thromboxane-b2 and Coronary-Disease

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Circulation; Cerebrovascular Disorders; Coronary Disease; Drugs, Chinese Herbal; Humans; Medicine, Chinese Traditional; Syndrome; Thrombosis; Thromboxane B2

The interaction between blood factors and the vessel wall is important in the development of common cardiovascular diseases. Clinical markers of these interactions should be sought to help in the understanding of the processes involved, and such markers should ideally be available to identify people at risk from the disease, screen relatives, help identify appropriate treatment, and monitor the outcome of the therapy. Various aspects of platelet interaction with the vessel wall can be used, as can some changes in levels of coagulation factors, fibrinolytic proteins, and natural anticoagulants. All have their advantages and disadvantages in terms of having the attributes of the ideal marker that would identify the pathophysiological processes and be reproducible, inexpensive, and easy to perform. This review will consider the value of various clinical markers, taking account of their advantages and disadvantages.

Topics: beta-Thromboglobulin; Blood Coagulation Factors; Blood Platelets; Coronary Disease; Coronary Thrombosis; Fibrinolysin; Fibrinolysis; Fibrinopeptide A; Humans; Muscle, Smooth, Vascular; Plasminogen; Platelet Aggregation; Platelet Factor 4; Thrombosis; Thromboxane B2

Evidence suggests that unstable angina, non-Q-wave myocardial infarction and Q-wave myocardial infarcts represent a continuum, such that transient reduction in coronary blood flow associated with platelet aggregation and dynamic vasoconstriction at sites of coronary artery stenosis and endothelial injury lead to abrupt development of unstable angina. Factors potentially responsible for the conversion from chronic to acute coronary artery disease include endothelial injury at sites of stenosis. The endothelial injury may be the result of plaque fissuring or ulceration, hemodynamic factors (including systemic arterial hypertension or flow shear stress), infection, smoking, coronary arteriography or balloon angioplasty. Clinical and experimental animal studies suggest that interference with thromboxane and serotonin contributions to platelet aggregation and dynamic coronary artery constriction may prevent chronic coronary artery disease syndromes from converting to acute disease. To protect against this process may require both thromboxane and serotonin receptor antagonists or a combination of thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist. Further studies are needed to test this hypothesis.

Topics: Angina, Unstable; Animals; Coronary Disease; Dogs; Myocardial Infarction; Receptors, Prostaglandin; Receptors, Serotonin; Receptors, Thromboxane; Serotonin; Thromboxane A2; Thromboxane B2

Topics: Angiography; Coronary Angiography; Coronary Artery Disease; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Coronary Vasospasm; Coronary Vessels; Humans; Platelet Aggregation; Thromboxane B2

The cardioprotective and antithrombotic activity of molsidomine, a novel therapeutic agent for the treatment of coronary heart disease, was investigated in a series of animal models of myocardial ischemia. Molsidomine given to dogs with marked ST segment elevation (epicardial electrogram), induced by a reduction of left descending coronary artery (LAD) flow to 20% to 30% of the original value, resulted within 40 minutes in complete normalization of ECG changes. In another animal model molsidomine given either before or after occlusion of the LAD significantly reduced infarct size. All these molsidomine effects were accompanied by a marked lowering of preload, resulting in a reduction of extravascular coronary artery resistance and in increased blood flow toward the ischemic zones. In a model of myocardial ischemia and reperfusion in the anesthetized dog, molsidomine had a marked protective effect against the incidence of spontaneous ventricular fibrillation. This effect could also be attributed to the anti-ischemic activity of molsidomine, which would reduce the disparity between the refractory periods in normal and ischemic areas and thus increase ventricular stability. The antithrombotic activity of molsidomine was investigated in dogs in which the left circumflex coronary artery was electrically stimulated, a procedure that leads to thrombotic occlusion. Molsidomine in a dose-dependent manner prevented coronary thrombotic occlusion and reduced thrombus wet weight and the size of the resulting infarction. These effects of molsidomine were not related to its hemodynamic activity, since nitroglycerin and isosorbide dinitrate had similar hemodynamic effects but did not prevent coronary thrombosis. The antithrombotic activity of molsidomine is probably related to its ability to lower coronary venous blood thromboxane levels.

Topics: Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Dogs; Electric Stimulation; Molsidomine; Nitroglycerin; Oxadiazoles; Sydnones; Thromboxane B2; Vasodilator Agents; Ventricular Fibrillation

There is an abundance of information suggesting that prostaglandins are involved in the development and clinical expression of atherosclerosis. Many studies demonstrate a relationship between prostaglandins and the risk factors for peripheral and coronary artery disease. Thus, part of the mechanism by which hyperlipidemia, diabetes mellitus, smoking, hypertension, sex hormones, age, heredity, emotional stress and diet contribute to the development and progression of atherosclerosis may be through an imbalance between thromboxane A2 and prostaglandin I2. Recent studies show a temporal relationship between acute ischemic events (specifically, unstable angina) and a transcardiac increase in thromboxane B2, while others demonstrate a salutary effect of disaggregatory and vasodilatory prostaglandins in such patients. If prostaglandins and thromboxane prove important in ischemic vascular disease, attention will be directed at the correction of their pathologic imbalance. This may be accomplished by dietary manipulation as well as by the development of prostaglandin receptor antagonists or inhibitors of specific prostaglandin pathways.

Topics: Age Factors; Arteriosclerosis; Coronary Disease; Diabetes Mellitus; Diet; Epoprostenol; Gonadal Steroid Hormones; Humans; Hyperlipidemias; Hypertension; Prostaglandin Antagonists; Prostaglandins; Receptors, Prostaglandin; Risk; Smoking; Stress, Physiological; Thromboxane A2; Thromboxane B2

Despite the use of anti-platelet agents such as acetylsalicylic acid (ASA) and clopidogrel in coronary heart disease, some patients continue to suffer from atherothrombosis. This has stimulated development of platelet function assays to monitor treatment effects. However, it is still not recommended to change treatment based on results from platelet function assays. This study aimed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel. The adhesion assay measures several aspects of platelet adhesion simultaneously, which increases the probability of finding conditions sensitive for anti-platelet treatment.. With a randomised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome. Also, 29 matched healthy controls were included to evaluate intra-individual variability over time. Platelet function was measured by flow cytometry, serum thromboxane B2 (TXB2)-levels and by static platelet adhesion to different protein surfaces. The results were subjected to Principal Component Analysis followed by ANOVA, t-tests and linear regression analysis.. The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity. Adenosine 5'-diphosphate (ADP)-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA. Flow cytometric measurements showed the same pattern (r2 = 0.49). In opposite, TXB2-levels decreased with ASA compared to clopidogrel. Serum TXB2 and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively. Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN-induced activation measured by flow cytometry were lower for clopidogrel compared to ASA. Furthermore, adhesion to collagen was lower for ASA and clopidogrel combined compared with either drug alone.. The indirect pharmacodynamic measures of the effects of ASA and clopidogrel might be used together with ADP-induced activation and serum TXB2 for evaluation of anti-platelet treatment. This should be further evaluated in future clinical studies where screening opportunities with the adhesion assay will be optimised towards increased sensitivity to anti-platelet treatment.

Topics: Aged; Aspirin; Case-Control Studies; Clopidogrel; Coronary Disease; Cross-Over Studies; Female; Fibrinogen; Flow Cytometry; Health; Humans; Male; Middle Aged; P-Selectin; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Principal Component Analysis; Regression Analysis; Thromboxane B2; Ticlopidine

To assess the prevalence of a lacking aspirin effect on cyclooxygenase-1 (COX-1) ("aspirin resistance") in patients with symptomatic, stable coronary heart disease (CHD) using test methods directly reflecting inhibition of COX-1.. Arachidonic acid (AA)-induced platelet aggregation and plasma thromboxane B2 (TXB2) were determined twice 3 weeks apart - prior to elective coronary angiography - in 289 patients on 75 or 160 mg aspirin daily, all prompted to take aspirin before testing. Subjects who demonstrated lacking any effect of aspirin (>/=20 % AA-induced aggregation) on one or both occasions were later given a third test. Forty-two patients not taking aspirin were used as TXB2 controls.. Eleven (3.8 %) had aggregation > or = 20 % in at least one of the two initial tests, but only two on both occasions. During the third test, all 11 patients had aggregation <20 %. The TXB2 distributions in controls and study patients differed markedly (mean 173 versus 19 pg/mL). Taking 45 pg/mL as the TXB2 cut-off level, sensitivity and specificity for detecting subjects taking aspirin were 90 % and 89 %, respectively. The area under the ROC curve was 0.96.. Repeated AA-induced platelet aggregometry showed that COX-1 could be blocked by low-dose aspirin in all 289 tested patients, suggesting that aspirin resistance is rare in patients with stable CHD.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Coronary Angiography; Coronary Disease; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Resistance; Female; Humans; Male; Middle Aged; Platelet Aggregation; Reference Values; Thromboxane B2

High postprandial serum lipid concentrations are associated with increased oxidative stress which, in turn, increases the risk of atherosclerosis. Epidemiological studies correlate lower incidence of cardiovascular disease with adherence to the Mediterranean diet. The aim of this study was to evaluate changes in inflammatory (TXB(2) and LTB(4)) and oxidative stress markers (urinary hydrogen peroxide levels and serum antioxidant capacity), in addition to classic lipid parameters, after a fat-rich meal administered to 12 normolipemic, healthy subjects. Following a Latin square design, subjects were divided into three groups, each one receiving a different kind of oil (extra virgin olive oil; EVOO, olive oil; OO or corn oil; CO, together with 150g of potatoes), with 2-week washout periods between treatments. Blood samples were drawn at baseline and after 1, 2, and 6h after the meal. A significant decrease in inflammatory markers, namely TXB(2) and LTB(4), after 2 and 6h after EVOO (but not OO or CO) consumption and a concomitant increase of serum antioxidant capacity were recorded. These data reinforce the notion that the Mediterranean diet reduces the incidence of coronary heart disease partially due to the protective role of its phenolic components, including those of extra virgin olive oil.

Topics: Adult; Antioxidants; Blood Glucose; Cardiotonic Agents; Cholesterol, HDL; Cholesterol, LDL; Corn Oil; Coronary Disease; Diet, Mediterranean; Dietary Fats, Unsaturated; Flavonoids; Humans; Hyperlipidemias; Inflammation; Leukotriene B4; Male; Olive Oil; Oxidative Stress; Phenols; Plant Oils; Polyphenols; Postprandial Period; Thromboxane B2; Triglycerides

The antiplatelet effect of aspirin is attributed to platelet cyclooxygenase-1 inhibition. Controversy exists on the prevalence of platelet resistance to aspirin in patients with coronary artery disease and effects of aspirin dose on inhibition. Our primary aim was to determine the degree of platelet aspirin responsiveness in patients, as measured by commonly used methods, and to study the relation of aspirin dose to platelet inhibition.. We prospectively studied the effect of aspirin dosing on platelet function in 125 stable outpatients with coronary artery disease randomized in a double-blind, double-crossover investigation (81, 162, and 325 mg/d for 4 weeks each over a 12-week period). At all doses of aspirin, platelet function was low as indicated by arachidonic acid (AA)-induced light transmittance aggregation, thrombelastography, and VerifyNow. At any 1 dose, resistance to aspirin was 0% to 6% in the overall group when AA was used as the agonist, whereas it was 1% to 27% by other methods [collagen and ADP-induced light transmittance aggregation, platelet function analyzer (PFA-100)]. Platelet response to aspirin as measured by collagen-induced light transmittance aggregation, ADP-induced light transmittance aggregation, PFA-100 (81 mg versus 162 mg, P < or = 0.05), and urinary 11-dehydrothromboxane B2 was dose-related (81 mg versus 325 mg, P = 0.003). No carryover effects were observed.. The assessment of aspirin resistance is highly assay-dependent; aspirin is an effective blocker of AA-induced platelet function at all doses, whereas higher estimates of resistance were observed with methods that do not use AA as the stimulus. The observation of dose-dependent effects despite nearly complete inhibition of AA-induced aggregation suggests that aspirin may exert antiplatelet properties through non-cyclooxygenase-1 pathways and deserves further investigation.

Topics: Adenosine Diphosphate; Adult; Arachidonic Acid; Aspirin; Blood Platelets; Collagen; Coronary Disease; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Female; Flow Cytometry; Humans; Male; Middle Aged; Nephelometry and Turbidimetry; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Glycoprotein GPIIb-IIIa Complex; Prospective Studies; Thrombelastography; Thromboxane B2

Diabetic patients may have a higher prevalence of platelet aspirin resistance than nondiabetic patients. Our goal was to analyze platelet aspirin responsiveness to various aspirin doses in diabetic and nondiabetic patients.. We examined the effect of aspirin (81, 162, and 325 mg/day for 4 weeks each) on platelet aspirin responsiveness in 120 stable outpatients (30 diabetic patients and 90 nondiabetic patients) with coronary artery disease (CAD) using light transmittance aggregometry (LTA), VerifyNow, platelet function analyzer (PFA)-100, and levels of urinary 11-dehydro-thromboxane B(2) (11-dh-TxB(2)).. In the total group, a low prevalence (0-2%) of aspirin resistance was observed with all aspirin doses as determined by arachidonic acid-induced LTA. Aspirin resistance was higher at the 81-mg dose in diabetic versus nondiabetic patients using collagen-induced LTA (27 vs. 4%, P = 0.001), VerifyNow (13 vs. 3%, P = 0.05), and urinary 11-dh-TxB(2) (37 vs. 17%, P = 0.03). Diabetic patients treated with 81 mg exhibited higher platelet function measured by VerifyNow, collagen- and ADP-induced LTA, and 11-dh-TxB(2) levels (P

Topics: Aged; Aspirin; Blood Platelets; Coronary Disease; Cross-Over Studies; Diabetic Angiopathies; Double-Blind Method; Drug Resistance; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Reference Values; Thromboxane B2

Complete and persistent suppression of platelet thromboxane (TX) A(2) biosynthesis by aspirin is mandatory to fulfill its cardioprotection. We explored the determinants of heterogeneity of TXB2 generation in clotting whole blood, a capacity index of platelet cyclooxygenase (COX) activity, in patients with coronary heart disease (CHD) versus healthy subjects treated with low-dose aspirin on a long-term basis.. We studied 30 patients with CHD (ie, chronic stable angina, unstable angina, and acute myocardial infarction) and 10 healthy subjects, who were treated with low-dose aspirin (100 mg daily) on a long-term basis, 12 hours after the administration of 160 mg aspirin to ensure saturation of platelet COX-1 activity. Serum TXB2 levels were assessed. The contribution of blood COX-2 to TXA2 biosynthesis was explored by evaluation of the effect of a selective COX-2 inhibitor (L-745,337) added to heparinized whole blood stimulated with Ca++ ionophore A23187 (20 micromol/L) for 1 hour or lipopolysaccharide (0.1 microg/mL) for 4 hours.. In healthy subjects serum TXB2 levels ranged from 0.6 to 7.9 ng/mL (median, 2.1 ng/mL; mean +/- SD, 3.2 +/- 2.6 ng/mL). In CHD patients we detected enhanced variability in serum TXB2 generation (median, 3.1 ng/mL [range, 0.15-47 ng/mL]; mean, 8.5 +/- 12.3 ng/mL), which in 8 patients (27%) exceeded the mean value + 2 SDs detected in healthy subjects (ie, 8.4 ng/mL), set as the limit value for an adequate inhibition of platelet COX-1 by aspirin. Elevated whole-blood TXB2 generation was not dependent on leukocyte count, COX-2 activity, or cigarette smoking but was plausibly a result of defective suppression of platelet COX-1 activity.. Heterogeneity in the suppression of platelet COX-1 activity by aspirin occurred in CHD patients. The measurement of the serum TXB2 level seems to be an appropriate biomarker to identify patients who have an inadequate inhibition of platelet COX-1 activity by aspirin.

Topics: Aged; Arachidonic Acid; Aspirin; Blood Platelets; Calcimycin; Coronary Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Female; Humans; Indans; Lipopolysaccharides; Male; Middle Aged; Neutrophils; Thromboxane A2; Thromboxane B2

Smoking is associated with endothelial dysfunction. Cytokines released by injured endothelium promote vascular interactions with leukocytes and platelets. We investigated whether (a) cigarette smoking is linked to increased cytokine production, which may mediate platelet activation and thrombin generation in chronic coronary artery disease (CAD), and (b) aspirin treatment inhibits smoking-related changes on cytokines, platelets, and thrombin.. Plasma macrophage-colony-stimulating factor (M-CSF) and C-reactive protein (CRP) were measured in 100 patients with chronic CAD, 60 of whom were chronic smokers. Prothrombin fragments 1+2 and urinary 11-dehydro-thromboxane B2 (TXB2) were additionally measured in 60 of 100 patients (30 of whom were smokers) and in 24 healthy controls. Smokers (n = 20) matched for age, myocardial ischemia, and other risk factors with 20 nonsmokers entered a double-blind crossover trial of aspirin (300 mg/d for 3 weeks) versus placebo. Blood and urine measurements were repeated after each treatment. Compared with nonsmokers, smokers had 3-fold median M-CSF (1499 vs 476 pg/mL), 2-fold CRP (1.5 vs 0.8 mg/L), and higher 11-dehydro-TXB 2 (3.6 vs 2.1 ng/mg creatinine, P < .01 for all comparisons). After aspirin treatment, M-CSF, CRP, 11-dehydro-TXB 2 , and prothrombin fragments 1+2 remained higher in smokers compared with nonsmokers despite a significant reduction of these markers by aspirin (P < .05). M-CSF remained related to 11-dehydro-TXB 2 excretion during both treatment phases (P < .01) suggesting that cytokine-mediated thromboxane A 2 production was not altered by aspirin.. Smoking is associated with increased M-CSF, CRP, and platelet activity. Although aspirin treatment reduces the proinflammatory and procoagulant markers in smokers, it does not abolish the proinflammatory effects of smoking in patients with chronic CAD.

Topics: Adult; Aged; Aspirin; C-Reactive Protein; Coronary Disease; Double-Blind Method; Female; Humans; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Peptide Fragments; Prospective Studies; Prothrombin; Smoking; Thromboxane B2

Dose-finding studies and trials of interaction of oral glycoprotein IIb/IIIa antagonists with other antiplatelet agents have been limited. We hypothesized that these detailed assessments could be first performed in patients with stable coronary artery disease (CAD) and then extrapolated to the target population. To this end, we performed 2 sequential studies. The first study examined the dose-related effects on indexes of platelet and vascular function induced by the oral inhibitor RPR 109891, when given alone and in combination with aspirin, in patients (n = 100) with stable CAD. The second study (the Antagonism of the FIbrinogen Receptor after Myocardial Events trial) assessed the pharmacodynamics and safety of derived regimens in patients (n = 320) with unstable coronary syndromes. In patients with stable CAD, platelet aggregation was dose dependently inhibited by RPR 109891, and the dose-response relation was shifted to the right by the concomitant administration of aspirin (p = 0.0001). The degree of platelet inhibition induced by 3 doses of RPR 109891 (plus aspirin) was lower in patients with unstable than stable CAD. No drug-related major bleeding occurred in either study. RPR 109891 treatment was associated with acute and delayed thrombocytopenia. In conclusion, chronic treatment with an oral glycoprotein IIb/IIIa antagonist (1) induces antiplatelet effects that are potentiated by concomitant administration of aspirin, (2) may require dose adjustment in syndromes of platelet activation, (3) is associated with a low rate of clinically significant bleeding when doses inducing incomplete inhibition of platelet aggregation are used, and (4) requires frequent monitoring of platelet count unless reliable predictors of delayed thrombocytopenia become available.

Topics: Administration, Oral; Adult; Aged; Aspirin; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Humans; Middle Aged; Peptides; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thrombocytopenia; Thromboxane B2

Thirty patients with coronary artery disease (CAD) were administered garlic (study group) while another 30 patients received the placebo (control group). Various risk parameters were determined at 1.5 and 3 months of garlic administration. Garlic, administered in a daily dose of 2 x 2 capsules (each capsule containing ethyl acetate extract from 1 g peeled and crushed raw garlic), reduced significantly total serum cholesterol and triglycerides, and increased significantly HDL-cholesterol and fibrinolytic activity. There was no effect on the fibrinogen and glucose levels. In vitro effects of the garlic oil on platelet aggregation (PAg) and eicosanoid metabolism were examined; it inhibited PAg induced by several platelet agonists, and also platelet thromboxane formation. Two important paraffinic polysulphides - diallyl disulphide (DADS) and diallyl trisulphide (DATS) - derived from garlic and are usual constituents of garlic oil, showed antiplatelet activity, and also inhibited platelet thromboxane formation. In this respect DATS was more potent than DADS. The nature of inhibition of PAg by DATS was found to be reversible.

Topics: Allyl Compounds; Antihypertensive Agents; Arachidonic Acid; Blood Glucose; Calcimycin; Cholesterol; Cholesterol, HDL; Collagen; Coronary Disease; Disulfides; Dose-Response Relationship, Drug; Fibrinogen; Fibrinolysis; Garlic; Humans; Ionophores; Lipids; Plant Extracts; Plant Oils; Plants, Medicinal; Platelet Aggregation; Platelet Aggregation Inhibitors; Sulfides; Thromboxane B2; Triglycerides

In a prospective randomized trial in 42 patients undergoing coronary artery bypass surgery, we analyzed the long term platelet inhibiting effects of 50 mg acetylsalicylic acid (ASA) by itself and in combination with dipyridamole (2 x 200 mg), in comparison with phenprocoumon. Three and six months therapy led to significant inhibition of maximum aggregation induced by collagen 1 microgram/ml in platelet rich plasma (PRP) by more than 50% (p < or = 0.05). In PRP stimulated with 5 micrograms/ml collagen maximum inhibition amounted to nearly 20% (n.s.). The groups treated with ASA/ASA + dipyridamole showed an ADP threshold concentration 2.5 times higher than the group treated with phenprocoumon (p < or = 0.05). After stimulation with collagen 1 microgram/ml and 5 micrograms/ml thromboxane B2 synthesis in vitro in both groups treated with ASA was reduced to 1% of the base line values (p < or = 0.01). Inhibition of aggregation in whole blood appeared evident, but was not statistically significant due to considerable fluctuation of measurement. An additional effect of dipyridamole was not detectable. In conclusion, treatment with 50 mg ADA/d results in a lasting, effective inhibition of aggregation of platelets in patients with coronary artery bypass surgery. There is no synergistic effect of additional dose of 400 mg dipyridamole/d.

