thromboxane-b2 and Myocardial-Ischemia

Topics: Aged; Aspirin; Coronary Angiography; Drug Monitoring; Drug Resistance; Echocardiography, Transesophageal; Electrocardiography; Exercise Test; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Activating Factor; Risk Factors; Severity of Illness Index; Thromboxane B2; Treatment Outcome

PSVT attack of >20min and frequency >160 is well-recognized model of myocardial dysfunction. We measured 6-keto-PGF1alpha and TXB(2) before and after adenosine administration to assess its cardioprotective potential. A total of 64 patients were randomly assigned as having acute episode of PSVT to adenosine or verapamil group. A bolus of 6mg of adenosine up to the maximum dose of 12 or 5mg of verapamil up to the maximum dose of 10mg were given, until the sinus rhythm was restored. The levels of PGI(2), TXA(2) and TAS were measured in three different time intervals. In adenosine group all parameters were normalized after 20min of conversion to sinus rhythm. The ratio of PGI(2)/TXA(2) increased after 5min of conversion to SR (P<0.01). Also, the ratio of TXA(2)/TAS was decreased for ADO (P<0.01). This is the first study to demonstrate that adenosine exerts cardioprotective effect.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine; Adult; Cardiotonic Agents; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Prostaglandins; Tachycardia, Paroxysmal; Tachycardia, Supraventricular; Thromboxane A2; Thromboxane B2; Verapamil

We performed a placebo-controlled, randomized study to address whether celecoxib or ibuprofen undermines the functional range of inhibition of platelet cyclooxygenase (COX)-1 activity by aspirin in patients with osteoarthritis and stable ischemic heart disease.. Twenty-four patients who were undergoing long-term treatment with aspirin (100 mg daily) for cardioprotection were coadministered celecoxib, 200 mg twice daily, ibuprofen, 600 mg 3 times daily, or placebo for 7 days.. The coadministration of placebo or celecoxib did not undermine the aspirin-related inhibition of platelet COX-1 activity, as assessed by measurements of serum thromboxane B(2) (TXB(2)) levels, as well as platelet function. In contrast, a significant (P < .001) increase in serum TXB(2) level was detected on day 7 before drug administration (median, 19.13 ng/mL [range, 1-47.5 ng/mL]) and at 24 hours after the coadministration of aspirin and ibuprofen (median, 22.28 ng/mL [range, 4.9-44.4 ng/mL]) versus baseline (median, 1.65 ng/mL [range, 0.55-79.8 ng/mL]); this was associated with a significant increase in arachidonic acid-induced platelet aggregation (P < .01) and adenosine diphosphate-induced platelet aggregation (P < .05) and a decrease in the time to form an occlusive thrombus in the platelet function analyzer (P < .01). The urinary excretion of 11-dehydro-TXB(2), an index of systemic thromboxane biosynthesis, was not significantly affected by the coadministration of treatment drugs. At steady state, a comparable and persistent inhibition of lipopolysaccharide-stimulated prostaglandin E(2) generation, a marker of COX-2 activity ex vivo, was caused by ibuprofen (>or=80%) or celecoxib (>or=70%) but not placebo.. Unlike ibuprofen, celecoxib did not interfere with the inhibition of platelet COX-1 activity and function by aspirin despite a comparable suppression of COX-2 ex vivo in patients with osteoarthritis and stable ischemic heart disease.

Topics: Adenosine Diphosphate; Aged; Arachidonic Acid; Aspirin; Celecoxib; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Ibuprofen; Male; Middle Aged; Myocardial Ischemia; Osteoarthritis; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Pyrazoles; Sulfonamides; Thromboxane B2; Treatment Outcome

To evaluate whether aspirin reduces the incidence and frequency of daily life myocardial ischaemia in a cohort of patients with chronic stable coronary artery disease.. Tertiary referral centre.. 60 patients with chronic stable coronary artery disease underwent 48 hour Holter monitoring to assess the incidence and frequency of daily life myocardial ischaemia. Those with myocardial ischaemia (40/60) entered a double blind, crossover trial of aspirin (300 mg/day for three weeks) versus placebo. After each treatment arm, 48 hour Holter monitoring was repeated and urinary thromboxane (Tx) B2, 11-dehydro-TxB2, plasma prothrombin fragment F1+2, macrophage colony stimulating factor (MCSF), and interleukin (IL)-6 were measured.. Aspirin reduced the total number and duration of ischaemic episodes from 339 to 251 and from 1765 to 1365 minutes, respectively (p < 0.01 for both). TxB2 was also reduced from 0.2 to 0.1 ng/mg creatinine, 11-dehydro-TxB2 from 3.3 to 1.3 ng/mg creatinine, F1+2 from 1.5 to 1.2 nmol/l, MCSF from 991 to 843 pg/ml, and IL-6 from 3.5 to 2.9 pg/ml (p < 0.05 for all). 11-dehydro-TxB2 excretion with and without aspirin was related to MCSF concentrations (p < 0.01), and the percentage reduction of MCSF by aspirin was related to the reduction of 11-dehydro-TxB2 (p < 0.05) and the reduction of the ischaemic burden compared with placebo (p < 0.05).. In patients with daily life ischaemia, aspirin reduces the incidence and frequency of ischaemic episodes as well as the systemic concentrations of haemostatic/inflammatory markers. Aspirin may prevent transient coronary flow reductions through platelet, thrombin, and cytokine inhibition.

Topics: Adult; Aged; Aspirin; Biomarkers; Cohort Studies; Coronary Artery Disease; Cross-Over Studies; Double-Blind Method; Electrocardiography, Ambulatory; Female; Humans; Interleukin-6; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Myocardial Ischemia; Peptide Fragments; Platelet Aggregation Inhibitors; Prothrombin; Thromboxane A2; Thromboxane B2

The evidence that inflammation plays a pivotal role in the pathophysiology of acute coronary syndromes prompted us to investigate the effects of glucocorticoid treatment on leukotriene (LT) C4 and thromboxane (TX) A2 biosynthesis in unstable angina.. Urinary LTE4 and 11-dehydro-TXB2 were significantly higher in 12 patients with unstable angina than in 12 patients with stable angina and 12 patients with nonischemic chest pain. Furthermore, we randomized the unstable angina patients to receive intravenous 6-methylprednisolone (6-MP; 1 mg/kg BID for 2 days) or matching placebo and collected 12 consecutive 6-hour urine samples before and during the infusions. LTE4 excretion showed a time-dependent decrease in the 6-MP group but did not decrease during placebo. Furthermore, during myocardial ischemia, LTE4 was significantly higher before 6-MP infusion than during steroid therapy. In contrast, 11-dehydro-TXB2 did not differ significantly during 6-MP versus placebo. Myocardial ischemia elicited by stress test in the stable angina patients was not accompanied by any change in LTE4 and 11-dehydro-TXB2, thus ruling out a role of ischemia per se in the induction of increased eicosanoid production.. Increased production of vasoactive LT and TX may occur in unstable angina despite conventional antithrombotic and antianginal treatment. Glucocorticoids can suppress LTC4 biosynthesis in the short term and may provide an interesting tool to explore the pathophysiological significance of inflammatory cell activation in this setting.

