thromboxane-b2 and Brain-Ischemia

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Circulation; Drugs, Chinese Herbal; Free Radical Scavengers; Malondialdehyde; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Brain Ischemia; Dinoprostone; Eicosanoids; Fetal Diseases; Fetus; Rats; Thromboxane B2; Tritium

Uncertainty remains regarding the impact of enteric-coated (EC) aspirin as it relates to the reduction of cardiovascular risk. We hypothesize that EC formulation based on a previous report may blunt aspirin response as evidenced by reduced Thromboxane A2 (TXA 2) levels in diabetic patients. Thus, it was imperative to ascertain and validate the effect of the EC formulation of Aspirin on the Thromboxane B2 (TXB2) level.. An open-label consecutive randomized interventional controlled trial. Patients with newly diagnosed ischemic stroke who are just about to start Aspirin were assessed for eligibility and inclusion in our trial. Consecutive patients (admitted to the stroke unit of Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar) will be randomized to receive either EC aspirin or plain Aspirin. They will be required to continue taking them throughout the study (3 days). Demographics and laboratory records of the study participants will be abstracted from online records. Further study variables will be obtained manually in designated case record forms (CRF). The primary outcomes are the incidence of aspirin non-responders (level of residual serum TXB2 associated with elevated thrombotic risk (<99.0% inhibition or TXB2 >3.1 ng/mL) within 72 h after three daily aspirin doses). Whereas secondary outcomes are the incidence of GIT bleeding of various preparations of Aspirin. The study was approved by MRC and IRB of Hamad Medical Corporation (MRC number: 01-18-156).. This trial will determine potential differences in the efficacy of EC Aspirin and plain Aspirin on the Thromboxane B2 level. Additionally, it will ascertain the tolerability and safety of both formulations of Aspirin in patients with newly diagnosed ischemic stroke. These results will either support the current notion of no difference between the two formulations. However, if a difference is found, this will invite for future trials exploring clinical outcomes occurrence between various formulations.. Clinicaltrials.gov NCT04330872 registered on April 2, 2020.

Topics: Adolescent; Adult; Aged; Aspirin; Blood Platelets; Brain Ischemia; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Single-Blind Method; Socioeconomic Factors; Stroke; Tablets, Enteric-Coated; Thromboxane B2; Young Adult

To observe the therapeutic effects of midnight-noon ebb-flow method of selecting acupoints (MNEFMSA) for acute ischemic cerebrovascular diseases (AICD) and its influence on hemorrheology and on the levels of interleukin-6 (IL-6), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha).. The 90 cases were randomly divided into 3 groups, each consisting of 30 cases. The drug group was treated mainly by routine medication; in addition to medication, the affected-channel group was treated by acupuncture at points along the course of the affected channel, and the MNEFMSA group was treated by MNEFMSA.. The total effective rate of MNEFMSA group, affected-channel group and drug group was 96.67%, 90% and 73.33% respectively. The total effective rate of MNEFMSA group was obviously superior to that of the drug group (P < 0.01), and cure rate and marked improvement rate were obviously superior to those of the drug group and the affected-channel group (P < 0.05 or P < 0.01). After treatment, the three groups all got improvements in the hemorheological indexes, of which MNEFMSA group got marked improvements in the whole blood viscosity and erythrocyte deformability rate, significantly different from the other two groups (P < 0.05). At the early stage of treatment and after treatment, the three groups all had IL-6, TXB2 and 6-keto-PGF1alpha obviously improved (P < 0.05 or P < 0.01), of which MNEFMSA group got obvious improvement in 6-keto-PGF1alpha and IL-6 ever since the early stage of the treatment (P < 0.05).. In the treatment of acute ischemic cerebrovascular diseases, MNEFMSA can markedly raise the clinical therapeutic effects by improving the hemorheological indexes, lowering the level of IL-6, and restoring the dynamic equilibrium between TXB2 and6-keto-PGF1alpha, so as to promote the recovery of cerebral nervous function.

Topics: 6-Ketoprostaglandin F1 alpha; Acupuncture Points; Acupuncture Therapy; Adult; Aged; Aged, 80 and over; Brain Ischemia; Female; Humans; Interleukin-6; Male; Medicine, Chinese Traditional; Middle Aged; Thromboxane B2

Aspirin-clopidogrel combination therapy inhibits platelet aggregation. The effect on platelet recruitment is unknown.. Thirty chronic ischemic stroke patients taking aspirin alone followed by aspirin-clopidogrel combined therapy had platelet reactivity tests performed over 3 months: ex vivo platelet aggregation, platelet recruitment and urinary 11-dehydro-thromboxane B(2) (11-dhTxB(2))excretion. Statistical analysis of variance compared platelet aggregation and recruitment between aspirin alone and aspirin-clopidogrel, and longitudinal regression analysis estimated platelet recruitment over time. Nonlinear mapping defined variable connections in each patient.. Statistically significant differences were found between aspirin alone and aspirin-clopidogrel for (1) adenosine-diphosphate- and collagen-induced platelet aggregation and maximum inhibition of platelet recruitment and (2) increasing inhibition of platelet recruitment over time. Urinary 11-dhTxB(2) excretion did not predict platelet aggregation response. Nonlinear mapping showed patient-unique variable interconnections.. Platelet inhibition with aspirin-clopidogrel may increase over time, and future studies should focus on this finding in the context of vascular complications.

Topics: Aspirin; Brain Ischemia; Clopidogrel; Cohort Studies; Drug Therapy, Combination; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Stroke; Thromboxane B2; Ticlopidine

A large number of patients experience ischemic stroke despite treatment with aspirin (acetylsalicylic acid, ASA). It is not clear whether all of these patients with ischemic stroke respond normally to ASA or are hyporesponsive as assessed by inhibition of aggregation and thromboxane (TX) synthesis.. We studied the effect of ASA given orally and ASA in vitro on collagen- and arachidonic-acid-induced TX formation and aggregation in platelet-rich plasma of 90 patients with ischemic stroke and 25 healthy control subjects.. Thirty-seven patients were being treated with ASA at the time of stroke. Arachidonic-acid-induced TX formation was not depressed below a predefined threshold of 25 ng/ml in 9 patients. Eight of these however exhibited a normal platelet sensitivity to ASA in vitro, suggesting poor compliance or a pharmacokinetic mechanism of nonresponse. The addition of ASA in vitro did not inhibit arachidonic-acid-induced TX formation below the above threshold in 6 patients (11%) in the group of 53 stroke patients not receiving oral ASA, indicating an impaired response to ASA at the platelet level. Moreover, platelets from stroke patients showed an increased collagen-induced, TX-independent aggregation as compared with those of healthy individuals.. Different categories of ASA nonresponders can be distinguished in patients with ischemic stroke. These include patients with poor bioavailability or noncompliance, an impaired platelet response to ASA in vitro and an increased, TX-independent hyperreactivity to collagen.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Arachidonic Acid; Aspirin; Biological Availability; Blood Platelets; Brain Ischemia; Collagen; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; Male; Middle Aged; Patient Compliance; Platelet Aggregation; Platelet Aggregation Inhibitors; Stroke; Thromboxane B2; Treatment Outcome

The aim of this study was to determine the extent of change in platelet and coagulation markers in the acute phase of ischemic stroke and to assess the utility of marker measurement in stroke subtype classification. Urinary 11-dehydro-thromboxane B(2) (11-dTXB2), a marker of in vivo platelet activation, and markers of coagulation activation, including prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and fibrinogen, were measured in 25 patients with ischemic stroke within 24 h of onset of symptoms. Marker levels in patients with ischemic stroke were compared with those in 19 age-matched controls who had not taken aspirin for at least 2 weeks before sampling and 25 healthy controls. Median marker levels were significantly increased in stroke over those in age-matched controls for fibrinogen (344 vs. 289 mg/dl; P=0.030), F1+2 (1.40 vs. 0.80 nmol/l; P=0.003), and TAT (6.65 vs. 2.20 microg/l; P<0.0001). Median marker levels for seven patients with cardioembolic stroke and 18 with non-cardioembolic stroke were not significantly different for any marker test. Eight patients taking aspirin at the time of the stroke had significantly lower 11-dTXB2 values than patients not taking aspirin (964 vs. 4,314 pg/mg of creatinine; P=0.007). Stroke patients not taking aspirin had significantly higher 11-dTXB2 concentration than age-matched controls (4,314 vs. 1,788 pg/mg of creatinine; P=0.006). Coagulation and platelet activation markers are increased in the acute phase of stroke regardless of the clinical mechanism. This finding suggests that the markers may not be useful for predicting clinical subtype of ischemic stroke in the acute phase.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Aspirin; Biomarkers; Blood Coagulation; Brain Ischemia; Fibrinogen; Humans; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Stroke; Thromboxane B2

It has been suggested that daily intake of aspirin is associated with a reduction of cognitive decline, both in normal and in demented subjects, but the mechanism is unclear. We have therefore studied the relationship between thromboxane (TX) A(2) biosynthesis, as reflected by the urinary excretion of 11-dehydro-TXB(2), and the presence of dementia in patients after acute stroke.. Patients from the Rotterdam Stroke Databank were screened for dementia between 3 and 9 months after stroke. Patients had a full neurological examination, neuropsychological screening, and, if indicated, extensive neuropsychological examination. Criteria used for the diagnosis of dementia were from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (Revised). Urine samples were taken at the time of screening. Urinary 11-dehydro-TXB(2) was measured by means of a previously validated radioimmunoassay.. Dementia was diagnosed in 71 patients, and urine samples were available for 62. Median value (range) of 11-dehydro-TXB(2) was 399 (89 to 2105) pmol/mmol creatinine for demented patients versus 273 (80 to 1957) for 69 controls with stroke but without dementia (P=0.013). No difference was found between 44 patients with vascular dementia, 404 (89 to 2105) pmol/mmol creatinine, and 18 patients with Alzheimer's disease plus cerebrovascular disease, 399 (96 to 1467) pmol/mmol creatinine (P=0.68). In a stepwise logistic regression analysis, in which possible confounders such as use of antiplatelet medication, cardiovascular risk factors, and type of stroke were taken into account, increased urinary excretion of 11-dehydro-TXB(2) remained independently related to the presence of dementia (OR 1.12, 95% CI 1.03 to 1.22 per 100 pmol/mmol creatinine). The difference in metabolite excretion rates between demented and nondemented patients was most prominent within the subgroup of ischemic stroke patients who received aspirin (P<0.01).. Increased thromboxane biosynthesis in the chronic phase after stroke is associated with the presence of but not the type of poststroke dementia. It is particularly apparent in patients on aspirin, thereby suggesting the involvement of extraplatelet sources of TXA(2) production in this setting.