Topics: Anticoagulants; Aspirin; Blood Platelets; Coronary Artery Bypass; Coronary Disease; Dipyridamole; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Phenprocoumon; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Thromboxane B2; Time Factors

Experimental data suggest that formation of thromboxane A2 may be suppressed during administration of a glycoprotein IIb/IIIa antagonist. We determined the dose of one such compound, fradafiban, required to provide > 80% occupancy of the platelet glycoprotein IIb/IIIa and examined its effects on thromboxane A2 formation in patients undergoing PTCA. The dose response to fradafiban and additional effects of aspirin were explored initially in patients with stable coronary artery disease. Fradafiban induced a dose-dependent inhibition of platelet aggregation that correlated with fibrinogen receptor occupancy and plasma drug concentration. Addition of aspirin 300 mg had no effect on these parameters. At the highest dose, mean fibrinogen receptor occupancy was 89.7 +/- 1.2% (n = 3) at 4 hours and platelet aggregation had decreased by 93.4 +/- 2.7%. Eighteen patients undergoing coronary angioplasty were randomized to receive either aspirin 330 mg or that dose of fradafiban producing > 80% fibrinogen receptor occupancy. Platelet aggregation was suppressed throughout the infusion of fradafiban to a greater extent than with aspirin. However, there was a marked increase in urinary excretion of 11-dehydrothromboxane B2 in patients treated with fradafiban: from 1973 +/- 889 to a peak of 9760 +/- 3509 pg/mg creatinine (P = .0046). Despite this evidence of continued platelet activation in vivo, there were no cases of coronary thrombosis. In conclusion, fradafiban suppresses platelet aggregation and may be a useful alternative to aspirin in the prevention of thrombotic events in patients undergoing PTCA. However, there is continued formation of thromboxane A2, which may continue to exert its effects as a potent vasoconstrictor and vascular smooth muscle mitogen.

Topics: Administration, Oral; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Biphenyl Compounds; Bleeding Time; Cell Division; Coronary Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Fibrinogen; Heparin; Humans; Infusions, Intravenous; Male; Middle Aged; Muscle, Smooth, Vascular; P-Selectin; Pilot Projects; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrrolidines; Thrombosis; Thromboxane A2; Thromboxane B2; Vasoconstriction

Seasonal variation in the plasma lipids and lipoproteins is reported in the literature. Whether this variation is the result of changes in diet or other factors has not been adequately addressed. We investigated the effects of a controlled diet on the seasonal variation in the levels of plasma lipids and apolipoproteins and also on the excretion of urine metabolites of TXA2 and PGI2 in healthy males. Two well-controlled diet studies were conducted to evaluate effects of dietary fatty acids on plasma lipids (Studies 1 and 2; n = 33) and eicosanoid excretion (Study 2 only; n = 15). Participants consumed whole-food test diets in a randomized, four-period crossover design during each 26-day experimental period. A non-intervention control group also participated in each study (Study 1, n = 12; Study 2, n = 11). Blood was collected monthly and analyzed for plasma lipids and apolipoproteins A-1 (Apo A-1) and B100 (Apo B). Twenty-four hour urine samples were collected monthly only in Study 2 and analyzed for TXB2 and 6-keto-PGF1 alpha by RIA. Seasonal fluctuations were observed in all subjects in plasma Apo A-1 (zenith = July, with 95% CI June-July; P < 0.05) and Apo B (zenith = October, 95% CI September-November, P < 0.05). Although there was no significant variation in plasma cholesterol levels, the increase in Apo B is consistent with an increase in LDL particle number during the fall/winter. Additionally, excretion of both eicosanoid metabolites and the ratio of 6-keto-PGF1 alpha/TXB2 was markedly elevated in July (95% CI June-July, P < 0.001). Three seasonal fluctuations were observed both in participants who consumed a highly-controlled experimental diet and in the non-intervention controls. Thus, these results suggest a diet-independent seasonal variation in parameters thought to be involved in coronary heart disease risk status. An understanding of these variations is important not oly for clinical evaluation and metabolic study design issues, but more importantly, to clarify their clinical significance with the seasonal incidence of CHD events.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Apolipoprotein A-I; Apolipoproteins B; Cholesterol; Coronary Disease; Cross-Over Studies; Dietary Fats; Epoprostenol; Food, Formulated; Humans; Lipids; Lipoproteins; Male; Risk; Seasons; Thromboxane A2; Thromboxane B2

The platelet-aggregatory response, platelet-release factors and markers of thrombin generation in vivo were studied prospectively in 53 patients participating in a randomized clinical trial evaluating the influence of nicardipine on the progression of coronary atherosclerosis. Coronary lesions were measured quantitatively and progression was defined as a decrease in minimum diameter by > or = 0.4 mm. At repeat angiography 24 months after study entry, 20 of the 53 patients had progression of 28 coronary narrowings. Only thrombin-induced enhanced platelet aggregation differentiated patients with from those without coronary disease progression, with an estimated odds ratio of 2.49 (95% confidence interval 1.10 to 5.66). The aggregatory response to adenosine diphosphate, collagen, epinephrine and platelet-activating factor were not different in the 2 groups of patients, nor were measurements of platelet factor 4, beta-thromboglobulin, thromboxane B2, 6-keto-prostaglandin F1 alpha and fibrinopeptide A. During 46.8 months of follow-up after repeat angiography, coronary events occurred in 11 of the 20 with and 6 of the 33 without progression (difference 37%, p = 0.013, confidence interval 11 to 63%). Those with coronary disease progression and an enhanced thrombin-induced platelet aggregation had a worse prognosis than those with no disease progression and a low thrombin-induced platelet aggregation. Thus, patients with coronary disease progression and future coronary events have an enhanced thrombin-induced platelet aggregation. This platelet abnormality may be a marker of increased risk and may play a causative role in the development of coronary events.

Topics: 6-Ketoprostaglandin F1 alpha; beta-Thromboglobulin; Coronary Angiography; Coronary Disease; Double-Blind Method; Female; Fibrinopeptide A; Follow-Up Studies; Humans; Male; Middle Aged; Nicardipine; Placebos; Platelet Aggregation; Platelet Factor 4; Prospective Studies; Survival Rate; Thrombin; Thromboxane B2

The purpose of this study was to examine the possible role of nicotine in enhancing coagulation and to assess the potential cardiovascular toxicity of transdermal nicotine therapy for smoking cessation.. Cigarette smoking increases the risks of acute coronary events. A likely contributing mechanism is activation of coagulation. The role of nicotine in enhancing coagulability has not been resolved.. We compared in a crossover study the effects of cigarette smoking, transdermal nicotine and placebo transdermal nicotine, each for 5 days, in 12 healthy smokers.. Cigarette smoking increased the urinary excretion of 11-dehydro-thromboxane B2 (reflecting thromboxane A2 generation) and increased plasma concentration of the platelet alpha-granule constituents, platelet factor 4 and beta-thromboglobulin, compared with placebo treatment, indicating in vivo platelet activation. Cigarette smoking was also associated with higher levels of fibrinogen in plasma. Transdermal nicotine produced plasma levels of nicotine in the same range as those during smoking but had no effect on thromboxane A2 metabolite excretion, platelet alpha-granule release or plasma fibrinogen, compared with placebo. Excretion of 2,3-dinor-6-keto-PGF1 alpha (reflecting prostacyclin generation) was not significantly influenced by any treatment. These results suggest that nicotine as such is not responsible for the platelet activation or elevation of plasma fibrinogen seen in smokers. However, we cannot exclude the possibility that intermittent bolus-like dosing of nicotine from cigarettes could have different effects from those produced by continually released transdermal nicotine. Other findings were that cigarette smoking and transdermal nicotine treatment were both associated with a higher white blood cell count compared with the placebo patch condition, suggesting a direct effect of nicotine to increase circulating white cells. Factor VII coagulant activity (VIIc) was significantly lower during cigarette smoking, than during either nicotine or placebo patch conditions.. Transdermal nicotine has less effect on platelet activation and catecholamine release than does cigarette smoking, and its use in smoking cessation treatment of patients with coronary heart disease is likely to be safer than cigarette smoking.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Cutaneous; Adult; Aged; beta-Thromboglobulin; Blood Coagulation; Cell Adhesion Molecules; Coronary Disease; Eicosanoids; Factor VII; Fibrinogen; Humans; Leukocyte Count; Male; Middle Aged; Nicotine; P-Selectin; Platelet Activation; Platelet Aggregation; Platelet Factor 4; Platelet Membrane Glycoproteins; Risk Factors; Smoking; Smoking Cessation; Thromboxane A2; Thromboxane B2

The effect of pravastatin on low density lipoprotein (LDL) cholesterol and platelet activation was studied in 16 patients with mild hypercholesterolaemia who had two or more additional cardiovascular risk factors. Patients were treated with either pravastatin (20-40 mg day-1) or placebo for 1 year. Plasma LDL and urinary excretion of 2,3-dinor-thromboxane B2 (an index of platelet activation in vivo) were determined at 0, 3, 6 and 12 months. There was a significant reduction in LDL at 6 and 12 months (2P less than 0.05) but this was not associated with any significant change in thromboxane metabolite excretion.

Topics: Aged; Anticholesteremic Agents; Cholesterol, LDL; Coronary Disease; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Male; Middle Aged; Naphthalenes; Platelet Activation; Pravastatin; Risk Factors; Thromboxane B2

Isosorbide monitrates (IS-2-MN and IS-5-MN), hepatic metabolites of isosorbide dinitrate, inhibit platelet function in vitro very differently, with IS-2-MN being much more potent than IS-5-MN. To assess their antiplatelet properties in vivo and to compare time and dosage requirements, we infused both IS-2-MN and IS-5-MN for 30 minutes, on 2 separate days, into nine patients with stable coronary artery disease, at rates of 4 mg/hr (n = 4) and 8 mg/hr (n = 5). Two additional patients received IS-5-MN at 16 mg/hr. Platelet aggregation and thromboxane (TX) B2 generation in response to various agonists, drug plasma concentrations, and blood pressure were monitored throughout the study. A significant decrease in platelet aggregation and TXB2 production by adenosine diphosphate and adrenaline occurred in seven of nine patients receiving IS-2-MN and in 7 of 11 patients receiving IS-5-MN. Response was dose related, with more patients responding at 8 mg/hr to IS-2-MN (five of five) than to IS-5-MN (three of five), and was maximum at the end of the infusion time, corresponding to peak plasma levels. Patients responding to drug infusions with an inhibition of platelet function were characterized by a greater vascular responsiveness compared to nonresponders, since the decrease in systolic blood pressure (mean +/- SEM) was significantly greater in the former (15.4 +/- 3.2) than in the latter (2.5 +/- 2.1, p less than 0.05). Therefore both mononitrates, when administered at infusion rates between 8 and 16 mg/hr, are accompanied by a consistent inhibition of adenosine diphosphate- and adrenaline-induced aggregation and TX generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Coronary Disease; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Infusions, Intravenous; Isosorbide Dinitrate; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

The effect of a chemically stable prostacyclin analogue (Iloprost) on platelet function was investigated in a controlled study in patients with angiographically confirmed stable angina pectoris after ischaemic exercise. In placebo experiments, ADP platelet aggregation was increased after exercise only when measured in whole blood and not in PRP. While plasma thromboxane B2 levels were unchanged, those of 6-keto PGF1 alpha were significantly although transiently increased after exercise. Iloprost displayed a potent antiaggregating activity in PRP and also reversed platelet hyperaggregation occurring in whole blood determinations after exercise. Plasma thromboxane B2 levels were significantly reduced but occasionally a rebound increase occurred 30 min. after end of the infusion. In contrast plasma level of 6-keto PGF1 alpha did not change after Iloprost and its recorded post-exercise increase was counteracted, thus suggesting a negative feed-back mechanism between Iloprost and natural prostacyclin. The data also suggest that degradation of the analogue is probably accomplished through pathways different from those of PGI2.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Angina Pectoris; Blood Platelets; Cardiovascular Agents; Coronary Disease; Epoprostenol; Humans; Iloprost; Male; Middle Aged; Physical Exertion; Platelet Aggregation; Platelet Function Tests; Random Allocation; Thromboxane B2

To determine if the calcium antagonist nicardipine protects the myocardium against ischemia, myocardial lactate, hypoxanthine and prostanoid function was studied in 12 patients during percutaneous transluminal coronary angioplasty (PTCA). Values were obtained before balloon inflation and during 4 minutes after deflation. Intracoronary injection of 0.2 mg of nicardipine distal to the stenosis was done randomly before the first or second inflation; the other inflation served as a control. One minute after deflation, coronary sinus flow levels were similar during the nicardipine and control procedure (161 +/- 61 vs 159 +/- 72 ml/min); lactate (-9 +/- 21% vs -17 +/- 21%, p less than 0.025) and hypoxanthine production (-107 +/- 85% vs -218 +/- 153%, p less than 0.05) were less severe after nicardipine pretreatment than after control. All patients reverted to lactate extraction 4 minutes after inflation plus nicardipine infusion, whereas lactate was still produced 4 minutes after control inflation. No significant changes in thromboxane B2 or prostacyclin levels were observed in the coronary sinus 1 minute after inflation, but higher arterial thromboxane B2 values were observed after control inflation than after inflation with nicardipine infusion (median values 169 vs 78 pg/ml, p less than 0.05). In conclusion, intracoronary infusion of nicardipine reduced signs of ischemia and alterations in prostanoid handling after coronary occlusion. The mechanisms of myocardial protection appeared unrelated to coronary sinus blood flow changes or to a systemic effect of nicardipine.

Topics: Angina Pectoris; Angioplasty, Balloon; Coronary Disease; Coronary Vessels; Epoprostenol; Humans; Hypoxanthine; Hypoxanthines; Injections, Intra-Arterial; Lactates; Myocardium; Nicardipine; Oxygen Consumption; Thromboxane B2

This study assessed the effect of low (40 mg) and high (324 mg) single dose aspirin on cardiac release of thromboxane A2 and prostacyclin as assessed by measurement of coronary sinus levels of metabolites in patients with coronary artery disease. Measurements were done in the resting state and in the presence of pacing stress prior to and 24 h after aspirin administration. There was no consistent response in prostaglandin release under conditions of tachycardia stress as compared to control. Following both doses of aspirin, thromboxane could not be detected at rest or with pacing, and prostacyclin metabolic levels were undetectable in six of seven patients. Prostaglandin levels were not related to myocardial lactate extraction or production and lactate levels had no consistent relationship to aspirin administration. These data indicate that both low and high doses of aspirin inhibit both thromboxane A2 and prostacyclin production in humans. Selective thromboxane inhibition might not be possible.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aspirin; Coronary Disease; Electrocardiography; Epoprostenol; Humans; Lactates; Lactic Acid; Male; Middle Aged; Thromboxane A2; Thromboxane B2

Patients undergoing aortocoronary bypass using autogenous saphenous veins were randomly divided into three comparable groups. Group 1 (n = 10) acted as a control, Group 2 (n = 14) received 80 mg of aspirin at midnight before the operation, and Group 3 (n = 12) received 80 mg of aspirin and 75 mg of dipyridamole at midnight and an additional 75-mg dose of dipyridamole at 6 AM. The purpose was to determine which regimen would maximally inhibit platelet function without depressing vascular prostacyclin synthesis. Serum thromboxane A2, saphenous vein wall and aortic wall prostacyclin, platelet aggregation, and bleeding time were measured in all patients. None was restarted on a regimen of aspirin or dipyridamole postoperatively. Aspirin alone and in combination with dipyridamole significantly inhibited thromboxane A2 and platelet aggregation in all treated patients but spared venous prostacyclin synthesis. Aortic prostacyclin synthesis was partially inhibited in both treated groups. Chest tube drainage was comparable in all three groups. These results indicate that the combination of aspirin and dipyridamole offers no measurable advantage over aspirin alone in the perioperative period.

Topics: Aspirin; Blood Platelets; Blood Vessels; Coronary Disease; Dipyridamole; Drug Evaluation; Drug Therapy, Combination; Epoprostenol; Humans; Platelet Aggregation; Premedication; Thromboxane A2; Thromboxane B2

Nafazatrom (Bay G 6575) is a novel antithrombotic compound, which acts by stimulation of prostacyclin as well as by inhibition of lipoxygenase enzymes. To determine its effects on exercise performance in coronary artery disease patients, a double-blind study was conducted. Twenty patients with coronary artery disease underwent an exercise stress test before and 2 hours after administration of placebo or nafazatrom (1.2 gm). Before the drug administration, there was evidence of enhanced platelet activity, as reflected by elevated resting plasma beta thromboglobulin and thromboxane B2 concentrations. Plasma 6-keto-PGF1 alpha levels were undetectable in most patients. All coagulation tests were in the normal range. None of these parameters changed with exercise. Administration of placebo or nafazatrom before the exercise stress test did not significantly influence any of the coagulation or platelet function parameters or plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha. This lack of effect was evident both at rest and upon exercise. Compared to placebo, nafazatrom did not significantly increase exercise tolerance time or exercise-induced symptoms. In conclusion, nafazatrom did not influence exercise performance in patients with coronary disease.

Topics: 6-Ketoprostaglandin F1 alpha; beta-Thromboglobulin; Blood Pressure; Coronary Disease; Exercise Test; Female; Fibrinolytic Agents; Heart Rate; Humans; Male; Middle Aged; Platelet Count; Platelet Factor 4; Pyrazoles; Pyrazolones; Thromboxane B2

1 We have performed a double-blind, randomized, 7-d cross-over study of the thromboxane synthetase inhibitor dazoxiben (UK 37248) in 20 patients with stable coronary heart disease. 2 All patients had a history of exertional angina of greater than two years duration and no patient had suffered a myocardial infarction in the preceding twelve months. 3 All patients had a positive exercise stress test for myocardial ischaemia and 15 had undergone coronary angiography. All these patients had a 50% narrowing in at least one vessel. 4 All patients were on conventional anti-anginal medication and the doses of their various therapies remained unchanged in the three months prior to and during the study period. 5 Therapy with dazoxiben 200 mg four times daily produced no alteration in the subjective or objective features of angina in these patients. There was no alteration in angina attack rate, glyceryl trinitrate consumption or duration of treadmill exercise. 6 Dazoxiben produced a highly significant reduction in both the resting and the post-exercise levels of serum thromboxane B2 levels, although there was no significant difference between the pre-exercise and post-exercise values. 7 Dazoxiben is an effective inhibitor of the synthesis of thromboxane but it has no effect on the subjective or objective features of stable coronary disease. This would suggest that the production of thromboxane and the development of circulating platelet aggregates play no part in the mechanism of angina in patients with stable coronary heart disease.

Topics: Angina Pectoris; Coronary Disease; Double-Blind Method; Humans; Imidazoles; Nitroglycerin; Oxidoreductases; Physical Exertion; Platelet Aggregation; Thrombelastography; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Low high-density lipoprotein (HDL) levels are major predictors of cardiovascular (CV) events, even in patients on statin treatment with low-density lipoprotein (LDL) at target. In animal models HDLs protect LDL from oxidation and blunt platelet activation. Our study aimed to examine whether HDL levels are related to in vivo oxidative stress and platelet activation, as determinants of atherothrombosis.. Urinary 8-iso-PGF2α and 11-dehydro-TXB2, in vivo markers of oxidative stress and platelet activation, respectively, were measured in 65 coronary heart disease (CHD) normocholesterolemic patients with HDL ≤35 mg/dL, and in 47 CHD patients with HDL >35 mg/dL. The 2 eicosanoids were also measured before and after an intensive exercise program in sedentary people (n=18) and before and after fenofibrate treatment in otherwise healthy subjects with low HDL (n=10). Patients with HDL ≤35 mg/dL showed significantly higher urinary 8-iso-PGF2α (median [25th to 75th percentiles]: 289 [189 to 380] versus 216 [171 to 321] pg/mg creatinine, P=0.019) and 11-dehydro-TXB2 (563 [421 to 767] versus 372 [249 to 465] pg/mg creatinine, P=0.0001) than patients with higher HDL. A direct correlation was found between urinary 8-iso-PGF2α and 11-dehydro-TXB2 in the entire group of patients (ρ=0.77, P<0.0001). HDL levels were inversely related to both 8-iso-PGF2α (ρ=-0.32, P=0.001) and 11-dehydro-TXB2 (ρ=-0.52, P<0.0001). On multiple regression, only 8-iso-PGF2α (β=0.68, P<0.0001) and HDL level (β=-0.29, P<0.0001) were associated with urinary 11-dehydro-TXB2 excretion, independent of sex, age, smoking, hypertension, diabetes, previous myocardial infarction, total cholesterol, LDL, and triglycerides. Both intensive exercise and fenofibrate treatment significantly reduced the 2 eicosanoids in healthy subjects, in parallel with an HDL increase.. A low HDL phenotype, both in CHD patients and in healthy subjects, is associated with increased lipid peroxidation and platelet activation. These data provide novel insight into the mechanisms linking low HDL with increased CV risk.

Topics: Aged; Arachidonic Acids; Case-Control Studies; Cholesterol, HDL; Coronary Disease; Cross-Sectional Studies; Dinoprost; Exercise; Exercise Therapy; Female; Fenofibrate; Humans; Hypoalphalipoproteinemias; Hypolipidemic Agents; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Phenotype; Platelet Activation; Risk Factors; Sedentary Behavior; Thromboxane B2

Cyclooxygenase-derived prostaglandins modulate cardiovascular disease risk. We genotyped 2212 Atherosclerosis Risk in Communities study participants (1,023 incident coronary heart disease (CHD) cases; 270 incident ischemic stroke cases; 919 non-cases) with available DNA for polymorphisms in PTGS1 and PTGS2. Using a case-cohort design, associations between genotype and CHD or stroke risk were evaluated using proportional hazards regression. In Caucasians, the reduced function PTGS1 -1006A variant allele was significantly more common among stroke cases compared to non-cases (18.2 versus 10.6%, P=0.027). In African Americans, the reduced function PTGS2 -765C variant allele was significantly more common in stroke cases (61.4 versus 49.4%, P=0.032). No significant relationships with CHD risk were observed. However, aspirin utilization appeared to modify the relationship between the PTGS2 G-765C polymorphism and CHD risk (interaction P=0.072). These findings suggest that genetic variation in PTGS1 and PTGS2 may be important risk factors for the development of cardiovascular disease events. Confirmation in independent populations is necessary.