Topics: Adult; Angina, Unstable; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Double-Blind Method; Eicosanoids; Female; Glucocorticoids; Humans; Leukotriene E4; Male; Methylprednisolone; Middle Aged; Myocardial Ischemia; Thromboxane B2

The aim of the study was to investigate the effects of the antiplatelet agent triflusal on the changes in platelet function in patients who underwent a cardiopulmonary bypass for coronary arteries (CABG). In 20 surgical patients, blood was sampled before and at the conclusion of surgery, 48 h later (in the intensive care unit), and after 10 days of treatment with 600 mg/day triflusal (triflusal was administered from the first day after surgery). Adenosine diphosphate (ADP) and collagen-induced platelet aggregation in whole blood, granular release of beta-thromboglobulin and platelet release of thromboxane B2 were measured. Basal values were compared with results in a group of ten healthy volunteers. All platelet determinations of activation were higher in coronary patients than in healthy volunteers. Immediately after CABG, the platelet reactivity to ADP and collagen were significantly lower, and release of beta-thromboglobulin and thromboxane B2 were higher, than in the pre-CABG samples. During the patient's stay in the intensive care unit, all values tend to return to pre-CABG values. Triflusal inhibits both platelet beta-thromboglobulin (63% with respect to the post-CABG value) and thromboxane B2 (91% with respect to the post-CABG value) release. Platelet aggregation after 10 days of triflusal treatment tended to return to the pre-CABG values. In conclusion, Triflusal reduces platelet activation caused by the coronary artery bypass graft surgery.

Topics: Adenosine Diphosphate; Adult; Aged; beta-Thromboglobulin; Collagen; Coronary Artery Bypass; Erythrocyte Count; Female; Hematocrit; Hemoglobins; Humans; Leukocyte Count; Male; Middle Aged; Myocardial Ischemia; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Salicylates; Thromboxane B2; Time Factors

Eleven patients with ischemia heart disease (IHD) were treated with low dose aspirin (ASA, 50mg/day) for more than two weeks (ASA group). 29 cases with IHD not taking ASA served as patient control (NASA group) and 13 cases without IHD not taking ASA as normal control. Blood samples for measurement of plasma (serum) TXB2 and 6-keto-PGF1 alpha were simultaneously taken from aortic root (AO) and coronary sinus (CS). The results showed: ASA group had lower plasma TXB2 level in AO blood than NASA group (P < 0.05), but there was no significant difference in plasma 6-keto-PGF1 alpha level between the two groups. Both of plasma and serum TXB2/6-keto-PGF1 alpha ratios in AO blood in ASA group were significantly lower than those in NASA group (P < 0.05 and P < 0.0005 respectively). Plasma TXB2 CS/AO ratio and 6-keto-PGF1 alpha CS/AO ratio in ASA group were significantly lower than those in NASA group (P < 0.05), but not different from those in control group. Both ASA and NASA groups had lower serum TXB2 CS/AO ratios than control group (P < 0.05). The results suggest that low dose aspirin inhibits selectively TXA2 synthesis in systemic circulation and inhibits synthesis and/or release of TXA2 and PGI2 equally (no selectivity) in coronary circulation, but could not completely inhibit intracoronary platelet activation.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Blood Platelets; Coronary Circulation; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane B2

To investigate the effects of bepridil on silent myocardial ischemia and on eicosanoid metabolism, 10 patients with chronic stable angina underwent exercise treadmill testing and 48-hour ambulatory electrocardiographic monitoring both before and after 4 weeks of bepridil administration (150 mg/day). Fasting venous levels of thromboxane B2, 6-keto-prostaglandin F1 alpha, and leukotriene C4 were measured by radioimmunoassay. Bepridil decreased heart rate responses to daily activities during ambulatory monitoring, and significantly (p < 0.05) reduced the median frequency and duration of silent myocardial ischemic episodes (from 5.5 to 0 events/48 hours and from 86 to 0 minutes/48 hours respectively). Bepridil significantly decreased the blood pressure heart rate product at peak exercise and significantly prolonged the mean exercise tolerance time (from 456.6 to 527.0 second). Bepridil also significantly decreased the plasma levels of thromboxane B2 and leukotriene C4 at rest. These results suggest that bepridil may reduce silent myocardial ischemic episodes either by the reduction of cardiac oxygen demand during daily activities and exercise stress, or by controlling coronary and systemic vasomotor tone. The drug also has a salutary effect on eicosanoid metabolism, to which its efficacy on silent myocardial ischemic episodes may be related.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angina Pectoris; Arachidonic Acids; Bepridil; Chronic Disease; Electrocardiography, Ambulatory; Exercise Test; Female; Heart Rate; Humans; Leukotriene C4; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Radioimmunoassay; Single-Blind Method; Thromboxane B2

Plasma bradykinin and prostaglandin metabolism are related to the anginal pain modulating system in patients with ischemic heart disease. We carried out a placebo controlled single blind test of diltiazem (30 mg three times a day) in 15 patients with chronic stable angina. The effect of diltiazem was evaluated by exercise treadmill testing and 48-h ambulatory electrocardiographic monitoring. Plasma bradykinin, thromboxane B2, and 6-keto-prostaglandin F1 alpha levels were determined by radioimmunoassay prior to and during diltiazem therapy. Diltiazem significantly increased the exercise time and reduced episodes of angina. Diltiazem, however, did not appreciably improve either the frequency of silent myocardial ischemic episodes or the total duration of the silent myocardial ischemic episodes. Diltiazem also tended to decrease plasma bradykinin, thromboxane B2, and 6-keto-prostaglandin F1 alpha levels. When ischemic episodes on ambulatory electrocardiographic monitoring are categorized according to heart rate change at the onset of episode (type A, preceded by heart rate increase > or = 5 beats/min; type B, no preceding heart rate increase), diltiazem was only effective on type A ischemic episodes as well as on symptomatic ischemia. Further, bradykinin was significantly decreased by diltiazem only in patients with exercise-induced silent ischemia or no exercise-induced ischemia, while the thromboxane B2/6-keto-prostaglandin F1 alpha ratio was unaffected by the administration of diltiazem. Thus, silent and symptomatic ischemia may be associated with different bradykinin and prostaglandin responses.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angina Pectoris; Bradykinin; Diltiazem; Electrocardiography, Ambulatory; Exercise Test; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Single-Blind Method; Thromboxane B2

