, leading to protean manifestations (coronary artery disease [CAD], stroke, peripheral arterial disease [PAD]). The platelet plays a pivotal role in the perpetuation and clinical expression of these disorders. The platelet, once believed to have a role confined to modulation of thrombosis and haemostasis, also plays an active role in vascular inflammation. Antiplatelet agents have become first-line therapy for CVD, and their unequivocal benefits are demonstrated in various basic and experimental models and supported by overwhelming evidence from clinical trials. Search is underway for more effective and safer antiplatelet therapy. Novel therapies are emerging to target the redundant pathways of platelet adhesion, activation and aggregation. Efforts are also ongoing to enhance implementation of existent therapy, target therapy selectively to high-risk patients and to those likely to respond (pharmacogenomics), and study the incremental benefits and safety of various antiplatelet combinations and their interaction with other medications in patients with CVD treated with polypharmacy.

Topics: Adenosine Diphosphate; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thromboxane A2

Cyclooxygenase (COX)-1 and COX-2 catalyze the formation of prothrombotic and antithrombotic eicosanoids, respectively. Aspirin, conventional nonsteroidal anti-inflammatory drugs (NSAIDs), and COX-2-specific inhibitors exhibit different patterns of inhibition of COX-1-mediated thromboxane biosynthesis and COX-2-mediated prostacyclin biosynthesis. The relationship between the pharmacologic inhibition of these vasoactive eicosanoids and the thromboprophylaxis or thrombogenicity exhibited by different therapeutic agents is currently unclear. Future studies are needed to assess the antithrombotic properties of commonly used NSAIDs, the hypothetical thrombogenicity of COX-2-specific inhibitors in high-risk patients, the need for concomitant aspirin with selective versus nonselective COX inhibitors, and the antiplatelet and gastric toxicity of the aspirin/COX-2-specific inhibitor combination in comparison with the aspirin/conventional NSAID combination.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Interactions; Epoprostenol; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Risk Factors; Thrombosis; Thromboxane A2

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Blood Platelets; Cardiovascular Diseases; Celecoxib; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Depression, Chemical; Dinoprostone; Epoprostenol; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Incidence; Intestinal Mucosa; Isoenzymes; Lactones; Membrane Proteins; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Randomized Controlled Trials as Topic; Substrate Specificity; Sulfonamides; Sulfones; Thromboembolism; Thromboxane A2; Treatment Outcome

Topics: Animals; Cardiovascular Diseases; Cloning, Molecular; GTP-Binding Proteins; Humans; Receptors, Thromboxane; Second Messenger Systems; Structure-Activity Relationship; Thromboxane A2

Thromboxane A2 (TxA2) is the main arachidonic acid metabolite in human platelets and exhibits two major activities; stimulation of platelet function, including secretion of platelet-derived storage products, e.g., 5-HT, PDGF, and vasoconstriction. Platelet hyperreactivity is typical for advanced stages of atherosclerosis and is paralleled by elevated circulating thromboxane levels. This is the target for TX-antagonistic compounds. Three classes of selective compounds are available: inhibitors of thromboxane synthase, antagonists of thromboxane receptors, and mixed-type agents. Positive experimental data with all of these compounds are available. However, clinical experience is limited and, in general, not convincing. This review discusses possible reasons for that and suggests that, in particular, the use of combined-type agents as antithrombotics may be superior to acetyl-salicylic acid in several forms of ischemic cardiovascular diseases.

Topics: Animals; Blood Platelets; Cardiovascular Diseases; Fibrinolytic Agents; Humans; Platelet Aggregation; Receptors, Thromboxane; Signal Transduction; Thromboxane A2

This review of the clinical studies of thromboxane synthase inhibitors (TXSIs) and thromboxane receptor blocking drugs (TXRBs) covers the years 1981 to the present. Clinical studies on TXSIs include those in normal volunteers as well as those in patients with angina, peripheral vascular disease and Raynaud's syndrome, pulmonary hypertension, cerebral vasospasm, hepatorenal syndrome, adult respiratory distress syndrome, and those on cardiopulmonary bypass and hemodialysis. The compounds studied include dazoxiben, dazmagrel, CGS 13080, CV 4151, OKY 1581, OKY 046, and U 63557A. In volunteers, single-dose studies have demonstrated inhibition of thromboxane A2 (TXA2) formation, with some small increases in bleeding time but no marked effect on platelet aggregation. In general, the compounds tested were ineffective in both chronic stable angina and vasospastic angina but caused symptomatic improvement in patients with unstable angina. The TXSIs studied were found to produce no consistent effects in any of the other clinical conditions. Since none of the compounds tested produced a sustained inhibition of TXA2 synthesis, the disappointing clinical results with this class of drugs may be due to an incomplete blockade of thromboxane synthase with the dosage regimens used. Possible alternative or additional reasons for the general lack of success with TXSIs could be that some of the diseases studied do not involve TXA2 or that accumulating prostaglandin endoperoxides in the presence of thromboxane synthase inhibition substitute for TXA2 in causing platelet aggregation. TXRBs rely for their efficacy only on blockade of the TXA2 receptor and antagonize the deleterious effects of both TXA2 and prostaglandin H2 equally, so they represent a simpler pharmacological approach than TXSIs. Such drugs include AH 23848, GR 32191, BM 13.177, BM 13.505, and SQ 28668. All of these compounds are inhibitors of platelet aggregation induced by TXA2 or by its stable mimetic, U-46619. AH 23848 was ineffective in patients with stable angina but did benefit patients with peripheral vascular disease. BM 13.177 has also proven effective in preventing restenosis after angioplasty, occlusion of coronary artery bypass grafts, and the deleterious effects of TXA2 in renal disease. From these preliminary studies, it would appear that TXRBs may offer greater clinical potential than TXSIs. Further studies currently underway with TXRBs to resolve this question include those in unstable angina, angi

Topics: Biphenyl Compounds; Cardiovascular Diseases; Humans; Imidazoles; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