Topics: Aged; Aspirin; Biomarkers; Blood Platelets; Brain Ischemia; Cerebral Hemorrhage; Chronic Disease; Cognition; Creatinine; Dementia, Vascular; Female; Humans; Male; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Platelet aggregation was examined in 43 patients after ischemic stroke and in 16 healthy subjects using multiparametric aggregation index (MAI). The value of MAI was significantly higher in stroke patients (3.15 in patients and 0.92 l/mumol in controls, p < 0.0001). Patients who had increased MAI (n = 26) were treated with a daily dose of 100 mg acetilsalicylic acid (ASA). Platelet activity was measured before and on the 7th and 28th day of treatment measuring three parameters: MAI, spontaneous dysaggregation and collagen induced aggregation. All 3 methods showed a significant decrease in platelet aggregation on the 7th day of treatment, but further changes were not found on the 28th day. Serum levels of thromboxane-A2 (TXA2) and prostacycline (PGI2) metabolites (TXB2 and 6-keto-prostaglandin-F1 alpha) were determined before and on the 28th day of treatment. The effect of 100 mg ASA per day proved to be selective: comparing the serum levels before and after treatment, a significant decrease of TXB2 concentration was found without changes in the concentration of 6-keto-prostaglandin-F1 alpha. Evaluating MAI and the value of dysaggregation might reflect ineffectiveness of antiplatelet therapy in patients not responding to a daily dose of 100 mg of ASA. For these patients the increase of the daily dose of ASA, or changing to another antiplatelet drug might be recommended.

Topics: Aged; Aged, 80 and over; Aspirin; Blood Coagulation Tests; Brain Ischemia; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins F; Thromboxane A2; Thromboxane B2

To examine the antiplatelet effect of a novel pyrazolopyridine derivative (KC-764) in geriatric patients with ischemic stroke.. Randomized clinical trial of three graded dose levels.. A geriatric clinic attached to a nursing home.. Fifteen patients with a history of cerebral infarction with a mean age of 75 +/- 5 years (range, 65-83). Patients were divided into three groups and administered 10, 20, or 40 mg/day KC-764 for 8 weeks.. Platelet aggregation induced by arachidonate, ADP, collagen and platelet-activating factor. Plasma or serum levels of thromboxane B2 and 6-ketoprostaglandin F1 alpha.. Platelet aggregation was inhibited by KC-764 administration and returned to the control level after discontinuation. Although plasma thromboxane B2 levels were markedly decreased, plasma 6-ketoprostaglandin F1 alpha was not affected. However, the dose of 10 mg/day was not sufficient to maintain an effective plasma level of KC-764. There were no side effects or changes in laboratory findings.. We confirmed that KC-764 at a dose of 20 to 40 mg/day is an effective antiplatelet agent and a good candidate for a trial to see if it is feasible for long-term use for the prevention of ischemic stroke in high-risk patients.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Aged, 80 and over; Brain Ischemia; Bridged Bicyclo Compounds; Cerebrovascular Disorders; Chromatography, High Pressure Liquid; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Humans; Nicotinic Acids; Platelet Aggregation Inhibitors; Thromboxane B2

We studied platelet function in 41 patients with subarachnoid hemorrhage who were randomized to receive either nimodipine or placebo in a double-blind fashion. Nimodipine was given to 21 patients, intravenously for 7-10 days and then orally until 21 days after the subarachnoid hemorrhage. The other 20 patients received placebo in a similar manner. Nimodipine did not significantly influence platelet aggregability. For the first 1-5 days after the subarachnoid hemorrhage, nimodipine treatment did not have any notable effect on adenosine diphosphate-induced platelet thromboxane B2 release, but a significant (p less than 0.05) inhibitory effect was observed thereafter. During intravenous administration, nimodipine prevented the increase in thromboxane release otherwise observed after subarachnoid hemorrhage. Concomitant with the decrease in thromboxane release, nimodipine increased the platelet count both before and after surgery so that the capacity for thromboxane formation per liter of blood decreased less than expected on the basis of thromboxane release per 10(7) platelets. Our study suggests that nimodipine might diminish the chance of cerebral ischemia by inhibiting platelet thromboxane release.

Topics: Adult; Blood Platelets; Brain Ischemia; Double-Blind Method; Female; Humans; Male; Middle Aged; Nimodipine; Placebos; Platelet Aggregation; Platelet Count; Subarachnoid Hemorrhage; Thromboxane B2

Aspirin non-response due to persistent platelet reactivity has been associated with adverse vascular events. Light transmission aggregometry (LTA), the 'gold standard' for measuring the platelet response to aspirin therapy, is a cumbersome procedure and a simple and reliable alternative is required. Our aim was to explore whether serum thromboxane B2 (sTXB2) and soluble P-selectin can be used to identify patients who are at risk of increased platelet reactivity while on aspirin.. We recruited 293 ischemic stroke patients, taking aspirin for more than seven days, and performed LTA to classify them. Based on therapeutic serum salicylate levels, 63 patients were excluded due to suspected non-compliance, followed by ELISA measurement of TXB2 and P-selectin in serum. Accordingly, patients were classified into 'Responders' (n = 122, 53%), 'Semi-responders' (n = 76, 33%) and 'Non-responders' (n=32, 14%) by LTA. Patients who had platelet aggregation of ≥70% with 10μM ADP and ≥20% with 0.5mM AA were defined as 'Non-responders'. In comparison with 'Responders', 'Non-responders' had 8.63-fold increased risk of secondary vascular events (p = 0.008). ROC curve analysis revealed that sTXB2, at a cut-off level of >4.15 ng/mL, could distinguish the patient group with elevated platelet reactivity with a sensitivity of 84.3% (AUC = 0.84), and was in fair agreement with the LTA-based classification of patients. Soluble P-selectin levels, on the other hand, had no discriminatory ability.. We suggest sTXB2 measurement as an alternative to the LTA approach for identifying aspirin-treated ischemic stroke patients who are at risk of enhanced platelet reactivity and subsequent vascular events.

Topics: Aspirin; Brain Ischemia; Humans; Ischemic Stroke; P-Selectin; Thromboxane B2

Progressive ischemic stroke is a common cerebrovascular disease with high morbidity. This study aimed to investigate the relationship between changes of Thromboxane B2 (TXB2), 6-keto-prostaglandin Fla (6-k-PGFla), and blood glucose (BG) levels with progressive ischemic stroke.. A total of 106 patients with progressive ischemic stroke admitted to our hospital from December 2016 to December 2018 were recruited as the observation group, and 110 patients who received physical examination in our hospital during the same period were selected as the control group. The levels of TXB2, 6-k-PGFla, and BG in different groups were compared, the related risk factors affecting the prognosis of patients with progressive ischemic stroke were analyzed, and the receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of TXB2, 6-k-PGFla, and BG for the prognostic mortality of patients with progressive ischemic stroke.. The levels of TXB2, 6-k-PGFla, and BG in the observation group were significantly higher than those in the control group (P<0.05). The prognostic mortality of participants with abnormally increased expression of TXB2, 6-k-PGFla, and BG was significantly higher than that of patients with normal expression of TXB2, 6-k-PGFla, and BG (P<0.05). Hypertension, diabetes, collateral circulatory disorders, hyperlipidemia, TXB2 (abnormal increase), 6-k-PGFla (abnormal increase), and BG (abnormal increase) were risk factors affecting the prognosis of patients with progressive ischemic stroke (P<0.05). The area under the curve (AUC) of the ROC curve showed that TXB2, 6-k-PGFla, BG, and the combination of them were 0.846, 0.893, 0.835, and 0.971, respectively, showing that the AUC of the combination of them was the largest.. Hypertension, diabetes, collateral circulatory disorders, hyperlipidemia, TXB2 (abnormal increase), 6-k-PGFla (abnormal increase), and BG (abnormal increase) are risk factors affecting the prognosis of patients with progressive ischemic stroke. The combined detection of the 3 indicators showed high sensitivity and specificity in evaluating the prognostic mortality of patients with progressive ischemic stroke, indicating that clinicians might improve the early diagnosis rate of progressive ischemic stroke by combining the detection of TXB2, 6-k-PGFla, and BG to predict the prognosis of patients.

Topics: Blood Glucose; Brain Ischemia; Humans; Ischemic Stroke; Prostaglandins; Stroke; Thromboxane B2

Aspirin resistance has an incidence of 5%-65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A. A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB. Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233-0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080-6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590-42.638).. A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931-rs7756935) polymorphisms.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Asian People; Aspirin; ATP Binding Cassette Transporter, Subfamily B; Blood Platelets; Brain Ischemia; Female; Gene Frequency; Genetic Association Studies; Humans; Linkage Disequilibrium; Male; Middle Aged; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Receptors, Thromboxane A2, Prostaglandin H2; Stroke; Thromboxane B2; Treatment Failure

From previous studies, the prevalence of aspirin nonresponders is 5.5-45% in patients with various cardiovascular diseases. Those who have aspirin nonresponders have a greater risk of clinically cardiovascular events. The purpose of the study was to look for the prevalence, associated factors and the outcomes of aspirin nonresponders among patients with ischaemic stroke. Patients with ischaemic stroke who were treated during January 2011-August 2011 were included. Urine 11-dehydro-thromboxane B2 (dTXB2) was measured to determine the response to aspirin in patients. The demographics and vascular risk factors were compared between patients who were classified as aspirin responders or aspirin nonresponders. The outcomes of the study were favourable outcome, cardiovascular events and mortality. There were 182 patients included during the study period: 128 patients with an acute ischaemic stroke and 54 patients with a stable ischaemic stroke. Ninety patients (49.5%) were found to be aspirin nonresponders. Multivariate analysis revealed that stroke presentation (acute stroke) was the only factor associated with aspirin nonresponders [odds ratio (OR) 2.38, 95% confidence interval (CI) 1.193-4.746, P = 0.014]. With a mean follow-up time of 16 months, aspirin nonresponders had a less favourable outcome (54 vs. 83%, OR 0.24; 95% CI 0.11-0.51, P < 0.001), marginally higher cardiovascular events (11 vs. 2%, OR 4.48; 95% CI 0.92-21.37, P = 0.045) and higher mortality (12 vs. 1%, OR 10.52; 95% CI 1.3-85.28, P = 0.007). The prevalence of aspirin nonresponders was rather high in Thai patients with ischaemic stroke. Aspirin nonresponders had a less favourable outcome, higher cardiovascular events and death rate.

Topics: Aspirin; Brain Ischemia; Female; Humans; Male; Middle Aged; Multivariate Analysis; Platelet Aggregation Inhibitors; Risk Factors; Stroke; Survival Analysis; Thromboxane B2; Treatment Outcome

Aspirin achieves its antithrombotic effect through inactivation of cyclo-oxygenase (COX)-1, thereby preventing generation of thromboxane (TX)A2 from arachidonic acid (AA). The reported prevalence of aspirin "resistance" varies significantly and is usually based on platelet function tests (PFTs) that use AA-induced platelet reactivity as a surrogate measure of the effect of aspirin, rather than specific assessment of its effect on its therapeutic target (ie, COX-1 inhibition). The reported rates are not only assay specific but also condition specific, with particularly high rates (up to 70%) previously reported in the stroke population. We investigated whether pharmacological responses to aspirin can be reliably determined from a functional test of AA-induced whole-blood clotting.. A prospective study included 35 patients admitted with ischemic stroke and commenced on 300 mg aspirin. AA-induced whole-blood clotting was measured using short thrombelastography, a previously extensively validated near-patient PFT. Serum TXB2 and inflammatory biomarkers were also measured. The prevalence of apparent aspirin resistance measured using AA was high (range from 49% to 67%). However, serum [TXB2] was consistently low, thereby confirming adequate inhibition of COX-1 by aspirin. Mean inflammatory biomarker levels were elevated throughout.. This study demonstrates that although COX-1 activity is adequately and consistently suppressed by aspirin in stroke patients, this effect is not reliably indicated by whole-blood clotting in response to AA. These data help to explain why the reported prevalence of aspirin resistance in stroke from studies employing AA-induced platelet reactivity is high and cast doubt on the veracity of such reports.