Topics: Aspirin; Atherosclerosis; Biomarkers; Black or African American; Case-Control Studies; Coronary Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Thromboxane B2; United States; White People

The inability of aspirin (acetylsalicylic acid [ASA]) to adequately suppress platelet function is associated with future risk of myocardial infarction, stroke, and cardiovascular death. Genetic variation is a proposed but unproved mechanism for insufficient ASA responsiveness.. We examined platelet ASA responsiveness in 1880 asymptomatic subjects (mean age, 44+/-13 years; 58% women) recruited from 309 white and 208 black families with premature coronary heart disease. Ex vivo platelet function was determined before and after ingestion of ASA (81 mg/d for 2 weeks) with the use of a panel of measures that assessed platelet activation in pathways directly and indirectly related to cyclooxygenase-1, the enzyme inhibited by ASA. The proportion of phenotypic variance related to CHD risk factor covariates was determined by multivariable regression. Heritability of phenotypes was determined with the use of variance components models unadjusted and adjusted for covariates. ASA inhibited arachidonic acid-induced aggregation and thromboxane B2 production by > or = 99% (P<0.0001). Inhibition of urinary thromboxane excretion and platelet activation in pathways indirectly related to cyclooxygenase-1 was less pronounced and more variable (inhibition of 0% to 100%). Measured covariates contributed modestly to variability in ASA response phenotypes (r2=0.001 to 0.133). Phenotypes indirectly related to cyclooxygenase-1 were strongly and consistently heritable across races (h2=0.266 to 0.762; P<0.01), but direct cyclooxygenase-1 phenotypes were not.. Heritable factors contribute prominently to variability in residual platelet function after ASA exposure. These data suggest a genetic basis for the adequacy of platelet suppression by ASA and potentially for differences in the clinical efficacy of ASA.

Topics: Adult; Arachidonic Acid; Aspirin; beta-Thromboglobulin; Black or African American; Blood Platelets; Cardiovascular Diseases; Coronary Disease; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Resistance; Dyslipidemias; Female; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Variation; Humans; Hyperglycemia; Hypertension; Male; Membrane Proteins; Middle Aged; Phenotype; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Risk Factors; Sex Characteristics; Smoking; Thrombophilia; Thrombosis; Thromboxane B2; White People

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

Clinical studies have shown that low doses of aspirin (<300 mg/day) inhibit thromboxane A2 production and platelet aggregation but preserve prostacyclin synthesis. In contrast, high doses of aspirin (>1,000 mg/day) suppress the synthesis of both eicosanoids. Because the consequences of aspirin administration have never been investigated on coronary vasomotor tone in vivo, we investigated the effects of low and high doses of aspirin on systemic and coronary hemodynamics under basal conditions and after myocardial reactive hyperemia in conscious dogs. Dogs were instrumented with a Doppler flow probe and a hydraulic occluder. Coronary blood flow was measured in the conscious state at baseline and during myocardial reactive hyperemia after 10, 20, and 30 s of coronary occlusion. Thromboxane B2 serum concentrations, an index of platelet aggregation, decreased by >90% after long-term i.v. administration of aspirin, 100 mg/day for 7 days (low dose). Neither systemic and coronary hemodynamics nor reactive hyperemia were affected by the drug. After combined administration of this low dose of aspirin and of the nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NNA, 30 mg/kg/day/7 days), reactive hyperemia decreased to the same extent as when L-NNA was administered alone. After administration of a unique high-dose aspirin (1,000 mg, i.v.), myocardial reactive hyperemia was markedly reduced, and this effect was still observed after previous blockade of NOS and cyclooxygenase by L-NNA and diclofenac, respectively. Thus long-term treatment with a low antiaggregant dose of aspirin does not alter the ability of coronary vessels to dilate during myocardial reactive hyperemia in conscious dogs. In contrast, short-term administration of a high antiinflammatory dose of aspirin severely blunts myocardial reactive hyperemia through a mechanism that is independent of both cyclooxygenase and nitric oxide metabolic pathways.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Bradykinin; Coronary Disease; Coronary Vessels; Cyclooxygenase Inhibitors; Diclofenac; Dogs; Dose-Response Relationship, Drug; Hyperemia; Male; Myocardium; Nitric Oxide Synthase; Nitroarginine; Salicylic Acid; Thromboxane B2; Time Factors

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

Chloroquine is known to inhibit platelet activation by various mechanisms including arachidonic acid liberation from membrane phospholipids. We therefore examined the influence of chloroquine in addition to the conventional EDTA/acetylsalicylic acid cocktail on thromboxane B2-plasma values. In 11 healthy volunteers the influence of venous occlusion, needle diameter and EDTA (+ acetylsalicylic acid + chloroquine) was examined. In 27 healthy adults, 51 patients with clinically manifested coronary heart disease as well as in 31 patients with peripheral vascular disease parallel samples drawn in the presence of chloroquine showed lower thromboxane B2 in all these three groups of patients, especially in conditions associated with platelet activation and high thromboxane B2-values. These findings suggest that the routine addition of 10 mM chloroquine to the conventional stabilization cocktail can strongly be recommended.

Topics: Adult; Aged; Artifacts; Chloroquine; Coronary Disease; Female; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Radioimmunoassay; Reproducibility of Results; Sensitivity and Specificity; Specimen Handling; Thromboxane B2

The effect of nisoldipine, a dihydropyridine Ca2+ antagonist, on the platelet cytosolic Ca2+ concentration ([Ca2+]i), platelet aggregation, and various coagulation and fibrinolysis parameters was assessed in normotensive patients with coronary artery disease (CAD). Eleven patients with angiographically confirmed CAD (4 men, 7 women aged 67.3 +/- 5.4 years) were administered nisoldipine at 10 mg/day for two weeks. The [Ca2+]i was determined by use of fura2-loaded platelets, platelet aggregation was measured with an aggregometer, and coagulation/fibrinolysis parameters were measured by standard methods. Nisoldipine did not significantly affect blood pressure or heart rate. However, the [Ca2+]i decreased significantly (P<0.05) and platelet aggregation was also significantly inhibited. Plasma D-dimer levels decreased significantly (P<0.01). Thus, nisoldipine not only suppressed platelet activation but also affected the coagulation system, suggesting that it is not only a vasodilator and platelet inhibitor but also an antithrombotic agent.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Antithrombin III; beta-Thromboglobulin; Blood Coagulation; Blood Platelets; Blood Pressure; Calcium; Calcium Channel Blockers; Coronary Angiography; Coronary Disease; Cytosol; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Fibrinolytic Agents; Fluorescent Dyes; Fura-2; Heart Rate; Humans; Male; Nisoldipine; Peptide Hydrolases; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Factor 4; Thromboxane B2; Tissue Plasminogen Activator; Vasodilator Agents

Activity of erythrocyte superoxide dismutase (RBC-SOD), levels of serum malondialdehyde (MDA), plasma 6-keto-prostaglandin F 1 alpha (6-keto-PGF 1 alpha) and thromboxane B2(TXB2) were measured in 30 healthy subjects and 57 coronary heart desease (CHD) patients inoluding 21 cases complicated with diabetes and 36 without. Their characteristics of Syndrome Differentiation and typing were observed. The results showed that the activity of RBC-SOD, 6-keto-PGF 1 alpha in CHD patients were significantly lower than those in the healthy subjects, but the levels of TXB2, MDA were significantly higher. The levels of TXB2 in CHD patients with diabetes were significantly higher than tose without, but the activity of RBC-SOD were significantly lower. There were remarkably positive correlations between the levels of serum MDA and that of blood sugar, TXB2, TG and BMI in CHD patients with diabetes. There were remarkably negative correlations between the levels of serum MDA and plasma 6-keto-PGF 1 alpha. The results suggested that the metabolic abnormality of lipoperoxides was more serious in CHD patients with diabetes than without. The main Syndrome of CHD with diabetes was Qi-Yin Deficiency with Blood Stasis, while that of without diabetes was Qi Deficiency with Blood Stasis.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Pressure; Coronary Disease; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Humans; Lipid Peroxides; Male; Medicine, Chinese Traditional; Middle Aged; Superoxide Dismutase; Thromboxane B2; Yin Deficiency

Through a study of 504 cases of observation group with eye-signs in blood stasis syndrome (BSS) and 112 cases of control group without eye-signs in BSS, it has been found that in the observation group, the scores of the blood concentration, viscosity, aggregability and coagulability, level of plasma thromboxane B2 (TXB2), and the ratio of TXB2/6-keto-PGF1 alpha were obviously higher than those in the control group, but level of 6-keto-PGF1 alpha was obviously lower than that in the control group; the above-mentioned parameters of blood hyperviscosity syndrome, was obviously higher than that in the control group (90.08%:2.68%); comparisons between the two groups were significantly different (P < 0.001). Certain findings of the pathological base of eye-signs in BSS were found in the investigations.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Viscosity; Coronary Disease; Eye Diseases; Female; Hemorheology; Humans; Hypertension; Male; Medicine, Chinese Traditional; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Thromboxane B2

Disorders in arterial production of PGI2 and NO occur in atherosclerosis. Exogenous PGI2 and NO are capable of interacting pharmacologically. We claim that no such direct interactions occur between endogenous endothelial PGI2 and NO. Studying mechanisms of cardiac reactive hyperemia in guinea pigs and of thrombolysis in cats, we surmise that in vivo vascular intima releases PGI2 intraluminally while NO is secreted abluminally and thus these two ephemeral mediators do not see each other. Hence, in any disease, the disturbances in endothelial generation of PGI2 or NO have to be scrutinized separately. It may well be that endogenous PGI2 maintains endothelial thromboresistance while NO controls arterial myocytes and tissues in which microcirculation is embedded. These responsibilities remain unshared. Interactions between PGI2 and NO are confined to pharmacological domains.

Topics: Animals; Arteriosclerosis; Blood Pressure; Cats; Coronary Disease; Cyclic GMP; Epoprostenol; Guinea Pigs; Hyperemia; In Vitro Techniques; Male; Myocardium; Nitric Oxide; Thrombosis; Thromboxane B2

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

Urinary excretion of selected markers for renal injury, as well as urinary excretion rates of the thromboxane metabolite, 11-keto-thromboxane B2 (11k-TXB2), was studied in 36 male patients undergoing coronary bypass surgery using cardiopulmonary bypass (CPB). In all patients, excretion of both tubular (N-acetyl-beta-D-glucosaminidase [beta NAG]; alpha 1-microglobulin [alpha 1-MG]) and glomerular markers (albumin [Alb]; transferrin [Trf]; immunoglobulin G [IgG]) sharply increased on Day 1 after CPB, and they remained elevated throughout the observation period of 5 days. Urinary excretion rates of 11k-TXB2 markedly increased on Day 1 after surgery, and they rapidly decreased thereafter. In 12 of the 36 patients, a temporary increase of serum creatinine levels (> 1.30 mg/dl) was noted following surgery. A positive correlation was found between serum creatinine levels and excretion of the tubular enzyme beta NAG (r = 0.36; p < 0.05), but not between creatinine levels and alpha 1-MG or the glomerular markers. Furthermore, no correlation between urinary excretion of 11k-TXB2 and any of the urinary markers for renal injury could be detected. Our data do not strengthen the hypothesis that acute renal injury observed during CPB is related to exaggerated thromboxane biosynthesis in these patients. Monitoring of urinary markers for incipient renal damage, particularly excretion of beta NAG, might be of additional diagnostic value for detection of otherwise subclinical renal injury in patients undergoing CPB.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Aged; Albuminuria; Alpha-Globulins; Biomarkers; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Creatinine; Humans; Immunoglobulin G; Male; Middle Aged; Thromboxane B2; Transferrin

Continuous platelet aggregation does not occur in patients with stable coronary heart disease (CHD). However, there may be a latent potential for increased aggregation given appropriate stimuli, since increased in-vitro platelet aggregation appears to be predictive of cardiac events. This study evaluates the relationship between in-vitro platelet aggregation and coronary artery disease (CAD) as defined by angiography.. In-vitro platelet aggregation was assessed in a case-control study of 53 men with CHD younger than 50 years, and in 48 control subjects without CHD who were matched for age, sex, and socioeconomic status. All major risk factors were evaluated. Semi-quantitative composite scores of the extent of arterial wall involvement and composite scores for the severity of discrete lesions were documented from standard coronary angiography. Measures of platelet aggregation in response to adrenaline, adenosine diphoshate (ADP), and collagen included: (1) the maximum slope of the aggregation curve (rate); (2) lag time to 50% maximum aggregation (LT50%); and (3) the threshold concentration of each agonist to cause maximal aggregation.. The CHD patients had larger platelets than patients in the control group (mean platelet volume 9.40 +/- 0.73 versus 8.88 +/- 0.87; P < 0.01). The aggregation rate was significantly faster with adrenaline in the group with CHD than patients in the control group (rate of aggregation 13.9 +/- 8.8 versus 8.6 +/- 4.0 cm/s respectively, mean +/- SD; LT50% for adrenaline 130 +/- 70 versus 230 +/- 10 s respectively, mean +/- SD). Fewer CHD patients had no aggregation response to adrenaline than in the control group (8 versus 31%, P < 0.05). Adrenaline-induced platelet aggregation, as measured by LT50% for adrenaline, weakly but significantly correlated with the number and severity of discrete obstructive coronary lesions (r = -0.28, P < 0.05). This association remained significant after multivariate regression analysis. No association was found between any measure of platelet reactivity and the extent of disease as measured by a semi-quantitative composite score; this measured the extent of disease of the coronary artery walls visible by angiography.. These findings indicate that platelets from men with premature CHD are larger and aggregate more rapidly in response to platelet agonists, particularly adrenaline. An increased rate of aggregability with adrenaline predicted the severity of CAD lesion but not the extent of the disease, and this suggests that platelets play a role in the formation of localized obstructive lesions in coronary arteries, and therefore acute coronary events.

Topics: Adenosine Diphosphate; Adult; Age Factors; Blood Volume; Case-Control Studies; Cholesterol; Collagen; Coronary Angiography; Coronary Disease; Epinephrine; Humans; Lipoproteins; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Predictive Value of Tests; Regression Analysis; Risk Factors; Severity of Illness Index; Thromboxane B2

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

In 19 patients on a low-dose aspirin therapy with 100 mg/d, an insufficient effect of aspirin was observed in five patients (aggregations induced by arachidonic acid and collagen, thromboxane B2-formation in serum and after collagen). Aspirin added in vitro increased the inhibition to a degree comparable to that seen in the other 14 patients, i.e. the insufficient effect could be due to a lack of compliance or to a reduced availability of the drug. In another 20 patients there was a good inhibitory effect of aspirin; additional aspirin did not increase the inhibition of arachidonic acid-induced aggregation and serum-thromboxane B2, but slightly increased collagen-induced aggregation and thromboxane B2 formation. The effect was the same, whether the aspirin was given in vivo or added in vitro.

Topics: Adult; Aged; Aged, 80 and over; Arachidonic Acid; Aspirin; Collagen; Coronary Disease; Humans; Middle Aged; Platelet Aggregation; Thromboxane B2

To study the pathophysiological relation between Type A behavioral pattern and coronary artery disease, we analyzed the Type A behavioral pattern, serum triglycerides (TG), cholesterol (TC), high density lipoprotein cholesterol (HDLc), and TXB2, 6-keto-PGF1 alpha in 60 patients with coronary artery disease and 60 age-sex-matched healthy subjects. All of them had normal blood pressure. The results showed Type A behavioral pattern was more prevalent than Type B behavioral pattern in coronary artery diseased patients and the reverse was true in the controlled subjects (P < 0.025); TG, TC and TXB2/6-keto-PGF1 alpha ratio increased significantly in Type A behavioral pattern compared with Type B behavioral patients, but HDLc/(TC+TG) and the level of HDLc decreased significantly in the Type A behavioral pattern than in the Type B behavioral pattern (P < 0.05). The TG, TC increased significantly and 6-keto-PGF1 alpha HDLc decreased significantly in the coronary artery diseased patients (P < 0.05). However, the ratio of TXB2/6-keto-PGF1 alpha was inversely related to HDLc/(TC+TG) among the coronary artery diseased patients. The results of this cross-sectional study suggest that coronary artery disease is associated with Type A behavioral pattern through the metabolism of lipids and prostaglandins in various ways.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Cholesterol; Cholesterol, HDL; Coronary Disease; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Thromboxane B2; Triglycerides; Type A Personality

In order to study the biochemical and pathophysiological mechanism of the Blood Stasis Syndrome (BSS) or Non-BSS of coronary heart disease (CHD) patients, the activities of SOD, Selenium-glutathione peroxidase, the content of LPO in plasma and platelets and the contents of TXB2 and 6-keto-PGF1 alpha in plasma were determined in 109 BSS and Non-BSS of CHD patients compared with 98 healthy controls. It was discovered that the contents of TXB2, LPO, PL-LPO, and the ratio of TXB2/6-keto-PGF1 alpha were significantly increased in BSS-CHD patients compared with controls and Non-BSS-CHD patients. It was also discovered that the SOD activities and the contents of 6-keto-PGF1 alpha decreased significantly in Non-BSS-CHD patients. The results suggested that the injury of platelets by oxygen free radicals might be one of the primary injury factors in BSS-CHD patients. Our conclusion is that PGI2, SOD belong to the category of Heart-Qi, while TXA2, LPO to the Blood category. Therefore TXB2, 6-keto-PGF1 alpha, SOD, LPO should serve as some of the objective indexes for BSS patients of CHD.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Platelets; Coronary Disease; Diagnosis, Differential; Epoprostenol; Female; Glutathione Peroxidase; Humans; Lipid Peroxides; Male; Medicine, Chinese Traditional; Middle Aged; Superoxide Dismutase; Thromboxane A2; Thromboxane B2

The vasoactive eicosanoids, prostacyclin and thromboxane, are thought to play an important role in the genesis of cardiovascular disease. Since an altered basal production of these eicosanoids among individuals exhibiting the Type A behavior pattern had previously been observed by the authors, the present study evaluated the extent to which the TABP-eicosanoid relationship would be altered by two lifestyle variables known to affect platelet activity: alcohol consumption and stressful physical activity. 55 male participants aged 18-25 years, participated in the study. They were classified as either Type A or Type B on the basis of the Structured Interview and as either moderate, heavy, or abstinent alcohol drinkers. Bleeding times were performed and bleeding time thromboxane and prostacyclin metabolites were measured in all subjects both before and following treadmill exercise. The results indicated that following exercise, Type A participants, who reported moderate alcohol intake, had decreased levels of thromboxane B2 formation relative to Type As reporting heavy consumption. Further, prostacyclin production, measured as the primary metabolite, 6-keto-prostaglandin F1 alpha, was significantly suppressed following exercise among drinkers as compared with participants reporting abstinence. These results were discussed in relation to the proposition that moderate alcohol consumption reduces coronary heart disease risk.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Alcohol Drinking; Bleeding Time; Coronary Disease; Exercise; Humans; Male; Risk Factors; Thromboxane B2; Type A Personality

The blood taken from 35 patients with coronary heart disease and 30 healthy donors was irradiated with He-Ne laser, which resulted in a decrease in its count of segmented neutrophilic granulocytes. Lectins bound to various carbohydrate determinants onto the neutrophil surface were shown to affect changes occurring after luminol-depended chemiluminescence irradiation in patients and healthy persons in different ways. The patients' neutrophils contained lower levels of radiommunologically detectable leukotriene B4. Thromboxane B2 levels also dropped following the irradiation. The laser irradiation induced elimination of some less resistant cells from blood flow, i.e. "rejuvenation" of a cell population of neutrophilic granulocytes. The remaining cells differed in the composition and reactivity of surface lectin receptors and in the content of biologically active substances, which is likely to play the key role in the mechanism responsible for the therapeutical effect of He-Ne laser.

Topics: Coronary Disease; Female; Helium; Humans; In Vitro Techniques; Laser Therapy; Lectins; Leukotriene B4; Luminescent Measurements; Male; Neon; Neutrophils; Thromboxane B2

Restenosis after percutaneous transluminal coronary angioplasty (PTCA) was shown not to be preventable by antiplatelet therapy; residual platelet function under treatment with platelet inhibitors could be one cause of this. Therefore, in a prospective investigation, residual platelet function was assessed in 98 patients treated with acetylsalicylic acid (ASA) on three occasions during the first 3 months after successful PTCA. Control cardiac catheterization was obtained in 75 of these patients (77%) with 82 dilated stenoses 173 +/- 117 days after PTCA. Restenosis, defined as diameter stenosis greater than or equal to 50% at control angiography, occurred in 41% of the dilated vessels, and 43% of patients experienced restenosis in at least one vessel. The in vitro platelet aggregatory response to either ADP (0.5, 1, and 10 microM) or collagen (1 and 5 mg/L) as aggregating agents did not differ between patients with and without restenosis. In addition, neither the collagen-stimulated in vitro synthesis of thromboxane nor the basal or prostaglandin E1-stimulated concentrations of cyclic AMP in platelet-rich plasma (PRP) was different in the two groups. There was no significant correlation between any of the parameters of platelet function assessed and the change in coronary luminal diameter observed between immediately after PTCA and control coronary angiography. The mean dose of ASA ingested during follow-up was also not a determinant of the occurrence of restenosis. Thus, residual platelet function under treatment with ASA as measured in vitro in this study, did not influence the occurrence of restenosis after successful PTCA.