Sudden fissuring of an atherosclerotic plaque has been suggested as the primary trigger of transient spontaneous ischemia in both the coronary and cerebral circulation. Measurements of urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2, as well as results of Aspirin trials, have suggested that episodic platelet activation at the site of this acute vascular lesion is mediated, at least partly, by enhanced thromboxane (TX) A2 biosynthesis. Thus, episodic increases in metabolite excretion have been detected in unstable angina. Aspirin (75-325 mg/day) prevents about one third of all fatal and nonfatal thrombotic events in this setting. That a similar "dynamic" thrombotic process occurs during the early phase of acute myocardial infarction is suggested by thromboxane metabolite measurements and by the results of the ISIS-2 trial showing a similar impact of short-term Aspirin therapy to that seen in unstable angina. Percutaneous transluminal coronary angioplasty is associated with transiently enhanced TXA2 biosynthesis and Aspirin-suppressable periprocedural thrombotic complications. On the other hand, both non-insulin-dependent diabetes mellitus and type IIa hypercholesterolemia are associated with a relatively reproducible and persisting abnormality of TXA2-dependent platelet function. This association is likely to reflect a systemic rather than localized stimulus to platelet activation and a continuous rather than episodic alteration. Low-dose (50 mg/day) Aspirin can largely suppress thromboxane metabolite excretion in both diseases. Thus, low-dose Aspirin and/or selective prostaglandin H2/TXA2-receptor antagonists may be important tools to test the hypothesis that TXA2-dependent platelet activation represents an important transducer of the enhanced thrombotic risk associated with these metabolic abnormalities.

Topics: Aspirin; Cardiovascular Diseases; Humans; Platelet Activation; Risk Factors; Thromboxane A2; Thromboxane B2

A number of reports indicate the TX receptor antagonists may be useful in preventing coronary artery reocclusion following fibrinolytic therapy, reducing myocardial ischemia/reperfusion injury and consequent neutrophil accumulation, preventing thrombocardiac sudden death, and attenuating the sequelae of endotoxic shock. Limited clinical studies have been initiated, and no adverse clinical effects can be associated with specific TX receptor blockade. Further clinical studies will be required to confirm the provocative animal studies, as well as defining the role of TX as a mediator of coronary vasospasm, respiratory disorders, and renal failure and rejection episodes.

Topics: Animals; Cardiovascular Diseases; Coronary Thrombosis; Humans; Myocardial Infarction; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Thromboxane A2

Thromboxane (TX) A2 and the prostaglandin endoperoxides, PGG2 and PGH2, have a number of biological activities including contraction of vascular and bronchial smooth muscle, platelet secretion and aggregation, and lysis of cellular membranes. Activation of TXA2 receptors may have deleterious consequences in various pathophysiologies, including coronary thrombosis, myocardial infarction, hypertension and renal injury. In addition to cyclooxygenase inhibitors, TX receptor antagonists and TX synthase inhibitors are available as specific pharmacological tools to investigate the specific involvement of TXA2 and the prostaglandin endoperoxides in these conditions. Recent reports indicate that these agents may be useful to prevent coronary artery thrombosis, prevent coronary artery reocclusion following thrombolytic therapy, attenuate the sequelae of circulatory shock, and improve kidney function after renal injury. This review will discuss the specific involvement of TX in these disorders, and compare the efficacy of different pharmacological approaches to the manipulation of either TX formation or activity.

Topics: Animals; Cardiovascular Diseases; Humans; Kidney Diseases; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

The low incidence of myocardial infarction in Greenland Eskimos may be due to their intake of marine food with a high content of n-3 polyunsaturated fatty acids (PUFAs). In Eskimos the platelet count is lowered, the platelet aggregation is inhibited, the bleeding time is prolonged and the ratio between proaggregatory thromboxanes and anti-aggregatory prostacyclins is decreased, when compared to age- and sex-matched Danes. In this review, studies evaluating the effect of a fish diet or fish-oil supplementation on human platelet function are summarized. Most studies have demonstrated that supplementation with n-3 PUFAs can cause inhibition of platelet behaviour. The optimal dose of n-3 PUFAs and the patient groups most likely to profit from supplementation need to be defined. The safety and the clinical effect of the supplementation should be investigated in long-term studies.

Topics: Bleeding Time; Blood Platelets; Cardiovascular Diseases; Dietary Fats, Unsaturated; Epoprostenol; Fatty Acids, Unsaturated; Fish Oils; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Thromboxane A2

Thromboxane (Tx) A2 is a biologically potent and chemically unstable metabolite of prostaglandin endoperoxides. Recent developments in measurement techniques and the availability of both selective inhibitors of Tx synthetase and TxA2 receptor antagonists have facilitated the implication of TxA2 as a physiological modulator and as a mediator in thrombotic, vasospastic, and bronchospastic conditions. TxA2 is synthesized by platelets and contributes to platelet activation and irreversible platelet aggregation in physiological hemostasis and in thrombosis (e.g., unstable angina, stroke). TxA2 is also synthesized in intestinal, pulmonary, and renal tissues by cells other than platelets. Particularly in these tissues, TxA2 appears to act as a physiological modulator of changes in blood flow distribution and airway caliber. Strong stimuli for TxA2 release from these tissues may initiate ulcer, pulmonary hypertension, bronchoconstriction, and renal vasoconstriction. Evidence supports participation of TxA2 and/or TxA2 receptors in modulation of natural cytotoxic cell cytotoxicity, in tumor growth and metastasis, in complications of pregnancy (e.g., preeclampsia), and in the progression of ischemic injury after coronary artery occlusion. This evidence supports pivotal involvement of TxA2 in pathophysiology and provides a strong rationale for pursuing TxA2-blocking strategies in drug development.

Topics: Animals; Blood Platelets; Bronchial Spasm; Cardiovascular Diseases; Hemostasis; Humans; Muscle Contraction; Muscle, Smooth; Platelet Aggregation; Prostaglandin Endoperoxides; Receptors, Prostaglandin; Receptors, Thromboxane; Thrombosis; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

Topics: Acute Disease; Animals; Cardiovascular Diseases; Humans; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

Our current understanding of the physiology of the leukotrienes is far from complete. The abundant supply of synthetic products has directed researchers into examining what the mediators affect rather than the basic mechanism studies of their involvement in disease. It is clear that the peptide leukotrienes possess potent constrictor actions of the microvasculature and can enhance permeability. These actions alone represent a new avenue of interpreting pathologic processes and could lead to alternate means of treating certain diseases in the future. It is of special interest that a consistent action of the leukotrienes is to reduce coronary blood flow, decrease myocardial contractility, and reduce cardiac output without affecting the heart rate. This profile of action is the first indication that a mediator can play a significant role in unstable angina. The main physiologic actions of the leukotrienes in the cardiovascular system are currently believed to be associated with episodes of ischemia and shock. Their relative contribution to the shock states, especially when compared with the actions of other known mediators of shock such as the prostaglandins, thromboxane, angiotensin, serotonin, and histamine, awaits clarification. LTB4 is a proinflammatory mediator that has opened a completely new perspective on the physiologic role of phagocytic cells. Novel therapeutic approaches to inflammatory-related diseases may result from an inhibition of cell chemokinesis, aggregation, and degranulation. The role of LTB4 in the immune system awaits further clarification.