The peeled stem of Syringa pinnatifolia Hemsl. (SP) is a traditional medicine in Inner Mongolia, China. The powder form of SP has been widely used for hundreds of years to relieve "He-Yi" related myocardial ischemia independently or in a traditional Chinese medicine preparation.. SP was extracted with 95% and 80% ethanol. Chemical profiling was performed using HPLC-DAD and IT-TOF-ESI-MS analyses. Myocardial ischemia was produced by ligation of the left anterior descending (LAD) coronary artery to evaluate the anti-myocardial ischemia effect of SP. Male C57BL/6 mice were randomly divided into six groups (n=10 per group): a sham group, a model group, groups pretreated with SP at three dosages (20mg/kg, 40mg/kg, and 80mg/kg, intragastrically), and a positive control group (acetylsalicylic acid, ASA, 53mg/kg, intragastrically). Echocardiography was performed to determine heart function by measuring ejection fraction and fractional shortening. The levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in serum, and 6-keto-PGF1α and TXB2 both in plasma and in protein homogenate of myocardial tissue were also measured. The levels of cyclooxygenase (COX)-1 and -2 in the heart tissue and their expressions in mouse myocardial tissue were determined using Western blot and an immunofluorescence assay, respectively. Inflammatory cell infiltration and collagen deposition changes in the myocardial ischemic tissue were observed by pathological examination.. Intragastric pretreatment with SP produced a dose-dependent increase in cardiac function. SP at 80mg/kg significantly improved the EF (p<0.001) and FS (p<0.01) compared with the model group, as well as the levels of serum CK-MB and LDH decreased obviously (p<0.001), approaching those in the sham group. Besides, an obvious reduction in inflammatory cells infiltration and collagen deposition in the infarcted myocardial tissue was shown in each SP treatment group. In addition, SP increased 6-keto-PGF1α and decreased TXB2 levels in the plasma, whereas the opposite pattern was observed in the protein homogenate from the myocardial tissues at the infarction edge, but keeping balance the ratio of 6-keto-PGF1α and TXB2, which is better than ASA in plasma. The mechanisms is associated with the downregulated expressions of COX-1 (p<0.05) and COX-2 (p<0.001).. Ethanol extract of SP has a protective effect against myocardial ischemia via down regulation of COX-1 and COX-2 expression and by adjusting the ischemia-induced imbalance between 6-keto-PGF1α and TXB2. This study shows substantial evidence to support the clinical application of SP and indicates that such medicine has great potential for treating ischemia-induced heart disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatine Kinase, MB Form; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; L-Lactate Dehydrogenase; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Myocardial Ischemia; Myocardium; Phytotherapy; Plant Extracts; Plant Stems; Syringa; Thromboxane B2

Urinary 11-dehydro-thromboxane (TX)B2 has been described as a potential predictive biomarker of major adverse cardiovascular events (MACEs) in high cardiac risk patients. This part of LTIMI (Leukotrienes and Thromboxane In Myocardial Infarction) study aimed to evaluate the relationship between 11-dehydro-TXB2 and MACEs in patients with acute myocardial infarction (AMI).. LTIMI was an observational, prospective study in 180 consecutive patients with AMI type 1 referred for primary percutaneous coronary intervention. On admission and at follow-up visits (1 month, 1 year), 11-dehydro-TXB2 was measured in urinary samples by using high-performance liquid chromatography-tandem mass spectrometry. The primary outcome was occurrence of composite MACEs during 1-year after AMI. Left ventricular ejection fraction was assessed in echocardiography on admission and at 1-year follow-up. Analyses of 11-dehydro-TXB2 (pg/mg creatinine) were performed on log-transformed data and expressed as median with IQR (Q1-Q3). 11-Dehydro-TXB2 level on admission was 7.39 (6.85-8.01) and decreased at 1 month (6.73, 6.27-7.12; P<0.001) and 1-year follow-up (6.37, 5.91-6.94; P<0.001). In univariate analysis, baseline 11-dehydro-TXB2 was higher in patients with MACEs (n=60; 7.73, 7.07-8.60) compared with those without MACEs (n=119; 7.28, 6.68-7.79; P=0.002). In multivariate regression model, 11-dehydro-TXB2 and 3 other variables (diabetes, multivessel disease, and left ventricular ejection fraction) were found to be best 1-year cumulative MACE predictors with odds ratio for 11-dehydro-TXB2 of 1.58 (95% CI 1.095-2.33; P=0.017) and area under the curve (in receiver operating characteristic analysis of 0.8). Baseline 11-dehydro-TXB2 negatively correlated with both left ventricular ejection fraction on admission (R=-0.21; P=0.006) and after 1 year (R=-0.346; P<0.001).. 11-Dehydro-TXB2 predicts 1-year cumulative MACEs in AMI patients and provides prognostic information on the left ventricular performance.

Topics: Acute Disease; Aged; Biomarkers; Echocardiography; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Prognosis; Prospective Studies; Stroke Volume; Thromboxane B2; Time Factors

Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, mostly clopidogrel, is the default therapy in both acute coronary syndrome (ACS) and after intracoronary stents. It is well established that responses to antiplatelet therapy (APT), particularly clopidogrel, are subject to considerable interindividual variability.. We investigated whether responses to APT in individuals vary significantly over time.. Simultaneous assay with VerifyNow(™) and short thrombelastography (s-TEG) was performed before and at four time points over 6 months after hospital discharge in 40 patients receiving DAPT. Serum thromboxane B2 levels were also measured.. While aspirin response units (ARU) by VerifyNow(™) and serum thromboxane B2 levels remained stable over time, arachidonic acid (AA)-mediated platelet aggregation with s-TEG (i.e. area under the curve at 15 min in AA channel, AUC15AA ) increased at 1 week compared with predischarge (P < 0.008). In addition, platelet reactivity units (PRU) by VerifyNow(™) (P = 0.046) and adenosine diphosphate (ADP)-mediated platelet aggregation with s-TEG (i.e. AUC15ADP ) also increased at 1 week compared with predischarge (P = 0.026). There were no significant changes in either platelet reactivity or rates of high on-treatment platelet reactivity while receiving clopidogrel beyond 1 week.. This study demonstrates important variability in responses to APT within individuals between predischarge and 1 week but not thereafter. The use of a single early (predischarge) platelet function assay as an indicator of future response may therefore be flawed. The design of future strategies to assess individual responses for tailored therapy needs to take this into account.