Topics: Aged; Aged, 80 and over; Aspirin; Biomarkers; Brain Ischemia; Cytokines; Drug Resistance; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Stroke; Thrombelastography; Thromboxane B2

Among patients with stroke, the phenomenon of resistance to treatment with low-dose aspirin acetylsalicylic acid (ASA) is quite common. The study included 133 patients hospitalized with acute ischemic stroke. Impedance platelet aggregometry (IPA) and levels of vWF and thromboxane (TXB2) were assessed - with the efficacy of aspirin in daily clinical investigation. Responses to treatment with doses of 150 and 300 mg/day were measured. In addition, we analyzed the response of proinflammatory factors [fibrinogen, C-reactive protein (CRP), white blood corpuscles (WBC)], lipids and hemoglobin A1c, which may alter platelet aggregation response to treatment. After a week of treatment at 150 mg/day, ASA patients were classified as laboratory resistant (42%) or sensitive (58%). Values of IPA in the resistant group were significantly higher (472 ± 150 vs. 222 ± 59 AUC, P < 0.0001). In resistant patients were also found higher levels of fibrinogen (3.90 ± 0.89 vs. 3.46 ± 0.74 g/l, P = 0.0046), CRP (6.97 ± 5.66 vs. 4.17 ± 4.03 mg/l, P = 0.0011), WBC (9.2 ± 2.4 vs. 8.3 ± 2.2 × 10/l, P = 0.0207) and lower HDL cholesterol (46 ± 12 vs. 52 ± 15 mg/dl, P = 0.016). This research shows that aspirin resistance assessment by IPA well reflects the clinical status of patients and should be used routinely. Resistance generally fails to 'break' at higher doses, hence our suggestion that patients resistant to low doses of the drug immediately switch to a thienopyridine class antiplatelet agent, for example, clopidogrel.

Topics: Adult; Aged; Aspirin; Blood Platelets; Brain Ischemia; C-Reactive Protein; Cholesterol, HDL; Clopidogrel; Electric Impedance; Female; Fibrinogen; Glycated Hemoglobin; Humans; Leukocyte Count; Leukocytes; Male; Middle Aged; Pilot Projects; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Stroke; Thromboxane B2; Ticlopidine; von Willebrand Factor

Aspirin is the most commonly used antiplatelet drug for prevention of ischaemic stroke. In order to determine the prevalence and nature of aspirin failure, we studied 51 adults admitted with suspected ischaemic stroke and already prescribed daily aspirin. Within 48 hours (h) of onset, blood and urine samples were collected to assess platelet aggregation, activation and aspirin response by a range of methods. All tests were then repeated on a second sample taken 24 h after witnessed administration of 75 mg or 150 mg aspirin. At entry to the study, incomplete response to aspirin, measured by arachidonic acid (AA)-stimulated platelet aggregation, was found in 43% of patients. Following in-hospital aspirin administration, there was a significant decrease in AA-aggregation (p=0.001) suggesting poor adherence to therapy prior to admission. However, residual aggregation (10-15%) persisted in 11 subjects - suggesting alternative causes. In incomplete responders on admission, platelet aggregation with adenosine diphosphate (ADP) was significantly higher compared with responders (p<0.05) but there were no significant differences in collagen aggregation, platelet fibrinogen binding or P-selectin expression, plasma von Willebrand factor, fibrinogen, high-sensitivity C-reactive protein, or the urinary metabolite, 11-dehydro-TxB2. Incomplete platelet inhibition is common around the time of acute cerebrovascular ischaemic events in patients prescribed aspirin. Up to 50% of these observations appear due to incomplete adherence to aspirin therapy. Intervention studies are required to determine the clinical relevance of measured platelet response to aspirin in terms of outcome, and the effectiveness of improved pharmacotherapy for stroke prevention.

Topics: Acute Disease; Aged; Aged, 80 and over; Arachidonic Acid; Aspirin; Brain Ischemia; Drug Resistance; Female; Humans; Male; P-Selectin; Patient Compliance; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Thromboxane B2

Arachidonic acid (AA) and its vasoactive metabolites have been implicated in the pathogenesis of brain damage induced by cerebral ischemia. The membrane AA concentrations can be reduced by changes in dietary fatty acid intake. The purpose of the present study was to investigate the effects of chronic ethyl docosahexaenoate (E-DHA) administration on the generation of eicosanoids of AA metabolism during the period of reperfusion after ischemia in gerbils. Weanling male gerbils were orally pretreated with either E-DHA (100, 200 mg/kg) or vehicle, once a day, for 10 weeks, and subjected to transient forebrain ischemia by bilateral common carotid occlusion for 10 min. E-DHA (200 mg/kg) pretreatment significantly decreased the content of brain lipid AA at the termination of treatment, prevented postischemic impaired regional cerebral blood flow (rCBF) and reduced the levels of brain prostaglandin (PG) PGF(2alpha) and 6-keto-PGF(1alpha), and thromboxane B(2) (TXB(2)), as well as leukotriene (LT) LTB(4) and LTC(4) at 30 and 60 min of reperfusion compared with the vehicle, which was well associated with the attenuated cerebral edema in the E-DHA-treated brain after 48 h of reperfusion. These data suggest that the E-DHA (200 mg/kg) pretreatment reduces the postischemic eicosanoid productions, which may be due to its reduction of the brain lipid AA content.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Brain; Brain Chemistry; Brain Edema; Brain Ischemia; Cerebrovascular Circulation; Dinoprost; Docosahexaenoic Acids; Eicosanoids; Fatty Acids; Gerbillinae; Leukotriene B4; Leukotriene C4; Lipids; Male; Reperfusion; Thromboxane B2

Inosine is a naturally occurring nucleoside degraded from adenosine. Recent studies have demonstrated that inosine has potent immunomodulatory and neuroprotective effects. In the present study, we further investigated the inhibitory effects of inosine on platelet activation in vitro and in vivo, as well as in attenuating middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats.. Inosine concentration-dependently (0.5 to 6.0 mmol/L) inhibited platelet aggregation stimulated by agonists. Inosine (1.5 and 3.0 mmol/L) inhibited phosphoinositide breakdown, [Ca+2]i, and TxA2 formation in human platelets stimulated by collagen (1 microg/mL). In addition, inosine (1.5 and 3.0 mmol/L) markedly increased levels of cyclic guanylate monophosphate (GMP) and cyclic GMP-induced vasodilator-stimulated phosphoprotein Ser157 phosphorylation. Rapid phosphorylation of a platelet protein of molecular weight 47,000 (P47), a marker of protein kinase C activation, was triggered by collagen (1 microg/mL). This phosphorylation was markedly inhibited by inosine (3.0 mmol/L). Inosine (1.5 and 3.0 mmol/L) markedly reduced hydroxyl radical in collagen (1 microg/mL)-activated platelets. In in vivo studies, inosine (400 mg/kg) significantly prolonged the latency period of inducing platelet plug formation in mesenteric venules of mice, and administration of 2 doses (100 mg/kg) or a single dose (150 mg/kg) of inosine significantly attenuated MCAO-induced focal cerebral ischemia in rats.. Platelet aggregation contributes significantly to MCAO-induced focal cerebral ischemia. The most important findings of this study suggest that inosine markedly inhibited platelet activation in vitro and in vivo, as well as cerebral ischemia. Thus, inosine treatment may represent a novel approach to lowering the risk of or improving function in thromboembolic-related disorders and ischemia-reperfusion brain injury.

Topics: Animals; Brain Ischemia; Calcium; Cell Adhesion Molecules; Collagen; Contrast Media; Cyclic AMP; Cyclic GMP; Fluorescein; Free Radical Scavengers; Humans; Infarction, Middle Cerebral Artery; Inosine; Male; Mice; Microcirculation; Microfilament Proteins; Phosphatidylinositols; Phosphoproteins; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Protein Kinase C; Rats; Rats, Wistar; Thrombosis; Thromboxane B2

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.

Topics: Animals; Antithrombins; Arginine; Blood Coagulation; Blood Platelets; Brain Ischemia; Disease Models, Animal; Guinea Pigs; Infarction, Middle Cerebral Artery; Male; Methacrylates; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Reperfusion Injury; Sulfonamides; Thromboxane B2

The plasma expression levels of ET-1, TXB2, 6-keto-PGF1alpha, vWF at different time after cerebral ischemia were assayed for observing the effects of baicalin, jasminoidin, cholalic acid, hydrolysis fluid of nacre and the combined prescription (CP) on cerebral vasoconstriction and endothelial cells in MCAO rats.. The plasma levels of ET-1, TXB2, 6-keto-PGF1alpha in MCAO rats were detected by the method of RIA and the plasma expressions of vWF were observed by ELISA.. The levels of ET-1, TXB2/6-keto-PGF1alpha and vWF all increased at different time after cerebral ischemia, so do TXB2 at 12 hours after ischemia. The expression of 6-keto-PGF1alpha significantly reduced at different time point after ischemia in MCAO rat. There were no significant changes after medicine treating 12 hours except baicalin's increasing 6-keto-PGF1alpha level. Jasminoidin and CP significantly reduced the expression of ET-1 at 24 hours after ischemia, so do all effective components except CP on expression of TXB2 at 12 hours after ischemia. The expression of TXB2 was significantly decreased by baicalin and CP at 24 hours after cerebral ischemia. Both baicalin and cholalic acid significantly increased the expression of 6-keto-PGF1alpha at 12 hours after ischemia while cholalic acid and hydrolysis fluid of nacre increased its level after ischemia for 24 hours. TXB2/6-keto-PGF1alpha ratio was reduced distinctively by baicalin, jasminoidin, cholalic acid, CP at the point of 12 hours, while decreased by baicalin and CP, and increased by jasmionoidin at the point of 24 hours. On the other hand, baicalin, hydrolysis fluid of nacre significantly reduced and jasminoidin increased the expression of vWF at the point of 12 hours. At the point of 24 hours, expression of vWF reduced by hydrolysis fluid of nacre and increased by baicalin.. The higher plasma expression of ET-1, TXA2 in plasma aggravated cerebral vasoconstriction and damaged endothelial cells. At the same time, the effective components of "Qing Kai Ling" inhibit the expression of ET-1 , TXA2 and reduce both TXB2/6-keto-PGF1alpha ratio and level of vWF. As a result, they relax cerebral microvessel and protect endothelial cells by different pathway at different target points.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain Ischemia; Cholic Acid; Drugs, Chinese Herbal; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Flavanones; Male; Rats; Rats, Sprague-Dawley; Thromboxane B2; Time Factors; von Willebrand Factor