Topics: Animals; Blood Platelets; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cerebrovascular Circulation; Coronary Disease; Coronary Vasospasm; Humans; Leukotriene B4; Lung; Muscle Contraction; Muscle, Smooth, Vascular; Neutrophils; Skin; SRS-A; Thromboxane A2

Thromboxane A2 (TxA2), the predominant cyclooxygenase product of human platelets, is a potent vasoconstrictor and platelet agonist. Although its biological properties are readily appreciable in vitro, it has been difficult to define its biological importance in vivo. To a large extent this reflected the problems associated with efforts to monitor biosynthesis of this eicosanoid and the lack of selective pharmacological probes that prevented the synthesis of TxA2 or antagonized its biological action in vivo. Recently the analysis of urinary metabolites of TxB2 has become simplified so that the methodology is readily applicable to clinical studies. This provides a noninvasive, time-integrated index of Tx biosynthesis. Although one cannot definitively establish a tissue of origin for metabolites measured in urine, indirect evidence suggests that urinary TxB2 derives primarily from the kidney whereas its dinor metabolite predominantly reflects platelet biosynthesis under physiological conditions. Although plasma concentrations of TxB2 are readily confounded by platelet activation ex vivo, the enzymatic metabolites formed from TxB2 have recently been identified and appear to bypass this problem. Combined analysis of long-lived (e.g., 11-dehydro-TxB2) and short-lived (e.g., 2,3-dinor-TxB2) metabolites in plasma promise to more accurately localize phasic increases in the biosynthesis of TxA2 and have been paralleled by the development of antagonists of the TxA2/prostaglandin endoperoxide receptor and their study of humans. The use of such specific probes in conditions characterized by abnormal biosynthesis of TxA2 promises to define the biological role of this mediator for humans.

Topics: Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cardiovascular Diseases; Diabetes Mellitus; Female; Humans; Liver; Male; Prostaglandin Endoperoxides; Thromboxane A2; Thromboxane B2

Thromboxane A2, the predominant cyclooxygenase product in platelets, is a potent platelet agonist and vasoconstrictor in vitro. Prostacyclin, the major product of vascular endothelium, has opposite effects on platelet function and vascular tone. These properties prompted the hypothesis that a "balance" between these compounds regulated interactions between platelets and the vessel wall in vivo. Although this possibility has been addressed extensively through experiments in vitro, clinical investigations commonly have been confounded by problems with analytic methodology, by selection of inappropriate metabolic targets for analysis, and by artifacts of trial design. The most reliable forms of assessing biosynthesis that are currently available still do not provide definitive information as to the tissue of origin of the compound studied and are directed toward stable but biologically inactive metabolites rather than the evanescent primary compounds themselves. Despite these limitations, both biochemical evidence and clinical trials clearly implicate thromboxane A2 as an important mediator of vascular occlusive disease in humans. The role of prostacyclin is much more conjectural. It does not circulate in concentrations sufficient to exert a systemic effect, but it may play a local homeostatic role in the regulation of platelet-vascular interactions. Whether preservation of the capacity to form prostacyclin coincident with inhibition of thromboxane A2 is of functional importance can be addressed only by clinical trials comparing inhibitors of thromboxane synthesis inhibition that are selective with cyclooxygenase inhibitors that also block the biosynthesis of prostacyclin. The recognition that multiple factors have the potential to regulate both platelet and vascular function at their interface renders the concept of a thromboxane A2-prostacyclin "balance" somewhat unlikely. However, both eicosanoids may interact with other factors to determine the development or persistence of vascular occlusion. Inhibition of the synthesis or function of thromboxane A2 remains the predominant mechanism for achieving interference with platelet function in vivo. Accumulating evidence for the efficacy of aspirin in human syndromes of vascular occlusion suggests that the biologic role of these compounds in humans should be pursued.

Topics: Cardiovascular Diseases; Eicosanoic Acids; Epoprostenol; Humans; Thrombosis; Thromboxane A2; Thromboxane B2

Topics: Adenosine Diphosphate; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Cyclic AMP; Cytochrome P-450 Enzyme System; Epoprostenol; Humans; Intramolecular Oxidoreductases; Prostaglandins; Thromboxane A2

Topics: Animals; Blood Circulation; Cardiovascular Diseases; Epoprostenol; Humans; Platelet Aggregation; Prostaglandins; Thromboxane A2; Vasodilation

Walnut consumption produces beneficial cardiovascular effects. The aim of the present study is to compare the effects of meat enriched in walnut paste (WM) and low-fat meat (LM) consumptions on platelet aggregation, plasma thromboxane A2 (TXA2, measured as TXB2), prostacyclin I2 (PGI2, as 6-keto-PGF1alpha) and the thrombogenic ratio (TXB2/6-keto-PGF1alpha) in volunteers at high CVD risk. Twenty-two adults were placed on a random, non-blinded crossover study involving two test periods (five portions WM/week for 5 week; five portions LM/week for 5 week) separated by a 4- to 6-week washout period. The participants were asked to complete a diet record throughout the study. Platelet aggregation, plasma TXB2, 6-keto-PGF1alpha production and the TXB2/6-keto-PGF1alpha ratio were determined at baseline and at weeks 3 and 5 for the two dietary periods. The WM diet contains a lower SFA content, a higher concentration of PUFA and a more favourable n-6/n-3 ratio than the LM diet. Significant time x treatment interactions were observed for TXB2 (P = 0.048) and the TXB2/6-keto-PGF1alpha ratio (P = 0.028). The WM diet significantly increased the level of 6-keto-PGF1alpha (P = 0.037) and decreased the TXB2/6-keto-PGF1alpha ratio (P = 0.048). At week 5, significant differences (P < 0.05) between treatments were found for maximum aggregation rate, TXB2 values and the TXB2/6-keto-PGF1alpha ratio. The effects on TXB2 and the TXB2/6-keto-PGF1alpha ratio were time-course dependent (P = 0.019 and 0.011, respectively). The WM and LM diets reduced TXB2 levels most (P = 0.050) in obese individuals, while the TXB2/6-keto-PGF1alpha ratio decreased most (P = 0.066) in volunteers whose serum cholesterol levels were > or = 2200 mg/l. The WM diet should be considered a functional meat because it improves the thrombogenic status mainly in individuals with high-cholesterol levels or high BMI.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Biomarkers; Body Mass Index; Cardiovascular Diseases; Cholesterol; Cross-Over Studies; Diet; Female; Humans; Juglans; Male; Meat; Middle Aged; Obesity; Phytotherapy; Platelet Aggregation; Risk; Smoking; Thromboxane A2; Thromboxane B2

