thromboxane-a2 and Vascular-Diseases

Patients surviving an acute coronary syndrome (ACS) remain at increased risk of ischemic events long term. This paper reviews current evidence and guidelines for oral antiplatelet therapy for secondary prevention following ACS, with respect to decreased risk of ischemic events versus bleeding risk according to individual patient characteristics and risk factors. Specifically, data are reviewed from clinical studies of clopidogrel, prasugrel, ticagrelor and vorapaxar, as well as the results of systematic reviews and meta-analyses looking at the benefits and risks of oral antiplatelet therapy, and the relative merits of shorter versus longer duration of dual antiplatelet therapy, in different patient groups.

Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Administration, Oral; Aging; Blood Platelets; Cyclooxygenase 1; Diabetes Mellitus; Drug Administration Schedule; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Purinergic P2Y Receptor Antagonists; Receptor, PAR-1; Receptors, Purinergic P2Y12; Renal Insufficiency; Risk Factors; Secondary Prevention; Thrombin; Thromboxane A2; Time Factors; Vascular Diseases

Topics: Animals; Antibodies; Arteries; beta-Thromboglobulin; Blood Coagulation; Blood Coagulation Factors; Blood Platelets; Disease Susceptibility; Humans; Megakaryocytes; Platelet Activation; Platelet Aggregation; Platelet Factor 4; Stress, Mechanical; Thrombosis; Thromboxane A2; Vascular Diseases

Arachidonic acid (AA) is metabolized by the cyclo-oxygenase and the lipoxygenase pathways to give a number of products, some of which have potent and sometimes opposing biological activities. Different cell types produce different metabolites, so that the chief AA metabolite produced by the platelet is the pro-aggregatory thromboxane A2 (TXA2), whereas that produced by the vascular endothelium is the anti-aggregatory prostacyclin. White blood cells, on the other hand, are the chief source of the leukotrienes, which are implicated in the inflammatory process. Generation of these products may be modified in certain pathological conditions, such as atherosclerosis and diabetes, where prostacyclin synthesis is reduced and TXA2 synthesis increased, resulting in a pro-thrombotic state. Synthesis of AA metabolites may be inhibited, either totally or selectively, using drugs which inhibit different enzymes in the metabolic pathway. These drugs may be beneficial in the treatment of thrombotic disorders and inflammation. AA metabolism may also be modified by dietary substitution with eicosapentaenoic acid, a fatty acid present in fish oils.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Cells; Blood Platelets; Blood Vessels; Dietary Fats; Eicosapentaenoic Acid; Enzymes; Epoprostenol; Humans; Leukocytes; Thromboxane A2; Vascular Diseases

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

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Blood Vessels; Cyclic AMP; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Endothelium; Epoprostenol; Fatty Acids, Unsaturated; Fibrinolytic Agents; Humans; Thromboxane A2; Thromboxane-A Synthase; Vascular Diseases

Pulmonary vascular disease, a serious complication of many congenital heart lesions, has three major components: increased muscularity of small pulmonary arteries; intimal hyperplasia, scarring and thrombosis; and reduced numbers of intraacinar arteries. The muscularity is due to increased stress on the vessel wall, and is reversible. The intimal changes may be due to endothelial damage, causing an imbalance between prostacyclin and thromboxane A2 production and leading to local platelet aggregation. This, in turn, may stimulate migration and division of myointimal cells, which thicken the intima and lead to scarring and thrombosis. Extensive intimal changes are probably irreversible, but the possibility of preventing them by use of agents that inhibit platelet aggregation needs to be considered. The mechanism of a decrease in numbers of intraacinar arteries is unexplained. The potential for growth of new vessels after corrective surgery of the cardiac defect is an important factor in restoring pulmonary vascular resistance to normal. Available evidence suggests that this growth potential is reduced after 2 years of age and argues for early surgical relief of pulmonary vascular stresses.

