thromboxane-a2 and Carotid-Artery-Diseases

To evaluate the efficacy of aspirin for the treatment and prevention of ischemic stroke and identify the minimum dose proven to be effective for each indication.. PubMed and MEDLINE searches (up to January 2010) were performed to identify primary literature, using search terms including aspirin, stroke prevention, acute ischemic stroke, acetylsalicylic acid, atrial fibrillation, myocardial infarction, and carotid endarterectomy. Additionally, reference citations from publications identified were reviewed.. Articles published in English were evaluated and relevant primary literature evaluating the efficacy of aspirin in the prevention of stroke was included in this review.. Antiplatelet therapy is the benchmark for the prevention of ischemic stroke. Aspirin has been proven to prevent ischemic stroke in a variety of settings. Despite the frequency at which aspirin continues to be prescribed in patients at risk of ischemic stroke, there remains confusion in clinical practice as to what minimum dose is required in various at-risk patients. A thorough review of the primary literature suggests that low-dose (50-81 mg daily) aspirin is insufficient for some indications. Acute ischemic stroke treatment requires 160-325 mg, while atrial fibrillation and carotid arterial disease require daily doses of 325 and 81-325 mg, respectively.. Available evidence suggests that aspirin dosing must be individualized according to indication. Recommendations provided by national guidelines at times recommend lower doses of aspirin than have been proven effective. Higher doses are indicated for stroke prevention in atrial fibrillation (325 mg) and acute ischemic stroke patients (160-325 mg). Aspirin has not yet been proven effective for primary prevention of strokes in men, and a minimum dose for these patients cannot be determined from the available data.

Topics: Aspirin; Atherosclerosis; Carotid Artery Diseases; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Ischemia; Myocardial Infarction; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Stroke; Thromboxane A2

Cardiovascular disease is the major cause of morbidity and mortality in diabetic patients, which in turn is also associated with low levels of serum testosterone. The working hypothesis was that diabetes might modify the mechanisms involved in the vascular actions of testosterone in isolated rabbit carotid arteries. Testosterone (10(-8)-3x10(-4)M) induced a concentration-dependent relaxation of precontracted carotid arteries, which was higher in diabetic than in control rabbits. In control rabbits neither endothelium removal nor the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine (l-NOArg, 10(-5)M) modified the relaxant action of testosterone, and the cyclooxygenase (COX) inhibitor indomethacin (10(-5)M) enhanced this relaxation. In contrast, in diabetic rabbits endothelium removal, l-NOArg (10(-5)M) or indomethacin (10(-5)M) inhibited the testosterone induced relaxation. In arteries from diabetic rabbits, eNOS, iNOS and COX-2 expression and testosterone induced release of prostacyclin resulted enhanced in comparison with arteries from control rabbits. Testosterone (10(-4)M) strongly inhibited CaCl(2) (10(-5)-3x10(-2)M) concentration-related contractions of the carotid artery both in control and diabetic rabbits. These results suggest that testosterone relaxes the rabbit carotid artery by blocking the extracellular calcium entry. Diabetes enhances the vasodilator response of the rabbit carotid artery to testosterone by a mechanism that at least includes an increased modulatory activity of the endothelial nitric oxide and an augmented release of COX-2 vasodilator, prostacyclin rather than the absence of COX-1 vasoconstrictor, thromboxane A(2). The hypotestosteronemia observed in diabetic rabbits could be a consequence of the increased expression of iNOS and could contribute to the hyperreactivity of the rabbit carotid artery to testosterone.

Topics: Animals; Apamin; Blood Glucose; Blotting, Western; Calcium; Carotid Arteries; Carotid Artery Diseases; Charybdotoxin; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dose-Response Relationship, Drug; Endothelium, Vascular; Epoprostenol; Immunoenzyme Techniques; Indomethacin; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Potassium; Potassium Channel Blockers; Rabbits; Testosterone; Thromboxane A2; Vasodilation

The plasma level of soluble CD40 ligand (sCD40L), which induces pro-inflammatory and pro-atherogenic responses, is known to be elevated in atherosclerotic patients. In this study, we investigated the mechanism of sCD40L release from human platelets, focusing on the involvement of thromboxane (TX) A(2).. We measured sCD40L release and TXA(2) production induced by ristocetin, an activator of GPIb/IX/V, from human platelets in vitro. Moreover, plasma sCD40L and TXA(2) levels in the 10 patients with severe carotid artery stenosis who were not taking any anti-platelet medicines were measured and compared with those obtained from non-atherosclerotic controls.. Ristocetin significantly promoted sCD40L release and TXA(2) generation from platelets in vitro. Aspirin and SC-560, a cyclooxygenase-1 inhibitor, suppressed the ristocetin-induced sCD40L release from platelets in parallel with TXA(2) production. Ozagrel, a TXA(2) synthase inhibitor and PTXA(2), a thromboxane receptor (TP) antagonist also suppressed sCD40L release. U46619, a TP agonist, reversed the suppressive effect of aspirin on sCD40L release. In vivo, plasma levels of sCD40L and TXA(2) in the patients were significantly higher than those in controls. Elevated plasma levels of TXA(2) and sCD40L in the patients were markedly diminished after 7 days of 100mg aspirin administration.. These results strongly suggest that GPIb/IX/V activation induces sCD40L release via TXA(2) from human platelets, and that sCD40L release via TXA(2) generation from platelets in atherosclerotic patients are up-regulated.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aged; Aspirin; Atherosclerosis; Blood Platelets; Carotid Artery Diseases; CD40 Ligand; Female; Humans; Male; MAP Kinase Kinase 4; Methacrylates; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pyrazoles; Ristocetin; Thromboxane A2