Topics: Angioplasty, Balloon, Coronary; Aspirin; Coronary Disease; Cyclic AMP; Female; Humans; Male; Platelet Aggregation; Recurrence; Thromboxane B2

We studied the changes in myocardial and aortic concentrations of prostacyclin and thromboxane A2 during acute coronary occlusion with or without reperfusion in rabbits fed with a cholesterol-enriched diet with or without fish oil supplementation for a short (5 days) or long period (6 weeks). New Zealand white male rabbits were divided into 5 groups: Group I, 15 control rabbits fed with a laboratory standard rabbit chow. In addition to the standard chow, the 4 study groups were treated with cholesterol or fish oil. Group II, 17 rabbits fed with a 1% high cholesterol diet for 5 days. Group III, 16 rabbits fed with a diet containing 1% cholesterol and 10% fish oil for 5 days. Group IV, 17 rabbits fed with the same diet as group II for 6 weeks. Group V, 18 rabbits fed with the same diet as group III for 6 weeks. Each group of rabbits was randomly divided into the coronary occlusion or occlusion-reperfusion mode of experiment. Acute coronary occlusion was induced by ligating the marginal branch of the left circumflex coronary artery for 1 h. Subsequent reperfusion for 4 h was performed in the occlusion-reperfusion rabbits. The aortic tissue above the aortic valve and the ischemic and normal (nonischemic) areas of the left ventricle were excised for the measurement of 6-keto-PGF1 alpha and thromboxane B2 levels by radioimmunoassay. Both during coronary occlusion and occlusion-reperfusion, rabbits showed higher myocardial concentrations of 6-keto-PGF1 alpha and thromboxane B2 in the ischemic area than in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta; Cholesterol, Dietary; Coronary Disease; Disease Models, Animal; Evaluation Studies as Topic; Fish Oils; Hypercholesterolemia; Lipoproteins; Male; Myocardial Reperfusion; Myocardium; Prostaglandins; Prostaglandins F; Rabbits; Radioimmunoassay; Thromboxane B2; Triglycerides

The effect of testosterone administration on plasma lipoproteins and eicosanoids was studied in 24 male cynomolgus monkeys. We hypothesized that elevated plasma testosterone would unfavorably alter plasma lipids as well as thromboxane A2 (TxA2) and prostacyclin (PGI2), two eicosanoids that have been linked to the increased incidence of atherosclerosis, myocardial ischemia, and thrombosis. To test our hypothesis, half of the monkeys (N = 12) were subjected to 10 wk of testosterone treatment, whereas the remaining monkeys (N = 12) received a sesame oil vehicle. The plasma concentrations of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, the stable metabolites of TxA2 and PGI2, respectively, were determined. Additionally, assays were conducted on total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Distribution of the HDL subfraction protein was measured by gradient gel electrophoresis. All monkeys exhibited significant increases in TC (P less than 0.001) and low density lipoprotein cholesterol (LDL-C) (P less than 0.001); however, monkeys who received testosterone also displayed significant increases in TxB2 (P less than 0.03) and decreases in HDL-C (P less than 0.03) compared with control monkeys. There was a trend in the HDL-C subfraction data, indicating that testosterone treatment may be associated with a decrease in the larger HDL2b subfraction and a corresponding increase in HDL3c. These results demonstrate that exogenous testosterone adversely alters cardiovascular risk profiles by increasing TXB2 production and decreasing HDL-C. Athletes who use testosterone as an anabolic androgenic steroid may have an increased risk for coronary heart disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Disease Models, Animal; Eicosanoids; Epoprostenol; Lipids; Macaca fascicularis; Male; Testosterone; Thromboxane A2; Thromboxane B2

Relationship between plasma thromboxane B2 concentration and serum total cholesterol level was studied in 129 healthy 3 to 18 years old children, 77 girls and 52 boys, without any family history of premature coronary artery disease and in 181 offspring, 105 girls and 76 boys, of parents suffering from acute myocardial infarction before the age of 45. It was identified an enhancement in serum total cholesterol level of endangered children, and an elevated release of thromboxane A2 in affected girls. A significant negative correlation was found between serum total cholesterol concentration and plasma thromboxane B2 level in healthy girls. However, there was no correlation between serum total cholesterol level and plasma thromboxane B2 concentration in the children whose parents had premature coronary artery disease. It appears, from our results, that this in an alteration of thromboxane A2 release of platelets in children of families with high risk of cardiovascular diseases.

Topics: Adolescent; Adult; Child; Child, Preschool; Cholesterol; Coronary Disease; Female; Humans; Male; Middle Aged; Myocardial Infarction; Risk; Thromboxane A2; Thromboxane B2

Monocytic production of peripheral blood thromboxane B2 and leukotriene B4, levels of cAMP and total lipids in these cells were examined in 58 patients with stable angina induced by exercise and 32 healthy donors. There was a hyperproduction of thromboxane B2 and leukotriene B4 by monocytes in the patients, a decrease in cAMP levels, and lipid accumulation in these cells in effort angina. The calcium antagonists verapamil and nifedipine abolished the above impairments. The author suggests that calcium antagonists should be regarded as a new class of antiathero-sclerotic agents that have effects predominantly on the cellular link of atherogenesis.

Topics: Angina Pectoris; Calcium Channel Blockers; Coronary Disease; Cyclic AMP; Humans; In Vitro Techniques; Leukotriene B4; Lipids; Monocytes; Nifedipine; Thromboxane B2; Verapamil

The effects of svate on platelet morphology and aggregation were studied and compare with Radix Salviae Miltiorrhizae. The results showed that svate remarkably inhibited platelet aggregation in patients with coronary heart disease and hypertension. Svate could increase plasma 6-keto-PGF1 alpha and decrease plasma TXB2. After treatment with svate, levels of platelet cAMP was increased. Svate enhanced platelet 5-HT and reduced plasma 5-HT. Electron microscopic study showed that the percentage of discoid and dendritic platelets were increased, while those of spread and aggregate platelets were decreased following svate therapy. It was found that svate is superior to Radix Salviae Miltiorrhizae in inhibition of platelet function. The results indicate that svate inhibits platelet aggregation and release through increasing prostacyclin generation in the vascular wall, raising platelet cAMP and inhibition of TXA2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Coronary Disease; Cyclic AMP; Drug Combinations; Drugs, Chinese Herbal; Elapid Venoms; Female; Humans; Hypertension; Male; Middle Aged; Phenanthrolines; Plant Extracts; Platelet Aggregation; Platelet Aggregation Inhibitors; Salvia miltiorrhiza; Serotonin; Thromboxane B2

It was found, that adaptation of rats to cold and physical exercise prevented ventricular fibrillation, caused by the occlusion of the left anterior coronary artery. An adaptation to cold only or to physical exercise do not prevent ventricular arrhythmias. An significant increase of prostacyclin/thromboxane index in plasma and heats was estimated in rats adapted to cold and physical exercise in relation to control non-adapted group in condition of functional rest or acute myocardial ischemia. It was assumed that an increase of prostacyclin/thromboxane ratio has a significant role in antiarrhythmic action of adaptation.

Topics: 6-Ketoprostaglandin F1 alpha; Adaptation, Physiological; Animals; Cardiac Complexes, Premature; Cold Temperature; Coronary Disease; Disease Models, Animal; Male; Rats; Swimming; Thromboxane B2; Ventricular Fibrillation

We studied the effects of cicletanine, an anti-hypertensive drug, on reperfusion arrhythmias in relation to 6-keto-PGF1 alpha, thromboxane B2 (TXB2), and ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia and reperfusion in hearts isolated from spontaneously hypertensive rats. Hearts were subjected to 30-min global ischemia followed by 10-min reperfusion. 6-keto-PGF1 alpha and TXB2 concentrations were determined by radioimmunoassay (RIA) from coronary effluents, and myocardial Na+, K+, Ca2+, and Mg2+ contents were measured by atomic absorption spectrophotometry from myocardial tissue. Two basic protocols were used: (a) acute administration when 3, 10, 30, or 100 mg/L cicletanine was included in the perfusion buffer; and (b) chronic application, in which rats received cicletanine 3, 10, 30, or 100 mg/kg/day orally for 14 days. Acute administration of the drug in low concentrations (3 or 10 mg/L), significantly increased endogenous 6-keto-PGF1 alpha production before ischemia and during reperfusion, whereas higher doses of cicletanine (30 or 100 mg/L) as well as chronic application of the drug failed to increase production of 6-keto-PGF1 alpha in the myocardium. TXB2 production was not influenced by either acute or chronic treatment with the drug. Neither treatment changed myocardial ion contents in comparison with control values (Na+ = 45 +/- 4, K+ = 252 +/- 7, Ca2+ = 1.4 +/- 0.1, and Mg2+ = 12.5 +/- 0.3 mmol/kg dry weight) in nonischemic hearts. Thirty-minute ischemia resulted in a two- and fourfold accumulation of myocardial Na+ and Ca2+ and a 50% decrease in both K+ and Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Body Water; Calcium; Coronary Disease; Diuretics; Electrocardiography; In Vitro Techniques; Magnesium; Myocardial Reperfusion Injury; Myocardium; Potassium; Pyridines; Rats; Rats, Inbred WKY; Sodium; Thromboxane B2

The effects of the two beta-blockers carvedilol and propranolol and the calcium antagonist verapamil on platelet aggregation induced by ADP, epinephrine, or collagen was examined in the serum of eight healthy volunteers. The inhibitory potential of the three drugs on the arachidonic acid-prostaglandin pathway was measured by the assessment of the formation of the stable metabolite thromboxane B2. Furthermore, the influence of drugs on intracellular cAMP levels was measured in platelets aggregated with ADP, epinephrine, or collagen. All three drugs were able to inhibit platelet aggregation induced by a threshold concentration of ADP, epinephrine (10 microM), or collagen (1 micrograms/ml) in a concentration-dependent manner, preventing aggregation completely in the high micromolar range. Propranolol is 1.6 and 2.3 times more active than verapamil and carvedilol in inhibiting ADP-induced platelet aggregation. Although the two beta-blockers were marginally more potent than verapamil in inhibiting platelet aggregation induced by collagen, this was not statistically significant. Both propranolol and verapamil were slightly more active than carvedilol in inhibiting epinephrine-induced platelet aggregation, a trend consistent with the IC50 values. Intracellular cAMP levels decreased in platelets aggregated with ADP, epinephrine, and collagen. The inhibition of platelet aggregation with the three drugs resulted in a return of intracellular cAMP levels to basal values. Carvedilol and propranolol were of similar potency and around 1.5-3 times as potent as verapamil for all agonists. The formation of thromboxane B2, an end product of the arachidonic acid pathway, could be completely inhibited by the three drugs. Propranolol was 2.4 and 2.1 times more potent than carvedilol and verapamil when platelets were aggregated with ADP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Antagonists; Blood Platelets; Carbazoles; Carvedilol; Coronary Disease; Cyclic AMP; Humans; In Vitro Techniques; Platelet Aggregation; Platelet Aggregation Inhibitors; Propanolamines; Propranolol; Thromboxane B2; Vasodilator Agents; Verapamil

Ubiquinone 6.2, 12.5 or 2.5 mg.kg-1 respectively twice iv 24 h and 30 min before coronary artery ligation, ameliorated the ischemic arrhythmia in conscious rats, and there was a close positive correlation between the ubiquinone concentration in myocardium and plasma and its anti-arrhythmic effect. Ubiquinone iv 3.1, 6.2, and 12.5 mg.kg-1 increased, while 25 mg.kg-1 decreased 6-keto-PGF1 alpha, and 12.5 and 25 mg.kg-1 decreased TXB2, which was in accordance with inhibitory effects on the synthesis of 6-keto-PGF1 alpha and TXB2 in vitro. But the ratio of metabolites of PGI2/TXA2 in vivo was increased in all ubiquinone groups. These results indicated that ubiquinone possesses protective effects on ischemic arrhythmia of conscious rats and the beneficial effects on myocardial ubiquinone content and PGI2/TXA2 seem to contribute to its myocardial protective action.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Coronary Disease; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Microsomes; Myocardium; Rats; Rats, Inbred Strains; Swine; Thromboxane B2; Ubiquinone

As many as 141 residents of an urbanized region of the Far North (92 patients with coronary heart disease [CHD] and 49 normal persons) and 75 persons (57 natives and 18 newcomers) living in one of rural settlements in the Far North were examined for the thrombocytic-vascular component of the hemostasis system measured by the levels of stable metabolites of prostacyclins and thromboxane A2. Some characteristics of the coagulation component of the hemostasis system were also analyzed. All the persons examined were males aged 40-59 years. The prostacyclin/thromboxane ratio in the normal northerners did not differ from that in residents of Siberia. The patients with CHD living in the Far North for a long time demonstrated a greater shift of homeostatic balance toward increase of blood proneness to intravascular platelet aggregation, which strongly increases a risk of thrombotic complications. The natives living in the rural region of the Far North manifested a high prostacyclin generative activity and hypocoagulation changes in the plasma component of the hemostatic system.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arctic Regions; Cold Climate; Coronary Disease; Coronary Vessels; Endothelium, Vascular; Epoprostenol; Humans; Male; Middle Aged; Platelet Aggregation; Siberia; Thromboxane B2

The effect of KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl) ethylidene]-6,11-dihydrodibenz[b,e] oxepine-2-carboxylate monohydrate, CAS 127166-41-0), a novel thromboxane A2 (TxA2) receptor antagonist, on collagen-induced coronary ischemia was studied in guinea-pigs. Under pentobarbital anaesthesia, intravenous injection (i.v.) of collagen (1 mg/kg) induced abnormal ECG changes such as ST-T changes, elevation of T-wave arrhythmia and cardiac arrest in severe cases. The changes of ECG (leads I, II and III) were recorded for 10 min following collagen injection. KW-3635 (25-50 mg/kg p.o.) remarkably improved the collagen-induced ischemic ECG changes. The effect of KW-3635 was more potent than those of daltroban, isbogrel and ticlopidine. Neither nifedipine nor propranolol had any effect. The plasma thromboxane B2 level in the KW-3635-treated animals was lower in comparison with those in both the control and daltroban-treated animals. These results suggest that TxA2 may play a role in this model of coronary ischemia and that KW-3635 is effective in the treatment of ischemic heart disease.

Topics: Animals; Arrhythmias, Cardiac; Benzimidazoles; Benzoxepins; Collagen; Coronary Disease; Cyclooxygenase Inhibitors; Electrocardiography; Guinea Pigs; Heart Arrest; Male; Nifedipine; Phenylacetates; Propranolol; Sulfonamides; Thromboxane A2; Thromboxane B2; Thromboxanes; Ticlopidine

We examined 3 infants with persistent pulmonary hypertension. They also showed signs of heart failure. The signs of cardiac dysfunction noted in the acute phase were resolved after treatment with catecholamines and vasodilators. Contrary to the general concept that transient myocardial dysfunction is secondarily caused by persistent pulmonary hypertension, left myocardial dysfunction accompanied pulmonary hypertension and was followed by right myocardial dysfunction. High blood concentration of thromboxane B2 was reported in 2 neonates with persistent pulmonary hypertension. We considered thromboxane A2 as a possible cause of coronary spasm, resulting in myocardial ischemia.

Topics: Catecholamines; Coronary Disease; Coronary Vasospasm; Echocardiography; Humans; Hypertension, Pulmonary; Infant, Newborn; Thromboxane B2; Vasodilator Agents

In continuation of investigations on primary hyperlipidaemias, we determined serum thromboxane (TX) B2 and prostaglandin (PG) F2 alpha after standardized blood clotting in patients without hyperlipidaemia and without (group 1, n = 11) or with coronary heart disease (CHD; group 2, n = 5), in patients with familial combined hyperlipoproteinaemia and without (group 3, n = 4) or with CHD (group 4, n = 5), as well as in patients with familial hypercholesterolaemia and CHD (group 5, n = 5). TXB2 was detected by gas chromatography and PGF2 alpha by means of radioimmunoassay. The TXB2 level did not differ significantly between the groups, but there was a tendency to higher values in hyperlipidaemia, while in group 5 the level tended to decrease with rising serum LDL-cholesterol and in group 3 it tended to increase with rising serum apolipoprotein B. The PGF2 alpha level was significantly lower in group 4 than in groups 1 and 3. It showed in group 5 a negative correlation with serum LDL-cholesterol and in group 3 a positive correlation with serum triglycerides.

Topics: Adult; Aged; Apolipoproteins A; Apolipoproteins B; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Dinoprost; Female; Humans; Hyperlipidemia, Familial Combined; Hyperlipoproteinemia Type II; Lipids; Male; Middle Aged; Thromboxane B2; Triglycerides

The safety of the combination of heparin and ridogrel therapy and its antiplatelet efficacy was examined in the setting of percutaneous transluminal coronary angioplasty (PTCA). In 32 patients without known aspirin intake for 10 days before PTCA, therapy with ridogrel (300-mg intravenous bolus) was begun just before PTCA and continued orally at a dose of 300 mg twice daily until discharge. Heparin was administered as a 10,000 IU bolus dose before PTCA and followed by an intravenous infusion at a rate of 1,000 IU/hour for 24 hours. Bleeding problems at the arterial entry site occurred in 13 patients, which required a blood transfusion in only 2 patients. One patient underwent emergency bypass surgery without specific problems of hemostasis. Ridogrel virtually eliminated thromboxane B2 from the serum (29,990 +/- 6,555 pg/0.1 ml before vs 63 +/- 7 pg/0.1 ml at 2 hours after ridogrel), with a concomitant increase in serum 6-keto-prostaglandin F1 alpha (511 +/- 34 pg/0.1 ml before vs 1,190 +/- 146 pg/0.1 ml at 24 hours after ridogrel). There were no acute reocclusions in the ridogrel-treated patients, whereas acute reocclusions occurred in 5.6% of the patients taking the standard aspirin + heparin regimen during the same period. Furthermore, at 6-month clinical follow-up patients treated with ridogrel compared favorably with those receiving standard treatment.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Angioplasty, Balloon, Coronary; Coronary Disease; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Male; Middle Aged; Pentanoic Acids; Pilot Projects; Pyridines; Radiography; Recurrence; Salicylates; Thromboxane B2; Thromboxane-A Synthase

We studied the effects of urokinase (UK), pro-urokinase (pro-UK), and recombinant tissue-type plasminogen activator (rt-PA) on platelet aggregation and the production of thromboxane A2 (TXA2) in vitro. Both UK and pro-UK inhibited the platelet aggregation induced by adenosine 5'-diphosphate (ADP), collagen, or thrombin in a concentration-dependent manner. In contrast, although a low dose of rt-PA (5 to 10 x 10(4) U/ml) blunted platelet aggregability, a high dose (40 to 60 x 10(4) U/ml) led to platelet hyperaggregation. UK and pro-UK markedly inhibited TXA2 synthesis during ADP-induced platelet aggregation. Despite the significant reduction of TXA2 synthesis by 10 x 10(4) U/ml rt-PA, a concentration of 60 x 10(4) U/ml rt-PA had no effect on synthesis. These results indicate that UK and pro-UK each inhibit platelet function, but a high concentration of rt-PA enhances platelet aggregability. This finding may at least in part contribute to the high incidence of reocclusion after initially successful thrombolysis with rt-PA.

Topics: Coronary Disease; Fibrinolytic Agents; Humans; Plasminogen Activators; Platelet Aggregation; Platelet Aggregation Inhibitors; Recombinant Proteins; Recurrence; Thromboxane B2; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Coronary Disease; Female; Glutathione Peroxidase; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Selenium; Superoxide Dismutase; Thromboxane B2

The complement system and arachidonic acid metabolites are involved in severe myocardial ischemia such as myocardial infarction. Furthermore, there is experimental evidence for C5a participation in thromboxane production.. We examined whether C5a and thromboxane are produced during brief and reversible episodes of myocardial ischemia induced in patients with stable angina. Twenty-five patients underwent either atrial pacing or percutaneous transluminal coronary angioplasty associated with arterial and coronary sinus blood sampling. Rapid atrial stimulation of patients with effort angina caused significant ST segment depression (delta ST = -1.7 +/- 0.2 mm), decreased fractional lactate extraction (from +12.8 +/- 2.5% baseline to -13.7 +/- 4.6% at peak ischemia, n = 13, p less than 0.001), and increased coronary sinus plasma thromboxane B2 levels (from 345 +/- 85 pg/ml baseline to 1,684 +/- 64 pg/ml at peak ischemia, p less than 0.01). Changes of fractional lactate extraction correlated significantly with changes of coronary sinus plasma levels of thromboxane B2. There was no change of coronary sinus 6-keto-PGF1 alpha levels. Similar pacing of control subjects (n = 6) did not cause release of lactate or thromboxane. Seventeen other patients underwent exercise testing with noninvasive measurements of thromboxane and prostacyclin metabolites in urinary samples collected before and after the test. No detectable increase of urinary 11-dehydrothromboxane B2 was measured in patients with stable angina after exercise-induced myocardial ischemia. However, basal 11-dehydrothromboxane B2 levels were significantly higher in patients with angina (105 +/- 25 pg/mmol creatinine, n = 9) than in control patients (45 +/- 8 pg/mmol creatinine, n = 8, p less than 0.05 between groups). Coronary sinus plasma levels of the anaphylatoxin C5a always remained below 4 ng/ml in patients undergoing pacing. More severe myocardial ischemia after coronary angioplasty (percent lactate extraction decreased from +24.8 +/- 2.7% baseline to -41.6 +/- 22.4% at peak ischemia, p less than 0.05) was not associated with C3a or C5b-9 generation. In all patients, there was neither platelet sequestration nor platelet alpha-granule release (no changes of beta-thromboglobulin/platelet factor 4 levels) into the coronary sinus plasma.. Patients with stable angina have chronically increased thromboxane synthesis as assessed by excretion of urinary metabolites. Thromboxane is acutely released into the coronary sinus during pacing-induced ischemia without significant intracoronary platelet aggregation. Complement does not appear to be activated in stable angina during brief and reversible episodes of myocardial ischemia and does not contribute to thromboxane production.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Cardiac Pacing, Artificial; Complement Activation; Complement C5a; Coronary Disease; Electrocardiography; Female; Humans; Lactates; Lactic Acid; Male; Middle Aged; Myocardium; Thromboxane B2

We have reported that thromboxane A2 and serotonin are two important mediators of coronary cyclic flow variations (CFVs) caused by recurrent platelet aggregation and dislodgement on a stenosed coronary arterial wall with endothelial injury. To test the hypothesis that blocking the synthesis of thromboxane A2 would not prevent serotonin release, 1.1, 4.6, and 9.2 mg/kg of aspirin were administered through the left atrium to 27 dogs with CFVs. The CFV elimination rate was 70% in the aspirin-treated dogs. Thromboxane B2 and serotonin concentrations were measured in different coronary arterial segments. There were significantly lower thromboxane B2 and 6-keto-PFG1a levels in the stenosed left arterior descending (LAD) segments with increasing dosage of aspirin-208 +/- 36, 24 +/- 31, 50 +/- 6 ng/g (P less than 0.0001) and 125 +/- 27, 58 +/- 38, 25 +/- 5 ng/g (P less than 0.0001), respectively. Serotonin levels were significantly higher in stenosed LAD (265.7 +/- 131.2 ng/g) than in LAD segments proximal or distal to the stenosis and in corresponding circumflex coronary artery segments, 17.1 +/- 3.7, 18.6 +/- 3.7, and 19.2 +/- 5.1 ng/g, respectively (P less than 0.05) following the highest dose of aspirin. In 41 additional dogs, electrical injury was used to initiate thrombosis in the circumflex artery and in those receiving aspirin (15 mg/kg) (n = 5), occlusive thrombus formation was inhibited. However, the local accumulation of serotonin was not significantly different between the control (194 +/- 27 ng/g) (n = 36) and the aspirin-treated group (167 +/- 19 ng/g) (n = 5). In vitro platelet aggregation induced by arachidonic acid was inhibited by the in vivo administration of 1.1 mg/kg of aspirin and abolished by 4.6 + 1.1 and 9.2 + 4.6 + 1.1 mg/kg of aspirin. However, serotonin-induced platelet aggregation was not affected following all doses of aspirin. Thus, aspirin eliminates CFVs in 70% of dogs, and markedly diminishes thromboxane A2 and prostacyclin concentrations in stenosed canine coronary arteries, but it does not prevent local serotonin accumulation. Similarly, aspirin prevents occlusive coronary thrombosis in dogs with electrically-induced endothelial injury, but it did not prevent local assumulation of serotonin. These experimental findings suggest that cyclo-oxygenese inhibition does not prevent serotonin accumulation at sites of coronary artery endothelial injury, and they thereby help provide a potential explanation of the lack of complete protec