Topics: Animals; Child; Child, Preschool; Dogs; Ductus Arteriosus, Patent; Epoprostenol; Female; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hyperplasia; Infant; Lung Diseases; Muscle, Smooth; Platelet Aggregation; Pregnancy; Pulmonary Artery; Tetralogy of Fallot; Thromboxane A2; Transposition of Great Vessels; Vascular Diseases; Vascular Resistance

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

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

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

Permanent inactivation of cyclooxygenase-1 and inhibition of platelet thromboxane A(2) (TxA(2)) constitute the main mechanisms underlying the prevention of vascular disease by aspirin.. We studied platelet TxA(2) synthesis and its impact on platelet reactivity and platelet-erythrocyte [platelet-rich plasma (PRP)-RBC] interactions in 533 aspirin-treated patients with vascular disease. Seventy aspirin-free and 16 aspirin-treated normal subjects were evaluated as controls. Collagen (1 mug mL(-1))-induced platelet activation ((14)C-5HT release) and recruitment (proaggregatory activity of cell-free releasates from activated platelets) were assessed in PRP, PRP + RBC, and whole blood (WB). TxA(2) was quantified in releasates from WB. Aspirin inhibited TxA(2) synthesis and platelet function in all patients, but to different degrees. Forty-two patients (8%) displayed partial (<95%) inhibition of TxA(2) relative to that of aspirin-free controls. They produced >3.5 ng mL(-1) TxA(2) and had higher platelet reactivity than 491 patients who had undetectable TxA(2) or produced residual TxA(2) (R-TxA(2);

Topics: Aged; Aspirin; Blood Platelets; Collagen; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Resistance; Erythrocytes; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Platelet-Rich Plasma; Serotonin; Thromboxane A2; Vascular Diseases

The present study was designed to assess whether cyclooxygenase-2 (COX-2) activation is involved in the effects of chronic aldosterone treatment on endothelial function of mesenteric resistance arteries (MRA) from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR).. Relaxation to acetylcholine was measured in MRA from both untreated and aldosterone-treated strains. Vasomotor responses to prostacyclin and U46619 were also analysed. Release of 6-oxo-prostaglandin (PG)F1alpha and thromboxane B2 (TxB2) was determined by enzyme immunoassay. COX-2 protein expression was measured by western blot.. Aldosterone reduced acetylcholine relaxation in MRA from both strains. In MRA from both aldosterone-treated strains the COX-1/2 or COX-2 inhibitor (indomethacin and NS-398, respectively), TxA2 synthesis inhibitor (furegrelate), prostacyclin synthesis inhibitor (tranylcypromine) or TxA2/ PGH2 receptor antagonist (SQ 29 548), but not COX-1 inhibitor SC-560, increased acetylcholine relaxation. In untreated rats this response was increased only in SHR. Prostacyclin elicited a biphasic vasomotor response: lower concentrations elicited relaxation, whereas higher concentrations elicited contraction that was reduced by SQ 29 548. Aldosterone increased the acetylcholine-stimulated production of 6-oxo-PGF(1alpha) and TxB2 in MRA from both strains. COX-2 expression was higher in both strains of rats treated with aldosterone.. Chronic treatment with aldosterone impaired endothelial function in MRA under normotensive and hypertensive conditions by increasing COX-2-derived prostacyclin and thromboxane A2. As endothelial dysfunction participates in the pathogenesis of many cardiovascular disorders we hypothesize that anti-inflammatory drugs, specifically COX-2 inhibitors, could ameliorate vascular damage in patients with elevated aldosterone production.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aldosterone; Animals; Blotting, Western; Cyclooxygenase 1; Cyclooxygenase 2; Endothelium, Vascular; Epoprostenol; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Vascular Diseases; Vascular Resistance; Vasoconstrictor Agents