Topics: Aged; Area Under Curve; Aspirin; Biomarkers; Blood Platelets; Clopidogrel; Drug Therapy, Combination; England; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Predictive Value of Tests; Prospective Studies; Receptors, Purinergic P2Y12; Reproducibility of Results; ROC Curve; Thrombelastography; Thromboxane B2; Ticlopidine; Time Factors; Treatment Outcome

Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low-dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11-dehydro-TXB2) is predictive of vascular events in high-risk patients. Myeloid-related protein (MRP)-8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP-14 has emerged as a powerful predictor of ACS.. We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP-8/14 release in the circulation is related to TX-dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low-dose aspirin-treated ACS patients. In ACS patients, plasma MRP-8/14 and urinary 11-dehydro-TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin-treated ACS patients, MRP-8/14 and 11-dehydro-TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11-dehydro-TXB2 significantly predicted higher MRP-8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R(2)=0.463 and adj R(2)=0.497) after multivariable adjustment. Conversely, plasma MRP-8/14 (P<0.001) and higher urinary 8-iso-prostaglandin F2α (P=0.050) levels were significant predictors of residual, on-aspirin, TX biosynthesis in ACS (adjusted R(2)=0.384).. Circulating MRP-8/14 is associated with TX-dependent platelet activation in ACS, even during low-dose aspirin treatment, suggesting a contribution of residual TX to MRP-8/14 shedding, which may further amplify platelet activation. Circulating MRP-8/14 may be a target to test different antiplatelet strategies in ACS.

Topics: Acute Coronary Syndrome; Aged; Aspirin; Calgranulin A; Calgranulin B; Chronic Disease; Dinoprost; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane B2

To investigate the changes in contents of cycloxygenase-2 (COX-2) and its downstream effectors in rat's myocardial ischemia/reperfusion (I/R) model and observe the effects of precondition with GBE50 (Ginkgo biloba extract 50) and Salviae miltiorrhizae (SM) on them.. Rat's I/R model was established by 30-min left anterior descending coronary artery occlusion followed with 60-min reperfusion. Animals were divided into the model control group, the sham-operated group and the tested groups (received 1-week precondition with GBE50 and SM respectively via intragastric infusion before modeling). COX-2 mRNA expression in myocardium was detected by real-time PCR; contents of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) were measured by radioimmunoassay.. The mRNA expression of COX-2 in the model group was obviously higher than that in the sham-operated group (P < 0.001), while that in the tested groups was down-regulated significantly (P < 0.01), and the content of TXB2 as well as the ratio of TXB2/PGF1alpha was reduced significantly (P < 0.05). Besides, SM also showed the up-regulation effect on 6-keto-PGF1alpha content in myocardium (P < 0.05).. COX-2 affects the myocardium through thromboxane A2 and prostacyclin after I/R; both GBE50 and SM can inhibit the production of COX-2, but they may act in different paths.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase 2; Drugs, Chinese Herbal; Ginkgo biloba; Ischemic Preconditioning, Myocardial; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; RNA, Messenger; Salvia miltiorrhiza; Thromboxane B2

Laboratory tests including optical platelet aggregometry (OPA), platelet function analyser (PFA-100), and thromboxane B2 (TXB2) metabolite levels have been used to define aspirin resistance. This study characterised the prevalence of aspirin resistance in patients with ischaemic heart disease (IHD) and investigated the concordance and repeatability of these tests.. Consecutive outpatients with stable IHD were enrolled. They were commenced on 150 mg aspirin daily (day 0) and had platelet function assessment (OPA and PFA-100) and quantitative analysis of serum/urine TXB2 at day > or =7 and then at a second visit approximately 2 weeks later.. We assessed the prevalence of aspirin resistance by each method, concordance between methods of measuring response to aspirin and association between time points to assess the predictability of response over time.. 172 patients (62.7 (SD 8.7) years, 83.1% male) were recruited. At visits 1 and 2, respectively, 1.7% and 4.7% were aspirin resistant by OPA, whereas 22.1% and 20.3% were aspirin resistant by PFA-100. There were poor associations between PFA-100 and OPA, and between TXB2 metabolites and platelet function tests. OPA and PFA-100 results were poorly associated between visits (kappa = 0.16 and kappa = 0.42, respectively) as were TXB2 metabolites, suggesting that aspirin resistance is not predictable over time.. The prevalence of aspirin resistance is dependent on the method of testing. Response varies on a temporal basis, indicating that testing on a single occasion is inadequate to diagnose resistance or guide therapy in a clinical setting.

Topics: Aspirin; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

It has been proven that nicotine contributes to cardiovascular diseases, although its precise mechanism of action is still unclear. The purpose of this study is to find how nicotine may complicate myocardial ischemia by affecting the thromboxane/prostacyclin (TXA(2)/PGI(2)) balance. We used four groups (n=7 each) of isolated and perfused rabbit hearts according to Langendorff method: (i) control group; (ii) group submitted to 1 microM nicotine perfusion during 60 min; (iii) group submitted to a regional ischemia by ligation of the left descending coronary artery during 60 min and (iv) group submitted to nicotine perfusion during ischemia. Levels of TXB(2) and 6-keto PGF(1alpha), the stable metabolites of TXA(2) and PGI(2) were then determined in the microsomes of the hearts by radioimmunoassay. The results showed that (1) a TXA(2) synthetase activity is present in the myocardium, and this activity, as well as that of PGI(2) synthetase, is decreased by a 60min ischemia; (2) TXA(2) and PGI(2) activities are not affected by nicotine in the normal myocardium and (3) nicotine infusion during ischemia contributes to the increase of TXA(2)/PGI(2) ratio further by decreasing PGI(2). Therefore, these results provide one explanation on how nicotine might worsen myocardial ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Epoprostenol; Heart; In Vitro Techniques; Intramolecular Oxidoreductases; Male; Microsomes; Myocardial Ischemia; Myocardium; Nicotine; Perfusion; Rabbits; Smoking; Thromboxane A2; Thromboxane B2

1. The effect of the nitro-derivative of aspirin, NCX4016, was assessed on ischaemic ventricular arrhythmias and myocardial infarct size in anaesthetized pigs in comparison to native aspirin. 2. Pigs were given aspirin (10 mg kg(-1); n=6), low dose NCX4016 (18.4 mg kg(-1); n=6) or high dose NCX4016 (60 mg kg(-1); n=7) orally for 5 days prior to coronary occlusion and reperfusion. None of the interventions had any effect on baseline haemodynamics prior to coronary occlusion in comparison to control pigs (n=9). Aspirin and high dose NCX4016 both prevented the generation of thromboxane A(2) from platelets activated ex vivo with A23187 (30 microM), whereas all three interventions markedly attenuated platelet aggregation in response to collagen in whole blood in comparison to controls. 3. None of the drug interventions had any effect on the incidence of ventricular fibrillation (VF) during myocardial ischaemia (100% in all groups). However, 60 mg kg(-1) NCX4016 significantly attenuated the total number of premature ventricular beats (PVB's) (62+/-16 vs 273+/-40 in control pigs; P<0.05) during the first 30 min of occlusion. The higher dose of NCX4016 also significantly reduced myocardial infarct size (22.6+/-3.7% of area at risk vs 53.0+/-2.8% of area at risk in control pigs; P<0.05). 4. These results suggest that the nitro-derivative of aspirin, NCX4016, is an effective antiplatelet agent, which unlike aspirin also reduces the extent of myocardial injury following ischaemia and reperfusion.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arrhythmias, Cardiac; Aspirin; Coronary Disease; Endothelium, Vascular; Hemodynamics; Leukocytes; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Platelet Aggregation; Swine; Thromboxane B2; Ventricular Fibrillation