to assess whether shunting during carotid reconstruction affects the release of inflammatory mediators from the ipsilateral hemisphere.. a catheter was placed in the ipsilateral jugular bulb during carotid endarterectomy (CEA) in 20 patients. Eight patients with ICBP (internal carotid backpressure) <40 mmHg received a shunt during CEA and 12 patients with ICBP >40 mmHg were operated upon without a shunt. Four patients with a carotid body tumour were used as controls. Blood was taken from the catheter as well as from the radial artery; before clamping, 5, 15, 30 min after clamping and 5 min after declamping. The oxygen extraction (AVO(2)) was calculated. Plasma concentrations of interleukin-1beta (IL-1beta), phospholipase A(2)(PLA(2)), thromboxane B(2)(TXB(2)), 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) and prostaglandin E(2)(PGE(2)) were measured by enzyme-linked immunosorbent assay (ELISA) technique.. all patients had a normal postoperative course except for one patient in the no-shunt group, who suffered a stroke 1 h later due to occlusion of the endarterectomy site. The AVO(2)extraction increased during clamping in patients operated upon without a shunt (p <0.05). This increase was partly recovered to pre-clamp levels 5 min after reperfusion. The extraction remained stable in the non-shunted patients and the control group. The increased extraction in the non-shunted group correlated with increased levels of IL-1beta during clamping ( p <0.05) and reperfusion ( p <0.01). PLA(2)also increased during reperfusion in the non-shunted group ( p <0.05). An increased ratio between TXB(2)and 6-keto-PGF1alpha was noted during clamping ( p <0.05) and further increased during reperfusion. The levels of PGE(2)remained stable in both CEA groups. The PLA(2)levels, as well as TXB(2), 6-keto-PGF1alpha and PGE(2)levels, remained unchanged during the procedure in the control group.. there is a metabolic response to carotid cross-clamping when no shunt is used. However, the clinical significance of this is unclear, since there were no intraoperative strokes.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Arteriovenous Shunt, Surgical; Blood Pressure; Brain Ischemia; Carotid Arteries; Dinoprostone; Endarterectomy, Carotid; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-1; Male; Middle Aged; Monitoring, Intraoperative; Phospholipases A; Prostaglandins F; Thromboxane B2

Enhanced thromboxane (TX) biosynthesis has previously been reported in the acute phase after ischemic stroke. We investigated whether enhanced urinary excretion of 11-dehydro-TXB2, a noninvasive index of platelet activation, was present in the chronic phase after a transient ischemic attack (TIA) or stroke, including intracerebral hemorrhage.. We obtained a single urinary sample from 92 patients between 3 and 9 months after onset of stroke or TIA. The urinary excretion of the major enzymatic metabolite of TXA2, 11-dehydro-TXB2, was measured by a previously validated radioimmunoassay. The excretion rates were compared with those of 20 control patients with nonvascular neurological diseases.. Urinary 11-dehydro-TXB2 averaged 294+/-139, 413+/-419, and 557+/-432 pmol/mmol creatinine for patients with TIA, ischemic stroke, and intracerebral hemorrhage, respectively; the values were higher in all subgroups (P<0.01) than that in control patients (119+/-66 pmol/mmol). Increased 11-dehydro-TXB2 excretion was present in 59% of all patients, in 60% (P<0.001) of patients with TIA, in 56% (P<0.001) of patients with ischemic stroke, and in 73% (P<0.001) of patients with intracerebral hemorrhage. Atrial fibrillation, no aspirin use, and severity of symptoms at follow-up contributed independently to the level of 11-dehydro-TXB2 excretion in a multiple linear regression analysis.. Platelet activation is often present in patients in the chronic phase after stroke, including those with intracerebral hemorrhage. Persistent platelet activation, which is associated with atrial fibrillation and poor stroke outcome, can be substantially suppressed by aspirin treatment.

Topics: Brain Ischemia; Cerebral Hemorrhage; Chronic Disease; Follow-Up Studies; Humans; Platelet Activation; Thromboxane B2

To explore the main pathogenic factors in the development of neuronal death during normothermic reperfusion in rabbits.. Ninety-six New Zealand rabbits were randomly allocated into two groups: group I served as non-ischemic controls; group II served as postischemic normothermic reperfusion models. Complete cerebral ischemia was induced by the four-vessel model for 30 minutes. After ischemia, rabbits in group II were further divided into three subgroups according to the duration of reperfusion: subgroup A, 30 minutes; subgroup B, 180 minutes and subgroup C, 360 minutes. Twenty-eight biochemical parameters in the brain were measured, and neuronal changes were observed by histomorphological assessment. Neurons of 12 regions were differentiated into four types: type A (normal), type B (mildly damaged), type C (severely damaged) and type D (necrotic). Bivariate correlate analysis between the levels of biochemical parameters and the percentages of each type of neurons was carried out.. The main parameters involved in the progressive decrement of type A neurons were VIP, beta-EP, PGI2, T3, T4 and Na+, K(+)-ATPase; in the increment of type B were beta-EP and TXB2; in the increment of type C were GLU and TXB2/PGI2 respectively; in the stepwise increment of percentages of type D neurons were T4, Na+, K(+)-ATPase, GLU, T3 and VIP (P < 0.05).. The main factors involved in the development of neuronal death during postischemic normothermic reperfusion in rabbits include hypermetabolism, deactivation of Na+, K(+)-ATPase, release of excitatory amino acids and disorder of neuropeptides.

Topics: Animals; beta-Endorphin; Brain Ischemia; Cell Death; Female; Male; Neurons; Rabbits; Random Allocation; Reperfusion Injury; Sodium-Potassium-Exchanging ATPase; Thromboxane B2; Vasoactive Intestinal Peptide

Both platelet activation and lipid peroxidation are potential sources of vasoactive eicosanoids that can be produced via the cyclooxygenase pathway, ie, thromboxane (TX) A2, or by free radical-catalyzed peroxidation of arachidonic acid, ie, isoprostanes. We investigated the biosynthesis of TXA2 and F2-isoprostanes, as reflected by the urinary excretion of 11-dehydro-TXB2 and 8-epi-prostaglandin (PG) F2 alpha respectively, in 62 consecutive patients (30 men, 32 women; mean age, 67 +/- 14 years) with acute ischemic stroke.. At least two consecutive 6-hour urine samples were obtained during the first 72 hours after onset of symptoms. Urinary eicosanoids were measured by previously described radioimmunoassays.. Repeated periods of enhanced thromboxane biosynthesis were found in 52% of patients. Urinary 11-dehydro-TXB2 averaged 221 +/- 207 (mean +/- SD; n = 197; range, 13 to 967) pmol/mmol creatinine in 30 patients treated with cyclooxygenase inhibitors (mostly aspirin) at the time of study versus 392 +/- 392 (n = 186; range, 26 to 2533) in 32 untreated patients (P < .001). The corresponding values for 8-epi-PGF2 alpha excretion were 74 +/- 42 (range, 14 to 206) and 83 +/- 65 (range, 24 to 570) pmol/mmol creatinine (P > .05). The correlation between the two metabolites was moderate in both untreated patients (r = .41, P < .001) and patients with cyclooxygenase inhibitors (r = .31, P < .001). In a multiple regression analysis, increased thromboxane production was independently associated with severity of stroke on admission, atrial fibrillation, and treatment with cyclooxygenase-inhibiting drugs.. We conclude that during the first few days after an acute ischemic stroke (1) platelet activation occurs repeatedly in a cyclooxygenase-dependent fashion; (2) platelet activation is not associated with concurrent changes in isoprostane biosynthesis; (3) platelet activation is independently associated with stroke severity and atrial fibrillation; and (4) isoprostane biosynthesis is largely independent of platelet cyclooxygenase activity.

Topics: Acute Disease; Aged; Atrial Fibrillation; Brain Ischemia; Cerebrovascular Disorders; Cyclooxygenase Inhibitors; Dinoprost; Female; Humans; Lipid Peroxides; Male; Middle Aged; Platelet Activation; Reference Values; Thromboxane B2

A previous communication of this laboratory demonstrated reduced mortality and neuronal damage by spontaneous locomotor activity preceding forebrain ischemia in Mongolian gerbils. The present experiments seek to elucidate potential mechanisms of protection by measurement of cerebral blood flow, cerebral tissue conductance as an indicator of ischemic cell swelling, and the cerebral release of eicosanoids.. Gerbils were maintained either in conventional cages (nonrunners) or with free access to running wheels (runners) for 2 weeks preceding 15 minutes of forebrain ischemia. During ischemia and 2.5 hours of reperfusion, cerebral tissue conductance was determined with a two-electrode system. Simultaneously, prostaglandin D2, prostaglandin F2 alpha, and thromboxane B2 were measured in ventriculocisternal perfusate. In additional animals cerebral blood flow was assessed by hydrogen clearance.. Decreases in tissue conductance during ischemia were similar in nonrunners (56 +/- 3%) and runners (62 +/- 3%) but normalized more rapidly in runners during reperfusion. In both groups reperfusion was accompanied by marked increases of perfusate prostaglandin D2, prostaglandin F2 alpha, and thromboxane B2. In nonrunners, however, thromboxane B2 was already elevated during ischemia (147 +/- 9%, P < .01) and remained elevated longer during recirculation (P < .05). Postischemic perfusion maxima were higher in runners (70.8 +/- 7.4 versus 47.0 +/- 5.0 mL/100 g per minute, P < .05) and were observed sooner (27.4 +/- 6.9 versus 62.2 +/- 12.3 minutes, P < .05). Both groups displayed delayed hypoperfusion of a similar magnitude (runners, 29.0 +/- 2.4 mL/100 g per minute; nonrunners, 30.1 +/- 2.4 mL/100 g per minute).. Protection by preischemic locomotor activity may involve enhanced postischemic reperfusion, leading to more rapid normalization of conductance and thus of cell volume. Enhanced reperfusion may be the consequence of attenuated thromboxane liberation during and after ischemia.

Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Gerbillinae; Locomotion; Prosencephalon; Prostaglandins; Reperfusion; Thromboxane B2

The cerebral ischemia rabbit model was made by using the occlusion of four vessels. The results showed that TXB2 and cAMP contents in brain tissues and the latter in plasma markedly increased (P < 0.05, P < 0.01), the 6-keto-PGF1 alpha in brain tissues significantly lowered (P < 0.05) in ischemia formed 30 minutes and 45 minutes after reperfusion. After intravenous injection of Astragalus membranaceus (AM) extracts (3.3 g/kg), Huoxuefang (HXFO and Yiqi Houxue Fang (YQHXF) consisted of AM and HXF before ischemia, the marked increase of TXB2 contents after reperfusion was inhibited (P < 0.05) and the 6-keto-PGF1 alpha in brain tissues after reperfusion were increased (P < 0.01) in HXF and YQHXF group, which change the AM extracts didn't have (P < 0.05). HXF could markedly inhibit the increase of cAMP in brain tissues after reperfusion P < 0.05), while the AM extracts and YQHXF couldn't (P > 0.05). All above-mentioned suggested that the above-mentioned suggested that the balance disorder of TXA2/PGI2 in brain tissues might participate in the occurrence of cerebral reperfusion injury and YQHXF might act against this injury by means of improving the balance of TXA2/PGI2 in brain tissues, which was mainly released by HX drugs of it.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Astragalus propinquus; Brain; Brain Ischemia; Cyclic AMP; Drugs, Chinese Herbal; Female; Male; Rabbits; Reperfusion Injury; Thromboxane B2

We investigated the effect of dietary docosahexaenoic acid (DHA) supplementation on the thrombolytic efficacy of recombinant tissue-type plasminogen activator (rt-PA), platelet aggregability, serum cholesterol and phospholipids. Male Wistar rats (6 weeks old) received dietary DHA supplementation (300 mg/kg per day) for 8 weeks. The rat middle cerebral artery (MCA) was occluded by a thrombus induced by photochemical reaction between rose bengal and green light which cause endothelial damage followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of photochemical reaction. The MCA blood flow was monitored using a laser Doppler flowmeter. rt-PA was administered 30 min after the middle cerebral artery had been occluded by a thrombus. This regimen produced a significant (P < 0.05) decrease in serum free-cholesterol and phospholipids levels, inhibited platelet aggregation ex-vivo induced by collagen in whole blood (P < 0.05), reduced thromboxane (TX) B2 formation (P < 0.01) in whole blood and prolonged the time for thrombotic MCA occlusion (P < 0.01) as compared with values obtained from animals on standard diet. Further, dietary DHA enhanced thrombolytic efficacy of rt-PA and reduced the size of ischaemic cerebral lesions. Our findings suggest that dietary DHA produces antithrombotic effects via metabolic conversion to non-atherogenic and non-platelet stimulant metabolites.

Topics: Administration, Oral; Animals; Blood Coagulation; Brain Ischemia; Cerebrovascular Circulation; Cholesterol; Diet; Docosahexaenoic Acids; Endothelium, Vascular; Intracranial Embolism and Thrombosis; Light; Male; Phospholipids; Photochemistry; Platelet Aggregation; Rats; Rats, Wistar; Recombinant Proteins; Rose Bengal; Single-Blind Method; Thrombolytic Therapy; Thromboxane B2; Tissue Plasminogen Activator

Berberine (Ber) 20 mg.kg-1.d-1 for 1, 3, or 5 d inhibited platelet aggregation induced by ADP, arachidonic acid (AA) and collagen (Coll) in rats with 24 h reversible middle cerebral artery occlusion (MCAO), and the platelet adhesiveness was inhibited as well. Using radioimmunoassay method, the thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) contents in rat plasma were measured 24 h after MCAO. The results indicate that the TXB2 levels after drug treatment were lower than those in ischemia control rats, but the 6-keto-PGF1 alpha levels showed no obvious difference between the two groups. The same dose of Ber was also shown to inhibit thrombosis formation. This suggests that the decline of platelet aggregation and decrease of TXB2 content may be one of the important factors involved in the anti-cerebral ischemia effect of Ber.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Berberine; Brain Ischemia; Male; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Thromboxane B2

The present study measured the production of eicosanoids in the gerbil brain during early reperfusion after either a 3-h unilateral carotid occlusion (UCO, model of focal ischemia) or a 10-min bilateral carotid occlusion (BCO, model of global ischemia). Arachidonic acid (AA) metabolites were examined to determine if pretreatment with the 21-aminosteroid lipid peroxidation inhibitor U-74006F (tirilazad mesylate) could influence postreperfusion synthesis of brain eicosanoids. In the 3-h UCO focal ischemia model, there was an early (5-min) postreperfusion elevation in brain levels of PGF2 alpha, TXB2 and LTC4 (P < 0.05 vs. sham for all three eicosanoids). LTB4 also rose but not significantly. On the other hand, PGE2 and 6-keto-PGF1 alpha tended to decrease during ischemia and at 5-min postreperfusion (P < 0.05 vs. sham for PGE2). Pretreatment with known neuroprotective doses of U-74006F in this model (10 mg/kg i.p. 10 min before and again immediately upon reperfusion) did not affect the increase in PGF2 alpha or TXB2 but significantly blunted the elevations in LTC4 and LTB4. The postreperfusion decrease in PGE2 was also attenuated. In the 10-min BCO global ischemia model, there was also an increase in each of the measured eicosanoids, except LTB4, at 5 min after reperfusion. Pretreatment with U-74006F (10 mg/kg i.p. 10 min before ischemia) selectively decreased the rise in LTC4 but did not significantly affect the other eicosanoids. In contrast, the antioxidant actually caused a significant enhancement of the postreperfusion increase in PGE2 vs. vehicle-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Brain Ischemia; Carotid Arteries; Constriction; Eicosanoids; Gerbillinae; Leukotrienes; Lipid Peroxides; Male; Pregnatrienes; Prostaglandins; Reperfusion; Thromboxane B2

In this study Mongolian gerbils were submitted to a normothermic bilateral carotid ligation lasting 5 min. A noncompetitive antagonist of NMDA receptors, MK-801, 0.8 mg/kg, was injected i.p. 30 min before ischemia, or the ganglioside GM1, 30 mg/kg, was given i.p. for 3 days, twice a day. The morphology of the hippocampal CA1 neurones and the brain content of cyclooxygenase metabolites of arachidonic acid: prostaglandin 6-keto PGF1 alpha and thromboxane Tx B2 were studied. Untreated ischemia induced the accumulation in brain of the 6-keto PGF1 alpha and Tx B2 immunoreactive materials, and resulted in a lesion of 70% of CA1 neurones. In the MK-801- and GM1-pretreated groups the postischemic levels of Tx B2 were significantly decreased. However MK-801 and GM1 did not prevent damage to the CA1 neurones in gerbils normothermic after ischemia, whereas a partial neuroprotection was observed in hypothermic, MK-801 treated gerbils. The results of this study indicate that NMDA receptors may participate in the mechanism of postischemic release of eicosanoids in brain. They also confirm a potential modulatory role of gangliosides. These results are discussed in terms of the involvement of cyclooxygenase metabolites of arachidonic acid in the mechanism of a selective delayed neuronal damage to the hippocampus CA1 after ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; Brain Ischemia; Dizocilpine Maleate; Female; G(M1) Ganglioside; Gerbillinae; Hippocampus; Male; Prostaglandins; Thromboxane B2

The effect of mild and moderate hypothermia on ischemia-induced glutamate release and eicosanoid production was evaluated in WKY rats subjected to incomplete forebrain ischemia. Under isoflurane anesthesia, microdialysis probes were inserted into the hippocampus and caudate nucleus. In four groups of rats, the intraischemic temperature was maintained at either 38 degrees C (normothermia), 36 degrees C, 34 degrees C (mild hypothermia) and 30 degrees C (moderate hypothermia). In these groups, normothermia was restored immediately upon reperfusion. In two additional groups, both intra- and post-ischemic temperatures were maintained at either 34 degrees C or 30 degrees C. The levels of glutamate were measured in the dialysate collected during ischemia and the levels of TxB2, 6-keto-PGF1 alpha and PGF2 alpha were measured in dialysate collected prior to and after ischemia. As expected, hypothermia reduced ischemia-induced glutamate release in both structures. However, the application of mild hypothermia did not attenuate post-ischemic levels of all eicosanoids measured. Moderate hypothermia (30 degrees C) attenuated the post-ischemic increase in the levels of PGF2 alpha. The data suggest that the processes that lead to eicosanoid formation are less sensitive to temperature reduction than those that lead to glutamate release.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Temperature; Brain Chemistry; Brain Ischemia; Caudate Nucleus; Dinoprost; Eicosanoids; Glutamic Acid; Hippocampus; Hypothermia; Microdialysis; Rats; Rats, Inbred WKY; Reperfusion; Thromboxane B2

Hippocampal slices of rats at postnatal day 7 were submitted to superfusion with Ca(2+)- and Mg(2+)-free, bicarbonate buffered ion balanced medium, and perfusate concentrations of eicosanoids: thromboxane B2 and 6-keto prostaglandin F1 alpha were determined by the radioimmunoassay. It was noted that the permanent presence of Ca2+ increased the basal eicosanoid level, and in these conditions modulation of eicosanoid production was lost, whereas temporary, a 20 min application of 1.3 mM Ca2+ did not influence significantly eicosanoid release. A 20 min application of the anoxic/aglycemic medium containing calcium did not change the content of eicosanoids in superfusates. A significant stimulation of the thromboxane B2 and 6-keto prostaglandin F1 alpha release was noted provided the application of the experimental medium was accompanied by a 10 min arrest of superfusion. This effect was inhibited by MK-801 and quinacrine, suggesting an involvement of NMDA receptors and phospholipase A2. We propose that a model of anoxic/aglycemic superfusion with a stop flow period allows retention of endogenous glutamate in the extracellular fluid, resembling a similar effect during in vivo ischemia, whereas during a continuous superfusion glutamate is immediately washed out. Consequently, an application of the anoxic/aglycemic medium accompanied by a temporary arrest of superfusion represents more adequate in vitro model of ischemia than a constant superfusion with this medium. In these conditions NMDA receptors mediate eicosanoid release.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Brain Ischemia; Calcium; Culture Techniques; Dizocilpine Maleate; Eicosanoids; Hippocampus; Hypoxia; N-Methylaspartate; Quinacrine; Radioimmunoassay; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Thromboxane B2

The products resulting from arachidonic acid metabolism of the both cyclo-oxygenase and lipoxygenase pathways possess strong physiological activities, such as vasoconstriction and the enhancement of vascular permeability. Therefore, it is likely that these metabolites are involved in cerebral circulatory disturbance and the formation of brain edema in cerebral ischemia. It is reported that intracerebral injection of leukotriene B4, C4, and E4 increased blood-brain barrier permeability. Thus, it is suggested that leukotrienes may induce vasogenic cerebral edema. We examined role of the products resulting from arachidonic acid of the cyclo-oxygenase and lipoxygenase pathways on the formation of ischemic cerebral edema in rats with focal cerebral ischemia. Focal cerebral ischemia was induced by the occlusion of right middle cerebral artery. Acyclo-oxygenase inhibitor, indomethacin (4mg/kg), was given intravenously 30 minutes before the occlusion of the middle cerebral artery. Also, azerastine hydrochloride (8mg/kg), which has an inhibitory effect on the production and release of leukotrienes from human neutrophil as well as an antagonistic action on leukotrienes and another inhibitory effect on the production of superoxide anion, was given intravenously 5 minutes prior to occlusion. Concentrations of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene C4 (LTC4) measured by radioimmunoassay. The percent water content of a cerebral hemisphere was determined by the wet-dry weight method. In the occluded hemisphere, PGE2, 6-keto-PGF1 alpha, TxB2 and LTC4 significantly increased at 2, 6, 12 hours respectively, following the MCA occlusion as compared to the control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Brain Edema; Brain Ischemia; Cerebral Arteries; Constriction; Dinoprostone; Leukotriene C4; Male; Rats; Rats, Wistar; Thromboxane B2