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Dogs; Electricity; Female; Male; Platelet Aggregation; Serotonin; Thromboxane B2

We have studied the relationship between levels of lipids and prostacyclin in 3- to 14-year-old children with a family history of ischaemic heart disease. The total levels of cholesterol in the serum of these children increased, while levels of the HDL-fraction and prostacyclin (measured as 6-keto-prostaglandin F1a) decreased significantly. Levels of thromboxane B2 in the plasma were unchanged. It is suggested that, in childhood, abnormalities of lipid metabolism co-exist with decreased levels of prostacyclin. The latter may be a new important indicator of early atherosclerotic disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Arteriosclerosis; Child; Child, Preschool; Cholesterol; Cholesterol, HDL; Coronary Disease; Female; Humans; Male; Risk Factors; Thromboxane B2

The effects of combined thromboxane synthetase inhibition and thromboxane receptor antagonism (TSI/TRA) were studied in conscious and in anesthetized canine models of sudden cardiac death. Administration of the TSI/TRA, R68070 10 mg/kg intravenously (i.v.), decreased thrombin-stimulated thromboxane synthesis and significantly antagonized platelet aggregation in response to the thromboxane-mimetic U46,619. In the conscious canine model, R68070 did not change ventricular refractoriness, did not prevent induction of ventricular arrhythmias by programmed electrical stimulation, and failed to prevent development of spontaneous ventricular fibrillation (VF) in response to ischemia produced at a site remote from the area of previous myocardial infarction (R68070 mortality = 70%, vehicle = 100%, p = NS). In the anesthetized canine model, R68070 prevented development of ischemia in 7 of 11 animals and reduced mortality significantly (R68070 27% and vehicle 73%; p = 0.038). R68070 inhibited thrombus formation in both models (R68070 conscious 7.0 +/- 2.6 mg and vehicle conscious 15 +/- 7.6 mg, p = NS; R68070 anesthetized 5.9 +/- 1.9 mg and vehicle anesthetized 17.7 +/- 4.3 mg; p less than 0.05). The results suggest that inhibition of thromboxane-dependent activity during acute recovery from infarction was able to protect the myocardium from developing ischemia in response to current-mediated intimal damage in a noninfarct-related artery. In the subacute phase of recovery from infarction, when the underlying myocardial substrate is susceptible to electrical derangement induced by transient ischemia, thromboxane inhibition in itself was unable to prevent ischemia-induced sudden cardiac death. Although R68070 may delay onset of ischemia due to thrombotic occlusion of the coronary artery, there does not appear to be an antiarrhythmic/antifibrillatory action to be derived from interfering with the synthesis or receptor-mediated action of thromboxane. Furthermore, R68070 does not alter the electrophysiologic properties of the heart which would result in an antiarrhythmic or antifibrillatory action.

Topics: Adenosine Diphosphate; Animals; Arachidonic Acid; Arachidonic Acids; Arrhythmias, Cardiac; Collagen; Coronary Disease; Death, Sudden; Disease Models, Animal; Dogs; Electric Stimulation; Electrophysiology; Female; Heart Rate; Male; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

The cardioprotective effects of a novel antiinflammatory drug, ONO-3144 (ONO), on ischemic-reperfused myocardium were investigated using an in situ pig heart model. Heart was subjected to 2 h of regional ischemia, with the final 1 h having superimposed global cardioplegic arrest followed by 1 h of reperfusion. ONO (20 microM) was administered after the arrest at the onset of reperfusion. Left ventricular developed pressure (LVDP), maximum rate of rise of left ventricular pressure (LV dp/dt), and left ventricular end-diastolic pressure (LVEDP) were measured under isovolumic conditions to assess cardiac contractility and compliance. ONO improved LVDP and LV dp/dt, and reduced LVEDP after 60 min of reperfusion compared to control. This drug also improved segment shortening and end-diastolic length significantly after 15 and 60 min of reperfusion. Slight improvements in oxygen consumption and creatine kinase (CK) release were also noted. In addition, ONO reduced lipid peroxidation and thromboxane formation but enhanced the production of prostaglandins. In vitro studied demonstrated ONO to be effective scavengers for both hydroxyl (OH.) and hypohalite (OCL.) radicals. The results suggest that myocardial reperfusion injury that developed after ischemic arrest was reduced significantly by ONO. This drug inhibited such injury, probably by directly scavenging potentially harmful radicals such as OH. and OCI., which are generated in ischemic-reperfused myocardium.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arachidonic Acids; Coronary Disease; Creatine Kinase; Female; Free Radicals; Heart Arrest, Induced; Heart Function Tests; Lipid Peroxidation; Male; Malondialdehyde; Myocardial Reperfusion Injury; Myocardial Revascularization; Oxygen Consumption; Propiophenones; Prostaglandins F; Superoxides; Swine; Thromboxane B2

This study investigated the effects of a low dose of nisoldipine (5 mg, p.o.) in 10 patients with ischemic heart disease. The patients were subjected to a 90-min exercise regimen before and after a 5 mg dose of nisoldipine, using a supine bicycle ergometer adjusted to each patient's limitations. The mean blood plasma level of nisoldipine was 3.8 +/- 3.1 (SD) ng/ml. The drug significantly decreased the systolic arterial pressure in patients throughout the experimental session, whereas a change in the diastolic arterial pressure appeared only at the submaximal stage of the exercise. Additionally, at maximal exercise, nisoldipine caused a decrease in the mean coronary sinus pressure from 11.4 +/- 7 mmHg to 6.5 +/- 5 mmHg (p less than 0.01). By contrast, while at rest, nisoldipine decreased the coronary vascular resistance from 1.5 +/- 0.7 mmHg/ml/min to 1.0 +/- 0.7 mmHg/ml/min (p less than 0.05). After exercise, the drug decreased thromboxane B2 levels from 1133 +/- 907 pg/ml to 720 +/- 379 pg/ml (p less than 0.05) in the coronary sinus blood, and increased the 6 keto-prostaglandin F1 alpha levels from 465 +/- 135 pg/ml to 559 +/- 167 pg/ml (p less than 0.05) in brachial artery blood. This suggests that a low, oral dose of nisoldipine can moderately improve the systemic and coronary hemodynamics and afterloads, and may assist in improving the prostaglandin metabolism in ischemic heart disease patients.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Adult; Aged; Blood Pressure; Coronary Circulation; Coronary Disease; Exercise Test; Hemodynamics; Humans; Middle Aged; Nisoldipine; Prostaglandins; Thromboxane B2; Vascular Resistance

Topics: Angina Pectoris; Cardiac Pacing, Artificial; Coronary Angiography; Coronary Disease; Electrocardiography; Female; Humans; Middle Aged; Thromboxane B2

The effect of EPA enriched marine oil on platelet function in 12 cases of hypertension, 15 cases of diabetes and 20 cases of coronary heart disease is reported. The result of our study showed that there was platelet hyperfunction of various degrees in patients with those three kinds of diseases. The murine oil had an effect of inhibition, which were manifested by the prolongation on bleeding time, and decreased on platelet adhesion and aggregation. TxB2 in plasma was reduced, while 6-keto-PGF increased. There was no influence of EPA enriched fish oil on blood sugar and liver or kidney function. The authors concluded that platelet hyperfunction is an important element in the development of cardio vascular and cerebro vascular complications and increases the mortality rates in these diseases. Treatment with such a drug has beneficial effect with clinical improvement.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Bleeding Time; Blood Coagulation; Blood Platelets; Coronary Disease; Diabetes Mellitus, Type 2; Eicosapentaenoic Acid; Female; Fish Oils; Humans; Hypertension; Male; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

Neutrophils have been implicated in the genesis of myocardial ischemia-reperfusion injury, and their mechanism of action has been linked to the production of reactive oxygen species, fatty acid-derived prostanoids, and leukotrienes. In this study, we examined the potential relation between production of reactive oxygen species and cyclooxygenase-derived autacoids by studying the effects of superoxide dismutase (SOD) and catalase (CAT) on the rise in thromboxane formation observed with myocardial ischemia and reperfusion. Immunoreactive thromboxane B2 was measured in cardiac lymph from conscious dogs during reperfusion after a 60-minute occlusion in the presence of infusions of SOD alone, CAT alone, and a combination of SOD and CAT. Reperfusion after 60 minutes of ischemia causes an immediate elevation in thromboxane B2. SOD and CAT infusion prevented this rise in thromboxane B2 as did infusion of SOD alone. The ability of SOD-CAT to suppress thromboxane B2 production dissipated within 3 hours after the cessation of infusion, at which time thromboxane B2 excretion increased. The modulation of fatty acid oxygenases by reactive oxygen species may be a very important pathogenic factor in considering the origin of the protective effect of antioxidants in the setting of myocardial ischemia-reperfusion injury.

Topics: Animals; Catalase; Coronary Disease; Dogs; Female; Lymph; Male; Multivariate Analysis; Myocardial Reperfusion; Myocardium; Superoxide Dismutase; Thromboxane B2; Time Factors

The responses of eicosanoids to acute myocardial ischemia induced by either exercise stress testing (EX) or percutaneous transluminal coronary angioplasty (PTCA) were investigated in 23 patients with effort angina pectoris (EAP). EX was useful procedure to determine the therapeutic plan in each cases, and PTCA is the novel therapeutic operation for EAP. The relations between these metabolites and either hemodynamics or coronary circulation were then evaluated. The effect of the calcium entry blocker nisoldipine (oral administration of 5 mg) was also studied in 10 patients with EAP. The plasma levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) and leukotriene C4 (LTC4) were determined by radioimmunoassay. in arterial and coronary sinus blood samples before and immediately after acute myocardial ischemia. The changes in hemodynamics and coronary circulation during exercise stress testing were assessed by measuring direct brachial artery pressure, cardiac output by the dye dilution method and coronary sinus flow by the thermodilution method. The TXB2/6KPGF1 alpha ratio in coronary sinus blood significantly increased after ischemia in both EX and PTCA, but there was no significant change in LTC4 levels of coronary sinus blood immediately after acute ischemia. The 6KPGF1 alpha levels in both arterial and coronary venous blood were significantly correlated to coronary perfusion pressure and mean brachial artery pressure. Arterial LTC4 levels tended to correlate to mean brachial artery pressure and coronary sinus flow. Nisoldipine improved the ischemic electrocardiography response to EX. Nisoldipine also significantly increased arterial 6KPGF1 alpha at peak exercise. It significantly decreased brachial artery pressure, pressure rate product (PRP), mean coronary sinus pressure and coronary vascular resistance both at rest and peak exercise. The response of PRP significantly correlated with the response of arterial 6KPGF1 alpha. These results suggest: 1 The imbalance of the TXB2/6KPGF1 alpha ratio may be induced more rapidly than LTC4. 2 PGI2 and LTC4 may have some role in the regulation of hemodynamics and coronary circulation during acute myocardial ischemia. 3 Nisoldipine may ameliorate myocardial ischemia through improvement of systemic hemodynamics and prostaglandin metabolism apart from through direct action on the heart.

Topics: 6-Ketoprostaglandin F1 alpha; Coronary Circulation; Coronary Disease; Eicosanoids; Exercise Test; Hemodynamics; Humans; Male; Middle Aged; Nisoldipine; SRS-A; Thromboxane B2

The effects of a new thromboxane A2 synthetase inhibitor (DP-1904) on electrical stability of the heart were tested in anesthetized, open chest dogs. The incidence of spontaneous ventricular arrhythmias, ventricular refractory period and ventricular fibrillation threshold (VFT) during ligation of the left anterior descending coronary artery (LAD) for 180 min and after reperfusion were measured as indices of stability. Ventricular fibrillation and ventricular tachycardia occurred spontaneously after ligation of LAD in 56% of 9 control dogs and 29% of 7 dogs which received intravenous DP-1904 (100 mg) before ligation of LAD (n.s.). In the control group, the ventricular refractory period decreased in the ischemic region; consequently, the difference in refractory period duration between the ischemic and non-ischemic regions (i.e., dispersion) increased 30 min after coronary ligation (7 +/- 9 ms vs 32 +/- 17 ms, p less than 0.05). The dispersion at 30 min after coronary ligation, though, was not affected in the DP-1904 treated group (2 +/- 4 ms vs 10 +/- 9 ms, n.s.). The VFT (determined with pulse trains) decreased from 28 +/- 5 mA to 15 +/- 11 mA (p less than 0.05) 30 min after coronary ligation in the control group, but was not affected (30 +/- 0 mA vs 27 +/- 4 mA) in the DP-1904 group. The plasma concentration of thromboxane B2 decreased after DP-1904 administration (baseline vs 30 min after coronary ligation: 475 +/- 165 pg/ml vs 165 +/- 74 pg/ml, n = 3, p less than 0.05), while the concentration of 6-keto-prostaglandin F1 alpha increased gradually. In conclusion, DP-1904 prevents a decline in electrical stability in the ischemic region of the canine heart during coronary occlusion.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Coronary Vessels; Dogs; Electrophysiology; Female; Heart Rate; Heart Ventricles; Imidazoles; Ligation; Male; Naphthalenes; Refractory Period, Electrophysiological; Reperfusion; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase; Ventricular Fibrillation

This paper analysed the relationship between pale tongue, purplish tongue and TXB2, 6-keto-PGF1 alpha levels in plasma of 70 cases with coronary heart disease (CHD) and 45 normal subjects. The results showed the following characteristics: The pale tongue group (217.76 +/- 30.5 pg/ml) showed no significant difference in TXB2 level compared with the normal group (164.49 +/- 10.85 pg/ml, P greater than 0.05), while both showed significant difference compared with the purplish tongue group (360.1 +/- 31.3 pg/ml) and that with purple spots (485.07 +/- 106.1 pg/ml, P less than 0.01). The pale tongue group (179.29 +/- 9.08 pg/ml) showed a significant difference in 6-keto-PGF1 alpha level compared with the normal group (244 +/- 19.31 pg/ml, P less than 0.01), but it showed no significant difference compared with the purplish tongue group (185.08 +/- 17.07 pg/ml) and that with purple spots (229.3 +/- 33.2 pg/ml, P greater than 0.05). The comparison between the groups of purplish tongue and that with purple spots and the normal group showed no significant difference (P greater than 0.05). The pale tongue group (1.33 +/- 0.18) showed a marked difference in TXB2/6-keto-PGF1 alpha ratio compared with the normal group (0.72 +/- 0.04, P less than 0.01), the purplish tongue group (2.12 +/- 0.22, P less than 0.01) and that with purple spots (2.25 +/- 0.55, P less than 0.05). The purplish tongue group and that with purple spots showed significant difference compared with the normal group (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Coronary Disease; Female; Humans; Male; Medicine, Chinese Traditional; Middle Aged; Thromboxane B2; Tongue

Anaesthetized mongrel dogs were subjected to occlusion of a coronary artery. The resulting myocardial infarction was observed for three hours. One hour after occlusion, infusion of the stable prostacyclin analogue iloprost or saline was started. In the control group myocardial infarction was associated with an increase of the ratio TXB2/6-keto-PGF1a which was abolished by iloprost treatment. After occlusion in the control group, the atherosclerosis index (TC-HDLC): HDLC was increased, but in the iloprost-treated group it was significantly decreased. The results of this study suggest that the administration of iloprost is able to prevent changes in eicosanoid metabolism and lipoprotein pattern after coronary artery occlusion in dogs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Dogs; Eicosanoic Acids; Epoprostenol; Female; Iloprost; Lipids; Male; Prostanoic Acids; Thromboxane B2

Platelet activation is markedly increased during coronary thrombolysis and limits the response to thrombolytic therapy. A possible mediator of platelet activation in this setting is thromboxane (TX) A2, a potent platelet agonist formed in greatly increased amounts during coronary thrombolysis in man. To address this hypothesis, we examined the role of TXA2 in modulating the response to intravenous tissue-type plasminogen activator (t-PA) in a chronic canine model of coronary thrombosis. Reperfusion occurred in 60 +/- 5 minutes and was complicated by spontaneous reocclusion. The times to reperfusion and reocclusion were platelet-dependent. Consistent with a role for TXA2 in this process, TXA2 biosynthesis, determined a excretion of its enzymatic metabolite, 2,3-dinor-TXB2, was markedly increased during coronary thrombolysis. Furthermore, inhibition of TXA2 by aspirin, given alone or in combination with a TXA2/prostaglandin endoperoxide receptor antagonist, accelerated reperfusion and partly inhibited cyclic flow variations during reperfusion. The delay in reperfusion and reocclusion induced by TXA2 appeared to be mediated by platelet aggregation since the F(ab')2 fragment of 7E3, a monoclonal antibody to the platelet GPIIb/IIIa, also accelerated reperfusion and prevented reocclusion without altering TXA2 biosynthesis. These finding suggest that platelet aggregation limits the response to coronary thrombolysis and that platelet activation in this setting is partly TXA2-dependent.

Topics: Angiography; Animals; Antibodies, Monoclonal; Blood Coagulation; Blood Platelets; Coronary Disease; Coronary Thrombosis; Dogs; Epoprostenol; Fibrinolytic Agents; Immunoglobulin Fab Fragments; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Tissue Plasminogen Activator

Truly effective prevention of reperfusion myocardial damage is precluded in part by a lack of understanding of the earliest events which accompany ischemia. The purpose of this study was to assess the coronary endothelial response to two forms of ischemic injury in an isolated crystalloid perfused rabbit heart. Global cardiac ischemia, confirmed by NADH fluorescence photography, was induced either by mechanically reducing coronary flow by 90% (MRCF, N = 11) or by an infusion of N-formyl-methionyl-leucyl-phenylalanine (fMLP, N = 11), a known stimulus for leukotriene synthesis and coronary vasospasm. Compared with control, MRCF resulted in an increase in effluent concentrations of both prostacyclin (152 +/- 22 pg/ml vs 951 +/- 214 pg/ml, P less than 0.05) and plasminogen activator (0.8 +/- .3 IU/ml vs 1.4 +/- 0.5, P less than 0.05) but no detectable increase in effluent thromboxane B2 or leukotriene C4 concentrations. fMLP infusion resulted in an immediate reduction in coronary flow coincident with diffuse myocardial ischemia. In contrast to MRCF, however, fMLP-induced ischemia resulted in a significant but smaller increase in effluent prostacyclin concentration (210 +/- 47 pg/ml vs 606 +/- .55 pg/ml, P = 0.05) and a marked increase in both thromboxane B2 (less than or equal to 33 +/- 4 pg/ml vs 1141 +/- 375 pg/ml, P less than 0.05) and leukotriene C4 (less than 0.25 ng/ml vs 3.3 +/- 1.2 ng/ml, P less than 0.05) concentrations. Additionally, fMLP caused a reduction in effluent plasminogen activator activity (0.5 +/- 0.1 IU/ml vs 0.39 +/- 0.1 IU/ml, N = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Endothelium, Vascular; Fluorescence; Male; N-Formylmethionine Leucyl-Phenylalanine; NAD; Photography; Rabbits; SRS-A; Thromboxane B2; Tissue Plasminogen Activator

The effects on platelet function of a four-week administration of aspirin at a low dosage (100 mg daily) were compared in two groups, 14 healthy young volunteers and 14 patients with coronary heart disease. In both groups there occurred a clear inhibition of platelet aggregation with collagen (1 and 5 micrograms/l) and arachidonic acid (1 mmol/l) during the aspirin period. The inhibitory effect reached its maximum after three days, remaining at maximum for the remainder of the four weeks. Platelet functions returned to normal within eight days of discontinuing aspirin. The inhibitory effects went together with a definite in-vitro decrease in thromboxane synthesis. In both groups there was no change in aggregation velocity with adenosine diphosphate (ADP) as aggregation-inducing substance, while the frequency of irreversible aggregation decreased with submaximal concentrations of ADP (0.5 and 1.0 mumol/l). The results indicate that low-dose aspirin causes a definite inhibition of platelet function, in a similar manner, in both healthy subjects and patients with coronary heart disease.