In this investigation, an anti-thromboxane A2 (TXA2) synthetase activity in the myocardial tissue, which can be modulated by ischemia and reperfusion, was observed. Regional ischemia was induced by 60 min occlusion of the left anterior descending coronary artery in isolated Langendorff rabbit hearts. Biosynthesis of TXA2 was carried out by using arachidonic acid (AA) as substrate, horse platelet microsomes (HPM) as the source of TXA2 synthetase and left ventricle microsomes (LVM) from ischemic and non-ischemic areas as effectors TXB2, the stable metabolite of TXA2, was determined by radioimmunoassay. Experiments carried out under the adopted conditions showed that LVM from control hearts were able to inhibit by up to 50% the biosynthesis of TXA2 from HPM. This anti-TXA2 synthetase activity was more pronounced when LVM from the non-ischemic area were used, rather then LVM from the ischemic one. A 60 min reperfusion decreased the anti-TXA2 activity. A superfused rabbit aorta strip was also used as a cascade bioassay to study the effect of LVM on the TX2-synthetase activity of HPM, and this confirmed our findings. These results suggest that the left ventricle possesses a self-defense mechanism against acute myocardial ischemia, independently from the circulation. The postulated mechanism may be initiated in the non-ischemic area.

Topics: Animals; Arachidonic Acid; Blood Platelets; Epoprostenol; Heart Ventricles; Horses; In Vitro Techniques; Male; Microsomes; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Rabbits; Thromboxane B2; Thromboxane-A Synthase

The changes in endothelium-derived vascular regulatory factors during dobutamine (DOB)-induced myocardial ischemia (MI) were investigated in 21 patients with Kawasaki disease aged from 11 months to 18 years. They were classified into an ischemia group (8 patients) and a non-ischemia group (13 patients) based on the results of 99mTc myocardial scintigraphy and DOB stress 99mTc myocardial scintigraphy. In the ischemia group, MI was relatively mild, because there were ischemic changes on the electrocardiogram and no significant symptoms during DOB stress. Catheters were positioned near the orifice of the coronary artery (Ao) and at the coronary sinus (CS). Hemodynamics and the blood concentrations of lactic acid and endothelin-1, as well as NO3-, 6-keto-prostaglandin F1alpha, and thromboxane B2, (which are inactive metabolites of nitric oxide, prostaglandin I2 and thromboxane A2, respectively), were measured at rest and after DOB stress (maximum dose: 30 microg x kg(-1) x min(-1)). The CS/Ao ratio was determined for all parameters. The rate-pressure product, an index of work load, and the cardiac index were significantly increased by DOB stress in both groups. Coronary angiography showed no vasospasm of the epicardial coronary arteries before or after DOB stress in either group. The plasma concentrations of endothelin-1 and 6-keto-prostaglandin F1alpha were significantly increased after DOB stress in the ischemia group, but the serum concentration of NO did not increase. The lack of an increase in NO production during DOB stress may have contributed to the worsening of MI in patients with Kawasaki disease.

Topics: Adolescent; Calcinosis; Cardiomyopathies; Child; Child, Preschool; Coronary Angiography; Dobutamine; Endothelin-1; Endothelins; Female; Hemodynamics; Humans; Infant; Lactic Acid; Male; Mucocutaneous Lymph Node Syndrome; Myocardial Ischemia; Nitrates; Nitric Oxide; Prostaglandins F; Rest; Stress, Physiological; Thromboxane B2

Efficacy of aspirin (Acetylsalicylic acid, ASA) antiaggregatory prevention was demonstrated in a series of clinical trials. The recommended ASA doses decreased gradually and doses 50-30 mg ASA/d are intensively studied at the present time. A group of 42 patients with coronary heart disease was evaluated: (1) Basal TXB2 production during spontaneous blood clotting was 360 +/- 37.6 ng/ml; (2) Two initial doses were tested: while 200 mg ASA inhibited, during spontaneous blood clotting, median TXB2 production by 99.9% (serum TXB2 concentration 1.35 ng/ml), 30 mg ASA median inhibition was just 42.0% (serum TXB2 151 ng/ml); (3) 30 mg ASA/d maintenance dose was evaluated for 3 months. The median TXB2 production inhibition was 98.5% (serum TXB2 3.75 ng/ml, first month) and 94.0% (serum TXB2 14.2 ng/ml, third month); (4) Four patients did not respond sufficiently, because of noncompliance verified by the determination of salicyluric acid urinary excretion, the lower limit of excretion being <3 micromol/2 h; (5) Both initial and maintenance ASA dose decreased metabolic TXA2 endproducts in urine; (6) 5HT platelet release did not decrease; (7) Potential changes of 5HT metabolic elimination were excluded by the simultaneous determination of 5-hydroxyindoleacetic acid (5HIAA). In conclusion, 200 mg initial dose and 30 mg ASA/d maintenance dose are suggested to be maximally inhibitory for TXB2 production without influence on 5HT release.

Topics: Aspirin; Blood Coagulation; Coronary Disease; Dose-Response Relationship, Drug; Humans; Myocardial Ischemia; Serotonin; Thromboxane A2; Thromboxane B2

The key role of prostanoids has been recognized in patients with ischemic heart disease. However, serial changes of thromboxane and prostacyclin during both brief and prolonged ischemia-reperfusion are poorly known. These plasma prostanoids were measured during myocardial stunning (MS) and acute myocardial infarction (AMI). The effects of magnesium (Mg), diltiazem, and a Mac-1 inhibitor on the level of the stable metabolites of thromboxane (TXB2) and prostacyclin (6-keto-PGF1 alpha) were elucidated. Forty-nine swine underwent brief (8 min) or prolonged (50 min) coronary artery occlusion followed by reperfusion. The occlusion phase was associated with a decline of plasma prostanoids, followed by a significant increase during reperfusion. Mg and diltiazem similarly affected plasma prostanoids by reducing TXB2 release at 1 h of reperfusion. There was, however, no effect on plasma 6-keto-PGF1 alpha. The Mac-1 inhibition was associated with stabilization of both antagonistic prostanoids as well. Ability of Mg, diltiazem, and leumedins to favorably modulate plasma prostanoid levels have direct clinical implications for the use of these agents in patients with coronary artery disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diltiazem; Enzyme-Linked Immunosorbent Assay; Female; Leucine; Macrophage-1 Antigen; Magnesium; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardial Stunning; Prostaglandins; Swine; Thromboxane B2