To evaluate the effect of estradiol, estradiol and norethisterone acetate (NETA), raloxifene and tibolone on the prostacyclin (PGI(2))/thromboxane A2 (TxA(2)) ratio in postmenopausal women after 8 weeks of treatment.. This was a randomized, double-blind, cross-over study. Each patient took 8-week courses of estradiol 2 mg, estradiol 2 mg + NETA 1 mg, tibolone 2.5 mg, and raloxifene 60 mg; there was an 8-week placebo wash-out between each different intervention. All volunteers took all four treatment options and were randomized to one of three possible sequences. Urine was collected and frozen at each visit. Urinary metabolites of PGI(2) and TxA(2) were then assessed at the end of the study.. The ratio of PGI(2)/TxA(2) was significantly increased for raloxifene. No other treatments showed statistically significant changes.. The relationship between cardiovascular risk and hormone replacement therapy remains poorly understood. Raloxifene may have additional cardioprotective effects that the other treatments did not demonstrate, and none of the treatments statistically worsened the PGI(2)/TxA(2) ratio. This ratio may be under-utilized as a marker of net effect on cardiovascular health, but more research is needed to link it to health outcomes.

Topics: Cardiovascular Diseases; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epoprostenol; Estradiol; Estrogen Replacement Therapy; Female; Humans; Middle Aged; Norethindrone; Norethindrone Acetate; Norpregnenes; Raloxifene Hydrochloride; Thromboxane A2

There is emerging evidence of a considerable variability of the impact of aspirin on clinical outcome and laboratory findings. Persistent TxA2 production seems to be the most likely reason. Aim of this study was to determine whether the mechanism responsible for TxA2 persistent production is, at least partially, dependent upon aspirin-insensitive platelet COX-2 enzymatic pathway.. In 100 consecutive patients, under chronic aspirin anti-platelet treatment (100-160 mg/day) selected on the basis of detectable plasma salicylate levels, serum and Arachidonic Acid (AA)-induced platelet TxA2 production, immunoblot analysis of platelet COX-1/COX-2 expression and COX-2 activity were studied. Immunoblot revealed COX-2 expression in 46% patients, in an amount that was markedly lower than COX-1. In 10 COX-2 positive patients with TxA2 levels over the median, AA-induced TxA2 production performed in vitro in the presence of the COX-2 inhibitor CAY10404 and aspirin demonstrated that COX-2 dependent TxA2 production is less than 2%.. Our data demonstrate that the inter-individual variability of platelet sensitivity to aspirin is due to a reduced efficacy of aspirin on platelet COX-1 despite ascertained patient compliance. We suggest that serum TxA2 assay might be performed in future clinical studies to improve our knowledge on the residual TxA2 production in aspirin-treated patients.

Topics: Aged; Algorithms; Aspirin; Blood Platelets; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase 2; Dose-Response Relationship, Drug; Drug Resistance; Female; Hematology; Humans; Male; Middle Aged; Patient Compliance; Platelet Aggregation Inhibitors; Thromboxane A2

Rheumatoid arthritis (RA) is associated with increased risk for cardiovascular (CV) events through multiple factors. Fish oil has been shown to reduce symptoms in RA and to reduce CV risk. We assessed the effect of an antiinflammatory dose of fish oil on CV risk factors within a program of combination chemotherapy for patients with early RA.. Patients who chose not to take fish oil (n = 13) were compared with patients who achieved a sustained elevation of eicosapentaenoic acid (EPA) in plasma phospholipid fatty acids (> 5% total fatty acids) while taking fish oil over a 3-year period (n = 18). We examined cellular content of arachidonic acid (AA), synthesis of thromboxane A2 and prostaglandin E2, use of nonsteroidal antiinflammatory drugs (NSAID), traditional CV lipid risk factors, and disease activity at 3 years.. At 3 years, AA (as a proportion of AA plus long-chain n-3 fatty acids that can compete with AA for cyclooxygenase metabolism) was 30% lower in platelets and 40% lower in peripheral blood mononuclear cells in subjects taking fish oil. Serum thromboxane B2 was 35% lower and lipopolysaccharide-stimulated whole-blood prostaglandin E2 was 41% lower with fish oil ingestion compared to no fish oil. NSAID use was reduced by 75% from baseline with fish oil (p < 0.05) and by 37% without fish oil (NS). Favorable changes in fasting blood lipids were seen with, but not without fish oil. Remission at 3 years was more frequent with fish oil use (72%) compared to no fish oil (31%).. Fish oil reduces cardiovascular risk in patients with RA through multiple mechanisms.