Topics: Adenosine Diphosphate; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Collagen; Coronary Disease; Dose-Response Relationship, Drug; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Thromboxane B2; Time Factors

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Coronary Disease; In Vitro Techniques; Myocardial Reperfusion Injury; Prostaglandins; Rats; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adenylyl Cyclases; Blood Platelets; Coronary Disease; Epoprostenol; Female; Humans; Male; Middle Aged; Physical Exertion; Platelet Aggregation; Thromboxane B2

Activated polymorphonuclear leukocytes (PMNs) contribute to myocardial injury during ischemia and reperfusion. There is evidence that activation of the complement pathway may be one of the mechanisms of PMN activation during ischemia. Intracoronary infusion of complement C5a during normal perfusion pressure is associated with decreased coronary flow, contractile dysfunction, and PMN accumulation. The mechanisms responsible for these changes have not been identified. Thromboxane A2 (TXA2) is a potential mediator of this myocardial ischemic response. Activated PMNs produce TXA2, a known coronary vasoconstrictor, and TXA2 was shown to be a mediator of the pulmonary hypertensive response to activated complement. The goal of the present study was to determine if an enhanced TXA2 production is associated with the myocardial response to C5a and whether cyclooxygenase blockade would reduce the myocardial ischemia. In open-chest pigs, intracoronary C5a (500 ng) caused reversible reductions in blood flow (50.0% of control), regional contractile function (25.8% of control), leukocyte trapping (1.0 x 10(6) cells/g myocardium or a peak artery-coronary venous difference of 5.3 x 10(3) cells/microliters blood), and increased coronary venous TXB2 (the TXA2 breakdown product) from 1.6 pmol/ml to a peak of 6.9 pmol/ml. Cyclooxygenase blockade with aspirin or indomethacin, which prevented TXB2 production, did not alter the response in flow, function, or PMN trapping. Ibuprofen, a known direct inhibitor of PMNs in addition to its cyclooxygenase blockade effect, reduced the response slightly. The pig coronary vascular bed was responsive to the TXA2 agonist U46619, which reduced flow and function without PMN trapping. Mechanical reductions in coronary flow to levels equivalent to those during the C5a infusions did not increase coronary venous TXB2 nor cause PMN trapping but did cause equivalent contractile dysfunction. Incubation of whole blood with C5a at concentrations equivalent to those achieved in vivo did not cause TXB2 production. We conclude that 1) TXA2 is produced in response to intracoronary C5a and 2) cyclooxygenase blockade does not prevent the C5a-induced myocardial ischemia, contractile dysfunction, and PMN trapping. The TXA2 production likely involves a vascular site or a blood cell-vascular interaction. This model system indicates the potential for persistently activated PMNs to cause continued ischemia during myocardial reperfusion.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aspirin; Complement C5a; Coronary Disease; Coronary Vessels; Cyclooxygenase Inhibitors; Female; Indomethacin; Injections, Intra-Arterial; Leukocyte Count; Leukocytes; Male; Myocardium; Prostaglandin Endoperoxides, Synthetic; Swine; Thromboxane B2; Thromboxanes

Divergent reports of the effects of exercise-induced myocardial ischaemia on platelet function require clarification. This study examines the relationship between exercise, exertional myocardial ischaemia, and in vivo and ex vivo platelet function in 27 male patients, aged 35 to 69, with stable coronary heart disease (CHD). All medications were ceased at least 5 days prior to a maximal exercise test. Blood was sampled before and after exercise to measure plasma and serum thromboxane B2 (TXB2), plasma beta-thromboglobulin (BTG), platelet count ratio (PCR), platelet count (PC), haemoglobin (Hb), haematocrit (Hct) and white cell count (WCC). The exercise test and blood measurements were repeated 5 weeks later, under the same conditions to confirm the reproducibility of any changes. Thirteen patients had a positive test for ischaemia and 14 a negative test. The PC, Hb, Hct and WCC increased in all patients after exercise, confirming earlier reports. The BTG level increased (25 +/- 9 to 30 +/- 15 ng/ml, p less than 0.05; and 24 +/- 9 to 32 +/- 8 ng/ml, p less than 0.004 in the repeat test) and was unrelated to exertional ischaemia. A decrease in the PCR only occurred in the non-ischaemic group in the initial test (0.84 +/- 0.14 to 0.78 +/- 0.13, p less than 0.02) but was not reproducible (0.84 +/- 0.10 to 0.82 +/- 0.13). No change occurred in plasma TXB2 levels. Serum TXB2 increased after exercise in the ischaemic group (255 +/- 150 to 314 +/- 190 ng/ml, and 240 +/- 139 to 370 +/- 169 ng/ml, p less than 0.05) but not in the negative test group (467 +/- 255 to 441 +/- 174 ng/ml, and 421 +/- 299 to 464 +/- 297 ng/ml, p greater than 0.1). Serum TXB2 discriminated poorly between individuals with positive and negative exercise tests. Thus, stable exertional ischaemia does not activate circulating platelets nor is it associated a priori with activated platelets. It may be associated with an increase in maximum thromboxane A2 production capability. Brief strenuous exercise may activate platelets in CHD patients independent of exertional ischaemia.

Topics: beta-Thromboglobulin; Blood Platelets; Coronary Disease; Exercise; Exercise Test; Humans; Male; Middle Aged; Platelet Activation; Platelet Count; Platelet Function Tests; Thromboxane B2

Topics: Arrhythmias, Cardiac; Blood Viscosity; Coronary Disease; Dinoprost; Heart Conduction System; Humans; Nucleotides, Cyclic; Platelet Aggregation; Prognosis; Thrombosis; Thromboxane B2

Bradykinin, alone or in combination with prostaglandin, is thought to produce pain in patients with coronary heart disease. To elucidate this further, we have investigated and compared serum bradykinin, TXB2 and 6 KPGF1 alpha levels in patients with silent myocardial ischemia (SMI, n = 18), painful myocardial ischemia (PMI, n = 8) and normal subjects (NL, n = 18). In addition, SMI and PMI subjects were given exercise testing and the results then compared. After Holter monitoring for 48 hours, exercise testing was performed. Blood was sampled in the morning between the Holter and exercise regimen. Maximal heart rate, systolic blood pressure and the double products were not significantly different between the SMI and PMI groups. The duration of exercise for the SMI group was 7.08 +/- 2.1 min vs 5.9 +/- 1.9 in the PMI group (p less than 0.10). Plasma bradykinin was 14 +/- 3 pg/ml in the SMI group and 15 +/- 3 in the PMI group (N.S), whereas it was 7 +/- 4 in the NL (p less than 0.05). The TXB2/6KPGF1 alpha for the SMI group was 1.3 +/- 0.3, which was significantly higher than that for the NL group (0.8 +/- 0.3, p less than 0.01), though this did not greatly differ from the PMI group (1.2 +/- 0.3). These results suggest that SMI patients under Holter monitoring who manifest no symptoms but show significant ST segment depressions must receive the same careful attention given to PMI patients. In both group of patients bradykinin and prostaglandin metabolism is similarly changed, as was demonstrated by exercise stress testing.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angina Pectoris; Bradykinin; Coronary Disease; Electrocardiography, Ambulatory; Exercise Test; Humans; Male; Middle Aged; Thromboxane B2

In mild stenosis, coronary blood flow (CBF) was unchanged, thromboxane (TX) B2/6-ketoprostaglandin (PG) F1a ratio rose with no change in PAgT. In critical stenosis, CBF was slightly decreased, PAgT, TXB2 and TXB2/PGF1a ratio rose with cyclical reduction in CBF. In severe stenosis, CBF was markedly decreased; PAgT, TXB2 and TXB2/6-keto-PGF1a ratio rose and 6-keto-PGF1a decreased with cyclical blood flow reduction. Histopathologic examination confirmed the presence of damaged endothelial cell with coronary thrombosis and platelet/fibrin microemboli in critical and severe stenosis. It is concluded that coronary artery stenosis leads to a damage of endothelial cell, which causes an abnormality in platelet function and coronary thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Coronary Disease; Coronary Vessels; Dogs; Endothelium, Vascular; Female; Male; Platelet Aggregation; Thromboxane B2

Experiments were performed on 54 anesthetized, open-chest dogs to observe the effect of cardiac sympathetic nerves and alpha- and beta-adrenoceptor blockades on changes of platelet function during the early phase of myocardial ischemia. It was shown that contents of TXB2 and 6-keto-PGF1 alpha after coronary occlusion were markedly increased, and the platelet count was reduced in the coronary venous blood of ischemic myocardium. It was found that the changes in parameters of platelet function after coronary occlusion were significantly relieved by topical application of lignocaine-soaked gauze pads to the ischemic area of the heart or by bilateral stellectomy for blocking impulse of afferent and efferent of cardiac sympathetic nerves, compared with changes in parameters of control group, P less than 0.01. On the other hand, changes in parameters of the control group could be restored by intravenous infusion of noradrenaline to dogs which bilateral stellectomy was performed on, but not by infusion of normal saline. Different effects of alpha- and beta-adrenoceptor blockades on the changes in aforementioned parameters were found. The changing degrees in elevation of TXB2 and 6-keto-PGF1 alpha and in decrease of platelet count were significantly relieved by intravenous infusion of yohimbine (an alpha 2-blocker), phentolamine (a nonselective alpha-blocker), and propranolol (a beta-blocker), but not by infusion of prazosin (an alpha 1-blocker). Results were compared with the control group, P less than 0.01. These results suggest that cardiac sympathetic nerves play an important role for the changes of platelet function during the early phase of myocardial ischemia and that, yohimbine and phentolamine may exert an improving effect by blocking alpha 2-receptors on the platelet membrane, and propranolol may directly contribute to stabilization of the platelet membrane.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Dogs; Female; Heart; Male; Sympathetic Nervous System; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Dogs; Kinetics; Myocardium; Thromboxane B2

We studied the effect of pretreatment with two doses of the thromboxane antagonist BM 13.177 and its solvent on the development of electrically induced coronary artery thrombosis in pigs. Results were compared with those obtained in animals pretreated with intravenously administered acetylsalicylate and its solvent. The effects of both compounds on the overall cardiovascular performance (heart rate, mean arterial blood pressure, cardiac output, systemic vascular resistance) were minimal. In the animals receiving solvent or acetylsalicylate the time to occlusive coronary thrombosis was 33 +/- 4 and 32 +/- 6 min, respectively. BM 13.177, in a dose of 5 mg.kg-1, did not modify the time to thrombotic occlusion (35 +/- 7 min), but in six of the eight animals that had received 10 mg.kg-1 BM 13.177, there was no occlusion within 120 min. In the acetylsalicylate-treated animals, collagen-induced platelet aggregation and plasma thromboxane B2 declined by 72 and 82%, respectively. The decreases were 46 and 20%, respectively, with the higher dose of BM 13.177. It is concluded that, in this porcine model of coronary artery thrombosis, the thromboxane antagonist BM 13.177 effectively suppressed formation of occlusive thrombi whereas acetylsalicylate was ineffective at a dose that lowered arterial thromboxane levels.

Topics: Animals; Anti-Arrhythmia Agents; Aspirin; Coronary Disease; Coronary Thrombosis; Electric Stimulation; Hemodynamics; In Vitro Techniques; Platelet Aggregation; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Swine; Thromboxane B2

We studied the effects of a thrombolytic agent (t-PA) and a thromboxane synthetase inhibitor (CGS-13080) in a model of myocardial ischemia and reperfusion. Occlusion of the left anterior descending coronary artery for 2 hours followed by 4 hours of reperfusion in anesthetized cats results in a large washout of creatine kinase into the blood (32 +/- 7 IU/mg protein) and an area of necrotic tissue comprising 52 +/- 5% of the area at risk and 9 +/- 0.6% of the left ventricle. Intravenous administration of t-PA (500 IU/kg.min) for 30 minutes alone at reperfusion or infusion of CGS-13080 (500 micrograms/kg.hr) had no effect on washout of creatine kinase or extent of necrotic tissue development. Administration of the same doses of both t-PA and CGS-13080 together markedly attenuated creatine kinase release to 10 +/- 2 IU/mg protein (p less than 0.01) and reduced the area of necrotic tissue to 9 +/- 2% of the area at risk and only 1.3 +/- 0.3% of the left ventricle (p less than 0.001). No significant sustained effects of these agents were observed on mean arterial blood pressure, heart rate, or the pressure rate index in these experiments. Thus, t-PA and CGS-13080 exert synergistic effects in preserving myocardial integrity in cats subjected to acute myocardial ischemia followed by reperfusion. The mechanism of this beneficial effect does not appear to be via reduced myocardial oxygen demand, increased myocardial oxygen supply, or enhanced inhibition of thromboxane A2 formation. The mechanism of this anti-ischemic effect is not clear but may involve a metabolic or a cytoprotective effect.

Topics: Animals; Cats; Coronary Disease; Creatine Kinase; Drug Synergism; Hemodynamics; Imidazoles; Male; Myocardium; Necrosis; Pyridines; Thromboxane B2; Thromboxane-A Synthase; Tissue Plasminogen Activator

It has been suggested that coronary ischemia increases extravascular lung water. To determine whether pulmonary microvascular permeability is increased by coronary ischemia, we measured pulmonary hemodynamics, lung lymph flow (QL), and lymph-to-plasma protein concentration ratio (L/P) in 12 sheep with chronic lung lymph fistulas. Studies were done in 3 groups: in group 1 (n = 7) a marginal branch of the left circumflex artery (Lcx) was occluded, in group 2 (n = 5) left atrial pressure (Pla) was mechanically raised by 10 mmHg, and in group 3 (n = 5) Lcx was occluded and Pla was raised by 10 mmHg. In group 1, coronary occlusion increased QL (4.6 +/- 0.4 to 8.3 +/- 2.6 ml/h) without changes in L/P. In group 2, elevated Pla increased QL (5.1 +/- 1.2 to 10.1 +/- 3.0 ml/h) with decreases in L/P (0.71 +/- 0.02 to 0.61 +/- 0.02). In group 3, coronary occlusion with elevated Pla caused a further increase in QL (5.0 +/- 1.5 to 16.9 +/- 4.6 ml/h) without significant decreases in L/P (0.71 +/- 0.01 to 0.65 +/- 0.06). Lung lymph concentrations of 6-keto-prostaglandin F1 alpha (a degradation product of prostacyclin) increased transiently after coronary occlusion. These results indicate that coronary occlusion can increase transcapillary protein transport in lungs of conscious sheep and simultaneously increase prostacyclin production in the lung.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Permeability; Coronary Disease; Extracellular Space; Hemodynamics; Leukocyte Count; Lung; Lymph; Myocardial Infarction; Oxygen; Platelet Count; Sheep; Thromboxane B2

Prostaglandin endoperoxides (PGG2/PGH2), precursors of thromboxane (TX) A2 and prostaglandins, may accumulate sufficiently in the presence of a TXA2 synthase inhibitor to exert biological activity. To address whether this modulates the response to TXA2 synthase inhibition in the setting of thrombosis in vivo, we examined the interaction of a TXA2 synthase inhibitor (U63,557a) and a TXA2/prostaglandin endoperoxide receptor antagonist (L636,499) in a canine model of coronary thrombosis after electrically induced endothelial injury. U63,557a exerted little inhibitory effect in this model despite a marked reduction in serum TXB2 and urinary 2,3-dinor-TXB2, an index of TXA2 biosynthesis. Combination of the two drugs was more effective than either drug alone. The enhanced effect achieved upon addition of the TXA2/prostaglandin endoperoxide receptor antagonist to the TXA2 synthase inhibitor suggests that the response to the latter compound was limited by the proaggregatory effects of prostaglandin endoperoxides. The increased effect of the combination over the receptor antagonist alone may reflect metabolism of PGG2/PGH2 to platelet inhibitory prostaglandins. This is supported by the following findings: (a) urinary 2,3-dinor-6-keto-PGF1 alpha, an index of prostacyclin biosynthesis, increased after administration of the synthase inhibitor, an effect that was exaggerated in the presence of thrombosis; (b) inhibition of arachidonate-induced platelet aggregation by U63,557a was dependent on the formation of a platelet-inhibitory prostaglandin; and (c) pretreatment with aspirin abolished the synergism between these compounds. These studies demonstrate that prostaglandin endoperoxides modulate the response to TXA2 synthase inhibition in vivo and identify a drug combination of potential therapeutic efficacy in the prevention of thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Coronary Thrombosis; Dibenzothiepins; Dogs; Male; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Thromboxane B2; Thromboxane-A Synthase

The role of thromboxane as a contributor to the genesis of ventricular tachycardia and fibrillation was examined in conscious dogs which had been subjected to myocardial infarction. CGS 12970, a thromboxane synthetase inhibitor was administered in a dose of 10 mg/kg (i.v.) every 12 h. Ex vivo thrombin-activated thromboxane synthesis, as determined by assay for thromboxane B2, was reduced to 15% of baseline 2 h after administration of CGS 12970. Drug administration was found to inhibit ex vivo platelet aggregation significantly in response to arachidonic acid, while aggregation to ADP and collagen was unaffected. CGS 12970 did not protect against the induction of ventricular tachycardia by programmed electrical stimulation of the postinfarcted heart. During provocative electrical stimulation, 9 of 11 (82%) animals continued to respond in the post-treatment period with the development of VT. Pretreatment with CGS 12970 failed to prevent the spontaneous development of ventricular fibrillation which occurred in 7 of 10 (70%) animals when a secondary ischemic event was superimposed in the region of the noninfarct-related circumflex coronary artery. The results suggest that the thromboxane synthetase inhibitor, CGS 12970, when administered in the subacute phase of recovery from myocardial infarction, does not protect against the induction of ventricular tachycardia by programmed electrical stimulation or the spontaneous development of ventricular fibrillation in the postinfarcted canine heart. The findings suggest that thromboxane may not serve a critical role in the genesis of ventricular tachyarrhythmias and ventricular fibrillation in the postinfarcted canine heart.

Topics: Animals; Coronary Disease; Coronary Thrombosis; Death, Sudden; Dogs; Electric Stimulation; Electrodes, Implanted; Electrophysiology; Female; Heart Rate; In Vitro Techniques; Male; Myocardial Infarction; Platelet Aggregation; Pyridines; Tachycardia; Thromboxane B2; Thromboxane-A Synthase; Ventricular Fibrillation

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cholesterol, Dietary; Coronary Disease; Humans; Iodine Radioisotopes; Rabbits; Radioimmunoassay; Thromboxane B2

Topics: Animals; Coronary Disease; Humans; Radioimmunoassay; Rats; Thromboxane B2

The lamprey (Entosphenus japonicus Martens) has been recommended in Japan as an efficacious diet for curing some of chronic inflammatory disorders. Fresh lamprey is rich in n-3 unsaturated fatty acids (e.g., eicosapentaenoic and docosahexaenoic acids) with minimal seasonal variation. The dietary effect of lamprey oil on acute myocardial ischemia was therefore investigated. Rats were fed a control diet or a diet supplemented with 5% safflower oil (SO) or 5% lamprey oil (LO) for 4 weeks. After coronary artery ligation, rats fed the LO diet demonstrated a higher 24-h survival rate and a reduced loss of creatine kinase activity from ischemic myocardium when compared with rats fed the control or SO diet. Moreover, the intracellular redistribution of lysosomal enzyme activity in the ischemic myocardium was significantly suppressed in the LO diet group. Analysis of the fatty acid composition of myocardial phospholipids in rats fed LO showed marked elevation of n-3 fatty acids, whereas arachidonic acid (n-6) content was significantly reduced. Hence, the n-3/n-6 ratio of myocardial phospholipids was markedly increased in the LO diet group. In addition, there was more than a 77% reduction in TXB2 synthetic capacity in whole blood in rats fed the LO diet when compared with rats fed either the control or SO diet. In conclusion, dietary supplementation with LO prevents sudden cardiac death and limits the extension of cellular damage from acute myocardial ischemia in rats. Both changes in thromboxane generation and altered membrane fatty acid composition may be involved in the observed reduction of ischemic damage in the heart.

Topics: Animals; Body Weight; Coronary Disease; Dietary Fats, Unsaturated; Fatty Acids; Fish Oils; Heart; Hematologic Tests; Lampreys; Male; Organ Size; Rats; Rats, Inbred Strains; Thromboxane B2

The metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), 6-keto-PGF1 alpha and thromboxane B2 (TxB2), were investigated during reperfusion (RP) following warm (37 degrees C, 60 min, n = 9) or cold (15 degrees C, 120 min, n = 11) ischemia induced by cold (4 degrees C) or normothermic (30 degrees C) K+ cardioplegia (CP) in isolated canine hearts subjected to global ischemia and RP. 6-Keto-PGF1 alpha flux was significantly higher (p less than 0.025) in the warm group at 1, 5, and 10 min of RP (4,202 +/- 1,412, 2,475 +/- 1,875, and 1,255 +/- 633 pg/g.min, mean +/- SD) compared to those in the cold group (1,504 +/- 1,245, 434 +/- 641, and 370 +/- 329 pg/g.min). TxB2 flux was small in amount compared to 6-keto-PGF1 alpha in both groups. Regarding the coronary hemodynamics, the cold group alone showed statistically significant relationships of coronary sinus blood flow to TxB2 level and TxB2/6-keto-PGF1 alpha ratio in coronary sinus blood. Also, coronary vascular resistance showed linear relations to these two parameters of the metabolites. In a supplementary experiment only with cold ischemia for 180 min, 6-keto-PGF1 alpha was released at each coronary flush-out by CP and the incremental amount showed a gradual increase during ischemia. These results indicated that significant production and release of PGI2 occurred during ischemia and RP following CP arrest and these related to the degree of myocardial damage while the response of TxA2 seemed less significant. The role of PGI2 release during RP following cardioplegic arrest was discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Dogs; Epoprostenol; Hemodynamics; In Vitro Techniques; Perfusion; Temperature; Thromboxane A2; Thromboxane B2

Reperfusion of ischemic tissue is responsible for production of metabolites with deleterious local vascular effects. Thromboxane A2, a potent vasoconstrictor and platelet aggregator, has been implicated as a mediator of the "reperfusion injury." We studied the effect of an experimental thromboxane synthetase inhibitor, OKY-046, on coronary sinus thromboxane levels, ventricular irritability, myocardial contractility, infarct salvage, and histologic features of reperfusion. Sixteen sheep were randomized to OKY-046, 3 mg/kg, or saline vehicle before 3-hour occlusion and subsequent reperfusion of the left anterior descending artery. The OKY group demonstrated less ventricular irritability as measured by incidence of ventricular fibrillation and necessity for countershock to reverse tachyarrhythmias. Coronary sinus thromboxane levels were significantly lower in the OKY group compared with the control group. There is additional evidence to suggest that OKY increases infarct salvage and attenuates histologic features of microcirculatory damage.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Methacrylates; Microcirculation; Myocardial Contraction; Random Allocation; Sheep; Thromboxane B2; Thromboxane-A Synthase; Ventricular Fibrillation

Two different methods of causing myocardial oxygen demand and supply imbalance; symptom limited treadmill exercise and right atrial pacing stimulation, were used to examine the alteration of hemodynamics and the effects upon sympathetic nerve activities, platelet functions and prostaglandin synthesis in patients with coronary artery disease (CAD). Age and sex distributions, the cardiothoracic ratio, left ventricular end-diastolic pressure, ejection fraction and coronary artery obstructions of the patients did not differ significantly between the two tests. Arterial blood samples were obtained to assay for plasma catecholamine, beta-thromboglobulin (beta TG), platelet factor 4 (PF4), TXB2 (thromboxane B2) and 6 keto-PGF1-alpha (6 ketoprostaglandin F1-alpha) without any difficulties before and immediately after testing. The arterial systolic pressure and pressure rate product (PRP) were changed more significantly by treadmill exercise than pacing, while the DPTI/TTI (diastolic pressure time index/tension time index) ratio and ST segment deviations showed similar changes with both tests. The plasma NE (norepinephrine) level, beta TG, PF4, and TXB2/6 keto-PGF1-alpha were significantly elevated by treadmill exercise, but not by pacing. 6 keto-PGF1-alpha was not markedly affected by either tests. There were no significant differences between the patients with and without anginal pain either in hemodynamics or metabolites. Significant relationships were observed between changes in plasma NE levels and the PRP (r = 0.76, n = 26, p less than 0.01) and also changes in the arterial systolic pressure (r = 0.64, n = 26, p less than 0.01), but there were no significant correlations between any other hemodynamic parameters with plasma NE, platelet function, prostaglandin activity, or between each metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; beta-Thromboglobulin; Cardiac Pacing, Artificial; Chronic Disease; Coronary Disease; Electrocardiography; Epinephrine; Exercise Test; Female; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Platelet Factor 4; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; beta-Thromboglobulin; Coronary Disease; Female; Humans; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Middle Aged; Plant Extracts; Plants, Medicinal; Platelet Aggregation; Platelet Factor 4; Thromboxane B2

We studied the levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), platelet aggregability, beta-thromboglobulin and platelet factor 4 in 30 coronary artery disease (CAD) patients and 21 normal subjects during exercise. During treadmill exercise, 13 of 30 CAD patients reported chest pain. We administered a selective thromboxane synthetase inhibitor (OKY-046) for 2 weeks to 10 CAD patients with exercise-induced chest pain and studied its effects. At rest, the plasma TXB2 levels and platelet aggregation were significantly lower in normal subjects than in CAD patients, and there was no difference between CAD patients with and without exercise-induced chest pain. On treadmill testing, plasma TXB2 levels and platelet aggregation increased significantly only in the CAD patients with exercise-induced chest pain. Plasma 6-keto-PGF1 alpha levels in normal subjects were significantly higher than those in CAD patients both at rest and during exercise. After administration of OKY-046, mean exercise time increased significantly from 7.5 to 8.6 min (p less than 0.001). Plasma TXB2 level and platelet aggregation decreased significantly after OKY-046 administration both at rest and during exercise. These results suggest that a marked increase in TXA2, with only a minimal change in PGI2, during exercise may contribute to exercise-induced myocardial ischemia, and that OKY-046 is useful in the treatment of CAD patients.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Angina Pectoris; Coronary Disease; Epoprostenol; Female; Humans; Male; Methacrylates; Physical Exertion; Platelet Aggregation; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

The effects of ovariectomy on serum 6-keto-PGF1 alpha and TXB2 concentrations and platelet fatty acids were investigated. One month after ovariectomy the levels of 6-keto-PGF1 alpha were unaltered, whereas those of TXB2 were significantly increased. Ovariectomy had no effect on the fatty acid composition of platelets. Thus, the present study suggests that the hormonal changes at the time of menopause may modify the formation of metabolites of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Platelets; Coronary Disease; Fatty Acids; Female; Humans; Menopause; Middle Aged; Ovariectomy; Risk; Thromboxane B2

Platelet activation (aggregation, serotonin release, TXB2 synthesis) was studied in 8 normal subjects and 5 patients with unstable angina before and after molsidomine treatment. Serotonin release was the most altered parameter after molsidomine treatment in the group of normal subjects. No significant effect could be detected in patients since platelet reactivity varied in a wide range.