To determine whether the prostacyclin analog iloprost plays a beneficial role in crystalloid cardioplegia in isolated working rat hearts, 20 isolated rat hearts were studied after sustaining 90 min of cardioplegic arrest under hypothermia (20 degrees C). The findings indicated that thromboxane A2 (TXA2) levels in coronary effluent were increased during reperfusion. Iloprost (12 nm/l) inhibited the release of TXA2 and improved the recovery of cardiac hemodynamics after ischemia. These data demonstrated that cardiac-derived TXA2 appeared to mediate reperfusion injury after prolonged aortic clamp or cardiac transplantation and iloprost cardioplegic infusion resulted in the inhibition of release of cardiac-derived TXA2 and in a better preservation of cardiac function after ischemic arrest.

Topics: Animals; Cardiac Output; Heart; Heart Arrest, Induced; Iloprost; In Vitro Techniques; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Thromboxane B2; Ventricular Function, Left; Ventricular Function, Right

Wistar rats were fed with grain produced in the areas prevalent of Keshan Disease, and supplemented by selenium (Se) and vitamin E (VE) for ten weeks, and an acute myocardial ischaemia animal model was established by ligation of left anterior descending coronary arteries. Results indicated activities of phospholipase A2 (PLA2), creatine kinase (CK) and lactate dehydrogenase (LDH), and levels of arachidonic acid (AA), thromboxane A2 (TXA2), leucotriene C4 (LTC4) and lipid peroxides (LPO) increased, but level of prostacyclin (PC) and activities of glutathione peroxidase (GSH-PO), copper-zinc superoxide dismutase (Cu-Zn-SOD) and catalase (CAT) decreased 48 hours after ligation of the coronary vessels in rats without supplement of Se and VE. Supplement of Se or VE in their feed could reverse the above effects and the best results could be got by supplement of both. It suggested that supplement of adequate amount of Se and VE in their feed could affect metabolism of AA and levels of its metabolites, improve myocardial function and metabolic status and reduce myocardial damage in rats under the stress of acute myocardial ischaemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Female; Male; Myocardial Ischemia; Rats; Rats, Wistar; Selenium; Thromboxane B2; Vitamin E

The levels of alpha-granule membrane protein (GMP-140) on the surface of platelet and serum TXB2 were determined in 55 patients with coronary heart disease (CHD) and 20 healthy individuals before and after exercise test. Among the 55 CHD patients, 36 had positive and 19 had negative results. The number of GMP-140 molecules on the platelet surface and serum TXB2 level were significantly increased in the patients with positive exercise test, P < 0.05. The increase was transient and GMP-140 returned to the preexercise level 15 minutes after the exercise test. In contrast, GMP-140 and TXB2 levels were not elevated in CHD patients with negative exercise test and also in normal subjects after exercise. The result indicates that platelet activation may be related to the exercise-induced myocardial ischemia in CHD patients.

Topics: Adult; Aged; Coronary Disease; Exercise Test; Female; Humans; Male; Middle Aged; Myocardial Ischemia; P-Selectin; Platelet Activation; Platelet Membrane Glycoproteins; Thromboxane B2

We investigated the ability of a newly developed calcium and serotonin (5-HT2) antagonist, nexopamil, to protect the heart from ischemia- and reperfusion-induced myocardial injury. Anesthetized open-chest minipigs were subjected to 1 h left anterior descending coronary artery (LAD) occlusion and 3-h reperfusion. Thirty minutes before occlusion, one group of pigs (n = 7) received nexopamil (0.1 mg/kg intravenously, i.v.) and another group (n = 9) received vehicle. Nexopamil reduced infarct size (IS: tetrazolium stain) from 47 +/- 4% (vehicle) to 21 +/- 7% of the ischemic area (p < 0.05). In nexopamil-treated pigs, this was paralleled by reduced release of creatine kinase (CK) into coronary venous blood. In addition, nexopamil prevented reperfusion-associated myocardial contracture. Nexopamil decreased left ventricular peak pressure (LVPP) and pressure rate index (PRI) immediately before coronary occlusion by 11 and 18%, respectively. Coadministration of methoxamine (2 mg/kg, n = 6) with nexopamil increased LVPP and PRI to values of vehicle-treated pigs but did not prevent reduction in infarct size or CK activity in plasma. During reperfusion, neutrophil granulocytes showed increased formation of reactive oxygen metabolites (chemiluminescence) after stimulation with zymosan. Neutrophil counts in coronary venous blood were significantly reduced at 3 h reperfusion. Both changes were attenuated in nexopamil-treated pigs. Coronary occlusion resulted in increased platelet reactivity in coronary venous blood (collagen-induced aggregation) that was prevented by nexopamil. Nexopamil significantly increased the transcardiac (coronary venous-arterial) concentration gradients of 6-oxo-prostaglandin F1 alpha (PGF1 alpha) without changing thromboxane (B2 (TBX2) concentrations, indicating a selective increase in cardiocoronary PGI2 formation. Nexopamil reduces myocardial injury in reperfused ischemic myocardium. Besides calcium channel blocking activity, inhibition of ischemia-induced neutrophil activation and enhanced endogenous PGI2 formation may be factors contributing to the beneficial effects of nexopamil.

Topics: Animals; Blood Platelets; Calcium Channel Blockers; Creatine Kinase; Diastole; Epoprostenol; Female; Granulocytes; Heart; Hemodynamics; Male; Methoxamine; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Serotonin Antagonists; Swine; Swine, Miniature; Thromboxane B2; Vasodilation; Verapamil

Activation of the complement cascade is involved in the myocardial injury resulting from transient ischemia and reperfusion. We previously showed that the complement anaphylatoxin C5a causes myocardial ischemia in vivo, mediated in part via thromboxane (Tx) A2. In the present study, we assess the role of platelets in the C5a-induced myocardial ischemia and Tx release. The left anterior descending coronary artery of anesthetized pigs was perfused with arterial blood at constant pressure and measured flow (coronary blood flow). Segment function (percent segment shortening) was measured with sonomicrometry, and regional coronary venous blood was sampled and assayed for TxB2 (by radioimmunoassay). We found that the C5a-induced decrease in coronary blood flow and percent segment shortening and the release of Tx were indistinguishable whether the left anterior descending coronary artery bed was perfused with normal arterial blood, with arterial blood obtained from animals depleted of platelets (cyclophosphamide, n = 6), or with arterial blood from aspirin-treated animals (n = 9) in which the platelets were unable to produce Tx. These data demonstrate that platelet-derived Tx does not contribute to the C5a-induced myocardial ischemia and Tx release in this model and that these cells do not play an integral role in this phenomenon.