Topics: Adult; Aged; Antirheumatic Agents; Arachidonic Acid; Arthritis, Rheumatoid; Cardiovascular Diseases; Dietary Supplements; Dinoprostone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eicosanoids; Female; Fish Oils; Humans; Hydroxychloroquine; Male; Methotrexate; Middle Aged; Risk Factors; Sulfasalazine; Thromboxane A2

Patients treated with aspirin may have a reduced sensitivity to its antiplatelet effect. The mechanism accounting for such a reduced sensitivity might involve an impaired interaction of aspirin with cyclooxygenase-1 (COX)-1.. We sought to investigate whether platelets from patients under chronic treatment with aspirin still produce TxA2 and whether there is any relationship between the eventual persistent TxA2 formation and platelet aggregation. Finally, whether platelet-derived TxA2 can be inhibited by in vitro addition of aspirin.. Collagen-induced platelet aggregation and thromboxane-A2 (TxA2) were measured in 196 patients treated with aspirin (100-330 mg day(-1)) because of previous vascular events or presence of risk factors of atherosclerosis.. Collagen-induced TxA2 production of the entire cohort was 128.7 +/- 21.6 pg 10(-8) cells, and was significantly correlated with platelet aggregation (Spearman's correlation coefficient = 0.44; P < 0.0001). Patients in the highest quartile of TxA2 showed higher platelet response to collagen (P < 0.0001) when compared with those in the lowest quartile. In a subgroup of 96 patients, platelets were treated in vitro with a TxA2 receptor antagonist (13-azaprostanoic acid) or aspirin before stimulation with collagen. 13-APA acid significantly inhibited platelet aggregation. Aspirin reduced (-72.9%) TxA2 production in patients with TxA2 values above the median but it was ineffective in those with TxA2 values below the median.. In some patients chronically treated with aspirin platelet production of TxA2 may persist and account for enhanced platelet aggregation. Incomplete inhibition of COX-1 seems to be implicated in persistent TxA2 production.

Topics: Aged; Aspirin; Blood Platelets; Cardiovascular Diseases; Collagen; Cyclooxygenase 1; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2

Chronic hyperglycemia contributes to vascular complications in diabetes. Resveratrol exerts anti-diabetic and anti-platelet action. This study aimed to evaluate the effects of resveratrol on metabolism and the function of blood platelets under static and in in vitro flow conditions in patients with type 2 diabetes. Blood obtained from 8 healthy volunteers and 10 patients with type 2 diabetes was incubated with resveratrol and perfused over collagen-coated capillaries. Isolated blood platelets were incubated with resveratrol and activated by collagen to assess platelet function, metabolism, ATP release, TXA

Topics: Blood Platelets; Cardiovascular Diseases; Collagen; Diabetes Mellitus, Type 2; Humans; Platelet Aggregation; Resveratrol; Thrombosis; Thromboxane A2

Elevated urinary 11-dehydro thromboxane B. Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB. The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB. PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A

Topics: Aged; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Carrier Proteins; Contactins; Europe; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Haplotypes; Humans; Incidence; Male; Middle Aged; Multicenter Studies as Topic; Phenotype; Polymorphism, Single Nucleotide; Primary Prevention; Progression-Free Survival; Randomized Controlled Trials as Topic; Risk Factors; RNA-Binding Proteins; Thromboxane A2; Thromboxane B2; Time Factors; White People

Omega-3 fatty acids suppress Thromboxane A(2) (TxA(2)) generation via mechanisms independent to that of aspirin therapy. We sought to evaluate whether baseline omega-3 fatty acid levels influence arachidonic acid proven platelet-cyclooxygenase-1 (COX-1) independent TxA(2) generation (TxA(2) generation despite adequate aspirin use).. Subjects with acute myocardial infarction, stable CVD or at high risk for CVD, on adequate aspirin therapy were included in this study. Adequate aspirin action was defined as complete inhibition of platelet-COX-1 activity as assessed by <10% change in light transmission aggregometry to ≥1 mmol/L arachidonic acid. TxA(2) production was measured via liquid chromatography-tandem mass spectrometry for the stable TxA(2) metabolite 11-dehydro-thromboxane B2 (UTxB2) in urine. The relationship between baseline fatty acids, demographics and UTxB(2) were evaluated. Baseline omega-3 fatty acid levels were not associated with UTxB(2) concentration. However, smoking was associated with UTxB(2) in this study.. Baseline omega-3 fatty acid levels do not influence TxA(2) generation in patients with or at high risk for CVD receiving adequate aspirin therapy. The association of smoking and TxA(2) generation, in the absence of platelet COX-1 activity, among aspirin treated patients warrants further study.

Topics: Aged; Aspirin; Biomarkers; Blood Platelets; Cardiovascular Diseases; Chromatography, Liquid; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Fatty Acids, Omega-3; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Function Tests; Smoking; Tandem Mass Spectrometry; Thromboxane A2; Thromboxane B2

Cardiovascular dysfunction is a primary independent predictor of age-related morbidity and mortality. Frailty is associated with activation of inflammatory pathways and fatigue that commonly presents and progresses with age. Interleukin 10 (IL-10), the cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine produced by immune and non-immune cells. Homozygous deletion of IL-10 in mice yields a phenotype that is consistent with human frailty, including age-related increases in serum inflammatory mediators, muscular weakness, higher levels of IGF-1 at midlife, and early mortality. While emerging evidence suggests a role for IL-10 in vascular protection, a clear mechanism has not yet been elucidated.. In order to evaluate the role of IL-10 in maintenance of vascular function, force tension myography was utilized to access ex-vivo endothelium dependent vasorelaxation in vessels isolated from IL-10 knockout IL-10(tm/tm) and control mice. Pulse wave velocity ((PWV), index of stiffness) of vasculature was measured using ultrasound and blood pressure was measured using the tail cuff method. Echocardiography was used to elucidated structure and functional changes in the heart.. Mean arterial pressures were significantly higher in IL-10(tm/tm) mice as compared to C57BL6/wild type (WT) controls. PWV was increased in IL-10(tm/tm) indicating stiffer vasculature. Endothelial intact aortic rings isolated from IL-10(tm/tm) mice demonstrated impaired vasodilation at low acetylcholine doses and vasoconstriction at higher doses whereas vasorelaxation responses were preserved in rings from WT mice. Cyclo-oxygenase (COX-2)/thromboxane A2 inhibitors improved endothelial dependent vasorelaxation and reversed vasoconstriction. Left ventricular end systolic diameter, left ventricular mass, isovolumic relaxation time, fractional shortening and ejection fraction were all significantly different in the aged IL-10(tm/tm) mice compared to WT mice.. Aged IL-10(tm/tm) mice have stiffer vessels and decreased vascular relaxation due to an increase in eicosanoids, specifically COX-2 activity and resultant thromboxane A2 receptor activation. Our results also suggest that aging IL-10(tm/tm) mice have an increased heart size and impaired cardiac function compared to age-matched WT mice. While further studies will be necessary to determine if this age-related phenotype develops as a result of inflammatory pathway activation or lack of IL-10, it is essential for maintaining the vascular compliance and endothelial function during the aging process. Given that a similar cardiovascular phenotype is present in frail, older adults, these findings further support the utility of the IL-10(tm/tm) mouse as a model of frailty.