Topics: Administration, Oral; Adult; Blood Platelets; Coronary Disease; Female; Humans; Male; Molsidomine; Platelet Aggregation; Serotonin; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Coronary Disease; Female; Humans; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Middle Aged; Plant Extracts; Plants, Medicinal; Platelet Adhesiveness; Platelet Aggregation; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Coronary Disease; Female; Humans; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Middle Aged; Plants, Medicinal; Thromboxane B2

Topics: Adult; Aged; Animals; Coronary Disease; Diabetes Mellitus; Endotoxins; Escherichia coli; Female; Humans; Male; Middle Aged; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2; Toxemia

Blood endogenous prostaglandins, E, F2 alpha, prostacyclin and thromboxane levels were measured in the ascending aorta and the coronary sinus of 32 patients (29 males and 3 females) with paroxysmal supraventricular arrhythmias (atrial fibrillation and supraventricular tachycardia) during the sinus rhythm and an arrhythmic paroxysm. Group 1 was made up by 22 patients with idiopathic cardiac rhythm disorders, and group 2 comprised 10 coronary patients with arrhythmias. A relationship was demonstrated between cardiac endogenous prostanoids balance and the clinical pattern of cardiac rhythm abnormality (duration and frequency of paroxysms) as well as changes in cardiac prostanoid rations associated with tachyarrhythmic paroxysms.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Chronic Disease; Coronary Disease; Dinoprost; Female; Humans; Male; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Tachycardia, Paroxysmal; Tachycardia, Supraventricular; Thromboxane B2

Blood platelets have been implicated in several mechanisms leading to and/or modifying myocardial ischemia. Cardiac lymph examination allows insight into the extracellular fluid that is in equilibrium with the capillary blood. In order to obtain an index of platelet activation during coronary artery events in the awake chronic animal, we wished to ascertain whether evaluation of cardiac lymph would detect changes in platelet activation resulting from a vascular occlusion. The study used conscious dogs in which cardiac lymph vessels had been previously cannulated by open-chest surgical protocol. The concentrations of immunoreactive thromboxane B2 and platelet counts were assessed in the cardiac lymph during the control period, the 10-60 minute occlusions, and the reperfusion periods. The same protocols were effected on another series of dogs after infusion of ibuprofen or prostacyclin. Initially, immunoreactive thromboxane B2 concentrations in the systemic blood and cardiac lymph were identical. A three-fold increase in immunoreactive thromboxane B2 concentrations occurred in untreated animals and was accompanied by a fall in platelet count in the lymph. The infusion of ibuprofen or prostacyclin, which inhibit platelet aggregation by different mechanisms, prevented both the decrease in platelets and the increase in immunoreactive thromboxane B2. In this study, intravascular events resulting from coronary occlusion invoke a rapid rise of immunoreactive thromboxane B2 in the extravascular fluid. A decrease in platelet escape into the extravascular compartment is interpreted as a result of intravascular aggregation promoting decreased platelet numbers. Thus, examination of continuously flowing cardiac lymph allows rapid detection of intravascular activation of platelets in the awake animal in the absence of surgical trauma.

Topics: Animals; Blood Platelets; Coronary Disease; Dogs; Epoprostenol; Ibuprofen; Lymph; Platelet Aggregation; Platelet Count; Thromboxane B2

The antithrombotic potential of the thromboxane (TX) synthetase inhibitor CGS 13080 (CGS) was studied in an anesthetized open-chest canine model of coronary artery intimal wall injury induced by the local application of a low amperage electrical current (100 microA for 6 hr). CGS was administered by i.v. infusion (1 mg/kg/min) beginning 30 min before applying the direct current to the intimal wall of the vessel. CGS did not alter basal values for heart rate, blood pressure or coronary blood flow. After 6 hr of current application to the vessel, 1 of 10 CGS-treated dogs exhibited complete thrombotic occlusion of the circumflex coronary artery compared to 8 of 10 nontreated control dogs (P less than .01). Thrombus masses within the injured left circumflex coronary artery were: Control, 25.9 +/- 4.5 mg (n = 10) and CGS, 11.0 +/- 2.8 mg (n = 10); P less than .01. The concentration of TXB2 determined ex vivo in serum from thrombin-activated whole blood was decreased by CGS administration: Control, 43.15 +/- 16.08 ng/ml (n = 9) vs. CGS, 1.72 +/- .69 ng/ml (n = 10); P less than .001. Ex vivo platelet aggregometry demonstrated that arachidonic acid (0.65 mM)-induced aggregation was reduced from a control value of 82.3 +/- 7.8% (n = 10) to 45.0 +/- 11.3% (n = 10) (P less than .05), whereas aggregation in response to ADP (5 micrograms/ml) or collagen (156 and 312 micrograms/ml) was unaffected. CGS was compared with two other TX synthetase inhibitors, U63557A and OKY1581, for the ability to divert cyclic endoperoxide metabolism to the synthesis of prostaglandin (PG) E2 and prostacyclin in response to stimulation of whole blood in vitro with collagen (25 micrograms/ml). CGS, U63557A and OKY 1581 were found to be equally effective with respect to PGE2 and 6-keto PGF1 alpha production in vitro. The data demonstrate that CGS is an effective antithrombotic agent in vivo and that it selectively inhibits arachidonic acid-induced platelet aggregation ex vivo and the formation of TXA2 in thrombin-activated whole blood.

Topics: Animals; Blood Pressure; Collagen; Coronary Circulation; Coronary Disease; Dogs; Heart Rate; Imidazoles; Male; Platelet Aggregation; Pyridines; Thromboxane B2; Thromboxane-A Synthase

We studied the effect of cod-liver oil on the development and progression of coronary artery disease in swine subjected to coronary balloon abrasion and fed an atherogenic diet for eight months. Sections from serial 3-mm segments of the coronary arteries were analyzed morphometrically in 7 pigs given a cod-liver-oil supplement and 11 control animals not given the supplement. Significantly less disease was seen in the sections from the animals fed cod-liver oil. The mean lesion area per vessel, mean luminal encroachment per vessel, and mean maximal luminal encroachment per vessel were reduced in animals fed cod-liver oil, as compared with controls, (P = 0.05, P = 0.016, and P = 0.011, respectively). Both groups of animals had severe hyperlipidemia throughout the study. Differences in the extent of coronary atherosclerosis were not related to differences in plasma lipid levels. Platelet arachidonate was markedly reduced, platelet eicosapentaenoic acid was increased, and serum thromboxane was decreased in the oil-fed group as compared with the control group. We conclude that in our animal mode, dietary cod-liver oil retarded the development of coronary artery disease, possibly through changes in prostaglandin metabolism.

Topics: Animals; Arachidonic Acids; Blood Platelets; Cod Liver Oil; Coronary Disease; Coronary Vessels; Diet, Atherogenic; Disease Models, Animal; Fish Oils; Hyperlipidemias; Lipids; Male; Swine; Thromboxane B2

The levels of TxB2 and 6-keto-PGI alpha in the coronary sinus and thoracic aorta blood were determined in 14 patients with angina pectoris and signs of coronary atherosclerosis. 12 patients were involved in a dynamic study: before, during and 10 minutes after ischaemia-inducing atrial pacing. In all the patients atrial pacing resulted in a typical episode of angina, in 7 of them ST-segment depression of not less than 2 mm was seen on the ECG. In one patient arachidonic acid metabolites were evaluated during the control period and during a spontaneous episode of angina accompanied by ST-segment elevations. In 8 of 9 patients TxB2 was produced by the myocardium during atrial pacing. During monitored evaluation of arachidonic acid metabolites one patient with spontaneous angina demonstrated a gradual lowering of the 6-keto-PGI alpha, it being minimal by the beginning of the episode; TxB2 level increased more rapidly.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Angina Pectoris; Coronary Disease; Electric Stimulation; Heart Atria; Humans; Male; Middle Aged; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Coronary Disease; Humans; Hyperlipoproteinemias; Lipids; Male; Middle Aged; Oxidation-Reduction; Thromboxane B2

Ten weeks old male Sprague-Dawley rats were used. One mg/kg of a calfskin type III collagen was injected into a tail vein under pentobarbital anesthesia, and the electrocardiogram (ECG) was recorded via leads I, II and III for 10 min. Abnormal ECG patterns, i.e., ST-T changes and incidence of arrhythmia, were shown after collagen injection, and some rats suffered cardiac arrest. Oral administration of (E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151), a thromboxane synthetase inhibitor, at the dose of 10 mg/kg two hr before the collagen injection made the ST-T changes small, and it reduced the incidence of cardiac arrest. The effect of CV-4151 was greater than that of 30 mg/kg of ticlopidine with the same type of treatment. Neither CV-4151 nor ticlopidine had any affect on collagen-induced decreases in the blood platelet count. However, plasma thromboxane (TX) B2 level in the CV-4151-treated group was very low in comparison with those in both the control and ticlopidine-treated groups at 10 min after the collagen injection. These findings indicate that TXA2 may contribute, at least partly, to the collagen-induced ECG changes and indicate that CV-4151 might be a favorable agent for the prevention of TXA2-mediated cardiac ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Collagen; Coronary Disease; Electrocardiography; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Humans; Pyridines; Rats; Rats, Inbred Strains; Thiophenes; Thromboxane B2; Ticlopidine

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.

Topics: Adenosine Diphosphate; Animals; Arrhythmias, Cardiac; Cardiac Output; Coronary Disease; Dogs; Electrocardiography; Heart Rate; Heart Ventricles; Molsidomine; Oxadiazoles; Platelet Aggregation; Sydnones; Thromboxane B2; Vascular Resistance

Platelet aggregation, prostacyclin and thromboxane were studied in 35 individuals: 20 coronary patients with angina of effort and 15 high-risk patients before and after treatment with lidocaine and pyromecaine. Oral administration of lidocaine and pyromecaine pills considerably depresses platelet aggregation and even causes platelet disaggregation. However, lidocaine disaggregating effect is greater than that of pyromecaine. Both agents affect vascular hemostasis by reducing thrombaxane and raising prostacyclin levels. Hence, the anti-aggregant effect of anti-arrhythmic proocaines may be attributed to changes in vascular hemostasis. The results obtained are expanding the range of indications for the use of these drugs.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Blood Platelets; Blood Vessels; Coronary Disease; Female; Hemostasis; Humans; Lidocaine; Male; Middle Aged; Platelet Aggregation; Prostaglandins F; Pyrrolidines; Thromboxane B2; Time Factors

Platelet/vascular and plasma elements of hemostasis were investigated in normal subjects and coronary patients under stimulated emotional stress, following the assessment of vascular wall antithrombogenic properties on the basis of evidence from short-term local vascular ischemia (the cuff test). In normal subjects, vascular wall antithrombotic properties remained unchanged, providing a sufficient anticoagulant and thrombolytic support under emotional stress and thereby protecting the body against thrombosis. Coronary patients showed depressed vascular-wall antiaggregant, anticoagulant and fibrinolytic activity and latent disseminated intravascular microcoagulation that tended to progress under mental stress, creating a risk of intravascular thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Coagulation; Blood Platelets; Blood Vessels; Coronary Disease; Disseminated Intravascular Coagulation; Hemostasis; Humans; Middle Aged; Nucleotides, Cyclic; Thromboxane B2

Immunoreactive thromboxane B2 (i-TXB2) was measured by radio-immunoassay (RIA) in urines collected over eight hours on the day of admission in 25 patients who were admitted with the diagnosis of myocardial infarction. In 16 of the patients myocardial infarction was confirmed by ECG and plasma enzymes. Another patient presented with pulmonary embolism and the remaining eight patients had angina pectoris. A further eight hour urine collection was obtained 24 hours later from eleven of the sixteen patients with myocardial infarction. In these eleven patients myocardial infarction was associated with five fold higher urine i-TXB2 (2.72 +/- 0.48 ng/ml) at the day of admission when compared to patients admitted under the same diagnosis but found to have angina only (0.51 +/- 0.08 ng/ml, p less than 0.001). In patients with myocardial infarction the urine i-TXB2 values were reduced 24 hours later (1.58 +/- 0.27 ng/ml, p less than 0.01). One patient was followed with urine i-TXB2 from three days prior to diagnosis of myocardial infarction and to one day prior to a second infarction. In this patient i-TXB2 was highest three days prior to infarction. We conclude that this early elevation of urine i-TXB2 three days prior to diagnosis of infarction and the increased i-TXB2 in patients with myocardial infarction when compared to patients with angina suggest thromboxane is probably released from activated platelets prior to infarction. We suggest that urine i-TXB2 may be of value in the differential diagnosis between myocardial infarction and angina.

Topics: Aged; Aged, 80 and over; Angina Pectoris; Coronary Disease; Coronary Thrombosis; Diagnosis, Differential; Humans; Middle Aged; Myocardial Infarction; Pulmonary Embolism; Radioimmunoassay; Thromboxane B2

Release of thromboxane (TXA2) during acute myocardial infarction may be an important contributing factor in the genesis of ventricular fibrillation (VF). We assessed the effect of selective TXA2 inhibition on vulnerability to VF after total occlusion of the anterior descending coronary artery in chloralose-anesthetized cats. Animals were pretreated with vehicle or with CGS-13080, a TXA2 synthetase inhibitor, 3.0 or 9.0 mg/kg intravenously. There was an apparent dose-dependent protective effect following CGS-13080 administration, in which the decrease in VF threshold following coronary occlusion was attenuated. Also, the incidence of spontaneous ventricular arrhythmia in the first 30 minutes after occlusion was reduced by two thirds in the 9.0 mg/kg CGS-13080 group compared to the vehicle-treated animals. This protective effect does not appear to be due to a change in hemodynamics, effective refractory periods, or extent of ischemia. TXA2 released during coronary occlusion appears to be arrhythmogenic, and inhibiting its synthesis may be protective.

Topics: Animals; Blood Pressure; Cats; Coronary Disease; Female; Heart Rate; Imidazoles; Male; Pyridines; Thromboxane B2; Thromboxane-A Synthase; Ventricular Fibrillation

The effects of dietary interventions, based on changes of total fat, saturated fatty acids and cholesterol contents and of the polyunsaturated/saturated (P/S) fatty acid ratio of the diet, were studied in normal male and female subjects, living in North Karelia, Finland, and South Italy. In North Karelia the increase of P/S ratio (from 0.15 to 1.2) of the diet for a 6-week period resulted in reduced thromboxane B2 (TxB2) production by collagen-stimulated platelets only in male subjects, whereas plasma total, LDL and HDL cholesterol were reduced in both sexes. After a 6-week return to the original diet, plasma lipid levels were restored in all subjects. In the South Italy study, changes in platelet TxB2 production were observed only after return to the original diet in male subjects. Total and LDL cholesterol were significantly increased during the dietary intervention and returned toward baseline levels after switch back to the original diet. These data indicate that the increase of the P/S ratio in the diet reduces platelet TxB2 formation only in men.

Topics: Adult; Blood Platelets; Cholesterol; Collagen; Coronary Disease; Dietary Fats; Fatty Acids; Fatty Acids, Unsaturated; Female; Finland; Humans; In Vitro Techniques; Italy; Lipids; Lipoproteins; Male; Middle Aged; Sex Factors; Thromboxane B2

Spontaneous increase in platelet activity and change in coronary vasomotor tone have been implicated in the pathogenesis of acute myocardial ischemia. To define the mechanism of platelet "hypersensitivity" in acute myocardial ischemia, we examined the status of platelet alpha 2-adrenergic receptors in patients hospitalized with severe unstable angina. With the use of the specific alpha 2-receptor antagonist 3H-yohimbine, we identified a 26% decrease in the receptor binding sites on platelet membranes from patients with unstable angina compared with controls (155 +/- 32 vs. 210 +/- 29 fmol/mg protein, P less than or equal to 0.005). The dissociation constants of 3H-yohimbine binding to platelet alpha 2-receptors were similar in both groups (3.3 +/- 1.1 and 4.1 +/- 1.6 nmol/L, P not significant). To study the alterations in the affinity of platelet alpha 2-receptors for the agonists, effects of 1-epinephrine on specific binding of 3H-yohimbine were examined. We observed a marked reduction in 1-epinephrine concentration for inhibition of antagonist binding by 50% in acute myocardial ischemia (IC50: 4.2 +/- 3.9 X 10(-8) vs. 6.7 +/- 3.4 X 10(-7) mol/L, P less than or equal to 0.01), indicating increase in platelet alpha 2-receptor affinity for the agonist. Platelet aggregation and thromboxane A2 generation in response to epinephrine were also significantly increased in the acute phase of myocardial ischemia. This study suggests enhanced affinity of platelet alpha 2-receptors to the agonist 1-epinephrine as a possible mechanism of platelet hypersensitivity in acute myocardial ischemia.