Topics: Animals; Blood Platelets; Blood Pressure; Collagen; Complement C5a; Coronary Circulation; In Vitro Techniques; Myocardial Ischemia; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Reference Values; Swine; Thromboxane B2; Time Factors

To examine effects of a new thromboxane synthetase inhibitor, Y-20811, on infarct size, neutrophil accumulation, and arrhythmias, coronary artery was occluded for 90 min and reperfused for 6 h in anesthetized dogs. Y-20811 administered intravenously (i.v.) 30 min before occlusion decreased serum thromboxane B2 (TBX2) formation by 98% 30 min later and by 79% at 6 h after reperfusion. Ventricular fibrillation (VF) developed in 1 of 15 control and 3 of 10 treated dogs during occlusion (p = NS), whereas after reperfusion it occurred in 7 of 14 control and none of seven treated dogs (p < 0.05). The number of arrhythmias during the first hour of reperfusion was significantly reduced in treated dogs (134 +/- 74 beats/min in control vs. 14 +/- 4 beats/min in treated dogs, p < 0.05). Hemodynamics, area at risk, and collateral flow to the ischemic region were similar for the two groups. The extent of myocardial necrosis was 28.0 +/- 10.0% (n = 7) of the area at risk in control dogs and 27.6 +/- 6.2% (n = 7) in treated dogs (p = NS). The relation between the ratio of myocardial necrosis to area at risk and collateral flow was similar. The degree of neutrophil accumulation did not differ but correlated with infarct size (r = 0.85). Thus, Y-20811 reduced reperfusion arrhythmias but failed to limit infarct size and neutrophil accumulation after coronary artery occlusion/reperfusion in dogs.

Topics: Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Dogs; Female; Hemodynamics; Imidazoles; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Neutrophils; Thromboxane B2; Thromboxane-A Synthase

Intracoronary C5a in swine decreases coronary blood flow and regional myocardial segment shortening, responses mediated by thromboxane (Tx) A2-induced coronary vasoconstriction and intramyocardial trapping of granulocytes (PMNs). We sought to determine the origin of TxA2 and to investigate the role of CD18-dependent PMN function by utilizing an anti-CD18 monoclonal antibody, IB4. Isolated C5a-stimulated PMNs or platelets did not produce TxB2. However, together, C5a-stimulated PMNs and platelets produced TxB2. IB4 bound porcine PMN surface CD18 and blocked C5a-induced PMN functions. In vivo, IB4 loading (2 mg/kg) transiently decreased arterial blood pressure and circulating platelet counts in six of nine animals (390 +/- 31 vs. 176 +/- 41 X 10(6)/ml, control vs. IB4; P < 0.002) and significantly ameliorated C5a-induced decreases in coronary venous PMN count (-4.1 +/- 0.6 vs. -1.4 +/- 0.8 X 10(6) cells/ml), coronary artery blood flow (-10 +/- 1 vs. -4 +/- 1 ml/min), and segment shortening (-15 +/- 2 vs. -8 +/- 2%, C5a vs. C5a + IB4). We conclude that 1) production of TxB2 in response to C5a is mediated by a PMN-platelet interaction, 2) IB4 functionally blocks CD18 on porcine PMNs, and 3) C5a-induced myocardial PMN extraction is mediated, in part, by a CD18-dependent mechanism. These results suggest that PMN-platelet interactions and CD18-dependent PMN extraction are important in C5a-induced myocardial ischemia.

Topics: Animals; Antibodies, Monoclonal; Antigens, CD; Blood Platelets; Blood Pressure; CD18 Antigens; Cell Adhesion; Cell Aggregation; Chemotaxis, Leukocyte; Complement C5a; Coronary Circulation; Female; Heart Rate; Hemodynamics; Humans; Male; Myocardial Ischemia; Neutrophils; Platelet Count; Receptors, Leukocyte-Adhesion; Swine; Tetradecanoylphorbol Acetate; Thromboxane B2; Time Factors; Vasoconstriction; Ventricular Function, Left

Rabbit epigastric skin flaps were subjected to 21 h of ischaemia at 25 degrees C. In the first 40 min of reperfusion the flaps were infused intraarterially with either Hanks' balanced salt solution (controls), chicken CGRP or a derivative DADA-CGRP. Skin biopsies and blood specimens were taken immediately before and after 1-h reperfusion. The aim was to observe the effect of CGRP derivatives on compromised skin-flap survival and to help elucidate the critical biochemical mechanisms. It was found that chicken CGRP and DADA-CGRP produced a dose-dependent increase in blood flow, significant at and above 0.1 microgram/kg, but only the 0.1 microgram/kg DADA-CGRP infusion produced a statistically significant increase in flap survival (75.1%) as compared with controls (41.6%). CGRP infusions caused significantly more rapid restoration of tissue ATP levels and resulted in a smaller rise in blood thromboxane as compared with controls. However, CGRP caused no significant change in the tissue levels of myeloperoxidase, a measure of neutrophil infiltration, and lipid peroxidation, an indicator of free-radical activity. It is concluded that intraarterial CGRP infusions to ischaemic flaps at the time of reperfusion are indicated. However, an ideal infusion solution would also need to counteract free radicals and neutrophils which are believed to also play a major role in the inflammatory response leading to flap failure.

Topics: Animals; Biopsy; Calcitonin Gene-Related Peptide; Cell Movement; Dose-Response Relationship, Drug; Infusions, Intra-Arterial; Lipid Peroxidation; Myocardial Ischemia; Myocardial Reperfusion; Neutrophils; Rabbits; Regional Blood Flow; Salvage Therapy; Skin; Statistics as Topic; Thromboxane B2

The intracoronary infusion of complement C5a causes a decrease in coronary blood flow and contractile dysfunction mediated by thromboxane (TxA2) and leukotrienes. Although these effects are accompanied by polymorphonuclear leukocyte (PMN) sequestration, the role of PMNs and the source of these eicosanoids remain unknown. To assess the contribution of PMNs to the C5a-induced myocardial ischemic response, the left anterior descending (LAD) coronary artery of pigs (n = 13) was cannulated and pump perfused at constant pressure with either normal arterial blood or neutropenic arterial blood (PMN count 0.02 x 10(3) cells/microliters) obtained from animals treated with cyclophosphamide (50 mg/kg iv, given 4 days before). The coronary vein draining the LAD region was cannulated for measurement of leukocyte count and TxB2 levels. Two groups of animals were studied: group 1 (n = 7) neutropenic animals were instrumented and normal animals served as blood donors and group 2 (n = 6) normal animals were instrumented and neutropenic animals served as blood donors. The myocardial response to intracoronary C5a (500 ng) was determined in each animal during coronary perfusion with normal arterial blood and also with neutropenic arterial blood. During perfusion with normal arterial blood, C5a decreased coronary flow to 52.3% and contractile function to 58.8% of preinfusion values. This was accompanied by a transient myocardial accumulation of PMNs (arterial-coronary venous gradient of 5.4 x 10(3) cells/microliters) and increased TxB2 levels in coronary venous blood (from 0.31 to 17.5 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Cell Count; Complement C5a; Coronary Circulation; Female; Heart; Hemodynamics; Leukocyte Count; Male; Myocardial Ischemia; Neutrophils; Swine; Thromboxane B2