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

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

The effect of a selective thromboxane A2 (TxA2) receptor antagonist, SQ 30,741, on streptokinase-induced thrombolysis was examined in pentobarbital-anesthetized cynomolgus monkeys. The intimal surface of a stenosed carotid artery was stimulated with 100 microA anodal current to produce an occlusive thrombus. After 45 min of zero blood flow, a 1-h intraarterial (i.a.) infusion of streptokinase (680 U/min) was injected proximal to the thrombus. Five minutes before streptokinase (SK) intravenous (i.v.) infusions of heparin (200 U/kg + 120 U/h) and either SQ 30,741 (2 mg/kg + 2 mg/kg/min, n = 8) or vehicle (1 ml/h saline, n = 7) were started and maintained for 3 h. In four monkeys not given streptokinase or heparin, no recanalization was detected and occlusive thrombi were observed after 3 h. All animals receiving streptokinase were recanalized. SQ 30,741 had no effect on return of flow during streptokinase infusion, but increased average reflows during the second (60%, p less than 0.05) and third hours (159%, p less than 0.01). Average blood flows were decreased from the second to third hours with vehicle (p less than 0.001) and remained stable with SQ 30,741. Thromboxane antagonism also increased minimal blood flows during the third hour (438%, p less than 0.01) and decreased the total time reoccluded by 73% (p less than 0.05). However, SQ 30,741 had no effect on the time to recanalization, the maximum reflow, and both number of animals reoccluded and average number of reocclusions. Fibrinogen levels were equivalently diminished (8%, p less than 0.05), and platelet counts were unaffected in both treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Carotid Artery Diseases; Female; Macaca fascicularis; Male; Regional Blood Flow; Streptokinase; Thrombosis; Thromboxane A2

Prostacyclin (PGI2) and thromboxane A2 (TxA2) formation by whole-tissue segments of nine carotid endarterectomy specimens (CES), five normal aortic specimens (NAS), six saphenous vein specimens (SVS), and four platelet samples were determined by incubation with 10 mumol/L 1-14C-radiolabeled prostaglandin endoperoxide H2 (PGH2), and in other experiments with and without 10 mumol/L of CGS 13080, a TxA2 synthase inhibitor. PGI2 formation (expressed as picomoles 6-keto-PGF1 alpha/2-min incubation per sample) by nonatheromatous proximal intima of CES (307 +/- 23, mean +/- standard error) and distal intima of CES (260 +/- 22) was not statistically different; however, it was greater than atheromatous transitional plaque (159 +/- 13 pmol) (p less than 0.01) and ulceration regions (140 +/- 15 pmol) (p less than 0.01) of CES, NAS (204 +/- 16 pmol) (p less than 0.01), and SVS (165 +/- 9 pmol) (p less than 0.01). TxA2 formation (expressed as picomoles TxB2/2-min incubation per sample) by CES ulceration (51 +/- 2 pmol) was low but greater than proximal (17 +/- 2 pmol) (p less than 0.01), distal (19 +/- 3 pmol) (p less than 0.01), and transitional (23 +/- 3 pmol) (p less than 0.01) regions. TxA2 formation by NAS and SVS was not detected (less than 10 pmol). CGS 13080 inhibited TxA2 formation by CES below the limits of detection. Incubation of 1.9 x 10(5) intact platelets with 10 mumol/L of PGH2 formed a quantity of TxA2 equal to that of CES ulceration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aorta; Blood Platelets; Carotid Arteries; Carotid Artery Diseases; Epoprostenol; Humans; In Vitro Techniques; Intracranial Arteriosclerosis; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Saphenous Vein; Thromboxane A2

Imbalance between the two arachidonic acid metabolites, prostacyclin (PGI2) and thromboxane A2 (TXA2), is thought to be at least in part responsible for the development of cerebral vasospasm following aneurysm rupture. In 12 patients with subarachnoid hemorrhage the pre- and postoperative serum and CSF levels of PGI2 and TXA2 were measured as a function of their stable hydrolysis products, 6-Keto-PGF1 alpha (PGI2) and thromboxane B2 (TXA2), with a highly specific radioimmunoassay. Serum levels of both metabolites were elevated in half of the patients, but no correlation to the clinical course could be found. However, TXB2 concentration in the CSF was significantly increased preoperatively with close correlation to the amount of intracisternal blood, as detected by CT scan. Furthermore, it could be demonstrated that the postoperative course of the TXB2 concentrations in the CSF reflects the clinical course in such a way that a characteristic secondary rise of TXB2, concentration postoperatively is closely related to the occurrence of cerebral vasospasm and clinical deterioration. The conclusion is drawn that measurement of arachidonic acid metabolites in the CSF may provide important information concerning the pathophysiological events following subarachnoid hemorrhage, especially with regard to incipient cerebral vasospasm.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Blood-Brain Barrier; Carotid Artery Diseases; Carotid Artery, Internal; Epoprostenol; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Rupture, Spontaneous; Subarachnoid Hemorrhage; Thromboxane A2; Thromboxane B2