We have investigated the effects of moderate global undernutrition during gestation in the rat on the blood pressure of male and female offspring, and on the development of systemic vascular function. Pregnant Wistar rats were nutritionally restricted (R) by feeding with 70% of the normal gestation-matched dietary intake from 0 to 18 days gestation.R offspring were growth retarded at birth but of similar weight to controls (C) at 20 days. Systolic and/or diastolic and mean arterial blood pressures, measured directly by femoral artery catheter, were elevated from 60 days onward in male R offspring (mean arterial pressure: day 60, P < 0.01; day 100, P < 0.05; day 200, P < 0.005, R vs. C), and from 100 days onward in female R offspring (mean arterial pressure day 100 and day 200, P < 0.05; R vs. C). Maximal constriction to phenylephrine (PE) (P < 0.05) and to noradrenaline (NA) (P < 0.05) was reduced in isolated femoral arteries of day 20 R pups. These differences did not persist into adulthood. In male adult R offspring (200 days), maximal vasoconstriction to the thromboxane A2 mimetic, U46619 (P < 0.05) and sensitivity to potassium (P < 0.01) were enhanced. Moderate maternal undernutrition in rat gestation adversely affects cardiovascular function in the offspring. These abnormalities increase with age and are more pronounced in males.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Birth Weight; Blood Pressure; Diet; Energy Intake; Female; Gestational Age; Hypertension; Male; Muscle, Smooth, Vascular; Norepinephrine; Organ Size; Phenylephrine; Potassium; Pregnancy; Rats; Rats, Wistar; Thromboxane A2; Vascular Diseases; Vasoconstrictor Agents

This study investigated whether or not dietary restriction (DR), consisting of 60% of the daily caloric allowance of ad libitum fed (AL) rats, has a modulating effect on prostaglandins (PGs), thromboxane (TXA), and lipids in the serum of rats. Results showed that DR rats had consistently, 30-40% lower overall lipid peroxide levels than AL rats. On the other hand, the age-related increases in arachidonic acid contents observed in AL rats were significantly suppressed by DR during aging; while unsaturated/saturated fatty acid ratios remained consistently higher (15-50%) in DR rats than in AL rats. Serum PGE2 and PGF2 levels in DR rats were maintained at consistently higher levels (30-65% and 40-90%, respectively) than in AL rat serum. PGI2 levels (as measured by 6-keto PGF2) in serum of DR rats were also consistently higher (40-50%) than those of AL rats, while TXA2 levels sustained lower levels (15-20%) than those of AL rats, showing a significantly higher (27-38%) PGI2/TXA2 ratios in DR than in AL rats. Thus, our study clearly indicated that DR effectively modulates prostaglandin levels by preventing age-related decreases in PGI2 levels and increases in TXA2 levels. These findings, with the other known beneficial actions of DR, strongly suggest vascular activity to be well-regulated in DR animals.

Topics: Age Factors; Aging; Animals; Food Deprivation; Lipid Metabolism; Lipids; Male; Prostaglandins; Rats; Rats, Inbred F344; Specific Pathogen-Free Organisms; Thromboxane A2; Vascular Diseases

Angiotensin II (AGII) and thromboxane A2 (TXA2), potent vasoconstrictors, augmented the production of the precursor of tissue procollagenase/promatrixmetalloproteinase-1 (proMMP-1) and DNA synthesis in cultured human aortic smooth muscle cells (SMC) significantly compared with that in untreated SMC. Moreover, AGII and TXA2 stimulated hydrolysis of phosphoinositides and subsequent formation of inositol triphosphate (IP3), leading to an increase in the intracellular free Ca2+ concentration. These results suggest that the production of proMMP-1 increased by AGII and TXA2 in intimal SMC in relation to cell proliferation plays a role in arterial reconstruction in vascular diseases.