We have shown earlier that prostacyclin (PGI2) and its stable analogue: 7-oxo-prostacyclin(7-OXO) may induce a prolonged, late appearing (24-48 h after drug administration), dose dependent protection of the heart from harmful consequences of a subsequent severe ischaemic stress, such as myocardial ischaemia, life-threatening ventricular arrhythmias and early ischaemic morphological changes. In an other study we observed that a similar but shortlived (less than 1 h) cardioprotection, induced by 'preconditioning' brief coronary artery occlusions, is greatly reduced by blockade of the cyclooxygenase pathway, suggesting that prostanoids might play a role in this shortlasting protection. Objective of our present study was to elucidate the importance of some arachidonic acid (AA) metabolites, such as PGI2 and thromboxane A2 (TXA2) in the mechanism of the late appearing, prolonged cardioprotection. Estimation of the metabolites: 6-keto-PGF1 alpha (6-KETO) and thromboxane B2 (TXB2) was made from the perfusate of isolated Langendorff hearts of guinea-pigs pretreated with 50 micrograms/kg 7-OXO, 24 and 48 h before preparation. Pretreatment alone produced a slight, but significant elevation of 6-KETO (from 206 +/- 11 to 284 +/- 19 pg/ml/min after 24 h, and to 261 +/- 18 pg/ml/min after 48 h). No change was seen in TXB2 production. Global ischaemia for 25 min (followed by 25 min reperfusion) markedly increased the release of both AA metabolites; maximal values were observed in the third min of reperfusion (6-KETO from 206 +/- 11 to 1275 +/- 55 pg/ml/min and TXB2 from 29 +/- 4 to 172 +/- 12 pg/ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Guinea Pigs; Heart; Male; Myocardial Ischemia; Thromboxane A2; Thromboxane B2

After crystalloid cardioplegic arrest, cardiac-derived thromboxane A2 may be an important initiating mediator of no-reflow and hemodynamic deterioration during reperfusion because of its potent vasoactive properties. Although previous studies have already documented the increased release of cardiac thromboxane A2 after ischemia, none have studied the effects of cardiac thromboxane A2 on hemodynamics. We therefore tested the ability of cardiac thromboxane A2 to mediate deterioration of coronary flow and functional recovery during reperfusion after global ischemia. Crystalloid-perfused rat hearts that had undergone Langendorff preparation (n = 30) were subjected to 2 hours of global ischemia at 15 degrees C under cardioplegic protection with (n = 15) or without (n = 15) thromboxane A2 receptor antagonist SQ29548. In eight of 15 hearts in each group, preischemic and postischemic aortic flow, coronary flow, cardiac output, heart rate, and stroke work were determined. In the remaining seven hearts in each group, preischemic and postischemic coronary effluent levels of the stable hydrolysis product of thromboxane A2 and thromboxane B2 were determined with radioimmunoassay through the use of nonrecirculating perfusate. At the completion of the experiment, water content was determined by wet weight/dry weight calculations. In a separate group (n = 7) preischemic myocardial water content was determined. Within the group protected by cardioplegic solution alone, postischemic aortic flow, coronary flow, cardiac output, and stroke work were all significantly decreased (p < 0.05) compared with preischemic values (aortic flow, 50.8 +/- 2.7 versus 29.4 +/- 3.3 ml/min; coronary flow, 13.2 +/- 1.3 versus 8.5 +/- 1.3 ml/min; cardiac output, 64.0 +/- 3.8 versus 38.0 +/- 4.4 ml/min; stroke work, 12.5 +/- 0.7 versus 7.1 +/- 0.8 cm H2O.ml). In relation to the group with cardioplegic solution alone, postischemic aortic flow, coronary flow, cardiac output, and stroke work were all significantly greater (p < 0.05) in the group with the receptor antagonist (aortic flow: 49.5 +/- 2.4 versus 29.4 +/- 3.3 ml/min; coronary flow; 12.4 +/- 1.2 versus 8.5 +/- 1.3 ml/min; cardiac output, 62.0 +/- 2.8 versus 38.0 +/- 4.4 ml/min; stroke work, 12.6 +/- 0.8 versus 7.1 +/- 0.8 cm H2O.ml). Overall, postischemic coronary effluent thromboxane B2 levels were greater than preischemic values (105.6 +/- 12.4 versus 69.6 +/- 9.8, p < 0.05) and treatment with the receptor antagonist did not significant

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cardiac Output; Cardioplegic Solutions; Coronary Circulation; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Stroke Volume; Thromboxane A2; Thromboxane B2

Platelet-activating factor (PAF) is involved in experimental models of myocardial ischaemia, and PAF infusion can cause thromboxane release. Thromboxane is produced during brief episodes of reversible myocardial ischaemia in patients with coronary heart disease. To learn whether PAF synthesis is associated with thromboxane production in mild myocardial ischaemia, we performed rapid atrial pacing in four patients with angina pectoris which caused chest pain, ST segment depression (delta ST = -1.8 +/- 0.2 mm) and lactate excretion in the coronary sinus (percent lactate extraction decreased from 20 +/- 6% to -15 +/- 9%). Thromboxane B2 was produced causing a positive transmyocardial gradient (from 88 +/- 154 pg.ml-1 baseline to 1770 +/- 1407 pg.ml-1 at the peak) but there was no PAF release into coronary sinus blood. In four other patients we determined whether more pronounced ischaemia could be associated with PAF synthesis. Coronary sinus blood was sampled before and during balloon occlusion of a major coronary artery: PAF was not detected in coronary sinus, whereas percent lactate extraction decreased from 24 +/- 6% to -63 +/- 22% (n = 4). We conclude that PAF plays a minor role in short episodes of reversible ischaemia and does not participate in thromboxane production.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Humans; Myocardial Ischemia; Platelet Activating Factor; Thromboxane B2

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Bradykinin; Coronary Vessels; Female; Humans; Male; Myocardial Ischemia; Nociceptors; Pain Measurement; Thromboxane B2