Enhanced thromboxane biosynthesis has previously been reported in patients with acute ischemic stroke. In this study we examined the time course of thromboxane biosynthesis after the onset of symptoms in 13 patients with acute cerebral infarction.. We obtained five to eight consecutive 6-hour urine samples from each of these 13 patients within the first 48 hours after onset of symptoms to study the dynamics of platelet activation in this setting. The urinary excretion of the major enzymatic metabolite of thromboxane B2, 11-dehydro-thromboxane B2, was measured by a previously validated radioimmunoassay. The excretion rate was compared with that of 20 control patients with nonvascular neurological diseases.. Eleven patients (85%) had at least one value exceeding 2 SD of the control mean (251 pmol/mmol creatinine). The proportion of samples with an elevated 11-dehydro-thromboxane B2 level was markedly similar in each of the eight 6-hour collection periods (mean, 52 +/- 8%; range, 40% to 67%). In 4 patients (31%) the excretion rate was elevated in all measurements obtained. In the 11 patients with enhanced thromboxane biosynthesis, no uniform pattern of changes over time in metabolite excretion emerged, with 3 patients having peak values at 0 to 12 hours, 3 at 12 to 24 hours, 3 at 24 to 36 hours, and 2 at 36 to 48 hours. The level and dynamics of 11-dehydro-thromboxane B2 excretion were related neither to the neurological symptoms nor to the type or site of the cerebral ischemia.. We conclude that episodes of platelet activation occur repeatedly during the first 48 hours after the onset of symptoms of an acute ischemic stroke. Given its apparent dynamic nature, this ongoing process may be amenable to pharmacologic modulation.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Creatinine; Female; Humans; Male; Middle Aged; Platelet Activation; Risk Factors; Thromboxane B2

Policosanol is a mixture of higher primary aliphatic alcohols, isolated from sugar cane wax, whose main component is octacosanol. Policosanol (25, 50 and 200 mg/kg) administered by the oral route not only significantly reduced serum thromboxane B2 (TXB2) levels but also, at 200 mg/kg significantly increased 6-keto-PGF1 alpha in Mongolian gerbils. Policosanol at 200 mg/kg significantly protected against cerebral ischemia induced by unilateral ligation of common carotid artery in Mongolian gerbils. In this experimental model, combined administration of ineffective doses of policosanol (25 mg/kg) and aspirin (ASA) (30 mg/kg) significantly protected animals indicating a synergism between them.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Brain Ischemia; Drug Synergism; Epoprostenol; Fatty Alcohols; Gerbillinae; Thromboxane A2; Thromboxane B2

Clinical and experimental studies suggest that platelets have a major role in the pathogenesis of cerebral ischemia. However, ex vivo both platelet aggregation studies and measurements of platelet-derived products in patients with cerebral ischemia have shown inconsistent results. The present study was designed to resolve this inconsistency.. We have measured the urinary excretion of a thromboxane metabolite, 11-dehydro-thromboxane B2, by a previously validated radioimmunoassay technique in 51 patients with acute cerebral ischemia who had experienced either a transient ischemic attack (14 patients) or an ischemic stroke (37 patients) and in 20 control patients with nonvascular neurological disorders. The median time between the onset of symptoms and urine sampling was 24 hours (range, from 2 hours to 8 days).. The excretion rate of immunoreactive 11-dehydro-thromboxane B2 ranged between 39 and 478 pmol/mmol creatinine in patients with a transient ischemic attack and between 23 and 5,916 pmol/mmol creatinine in stroke patients, with 29% (p = 0.18) and 51% (p = 0.004) of the urine samples, respectively, exceeding the upper limit of the control samples (251 pmol/mmol creatinine [mean +/- 2 SD]) (p = 0.01). In stroke patients, metabolite excretion was not related to the type (cortical or "lacunar") or site of cerebral infarction. Low-dose aspirin (50 mg per day for 7 days) reduced the urinary excretion by approximately 85% in 11 consecutive stroke patients.. We conclude that 1) episodes of enhanced thromboxane biosynthesis are detected infrequently in patients with a transient ischemic attack, 2) aspirin-suppressible episodes of increased thromboxane formation can be detected during the early phase of acute ischemic stroke, and 3) this finding may provide a rationale for testing the efficacy and safety of this drug in this setting.

Topics: Acute Disease; Aged; Aged, 80 and over; Blood Platelets; Brain Ischemia; Cerebrovascular Disorders; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Prospective Studies; Thromboxane B2

Topics: Brain Ischemia; Female; Humans; Male; Sex Factors; Thromboxane A2; Thromboxane B2

Thirty three New Zealand rabbits were randomly divided into three groups, i.e. the control group, the high atmospheric pressure. (HAP) group and the hyperbaric oxygenation (HBO) group. The experimental animals were made into the models of reperfusion for acute incomplete cerebral ischemia. The blood-gas analyses drawn from the common carotid arteries and the internal jugular veins were carried out, and the 6-keto-PGF1a and TXB2 in the brain tissues determined. The results showed that the contents of 6-keto-PGF1a in the brain tissues of the HBO groups were significantly increased (P less than 0.01). While those of TXB2 were significantly decreased (P less than 0.01). The po2 in both the arterial and the venous blood were obviously elevated in the HBO group. Pathological examination showed that the brain tissue damages in the HBO group were the slightest among the three groups. It was postulated that the effect of HBO on 6-keto-PGF1a and TXB2 might reflect one of the mechanisms of HBO for the treatment of acute cerebral ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Gas Analysis; Brain Ischemia; Hyperbaric Oxygenation; Rabbits; Reperfusion Injury; Thromboxane B2

Thromboxane (Tx)B2 and 6-keto-prostaglandin (6-keto-PG) F1 alpha formation in the hippocampus and caudate nucleus were evaluated by microdialysis during and following forebrain ischemia. Spontaneously hypertensive rats were subjected to bilateral carotid artery occlusion with simultaneous hypotension for 8, 14, or 20 min. Dialysate was collected during the ischemic interval and during the reperfusion period. TxB2 and 6-keto-PGF1 alpha levels were measured by radioimmunoassay. In both structures, TxB2 production increased significantly during the reperfusion period in all three ischemic groups. By contrast, increased 6-keto-PGF1 alpha elaboration was observed after only the longest ischemic duration. While TxB2 levels gradually decreased during the 3-h reperfusion period in all groups, the levels in the group subjected to 8 min of ischemia returned to control values most rapidly. A relationship between the duration of ischemia and TxB2 production was therefore evident. 6-Keto-PGF1 alpha levels increased in only the group subjected to 20 min of ischemia and, by contrast to the pattern of TxB2 change, 6-keto-PGF1 alpha levels remained elevated throughout the reperfusion period. During reperfusion, the ratio of TxB2 to 6-keto-PGF1 alpha increased substantially versus the preischemic period in both structures. The data demonstrate that eicosanoid elaboration following cerebral ischemia can be evaluated by the microdialysis technique. In addition, they indicate that the thresholds (duration of ischemia) for the postischemic production and the temporal profiles of TxB2 and 6-keto-PGF1 alpha in the caudate and hippocampus differ. They also demonstrate that there is regional heterogeneity in the patterns of eicosanoid elaboration after forebrain ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain Ischemia; Caudate Nucleus; Dialysis; Hippocampus; Rats; Thromboxane B2

Adenosine diphosphate-induced platelet aggregation and associated thromboxane B2 release were studied in 52 patients with subarachnoid hemorrhage (SAH) in order to detect a possible association between altered platelet function and development of cerebral ischemic complications after SAH. Compared to the values on admission, the patients showed significantly increased platelet aggregability (p less than 0.05) and thromboxane release (p less than 0.001) 1 to 2 weeks after SAH. The highest values of thromboxane release were seen in patients who deteriorated due to delayed cerebral ischemia with a permanent neurological deficit. Thromboxane release was significantly higher (p less than 0.05) before the onset of severe delayed ischemia in six patients with preoperative ischemia compared to the patients without delayed ischemia. In five others, both ischemic deterioration and elevated thromboxane release occurred after operation. These patients had preoperative values similar to the values in those without ischemic symptoms. The observations suggest that increased platelet aggregability and thromboxane release are associated with delayed cerebral ischemia both before and after surgery.

Topics: Adult; Aged; Blood Platelets; Brain Ischemia; Female; Humans; Male; Middle Aged; Platelet Aggregation; Subarachnoid Hemorrhage; Thromboxane B2; Time Factors

By occluding the bilateral carotid arteries of rabbits to produce bilateral partial cerebral ischemia, and by using RIA and ELISA to measure the levels of Beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in plasma, the authors found that the levels of beta-TG, PF4 and TXB2 in plasma had significantly increased (P less than 0.01), but the level of 6-keto-PGF1 alpha in plasma showed no change (P greater than 0.05) after cerebral ischemia appeared. The results of the Ligusticum wallichii (Ligusticum) pre-treatment to the test-group showed that the levels of beta-TG, PF4 and TXB2 in plasma had significantly decreased (P less than 0.01), and the level of 6-keto-PGF1 alpha in plasma had significantly increased (P less than 0.05). This suggested that the Ligusticum treatment could effectively inhibit the platelet activation in vivo and correct the TXA2-PGI2 imbalance in blood after cerebral ischemia. In this study, some new approaches were explored to explain the mechanisms of Ligusticum for preventing and treating cerebral ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; beta-Thromboglobulin; Brain Ischemia; Drugs, Chinese Herbal; Female; Male; Platelet Factor 4; Rabbits; Thromboxane B2

We studied adenosine diphosphate-induced platelet aggregation and the associated release of thromboxane B2 in platelet-rich plasma from 88 patients with subarachnoid hemorrhage and 26 healthy controls. During the first 3 days after subarachnoid hemorrhage, the patients showed significantly decreased (p less than 0.05) platelet aggregability and thromboxane release relative to the controls, but these effects disappeared in a few days. Platelet count increased for 3 weeks after subarachnoid hemorrhage. Surgery in 67 patients was followed by significant increases in platelet aggregability (p less than 0.05) and thromboxane release (p less than 0.001). Greatest thromboxane release was found in the eight patients showing delayed (postoperative) ischemic deterioration with a permanent neurologic deficit. Although platelet hyperaggregability and increased thromboxane release were particularly prominent in these eight patients, the role of these hematologic parameters in the pathogenesis of delayed ischemic deterioration remains unclear.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Brain Ischemia; Female; Humans; Male; Middle Aged; Platelet Aggregation; Postoperative Complications; Postoperative Period; Subarachnoid Hemorrhage; Thromboxane B2

Topics: Adenosine Diphosphate; Aged; Aspirin; Brain Ischemia; Cerebrovascular Disorders; Female; Humans; Male; Middle Aged; Platelet Aggregation; Random Allocation; Thromboxane B2