Topics: Angiotensin II; Aorta, Thoracic; Calcium; Cell Division; Cells, Cultured; Collagenases; DNA; Enzyme Precursors; Humans; Inositol 1,4,5-Trisphosphate; Kinetics; Matrix Metalloproteinase 1; Muscle, Smooth, Vascular; Thromboxane A2; Thymidine; Vascular Diseases

It has been suggested that penile hypercoagulability predisposes to aging penile vascular changes and impotence, and that elevated thromboxane A2 during erection may contribute to hypercoagulability and atherosclerosis. Since the ratio of the prostacyclin concentration to the thromboxane A2 concentration is constantly maintained in normal hemostatic responses, an imbalance between thromboxane A2 and prostacyclin may be a factor to initiate vascular diseases and decrease blood flow. We assess the usefulness of the prostacyclin-to-thromboxane A2 ratio in penile blood during erection for diagnosis of arteriogenic impotence. The ratio in the arteriogenic impotence group was significantly lower (p less than 0.01) than in the psychogenic and venogenic impotence groups. Therefore, the prostacyclin-to-thromboxane A2 ratio seems to be useful to diagnose arteriogenic impotence.

Topics: Adult; Epoprostenol; Erectile Dysfunction; Humans; Male; Penile Erection; Penis; Thromboxane A2; Vascular Diseases

Cultured rat vascular smooth muscle cells from mesenteric artery produced prostaglandin (PG)E2, PGF2 alpha, PGI2 and thromboxane (TX)A2 in response to arachidonic acid, calcium ionophore A23187, vasopressin and angiotensin II. PGI2 was the major product among these PGs. PG synthesis in these cells decreased with in vitro aging, but the distribution pattern of PG synthesis did not change up to the passage level 56. Therefore, it is suggested that imbalance among PGs may not be directly implicated in vascular diseases in aging.

Topics: Aging; Animals; Cells, Cultured; Dinoprost; Dinoprostone; Epoprostenol; Muscle, Smooth, Vascular; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Thromboxane A2; Vascular Diseases

The influence of hypoxia on the spontaneous platelet aggregation (SPA) and thromboxane formation was studied. The analysis of aggregation curve was carried out according to Breddin. The hypoxia enhanced the aggregability from Q2norm = 2.46 +/- 0.40 (normoxia) to Q2hyp = 4.39 +/- 0.39 (hypoxia), n = 52, p less than 0.001. 10 samples of those showed no SPA under equilibration with air but the hypoxic stimulus provoked SPA (Q2norm = 0, Q2hyp = 1.19 +/- 60, n = 10, p less than 0.001). When the results were arranged according to the degree of the stimulation of SPA, two groups could be separated with low and high response to hypoxia. The hypoxia caused also an augmentation of the TXB2 level in comparison to normoxia. The stronger enhancement of the TXB2 formation during the incubation under hypoxic conditions was independent of the fact whether SPA took place or not. The present study suggests that hypoxic conditions alone may be a reason for a stimulated TXA2 formation of the platelets and that the enhanced TXA2 formation caused by hypoxia is possibly inducing or reinforcing the SPA.

Topics: Adult; Aged; Blood Platelets; Humans; Hydrogen-Ion Concentration; Hypoxia; Middle Aged; Oxygen; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Vascular Diseases

Topics: Blood Platelets; Humans; Hypoxia; In Vitro Techniques; Platelet Aggregation; Thromboxane A2; Vascular Diseases

One year aged rabbits were exposed to a single dose of 100, 500 or 1000 rd (1.0, 5.0 or 10 Gy) to the abdominal aorta. The non-irradiated thoracic aortic segment served as control. The animals were killed between one and 336 hours after the irradiation. Four animals were examined in each group. The prostacyclin formation was assessed by means of a radioimmunoassay against its stable breakdown 6-oxo-PGF1 alpha, the thromboxane A2-formation using a radioimmunoassay for thromboxane B2. Local irradiation causes a temporary increase of both the compounds. In contrast to thromboxane B2, the 6-oxo-PGF1 alpha exhibits a long-lasting depression. The higher the radiation dose, the more intensive the increase and the long-lasting depression of 6-oxo-PGF1 alpha. The liberation of eicosanoids and subsequent hemostatic dysregulation at different intervals after irradiation might contribute to an important extent to the radiation induced vasculopathy.