Topics: Age Factors; Aging; Animals; Aorta; Arterial Pressure; Cardiovascular Diseases; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Echocardiography, Doppler; Endothelium, Vascular; Genotype; Inflammation; Inflammation Mediators; Interleukin-10; Mice; Mice, Inbred C57BL; Mice, Knockout; Myography; Phenotype; Pulse Wave Analysis; Stroke Volume; Thromboxane A2; Vascular Stiffness; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Ventricular Function, Left

Growing evidence indicates that statins may reduce thromboxane A(2) synthesis and thrombin generation. We investigated the relationships between thromboxane production, thrombin generation, and oxidative stress in patients receiving aspirin before and after statin administration.. An open-label study was conducted in 112 men, aged 54.4 ± 7.3 years, at an increased cardiovascular risk receiving aspirin (75 mg/d). Prior to and following a 3-month simvastatin treatment (40 mg/d), we evaluated circulating thromboxane B(2) (TXB(2)), inflammatory markers, 8-isoprostane, and prothrombin fragment 1.2 (F1.2), a marker of thrombin generation, which was also measured in blood collected every 60s at the site of standardized skin incisions.. Subjects (n=28) with pretreatment TXB(2) concentrations in the highest quartile ("aspirin-resistant patients") were more frequently current smokers and had elevated C-reactive protein (CRP), interleukin-6, 8-isoprostane, shorter bleeding time, and increased F1.2 production in a model of microvascular injury, when compared with the 3 remaining quartiles (all, p<0.001). Simvastatin decreased serum TXB(2) in the whole group (by 20%, p=0.0008). Patients in the highest quartile of the baseline TXB(2) had still higher posttreatment TXB(2), CRP, interleukin-6, and F1.2 formation following injury (all, p<0.001). Simvastatin-induced change in TXB(2) correlated with the magnitude of changes in maximum levels and the velocity of F1.2 formation (all p<0.001) but not with changes in inflammatory markers or lipid profile.. The study shows that statins significantly reduce platelet TXA(2) formation in patients taking low-dose aspirin and this effect is associated with attenuated thrombin formation in response to vascular injury.

Topics: Aspirin; Cardiovascular Diseases; Drug Resistance; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Platelet Aggregation Inhibitors; Simvastatin; Thrombin; Thromboxane A2

to refine a role of free radical oxidation (FRO), anemia, and endothelial dysfunction in the development of cardiovascular events in patients with chronic renal failure (CRF) at diferent stages of the disease.. Eighty-six patients, including 46 (53%) women and 40 (47%) men with Stages II-IV CRF, were examined. The patients' mean age was 43.6 +/- 14 years. Echocardiography, measurements of the blood levels of hemoglobin, albumin, cholesterol, and uric acid, and determination of blood electrolytic composition were made. Blood creatinine concentrations in the group averaged 0.3 mmol/l. Glomerular filtration rate (GFR) calculated from the Cockroft-Goult formula averaged 33.96 +/- 13 ml/min; the duration of CRF was 9.3 +/- 1.6 years. Anemia was detected in 46 (53%) patients. Iron metabolism was estimated from serum ferritin levels. Special studies involved determination of FRO--malondialdehyde (MDA) and the activities of catalase and superoxide dismutase (SOD) in plasma and serum. The plasma concentrations of endohelin-1 (ET-1), thromboxane A2, and prostacyclin were measured by radioimmunoassay. Results. The higher concentrations of MDA and the decreased activities of catalase and SOD, i.e., FRO, correlated with the progression of renal failure. There were also increases in the levels of ET-1 and thromboxane A, and a reduction in the concentration of prostacyclin as blood creatinine levels elevated. Left ventricular hypertrophy was found in 43 (50%) of the 86 patients. Its severity depended on the decrease of creatine phosphokinase and the severity of anemia and arterial hypertension. There was a stable correlation between the changes in left ventricular myocardial mass, MDA levels, and catalase and SOD activities.. The higher level of MDA and the lower activities of catalase and SOD in patients with CRF, which correlate with diminished renal function, confirm that the disease is closely associated with FRO, that, by aggravating anemia and endothelial dysfunction, affects the magnitude of morphological and functional changes in the cardiovascular system in patients with CRF patients.

Topics: Adult; Cardiovascular Diseases; Catalase; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Free Radical Scavengers; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Malondialdehyde; Oxidative Stress; Prognosis; Superoxide Dismutase; Thromboxane A2

Several studies have shown that polyphenols reduce cardiovascular accidents in high-risk patients; in particular, the inhibition of platelet function may be responsible for part of this benefit. This research studied the antiplatelet effect of Wonderful variety pomegranate (Punica granatum) products, which contain primarily hydrolyzed tannins such as ellagitannins. We have investigated in vitro the effects of treatment with either pomegranate juice (PJ) or the polyphenol-rich extract from pomegranate fruit (POMx) on platelet aggregation, calcium mobilization, thromboxane A(2) production, and hydrogen peroxide formation, induced by collagen and arachidonic acid. PJ and POMx reduce all the platelet responses studied. POMx showed a stronger action in reducing platelet activation; moreover, POMx is active at the concentration that it is possible to obtain after polyphenol-rich food intake (2 microM). These results demonstrated that the cardiovascular health benefits of pomegranate may in part be related to the ability of polyphenols to inhibit platelet function. In fact, PJ and pomegranate extract have similar effects at concentrations expected for normal intake.