Reperfusion of ischemic brain is associated with production of thromboxane A2 (TXA2), a proaggregatory vasoconstrictor. We used an animal model of transient forebrain ischemia to study the effects of 1-benzylimidazole (1-BI), a selective inhibitor of thromboxane synthase, upon cerebral eicosanoid levels and cerebral blood flow. Male Wistar rats were subjected to 30 minutes of four-vessel occlusion. The mean +/- SEM brain level of TXB2, the stable metabolite of TXA2, determined after 60 minutes of reperfusion was 101 +/- 20 pg/mg brain protein in five ischemic control rats. Infusion of 10 micrograms/g 1-BI reduced mean +/- SEM cerebral TXB2 concentration to 11 +/- 3 pg/mg brain protein in five rats (p less than or equal to 0.002). Mean +/- SEM hemispheric cerebral blood flow measured in four ischemic control rats after 60 minutes of reperfusion was 42 +/- 9 ml/100 g brain/min compared with 104 +/- 13 ml/100 g brain/min in three 1-BI-treated rats (p less than or equal to 0.001). Mean +/- SEM hippocampal blood flow in four ischemic control rats after 60 minutes of reperfusion was 51 +/- 14 ml/100 g brain/min compared with 125 +/- 25 ml/100 g brain/min in three 1-BI-treated rats (p less than or equal to 0.04). We conclude that selective inhibition of thromboxane synthase may alleviate ischemic brain damage by reducing cerebral TXA2 concentrations and elevating cerebral blood flow.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Brain Ischemia; Cerebrovascular Circulation; Eicosanoic Acids; Male; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase

We explored the temporal and topographic relations between local cerebral blood flow and regional brain prostaglandin profile following prolonged or transient occlusion of the middle cerebral artery in cats. Each experimental group was subjected to a sham operation, prolonged ischemia, or recirculation. Local cerebral blood flow was measured by the hydrogen clearance method. Following in situ freezing, cortical samples were obtained from each gyrus for determination of prostaglandin (PG) F2 alpha, PGE2, 6-keto-PGF1 alpha, and thromboxane (TX) B2 concentrations by radioimmunoassay. During prolonged ischemia, the concentrations of PGF2 alpha and PGE2 within the middle cerebral artery territory were significantly increased. Immediately after recirculation, there was a prominent but transient increase in PGF2 alpha and PGE2 in gyri that had been exposed to moderate ischemia (perifocal area). By contrast, the increases in these prostaglandins were slow and less prominent in gyri that had been exposed to severe ischemia (the focal area). The concentration of 6-keto-PGF1 alpha did not change during prolonged ischemia but transiently increased following recirculation in both the focal and perifocal areas. The TXB2 concentration did not change in any experimental group. Our study revealed a homogeneous increase in the regional brain content of PGE2 or PGF2 alpha in spite of the heterogeneous reduction of local cerebral blood flow during prolonged ischemia. Following recirculation, the focal and perifocal areas exhibited different patterns of prostanoid content. No correlation was found between local cerebral blood flow and the regional concentration of any prostaglandin examined.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; Brain Ischemia; Cats; Cerebral Arteries; Cerebrovascular Circulation; Constriction; Dinoprost; Dinoprostone; Female; Male; Thromboxane B2

Effects of ischemia (20 min) on cerebral cortical prostanoid synthesis and microvascular responses to hypercapnia and topical acetylcholine were examined in anesthetized newborn pigs. Pial arteriolar dilation in response to hypercapnia (10% CO2 ventilation, 10 min) was absent 2 h after ischemia and reversed toward constriction by 24 h postischemia. In sham control piglets, hypercapnia increased cortical periarachnoid fluid prostanoid concentrations. After ischemia, hypercapnia did not affect prostanoid concentrations on the brain surface. Acetylcholine (10(-3) M)-induced pial arteriolar constriction was reversed toward dilation 24 h after cerebral ischemia. Further, acetylcholine-induced prostanoid synthesis was markedly attenuated after ischemia. We conclude that cerebral ischemia-reperfusion alters cerebral prostanoid synthesis and microvascular control in newborn pigs. These abnormalities persist for at least 24 h.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Animals, Newborn; Brain; Brain Ischemia; Cerebrovascular Circulation; Dinoprost; Dinoprostone; Hypercapnia; Prostaglandins; Swine; Thromboxane B2

The time-dependent release of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), thromboxane (Tx) B2, and 6-keto-PGF1 alpha (6-keto) from brain was measured before, during, and after a 15-min interval of total ischemia (four-vessel occlusion) in halothane-anesthetized cats using the technique of cerebroventricular perfusion. Resting levels of PGE2, PGF2 alpha, 6-keto, and Tx were: 253 +/- 75, 953 +/- 300, 650 +/- 200, and 550 +/- 170 pg/ml, respectively. During the 15-min ischemia, all prostanoids rose significantly, yet the highest levels were not observed until the first 15-60 min of the reflow at which time levels of PGE2, PGF2 alpha, 6-keto, and Tx, as compared with the preischemic baseline, rose approximately 8, 3.4, 3, and 55-fold, respectively. Significantly, although all prostanoids showed increases relative to baseline, the ratios of PGF2 alpha/6-keto and PGE2/6-keto remained stable throughout the experiment in both groups of animals. In contrast, the Tx/6-keto ratio rose from approximately 1 to approximately 30 during the 60 min after reflow in untreated cats. Treatment with zomepirac sodium (5 mg/kg, i.v.), a cyclooxygenase inhibitor, resulted in highly significant reductions in the levels of all prostanoids during the preischemic period. In zomepirac sodium-treated animals, there were also highly significant reductions in the prostanoid response to ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; Brain Ischemia; Cats; Dinoprost; Dinoprostone; Extracellular Space; Female; Fibrinolytic Agents; Male; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxane B2; Tolmetin

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Brain; Brain Ischemia; Cell Membrane Permeability; G(M1) Ganglioside; Lactates; Male; Rats; Rats, Inbred Strains; Reperfusion; Thromboxane B2

Topics: Animals; Body Water; Brain; Brain Ischemia; Male; Rats; Rats, Inbred SHR; SRS-A; Thromboxane B2

Cerebral ischemia was induced in unanesthetized gerbils using bilateral carotid artery ligations. The effects of 20 min of global ischemia on the concentrations of prostaglandin F2 alpha (PGF2 alpha), PGE2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 were determined after 0-24 h of reperfusion. Ischemia had little effect on eicosanoid production, but significant increases were observed by 5 min of reperfusion, with maximal levels reached by 15 min of reperfusion. PGF2 alpha was the most concentrated prostaglandin in postischemic brain, whereas PGE2 was most concentrated in control cerebra. Pretreatment with anesthetic doses of pentobarbital supported increased accumulation of PGF2 alpha in postischemic cerebra, increased accumulation of 6-keto-PGF1 alpha during the ischemic episode, and decreased accumulation of PGE2 at 120 min of reperfusion. It appears that the protective effects of barbiturate anesthesia are not expressed by the reduced accumulation of the above eicosanoids.

Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Consciousness; Eicosanoic Acids; Gerbillinae; Male; Osmolar Concentration; Pentobarbital; Prostaglandins; Thromboxane B2

Topics: Animals; Brain; Brain Ischemia; Drugs, Chinese Herbal; Female; Male; Platelet Aggregation; Rats; Rats, Inbred Strains; Thromboxane B2

We found recently that exogenously administered PGD2, PGE1 and PGI2 showed a protective effect against cerebral hypoxia/ischemia in mice. In the present study, to find out whether these PGs play a pathophysiological role in cerebral hypoxia/ischemia, we examined a possible role of PGs in the development of adaptive protection against cerebral hypoxia/ischemia. Mice were pretreated with a sublethal dose of KCN, hypoxic gas mixture and electroshock 10-120 min before tests. Ten to thirty min after pretreatment with a sublethal dose of KCN, mice proved to be significantly protected against cerebral hypoxia/anoxia in all models studied: KCN-induced anoxia, normobaric hypoxia and decapitation-induced gasping. Similar results were observed when hypoxic gas and electroshock were used as pretreatments. These facts indicate that the protective effect does not depend on how cerebral hypoxia/anoxia is induced but on the substances formed in the brain after hypoxia/anoxia as well as electroshock. Brain concentrations of cyclooxygenase products markedly increased subsequent to hypoxia/anoxia as well as electroshock. The increase in PGs formation as well as resistance to hypoxia was prevented by pretreatment with indomethacin. These findings suggest that endogenously formed PGs at least including the three PGs, PGD2, PGE1 and prostacyclin in mouse brain during or after hypoxia/ischemia are responsible for the increase of resistance to hypoxia/ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Adaptation, Physiological; Animals; Brain; Brain Ischemia; Electroshock; Hypoxia, Brain; Indomethacin; Male; Mice; Nitrogen; Potassium Cyanide; Prostaglandins; Thromboxane B2

The aim of this study was to observe whether acetylsalicylic acid (ASA) had different effects in both sexes. Out of the ischemic stroke patients who were admitted to the National Taiwan University Hospital (NTUH), those who had not taken ASA or ASA-like drugs for more than 2 weeks were selected for this study. For the diagnosis of ischemic stroke, computed tomography (CT) of the brain was performed in all cases, and for differential diagnosis, other necessary procedures were employed in a few cases. The serum salicylate (SA) level was measured by Trinder's method, thromboxane B2 (TXB2) and 6-keto-PGF1 alpha by radioimmunoassay, threshold concentration of adenosine diphosphate (ADP) by Born's method, and circulating platelet aggregates (CPA) by Wu and Hoak's method. The present study showed that the means of serum SA levels after administration of the same dose of ASA were not significantly different between the two sexes. After ingestion of ASA, a single dose of 75 mg, 300 mg or 600 mg, or 300 mg 4 times a day, mean plasma TXB2 levels were significantly suppressed and mean threshold concentrations of ADP were significantly elevated in the two sexes. After administration of above-mentioned various doses of ASA, the abnormally high plasma TXB2 levels and abnormally low threshold concentrations of ADP and CPA ratios were significantly normalized in both male and female patients. Plasma 6-keto-PGF1 alpha levels were not influenced by ingestion of ASA 75 mg, but significantly depressed by administration of ASA 300 mg in both sexes. There were no sex differences in the antiplatelet effect of ASA in this experiment.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Aged; Aspirin; Blood Platelets; Brain Ischemia; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Platelet Aggregation; Salicylates; Salicylic Acid; Sex Factors; Thromboxane B2

Topics: Aged; Aspirin; Blood Platelets; Brain Ischemia; Female; Humans; Male; Middle Aged; Salicylates; Salicylic Acid; Thromboxane B2