Topics: Animals; Aorta, Abdominal; Blood Vessels; Dose-Response Relationship, Radiation; Epoprostenol; Male; Prostaglandins F; Rabbits; Radiation Injuries, Experimental; Thromboxane A2; Thromboxane B2; Vascular Diseases

The effect of a human fibrinogen preparation on in vitro platelet aggregation was assessed. Platelets were obtained from healthy volunteers. Human fibrinogen induced platelet aggregation in 65% of platelet rich plasma samples and enhanced submaximal platelet aggregation induced by heparin or by several conventional agonists in all samples. Aggregation induced by fibrinogen alone was reversed by the in vitro addition of human albumin. Fibrinogen induced aggregation was associated with the release of the vasoconstrictor, thromboxane A2. Preincubation with indomethacin inhibited both the aggregation and the release of thromboxane A2. Fibrinogen had no effect on in vitro vascular prostaglandin I2 synthesis (rat aortic rings) during a 60 minute incubation. The observed effects of fibrinogen on platelet function may be relevant to clinical conditions in which hyperaggregability of platelets is associated with hyperfibrinogenemia and thrombosis.

Topics: Animals; Aorta; Blood Platelets; Epoprostenol; Female; Fibrinogen; Humans; In Vitro Techniques; Indomethacin; Male; Platelet Aggregation; Prostaglandins A; Rats; Serum Albumin; Thromboxane A2; Vascular Diseases

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

Topics: Anti-Inflammatory Agents; Arachidonic Acids; Epoprostenol; Gastrointestinal Diseases; Humans; Kidney Diseases; Lung Diseases; Neoplasms; Prostaglandins; SRS-A; Thromboxane A2; Thromboxanes; Vascular Diseases

The ipsilateral kidney was removed from a rabbit 48h after unilateral partial renal-vein-constriction and was perfused with Krebs-Henseleit media at 37 degrees C. Hourly administration of a fixed dose of bradykinin to the renal-vein-constricted kidney demonstrated a marked time-dependent increase in the release of bioassayable prostaglandin E(2) and thromboxane A(2) into the venous effluent as compared with the response of the contralateral control kidney. The renal-vein-constricted kidney produced up to 60 times more prostaglandin E(2) in response to bradykinin after 6h of perfusion as compared with the contralateral kidney; thromboxane A(2) was not demonstratable in the contralateral kidney. Inhibition of protein synthesis de novo in the perfused renal-vein-constricted kidney with cycloheximide lessened the hormone-stimulated increase in prostaglandin E(2) by 94% and in thromboxane A(2) by 90% at 6h of perfusion. Covalent acetylation of the renal cyclo-oxygenase by prior oral administration of aspirin to the rabbit inhibited initial bradykinin-stimulated prostaglandin E(2) biosynthesis 71% at 1h of perfusion. However, there was total recovery from aspirin in the renal-vein-constricted kidney by 2h of perfusion after bradykinin stimulation. Total cyclo-oxygenase activity as measured by [(14)C]arachidonate metabolism to labelled prostaglandins by renal cortical and renal medullary microsomal fractions prepared from 6h-perfused kidneys demonstrated that renal-vein-constricted kidney-cortical cyclo-oxygenase activity was significantly greater than the contralateral-kidney-cortical conversion, whereas medullary arachidonate metabolism was comparable in both the renal-vein-constricted kidney and contralateral kidney. These data suggest that perfusion of a renal-vein-constricted kidney initiates a time-dependent induction of synthesis of prostaglandin-producing enzymes, which appear to be primarily localized in the renal cortex. The presence of the synthetic capacity to generate very potent vasodilator and vasoconstrictor prostaglandins in the renal cortex suggests that these substances could mediate or modulate changes in renal vascular resistance in pathological states.

Topics: Animals; Bradykinin; Constriction; Dinoprostone; In Vitro Techniques; Kidney; Perfusion; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Rabbits; Radioimmunoassay; Renal Veins; Stimulation, Chemical; Thromboxane A2; Thromboxanes; Vascular Diseases