Topics: Arachidonic Acid; Blood Platelets; Calcium; Cardiovascular Diseases; Collagen; Flavonoids; Fruit; Hydrogen Peroxide; Lythraceae; Phenols; Plant Extracts; Plant Preparations; Platelet Aggregation; Platelet Aggregation Inhibitors; Polyphenols; Thromboxane A2

Topics: Aspirin; Blood Platelets; Cardiovascular Diseases; Cyclooxygenase 1; Drug Resistance; Humans; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane A2

The recent demonstration that platelets express a functional toll-like receptor 4 (TLR4) prompted us to explore the influence of TLR4 polymorphisms (Asp299Gly alone or in combination with Thr399Ile) on thromboxane A(2) (TXA(2)) biosynthesis in vivo. In 17 subjects with TLR4 polymorphisms versus 17 wild type (untreated with aspirin, matched for age, sex, and cardiovascular risk factors), intima-media thickness in the common carotid arteries was significantly lower. Average urinary excretion of 11-dehydro-TXB(2), an index of systemic biosynthesis of TX, was significantly reduced by 65%. The urinary excretion of 2,3-dinor-6-keto-prostaglandin F(1alpha), an index of systemic biosynthesis of prostacyclin, was marginally depressed but the prostacyclin/TXA(2) biosynthesis ratio was significantly higher than in wild type. Selective inhibition of cyclooxygenase 2-dependent prostacyclin (by rofecoxib or etoricoxib) was associated with increased urinary excretion of 11-dehydro-TXB(2) in carriers of TLR4 polymorphisms, but not in wild-type, suggesting a restrainable effect of prostacyclin on platelet function in vivo in this setting. Reduced TXA(2) biosynthesis may contribute to the protective cardiovascular phenotype of TLR4 polymorphisms.

Topics: Cardiovascular Diseases; Carotid Artery, Common; Case-Control Studies; Epoprostenol; Female; Heterozygote; Humans; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Risk Factors; Thromboxane A2; Toll-Like Receptor 4; Ultrasonography

Aspirin (acetylsalicylic acid) irreversibly inhibits platelet cyclooxygenase (COX)-1, the enzyme that converts arachidonic acid (AA) to the potent platelet agonist thromboxane (TX) A2. Despite clear benefit from aspirin in patients with cardiovascular disease (CAD), evidence of heterogeneity in the way individuals respond has given rise to the concept of 'aspirin resistance.'. To evaluate the hypothesis that incomplete suppression of platelet COX as a consequence of variation in the COX-1 gene may affect aspirin response and thus contribute to aspirin resistance.. Aspirin response, determined by serum TXB2 levels and AA-induced platelet aggregation, was prospectively studied in patients (n = 144) with stable CAD taking aspirin (75-300 mg). Patients were genotyped for five single nucleotide polymorphisms in COX-1 [A-842G, C22T (R8W), G128A (Q41Q), C644A (G213G) and C714A (L237M)]. Haplotype frequencies and effect of haplotype on two platelet phenotypes were estimated by maximum likelihood. The four most common haplotypes were considered separately and less common haplotypes pooled.. COX-1 haplotype was significantly associated with aspirin response determined by AA-induced platelet aggregation (P = 0.004; 4 d.f.). Serum TXB2 generation was also related to genotype (P = 0.02; 4 d.f.).. Genetic variability in COX-1 appears to modulate both AA-induced platelet aggregation and thromboxane generation. Heterogeneity in the way patients respond to aspirin may in part reflect variation in COX-1 genotype.

Topics: Adult; Arachidonic Acid; Aspirin; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Resistance; Female; Haplotypes; Humans; Likelihood Functions; Male; Pharmacogenetics; Platelet Aggregation; Polymorphism, Single Nucleotide; Prospective Studies; Thromboxane A2

Topics: Adverse Drug Reaction Reporting Systems; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Approval; Drug Industry; Epoprostenol; Gastrointestinal Diseases; Humans; Isoenzymes; Isoxazoles; Lactones; Membrane Proteins; Naproxen; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Risk; Sulfonamides; Sulfones; Thromboxane A2; United States; United States Food and Drug Administration

Arsenic in drinking water is a worldwide health problem that is associated with cardiovascular disease, but the cause is currently unknown. Arsenic effects on platelets, which are important in development of cardiovascular disease, were examined in vitro and in a drinking water study using a rat animal model. Trivalent inorganic arsenic (arsenite) induced in vitro aggregation when platelets were exposed to subthreshold challenge by thrombin and several other agonists in a concentration-dependent manner, with arsenite being the most potent form tested. Arsenite also induced significant increases in serotonin secretion, thromboxane A(2) formation, and adhesion protein expression in platelets. Consistent with the in vitro studies, 4-week ingestion of arsenite-contaminated drinking water resulted in enhanced arterial thrombosis. Human platelets showed similar responses, suggesting that the effects seen in animal experiments are applicable to humans. These results will provide new insights into the mechanism of arsenic-induced cardiovascular disease. They will also allow regulatory agencies to estimate risk from arsenic-induced cardiovascular disease and to determine if drinking water regulatory levels based on human cancer studies will protect against noncancer effects associated with cardiovascular disease.

Topics: Animals; Arsenic; Blood Platelets; Cardiovascular Diseases; Humans; In Vitro Techniques; P-Selectin; Platelet Aggregation; Poisons; Rats; Rats, Sprague-Dawley; Serotonin; Thrombin; Thrombosis; Thromboxane A2; Water Supply

Topics: Aspirin; Blood Platelets; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Resistance; Risk Factors; Thromboxane A2; Thromboxanes

Topics: Anabolic Agents; Animals; Cardiovascular Diseases; Female; Humans; Incidence; Male; Mice; Middle Aged; Postmenopause; Premenopause; Receptors, Thromboxane; Risk Factors; Testosterone; Thromboxane A2

Topics: Aspirin; Blood Platelets; Cardiovascular Diseases; Eicosanoids; Epoprostenol; Humans; Thromboxane A2

The effects of estradiol and progesterone added to the growth medium of human umbilical vein endothelial cells for 72 h on the formation and release of prostacyclin were investigated. The influence on collagen-induced platelet aggregation and on the platelet formation of thromboxane A2 following aggregation, of the growth medium collected before and after thrombin stimulation of the endothelial cells, was studied simultaneously. Under basal conditions, endothelial cells grown with progesterone released significantly less prostacyclin into the growth medium than did controls (p less than 0.05). Following thrombin stimulation, endothelial cells grown with estradiol (p less than 0.05) or a combination of estradiol and progesterone (p less than 0.01) contained significantly less prostacyclin than controls. No significant effects on the platelet aggregation or platelet thromboxane formation could be found. This study indicates a lowering effect of both female sex hormones on the endothelial cell prostacyclin formation and release. This may be of significance for the increased risk of vascular disease in pregnant women and oral contraceptive users, but can hardly explain the consequences of the hormonal loss occurring at the menopause.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Platelets; Cardiovascular Diseases; Cell Communication; Culture Media; Endothelium, Vascular; Epoprostenol; Estradiol; Female; Humans; Menopause; Platelet Aggregation; Progesterone; Radioimmunoassay; Risk Factors; Thromboxane A2; Thromboxane B2

With a growing general conviction that thromboxane A2 does have a pathological role in occlusive vascular disease, there is a current debate on the ideal type of drug treatment needed. The more widely accepted view now seems to be that drugs that antagonize the actions of thromboxane A2 by blocking its receptors have greater clinical potential than those that block its synthesis. However, this premise has yet to be proven clinically. The historical development of thromboxane receptor blockers as a new class of medicines and, in particular, that of GR32191, are described here. The clinical evaluation of GR32191 should determine the importance of thromboxane A2 in cardiovascular disease.