A thrombo-embolic stroke model was produced by the internal carotid artery (ICA) infusion of arachidonic acid (AA). The differences in responses to AA ICA infusion were investigated in stroke-resistant spontaneously hypertensive rats (SHRSR) and Wistar-Kyoto (WKY) rats. The SHRSR showed a higher mortality, more severe brain oedema and brain metabolic impairment, more prominent elevation of TXB2 and 6-keto-PGF1 alpha. Electron microscopic observation revealed more severe endothelial damage, mitochondrial swelling and perivascular oedema and earlier thrombus formation in SHRSR than in WKY rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Brain Ischemia; Cerebrovascular Disorders; Hypertension; Male; Microscopy, Electron, Scanning; Rats; Rats, Inbred Strains; Thromboxane B2

The experimental study presented was undertaken to evaluate the role of thromboxane A2 contributing to aggravating cerebral ischemia, and to examine the effect of a thromboxane A2 synthetase inhibitor, trapidil on cerebral ischemia. Cerebral ischemia model was induced in 16 week old spontaneously hypertensive rats (SHR) by bilateral common carotid artery ligation (BLCL). Two doses of trapidil 15 mg/kg was intraperitoneally administered one dose 2 hr before and one dose 15 min after BLCL in SHR. While control animals only underwent BLCL. Brain tissue metabolites such as ATP, lactate and pyruvate, brain water content and plasma thromboxane B2 and 6 Keto PGF1 alpha were determined 3 hr after BLCL. Scanning electron microscopic observations were also recorded. ATP concentrations were 1.36 +/- 0.23 n moles/mg wet tissue in the trapidil treated group, 0.61 +/- 0.26 n moles/mg wet tissue in the control group, the difference between the treated and the control being significant (P less than 0.001). Lactate concentrations were 4.70 +/- 1.20 n moles/mg wet tissue in the treated group, 12.17 +/- 8.53 n moles/mg wet tissue in the control group, the difference between the treated and the control being significant (P less than 0.02). Pyruvate concentrations were 0.59 +/- 0.11 n moles/mg wet tissue in the treated group, 0.43 +/- 0.16 n moles/mg wet tissue in the control, the difference was also significant (P less than 0.05). Average water content was 78.87 +/- 0.59% in the treated group, 79.82 +/- 0.33% in the control.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Brain; Brain Ischemia; Cerebral Arteries; Lactates; Lactic Acid; Male; Microscopy, Electron, Scanning; Pyrimidines; Pyruvates; Pyruvic Acid; Rats; Rats, Inbred SHR; Thromboxane B2; Thromboxane-A Synthase; Trapidil

Thromboxane A2 and prostacyclin are two compounds which have been implicated as important modulators of local cerebral blood flow. Concentrations of the stable metabolites of these two compounds, thromboxane B2 and 6-keto-PGF1 alpha, were measured in cerebrospinal fluid (CSF) from eight acute ischaemic stroke patients and 14 patients with no evidence of cerebrovascular disease. Concentrations of thromboxane B2 ranged from 0.15 to 4.0 pg/ml and were significantly higher (P = 0.025) in the ischaemic stroke group when compared with the control group (0.1-0.3 pg/ml). Simultaneously acquired concentrations of 6-keto-PGF1 alpha were not elevated in the stroke group when compared to normals. These clinical findings support evidence from animal studies that emphasizes the importance of cerebral prostaglandins in mediating the secondary vascular changes of cerebral infarction. In conclusion there is an aberration in CSF thromboxane B2 concentrations in patients who have had a stroke. This may be an acute or chronic phenomenon.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Brain Ischemia; Humans; Middle Aged; Thromboxane B2

Vascular eicosanoids (E) thromboxane (measured as T X B2) and prostacyclin (measured as 6-keto-PGF1 alpha) may modulate hemodynamic parameters in brain circulation. We have studied (a) the effects of the administration of vasoactive drugs, in the rat, on T X B2 and 6-keto-PGF1 alpha levels and release in brain cortex, and (b) changes of brain vascular E levels during hypoxia and recovery, in the same animal species. Administration of vasoactive drugs (papaverine, dipyridamole, the carbochromene derivative AD6 and nifedipine) to rats resulted in differential effects on endogenous levels and post-decapitation release of both compounds. Reduction of the T X B2/6-keto-PGF1 alpha balance in brain cortex was obtained with papaverine and AD6, whereas nifedipine reduced 6-keto-PGF1 alpha more than T X B2. During hypoxia there was no significant modification of brain vascular E, but during recovery both compounds were decreased. Thus pharmacological treatments during recovery from hypoxia may normalize brain vascular E levels.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain Ischemia; Cerebral Cortex; Chromonar; Eicosanoic Acids; Papaverine; Rats; Thromboxane B2; Thromboxanes; Vasodilator Agents

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; Brain Edema; Brain Ischemia; In Vitro Techniques; Male; Rats; Rats, Inbred SHR; Thiobarbiturates; Thromboxane B2

This study examines the pathophysiology of stroke secondary to focal cerebral ischemia. The interaction of arachidonic acid metabolites and polyamines, a class of ubiquitous ornithine-derived molecules with important membrane effects on edema, Ca++-dependent endocytosis, platelet function, and prostaglandin (PG) formation, are correlated with regional changes in H2 clearance, cerebral blood flow (rCBF), ischemic edema, and somatosensory evoked responses (SSERs) after middle cerebral artery (MCA) occlusion. Thirty cats were studied up to 3 hours before and 6 hours after right MCA occlusion. Four areas of brain showing different levels of perfusion after MCA occlusion were sampled for tissue levels of PGs: 6-keto-PGF1 alpha, PGE2, and as well as thromboxane B2 (TXB2), ornithine decarboxylase activity (ODC) (a measure of polyamine activity) and gravimetric determination of cerebral edema. After right MCA occlusion, right hemisphere SSER amplitude decreased and interpeak latency increased markedly. rCBF was distributed into zones of dense, partial, and no ischemia ranging from 12.6 to 59.4 ml/100 g/minute. Ischemic edema was distributed inversely to rCBF and was increased in areas of dense ischemia (85.2 +/- 0.5%) and ischemia (82.7 +/- 0.7%), but not in partially ischemic or control areas. 6-Keto-PGF1 alpha (1257.3 pg/mg), PGE2 (1628.5 pg/mg), and TXB2 (1572.8 pg/mg) were all significantly (P less than 0.05) increased in areas of partial ischemia that had not yet developed edema. ODC levels were significantly elevated (3812 pmole/g/hour, P less than 0.05) and increased with time in areas of slightly denser ischemia that showed an intermediate increase in edema, but not the presence of infarction. This is the first demonstration that ODC, the rate-limiting enzyme for polyamine synthesis, is stimulated by cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain Edema; Brain Ischemia; Cats; Cerebral Cortex; Dinoprostone; Evoked Potentials, Somatosensory; Ornithine Decarboxylase; Polyamines; Prostaglandins; Prostaglandins E; Regional Blood Flow; Thromboxane B2

Bleeding time, thromboxane production and inhibition of platelet aggregation were studied before and during administration of acetylsalicylic acid in doses of 50, 100, 325 an 1000 mg daily in eighteen patients with cerebrovascular disease. Inhibition of thromboxane production and platelet aggregation was almost complete at 50 mg acetylsalicylic acid daily, and median bleeding time had increased significantly from 5.5 to 6.5 min at this dose and reached a maximum of 7.5 min at 100 mg daily. Further increase of the dose resulted in a slight decrease in bleeding time. It appears that a strong effect on platelet function can be achieved by small doses of acetylsalicylic acid, and that higher doses might be less effective.

Topics: Adult; Aged; Aspirin; Bleeding Time; Brain Ischemia; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Male; Middle Aged; Platelet Aggregation; Thrombosis; Thromboxane B2

The purpose of this investigation was to study the effects of a selective thromboxane A2 (TXA2) synthetase inhibitor (TSI) upon the evolution of cerebral infarction in the cat. Adult cats, lightly anesthetized with nitrous oxide, underwent right middle cerebral artery (MCA) occlusion for 4 hours followed by a 2-hour period of reperfusion before sacrifice. Ten cats received 3 mg/kg TSI intravenously immediately before, and 10 cats received 3 mg/kg TSI intravenously immediately after MCA occlusion. Ten cats were used as controls receiving no treatment. The bleeding time was determined at baseline and at the end of each experiment. Electroencephalographic (EEG) recordings were obtained before and after MCA clipping and MCA release, and at hourly intervals thereafter. Regional cerebral blood flow (rCBF) was measured using the xenon-133 (133Xe) clearance technique before and after MCA occlusion, after MCA reopening, and before terminating each experiment. Thirty minutes before each cat was sacrificed, Evans blue dye and sodium fluorescein were given intravenously. The animals were then perfused with colloidal carbon and the brains removed and evaluated for midline shift. Evans blue dye and sodium fluorescein extravasation, carbon staining, and infarct size. The bleeding time, arterial blood pressure, rCBF changes, brain swelling, and vital dye extravasation were not statistically different between the three treatment groups. The EEG changes, carbon staining, and infarct size differences between the three groups also failed to reach statistical significance, but there was a suggestion that these parameters were adversely affected in the cats pretreated with TSI. Ten additional cats undergoing MCA occlusion and reperfusion were used for pharmacological studies. Five of them received 3 mg/kg TSI intravenously immediately after MCA occlusion, and serial drug and thromboxane B2 (TXB2) levels (a stable metabolite of TXA2) were determined. Another five cats were not treated and serial TXB2 levels were obtained. Production of TXA2 was inhibited by 95% in cats receiving TSI. In conclusion, thromboxane synthetase inhibition failed to modify favorably the evolution of cerebral infarction. When TSI was given before MCA occlusion, cerebral infarction tended to be more extensive.

Topics: Animals; Brain Ischemia; Cats; Cerebral Infarction; Imidazoles; Oxidoreductases; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

The aggregability of platelets to arachidonic acid (AA) was investigated in 26 control subjects, 40 patients with essential hypertension, 20 patients with ischemic cerebrovascular diseases (CVD) not taking aspirin and 11 patients with CVD taking aspirin. The aggregability of platelets was evaluated on the basis of threshold concentrations of AA to induce irreversible platelet aggregation. The enhanced sensitivity of platelets to AA was observed more frequently in hypertensives and/or CVD patients not taking aspirin than in the controls. The relationship between platelet aggregation induced by AA and thromboxane B2 (TXB2) formation from AA or prostaglandin H2 (PGH2) in platelets was also studied in the subjects taking or not taking aspirin. It was proposed that the assessment of platelet aggregability with AA could provide a tool for identifying a subgroup of patients who might substantially benefit from the secondary preventive treatment with aspirin or other anti-platelet drugs. The clinical usefulness of this aggregation test for the management of the patients taking aspirin was also discussed.

Topics: Adolescent; Adult; Aged; Arachidonic Acids; Aspirin; Blood Platelets; Brain Ischemia; Female; Humans; Hypertension; In Vitro Techniques; Male; Middle Aged; Platelet Aggregation; Prostaglandins H; Thromboxane B2; Thromboxanes

Topics: Animals; Brain; Brain Ischemia; Cerebral Cortex; Convulsants; Fatty Acids, Essential; Gerbillinae; Hypoxia; Probenecid; Prostaglandins; Prostaglandins F; Rats; Seizures; Thromboxane B2