Topics: Animals; Biphenyl Compounds; Cardiovascular Diseases; Cyclooxygenase Inhibitors; Guinea Pigs; Heptanoic Acids; Humans; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

Topics: Cardiovascular Diseases; Humans; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2

Topics: Blood Preservation; Cardiovascular Diseases; Freezing; Humans; Thromboxane A2; Thromboxane B2; Thromboxanes

Despite the evanescence of TXA2 in biological fluids, recent developments promise to considerably enhance our insight into the role of this molecule in vivo. Clinical trials already suggest that it plays an important role in certain human diseases, such as unstable angina. Combined administration of TX antagonists and TX synthase inhibitors offers a theoretical advantage over aspirin which may ultimately justify their place in the therapy of vascular disease in humans.

Topics: Blood Platelets; Cardiovascular Diseases; Humans; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

Topics: Cardiovascular Diseases; History, 20th Century; Humans; Thromboxane A2

Topics: Animals; Aorta, Thoracic; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cardiovascular Diseases; Epoprostenol; Male; Rats; Rats, Inbred Strains; Smoking; Thromboxane A2

Topics: Aspirin; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Diet; Epoprostenol; Hemostasis; Humans; Platelet Aggregation; Prostaglandins; Prostaglandins E; Thromboxane A2; Vascular Diseases

Topics: Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cardiovascular Diseases; Coronary Disease; Eicosanoic Acids; Endothelium; Heart Failure; Humans; Leukocytes; Lipoxygenase; Muscle, Smooth, Vascular; Myocardial Infarction; Myocarditis; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thrombosis; Thromboxane A2

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

Topics: Animals; Biological Assay; Blood Platelets; Cardiovascular Diseases; Chromatography, Gas; Epoprostenol; Half-Life; Homeostasis; Humans; Mass Spectrometry; Prostaglandins; Radioimmunoassay; Radioisotope Dilution Technique; Thromboxane A2; Thromboxanes

After a brief survey of the already well known functions of tromboxane and prostacyclin both in physiological and pathological conditions, the data found in the literature on the therapeutical use of prostacyclin are discussed. The positive results obtained in the treatment of arteriosclerosis obliterans of the lower limbs, of Raynaud's syndrome, of ischaemic stroke and of ischaemic heart diseases, together with the very modest side effects of prostacyclin, suggest to continue with prostacyclin therapy even if its mechanism of action is not yet clear.

Topics: Arachidonic Acid; Arachidonic Acids; Arteriosclerosis Obliterans; Cardiovascular Diseases; Cerebrovascular Disorders; Coronary Disease; Cytochrome P-450 Enzyme System; Epoprostenol; Humans; Intramolecular Oxidoreductases; Raynaud Disease; Thromboxane A2

Topics: Angina Pectoris; Cardiac Pacing, Artificial; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Coronary Disease; Hemodynamics; Humans; Myocardial Infarction; Prostaglandins; Risk; Thromboxane A2; Thromboxane B2

Topics: Adult; Animals; Blood Platelets; Cardiovascular Diseases; Coronary Disease; Diet; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Female; Fish Oils; Fish Products; Humans; Male; Platelet Aggregation; Rabbits; Thromboxane A2

A proposal to account for the inter-relationships between established risk factors and cardiovascular disease is presented. In this concept, the critical substance is prostaglandin (PG) E1 which is a vasodilator, an inhibitor of platelet aggregation, an inhibitor of cholesterol and collagen biosynthesis and an inhibitor of smooth muscle proliferation. PGE1 biosynthesis is enhanced by the essential fatty acid, linoleic acid, by the platelet aggregating agent thromboxane (TX) A2, by cholesterol and by melatonin. These factors may participate in a negative feedback control loop. As a result of the operation of this loop, any tendency for PGE1 levels to fall is followed by increased cholesterol and TXA2 biosynthesis, and enhanced platelet aggregation, vasoconstriction, smooth muscle proliferation and collagen biosynthesis. Enhancement of PGE1 biosynthesis will have the opposite effects. Factors known to increase PGE1 biosynthesis include essential fatty acids, vitamin C, ethanol, pyridoxine, zinc and probably niacin, all of which are known to have some protective effects against cardiovascular disease. The hypothesis predicts that lowering of cholesterol biosynthesis by any method other than enhanced PGE1 formation, while reducing the risk of cardiovascular disease, will increase the risk of other disorders. The hypothesis suggest new approaches to treatment and new ways of combining existing treatments. Colchicine, which at low concentrations may imitate and action of melatonin, has particularly interesting possibilities. Colchicine and related compounds have already been shown to have potent cholesterol-lowering and anti-atherogenic actions in both humans and animals.

Topics: Cardiovascular Diseases; Cholesterol; Collagen; Fatty Acids, Essential; Feedback; Humans; Insulin; Life Style; Melatonin; Models, Biological; Platelet Aggregation; Prostaglandins E; Thromboxane A2; Thromboxanes; Vasoconstriction

Topics: Animals; Arteries; Aspirin; Cardiovascular Diseases; Dipyridamole; Epoprostenol; Fatty Acids; Hemostasis; Homeostasis; Humans; Lipid Peroxides; Platelet Aggregation; Prostaglandins; Thrombosis; Thromboxane A2

Topics: Animals; Arachidonic Acids; Cardiovascular Diseases; Fatty Acids, Unsaturated; Humans; Rabbits; Thromboxane A2

Topics: Animals; Arachidonic Acids; Butter; Cardiovascular Diseases; Diet; Epoprostenol; Humans; Margarine; Mice; Rabbits; Thromboxane A2