Topics: Acute Disease; Adrenergic alpha-Agonists; Aged; Angina Pectoris; Angina, Unstable; Blood Platelets; Catecholamines; Coronary Disease; Epinephrine; Humans; Male; Middle Aged; Platelet Aggregation; Receptors, Adrenergic, alpha; Thromboxane A2; Thromboxane B2; Yohimbine

Topics: Animals; Coronary Disease; Dogs; Epoprostenol; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Pyridines; Rats; Thrombosis; Thromboxane B2; Thromboxane-A Synthase

Plasma prostanoids and levels of cyclic nucleotides were studied in forty-nine outpatients with precordial pains and subjected to the treadmill exercise test. Blood samples were drawn before, immediately after and 30 minutes after exercise, from antecubital veins. Plasma TXB2, 6-keto PGF1 alpha, cyclic AMP and cyclic GMP levels were measured by radioimmunoassay. The results of exercise tests were evaluated according to the treadmill exercise score (TES) of Hollenberg et al. Patients were divided into two groups; those with TES (-) with ischemic findings in exercise and those with TES (+) with normal exercise response. There were no differences in TXB2 levels between the two groups before exercise. Immediately after exercise statistically significant differences in TXB2 levels were present between the two groups. There were increased levels in the TES (-) group and decreased levels in the TES (+) group (p less than 0.01). Although the 6-keto PGF1 alpha levels were the same between the two groups before exercise, 6-keto PGF1 alpha levels in the TES (+) group increased significantly immediately after exercise. Similar changes were noted in the case of cyclic nucleotides, and the differences increased immediately after exercise. We conclude that high responses of cyclic nucleotides and PGI2 are required to counteract increases in levels of TXA2 and diminution of these responses may be an important phenomenon involved in the physiological status of ischemic heart disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Coronary Disease; Cyclic AMP; Cyclic GMP; Exercise Test; Female; Humans; Male; Middle Aged; Physical Exertion; Thromboxane B2; Thromboxanes

The phospholipid platelet-activating factor (PAF) stimulates platelet aggregation and coronary vasoconstriction. In this study we determined whether PAF alters coronary flow patterns in vivo in a canine preparation with concentric coronary artery stenosis. This preparation is characterized by cyclic flow variations in coronary blood flow associated with transient platelet aggregation at the site of the coronary constriction. Thirty-nine male mongrel dogs were used in three protocols. In protocol 1, PAF (10(-9) or 10(-8) mol/min) was infused into the coronary artery proximal to the stenosis to determine (1) whether PAF induces cyclic flow variations and (2) whether PAF has an effect on systemic hemodynamics. Cyclic flow variations were induced in three of six dogs; in these animals, mean arterial pressure decreased by 5.5% and 42.1% 10 min after infusion of the lower and higher dose of PAF. In protocol 2, cyclic flow variations were abolished with either the thromboxane synthetase inhibitor UK38485 (mean dose 2.2 mg/kg iv), the serotonin antagonist ketanserin (0.5 mg/kg iv), or the alpha 2-adrenergic antagonist yohimbine (2 mg/kg iv). Subsequent administration of PAF restored the frequency of cyclic flow variations to the preantagonist levels. Thromboxane (Tx) B2 and 6-keto-PGF1 alpha, the stable metabolites of TxA2 and prostacyclin, respectively, were measured in blood obtained distal to the coronary stenosis. TxB2 levels increased substantially during cyclic flow variations and were returned to control values with the thromboxane synthetase inhibitor UK38485. Infusion of PAF subsequently restored cyclic flow variations without altering coronary arterial coronary arterial TxB2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic alpha-Antagonists; Animals; Arteriosclerosis; Coronary Circulation; Coronary Disease; Dogs; Hemodynamics; Imidazoles; Male; Platelet Activating Factor; Platelet Aggregation; Serotonin Antagonists; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Angina Pectoris; Coronary Disease; Humans; Methacrylates; Oxidoreductases; Physical Exertion; Platelet Aggregation; Prostaglandins; Thromboxane B2; Thromboxane-A Synthase

Topics: 6-Ketoprostaglandin F1 alpha; Angina Pectoris; Coronary Disease; Dinoprostone; Humans; Myocardium; Prostaglandins; Prostaglandins E; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Disease; Dogs; Epoprostenol; Lactates; Lactic Acid; Regional Blood Flow; Thromboxane B2; Thromboxanes

Platelet function and prostaglandin activity were evaluated in nine patients with coronary artery disease undergoing percutaneous left anterior descending coronary artery angioplasty (PTCA) and compared to nine normal controls. Transcoronary measurements (arterial-coronary sinus) of platelet counts, mean platelet volume, platelet factor 4 (PF4), beta thromboglobulin, thromboxane (B2), and 6-keto-PGF 1 alpha were made. When compared to normal controls, the patients with coronary artery disease had higher circulating baseline levels of PF4 in the coronary sinus. There was no transcardiac production of any factor at baseline or immediately after infusion of nitroglycerin or performance of PTCA. These results suggest that PTCA does not grossly alter arachidonic acid metabolism or platelet activity.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angioplasty, Balloon; beta-Thromboglobulin; Cardiac Catheterization; Coronary Disease; Humans; Middle Aged; Platelet Aggregation; Platelet Count; Platelet Factor 4; Prostaglandins; Thromboxane B2

The left anterior descending coronary artery (LAD) of five dogs was ligated, and blood was withdrawn from the great cardiac vein, left marginal cardiac vein, femoral vein, and aorta. After ligation, immunoreactive 6-ketoprostaglandin (PG) F1 alpha rose from less than 0.1 to a mean value of 1.2 pmol/ml plasma in the great cardiac vein (GCV) and 0.88 pmol/ml in the left marginal vein, with no change in peripheral circulation. Immunoreactive thromboxane (TX) B2 remained below 0.075 pmol/ml throughout the experiments. LAD of 11 dogs was stenosed 60-80% with consequent cyclical reductions in blood flow. 6-Keto-PGF1 alpha in GCV rose in seven dogs (range 0.5-2.2 pmol/ml) and remained unchanged in four. No change was observed in peripheral plasma levels of 6-keto-PGF1 alpha. In these experimental conditions TXB2 remained below 0.075 pmol/ml. Lactate concentrations rose in both experimental conditions in GCV but not in peripheral circulation or in the left marginal vein. This study confirms a link between cardiac ischemia and increased coronary prostacyclin release, but we were unable to detect a similar correlation with TXB2 in plasma.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteries; Constriction, Pathologic; Coronary Circulation; Coronary Disease; Dogs; Ligation; Male; Thromboxane B2; Thromboxanes

The action of AD6 as an anti-thrombotic agent was studied in a model of coronary artery thrombosis and on platelet aggregation in the dog. AD6 (10-100 microM) in vitro inhibited aggregation induced by ADP, epinephrine, collagen and PAF (platelet aggregating factor) used at their threshold concentration for maximal aggregation. Arterial thrombosis was induced in a coronary vessel by critically reducing (about 70%) the vessel lumen. Thrombus formation was estimated by measuring coronary flow in the stenosed vessel. Using this procedure on the left descending coronary artery (LAD), we obtained reproducible blood flow changes in 18 dogs. AD6 was given i.v. at three different doses. At 0.25 mg/kg two out of four dogs showed decreased thrombus formation at the stenosis site. Seven out of eleven dogs treated with 0.5 mg/kg and two out of three treated with 1.5 mg/kg showed decreased thrombus formation. Major decreases in coronary resistance, evaluated by measuring blood flow in the unstenosed left circumflex artery (LCX), were evident only after the highest dose. We conclude that AD6 has an inhibitory action on dog platelet aggregation and reduces thrombus formation in a stenosed coronary vessel.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Chromonar; Collagen; Coronary Disease; Coumarins; Disease Models, Animal; Dogs; Epinephrine; Male; Platelet Activating Factor; Platelet Aggregation; Regional Blood Flow; Thromboxane B2

The effects of aspirin on coronary hemodynamics and transcardiac concentrations of thromboxane B2 (the stable metabolite of thromboxane A2) were determined at rest and during pacing-induced myocardial ischemia in 11 patients with coronary disease. Control coronary sinus pacing increased both arterial thromboxane B2 (331 +/- 70 to 623 +/- 132 pg/ml, p less than 0.02) and coronary sinus thromboxane B2 (184 +/- 3 to 403 +/- 156 pg/ml, p less than 0.05), but positive transmyocardial gradients developed in only three patients. After 650 mg of oral aspirin, more than 90% inhibition of in vitro thromboxane B2 production was demonstrated and circulating thromboxane B2 was undetectable at rest and during pacing in all patients. Despite these changes in thromboxane B2 concentrations, coronary blood flow was unchanged by aspirin at rest (107 +/- 14 versus 112 +/- 13 ml/min, p = NS) and during pacing (189 +/- 29 versus 181 +/- 25 ml/min, p = NS). Myocardial lactate extraction was also unchanged at rest (24 +/- 7 versus 19 +/- 5%, p = NS) and during pacing (5 +/- 6 versus 9 +/- 5%, p = NS). No change occurred in the anginal threshold. Thus, aspirin does not have the vasoconstrictive properties that have been reported with another cyclo-oxygenase inhibitor, indomethacin. These findings also suggest that thromboxane A2 production does not play a major role in the pathogenesis of stress-induced ischemia. Nonetheless, intracoronary thromboxane A2 production in some patients may potentiate platelet activation and coronary thrombosis. Such patients may benefit from long-term aspirin therapy and can be treated with aspirin without risk of adverse coronary hemodynamic effects.

Topics: Administration, Oral; Adult; Aged; Angina Pectoris; Aspirin; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Disease; Female; Hemodynamics; Humans; Lactates; Lactic Acid; Male; Middle Aged; Myocardial Infarction; Thromboxane B2; Vascular Resistance

Platelet activation, with the subsequent generation of Thromboxane (Tx) A2, has been implied as a possible cause of resting as well as exercise induced myocardial ischemia. To verify the latter hypothesis, we measured the exercise release of TxB2, the stable metabolite of TxA2, in 9 patients with exertional angina and left anterior descending coronary artery disease. Three of the patients also suffered from angina at rest, due to coronary vasospasm. The great cardiac vein flow, venous efflux from the myocardial territory supplied by the left anterior descending, was determined by the thermodilution technique in the basal conditions, at peak exercise when angina and/or significant ST changes occurred, and 20 min after exercise. Simultaneous blood samples were drawn from the great cardiac vein and a peripheral artery for TxB2 measurements. Regional coronary resistances were calculated as the ratio of mean arterial pressure and coronary flow. At peak exercise the great cardiac vein flow increased and regional coronary resistances decreased in all patients, except in one who showed exercise induced coronary spasm. An increase in TxB2 release was found in 3 patients, a decrease in 3, while the remaining 3 patients did not show significant changes. After exercise the great cardiac vein flow and regional coronary resistances returned to control values in all, whereas both great cardiac vein and arterial TxB2 levels were increased in 6 patients. Our data show that no apparent relation exists between exercise-induced changes in coronary resistances and generation of TxB2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Coronary Circulation; Coronary Disease; Female; Humans; Male; Middle Aged; Physical Exertion; Thromboxane B2; Thromboxanes; Vascular Resistance

The hemodynamic effects of intracoronary leukotriene C4 (0.3 to 10.0 micrograms) in seven anesthetized dogs with normal and severely narrowed coronary arteries were examined. Intracoronary leukotriene C4 caused a significant dose-related reduction in coronary blood flow in both normal and narrowed coronary arteries with no effect on heart rate or mean arterial pressure. However, left ventricular end-diastolic pressure increased at the 10.0 micrograms dose. The reduction of blood flow in normal and narrowed coronary arteries in response to leukotriene C4 was similar. At the peak effects of leukotriene C4, there was evidence of intracoronary thromboxane A2 release. To examine the contribution of thromboxane A2 release to the coronary vasoconstrictor effects of leukotriene C4, dogs were administered leukotriene C4 after indomethacin pretreatment. The decrease in coronary blood flow was not significantly affected by pretreatment of the animals with indomethacin. However, indomethacin lowered baseline levels of thromboxane B2 and blocked the release of thromboxane A2 after leukotriene C4 administration. Thus, intracoronary leukotriene C4 causes direct dose-dependent decrease in coronary blood flow of similar magnitude in both normal and narrowed coronary arteries. These coronary hemodynamic effects of leukotriene C4 in dogs are not mediated by release of thromboxane A2. Leukotriene C4 released from activated leukocyte in the intracoronary thrombus or in the injured myocardium may reduce coronary blood flow and adversely influence the fate of the affected myocardial tissue.

Topics: Animals; Blood Pressure; Constriction, Pathologic; Coronary Circulation; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Female; Hemodynamics; Indomethacin; Leukocytes; Male; SRS-A; Thromboxane A2; Thromboxane B2

Radio-immunological assay of specific platelet substances in the serum allows assessment of in vivo platelet function at a given moment. Plasma levels of beta thromboglobulin (beta TG) platelet factor 4 (PF4) and thromboxane B2 (TXB2) were measured at rest and during exercise stress testing in 39 patients with known coronary artery disease with stable effort angina. The patients were divided into two groups according to the results of exercise ECG and thallium 201 myocardial scintigraphy: ischaemic (n = 28) and non-ischaemic (n = 11). Resting and exercise levels of the three platelet substances were compared with a group of normal controls (n = 14). The average control values at rest and on exercise were, respectively: PF4: 8.5 +/- 5 and 22 +/- 14 ng/ml; beta TG: 36 +/- 17 and 68 +/- 36 ng/ml and TXB2: 112 +/- 41 and 201 +/- 81 pg/ml. The average values of the non-ischaemic patients did not differ significantly, either at rest or during exercise. The variation of pathological values was higher in the ischaemic group. This seems to reflect the absence of univocal platelet behaviour and does not allow statistical comparison of mean values. Our results suggest the existence of an "unstable platelet syndrome", which seems to be associated with poor effort tolerance especially when present under resting conditions. There would seem to be a causal relationship between platelet instability and myocardial ischaemia, which would justify anti-platelet aggregation therapy in primary and secondary prophylaxis of myocardial infarction.

Topics: Adult; Aged; beta-Thromboglobulin; Blood Platelets; Coronary Angiography; Coronary Disease; Electrocardiography; Exercise Test; Female; Heart; Humans; Male; Middle Aged; Platelet Factor 4; Radioimmunoassay; Radioisotopes; Radionuclide Imaging; Thallium; Thromboxane B2

Topics: Adult; Angina, Unstable; Anticoagulants; Coronary Disease; Coronary Vessels; Electrocardiography; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Perfusion; Stroke Volume; Thiophenes; Thromboxane A2; Thromboxane B2; Ticlopidine; Tomography, Emission-Computed; Urokinase-Type Plasminogen Activator

The effects of the antithrombotic drug nafazatrom (BAY g 6575) were investigated in chloralose-anaesthetized greyhounds subject to coronary artery occlusion and reperfusion. Pretreatment with nafazatrom 10 mg/kg p.o. did not significantly reduce the number of extrasystoles or the incidence of ventricular fibrillation (VF) during the first 30 min occlusion of the left anterior descending coronary artery. However, the incidence of VF resulting from release of a 40-min coronary artery occlusion was markedly reduced (from 88% in the controls to 14% in the nafazatrom group). Both thromboxane B2 (TxB2) and 6-keto PGF1 alpha (breakdown products of TxA2 and prostacyclin respectively) were released from the acutely ischaemic myocardium in control dogs. Nafazatrom did not alter the release of TxB2 but the concentrations of 6-keto PGF1 alpha were elevated in blood draining from both the ischaemic and normal regions of the myocardium. The pronounced anti-fibrillatory effect of nafazatrom during reperfusion of the ischaemic myocardium may be related to the ability of this drug to elevate prostacyclin concentrations in the coronary circulation.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthesia; Animals; Arrhythmias, Cardiac; Coronary Disease; Dogs; Epoprostenol; Female; Fibrinolytic Agents; Male; Perfusion; Prostaglandins; Pyrazoles; Pyrazolones; Thromboxane B2

Topics: Adult; Aged; Angina Pectoris; Angina Pectoris, Variant; Angina, Unstable; Aorta; Aspirin; Blood Pressure; Coronary Circulation; Coronary Disease; Coronary Vessels; Epoprostenol; Female; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Prostaglandins; Thromboxane A2; Thromboxane B2

We investigated thromboxane B2 (TxB2), 6-keto-PGF1 alpha (6KPGF1 alpha reflecting prostacyclin), PGE2 and PGF2 alpha plasma levels; TxB2, PGE2 and PGF2 alpha platelet production and platelet aggregation response in ascending aorta (reflecting trans-pulmonary difference) and in venous coronary sinus (reflecting transcardiac difference) simultaneously in patients with ischemic heart disease, before and after right-atrial administration of 3 mg ISDN bolus. Transcardiac differences were scarce before as well as after ISDN administration. In aortic blood, ISDN administration into the right atria resulted in a significant increase in prostacyclin and PGF2 alpha plasma levels (472% and 242%, respectively), a decrease of both PGE2 plasma level (-173%) and PGE2 platelet production (-485%) and a marked lowering of platelet aggregation response to ADP, concomittantly. In contrast, TxB2-related features were poorly affected by ISDN. In coronary sinus blood, the aortic increase in 6KPGF1 alpha and PGF2 alpha plasma levels was detected to a lower extent whereas the characteristics of platelet aggregation had returned to control levels. By contrast, PGE2 plasma level (-191%) and PGE2 platelet production (-133%) were lower than prior ISDN administration. The results we report here, strongly support the view that ISDN promotes release of prostacyclin and PGF2 alpha from the lung and inhibit PGE2 production. These prostanoids may be responsible for the concomittant platelet reactivity lowering, thus providing a basis for understanding how ISDN might relieve myocardial ischemia favoring prostanoid mediated vasodilation and inhibition of platelet reactivity.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Aged; Coronary Disease; Dinoprost; Dinoprostone; Eicosanoic Acids; Epoprostenol; Humans; Isosorbide Dinitrate; Lung; Male; Middle Aged; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Thromboxane B2

Coronary blood flow decreases cyclically in a partially occluded coronary artery of anesthetized dogs. Spontaneous aggregation and deaggregation of platelet plugs in the constricted artery have been indicated to be responsible for this phenomenon. A current hypothesis is that platelet aggregation may be determined by a balance between proaggregatory platelet product, thromboxane A2 (TXA2), and antiaggregatory substance, prostacyclin (PGI2). To elucidate the relationship between the cyclical reduction of coronary flow (CRCF) and metabolic alterations of TXA2 and PGI2, we attempted to determine the plasma levels of their stable catabolites, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in the coronary circulation of 69 dogs. Of 40 cases, 20 cases exhibited CRCF accompanying a significant increase in TXB2 in the coronary sinus (CS) (P less than 0.05) and constant levels of 6-keto-PGF1 alpha in the CS and aorta (Ao). Another 20 cases did not exhibit CRCF that accompanied a marked increase in 6-keto-PGF1 alpha (P less than 0.05) with virtually no change in TXB2 in the CS and Ao. A higher dose of indomethacin (10 mg/kg, i.v.) was capable of evoking CRCF in cases not exhibiting CRCF spontaneously. Under these conditions, a significant decrease in 6-keto-PGF1 alpha was seen both in the CS and Ao compared with lower doses of indomethacin (1 to 3 mg/kg, P less than 0.01), that produced less pronounced reduction of 6-keto-PGF1 alpha without CRCF. Intravenous infusion of PGI2 (0.1 microgram/kg/min.) completely abolished spontaneously and indomethacin-induced CRCF with a marked elevation of 6-keto-PGF1 alpha in the CS and Ao. Although OKY-1580, a TXA2 synthetase inhibitor, relieved spontaneously-evoked CRCF with a marked increase in 6-keto-PGF1 alpha and a slight reduction of TXB2, indomethacin-induced CRCF was not abolished by this agent. These results are consistent with the hypothesis that the reduction of endogenous PGI2 synthesis in the vascular wall is related to the occurrence of CRCF after partial constriction of coronary artery and indomethacin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Epoprostenol; Female; Heart Rate; Indomethacin; Male; Myocardium; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Intracoronary nitroglycerin (NTG) increases coronary blood flow and NTG inhibits thromboxane (Tx) A2 production and release. However, whether an alteration in TxA2 is the mechanism by which NTG increases coronary blood flow is not known. Coronary sinus (CS) blood flow (BF) (by thermodilution) and the concentration of TxB2 (the stable metabolite of TxA2) in CS blood were measured in 23 patients (16 men and 7 women, aged 26 to 65 years) with coronary artery disease before, during and after injection of normal saline solution (n = 5, control subjects) or NTG, 100 micrograms (n = 18), into the left coronary artery. In the 5 control subjects, saline solution caused no change in CSBF or the concentration of TxB2 in CS blood. Ten of the 18 patients to whom NTG was given had received no cyclooxygenase inhibitors for 10 days. In these patients, NTG caused a marked increase in CSBF (from 112 +/- 64 to 152 +/- 70 ml/min, p less than 0.01) but no consistent change in the concentration of TxB2 in CS blood (141 +/- 132 to 160 +/- 155 pg/ml, difference not significant [NS]). The remaining 8 patients to whom NTG was given received aspirin before the study. In these patients, NTG caused a marked increase in CSBF (from 111 +/- 39 to 180 +/- 63 ml/min, p less than 0.01), even though the concentration of TxB2 in CS blood (8 +/- 10 to 6 +/- 6 pg/ml, NS) was lower (p less than 0.05) than that in control subjects and patients not receiving aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aspirin; Coronary Circulation; Coronary Disease; Coronary Vessels; Female; Humans; Male; Middle Aged; Nitroglycerin; Thromboxane A2; Thromboxane B2; Thromboxanes; Vasodilation

Topics: Adult; Aged; Blood Platelets; Coronary Disease; Female; Follow-Up Studies; Half-Life; Humans; Male; Middle Aged; Platelet Function Tests; Thromboxane B2; Thromboxanes

Recent studies suggest that platelet activation and subsequent thromboxane (TX) A2 release play important roles in certain coronary syndromes. To further test this possibility, we examined the ability of a selective TXA2-synthetase inhibitor, dazoxiben (UK-37-248), to abolish cyclic flow reductions (CFRs) that occur in experimentally stenosed canine coronary arteries. CFRs, which are characterized by progressive declines in coronary blood flow and interrupted by sudden and usually spontaneous restorations of flow, were produced by placing hard plastic cylindrical constrictors (5 mm long X 4.5 mm outer diameter) on the proximal left anterior descending or circumflex coronary artery in open-chest, anesthetized dogs. Coronary blood flow was measured with pulsed Doppler flow probes placed proximal to the constrictors and regional myocardial blood flow with 15 micron radiolabeled microspheres. CFRs were observed for 1 hr, during which coronary blood flow was monitored continuously. Regional myocardial blood flow was measured before constriction, when coronary blood flow appeared to be at its nadir, and after spontaneous restorations of flow. After 1 hr dazoxiben (2.5 mg/kg iv) or an equal volume of saline was given and coronary blood flow was monitored for another hour. Dazoxiben abolished CFRs completely in 18 of 28 dogs and significantly reduced their frequency in the dogs receiving the drug (10.1 +/- 0.8 vs 3.2 +/- 1.0 per hour [+/- SE]; p less than .001, n = 28). The frequency and magnitude of variations in cyclic blood flow were unchanged after saline (8.8 +/- 0.8 vs 9.0 +/- 1.0 per hour; p = NS, n = 13). The lowest levels of coronary blood flow before and after dazoxiben were 8.6 +/- 2.2% and 48.8 +/- 5.4% of control, respectively (p less than .001, n = 28), whereas this parameter remained unchanged after saline (18.7 +/- 5.7% vs 13.4 +/- 4.1%, respectively; n = 13). The levels of TXB2 and 6-keto-prostaglandin (PG) F1 alpha (stable breakdown products of TXA2 and prostacyclin, respectively) were measured in blood collected from aortic and distal coronary arterial catheters before coronary constriction (control), during CFRs, and after administration of dazoxiben. TXB2 levels measured distal to the stenosis were increased fivefold during CFRs (352 +/- 126 vs 71 +/- 18 pg/ml plasma; p less than .03) and were reduced to preconstriction (control) levels by dazoxiben (57 +/- 12 pg/ml). Aortic TXB2 levels almost doubled with CFRs and also returned to control le

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Female; Hemodynamics; Imidazoles; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Thromboxane B2

The action of pentoxifylline on some of the consequences of acute myocardial ischaemia was studied in cats in vivo. Occlusion of the left anterior descending coronary artery (LAD) for 5 h resulted in a significant elevation in the ST-segment of the ECG, a reduction in free platelet count in right atrial blood and a loss of creatine phosphokinase (CK) and cathepsin D activities in homogenates of the severely ischaemic myocardium as compared to non-ischaemic myocardium. Intravenous infusions of pentoxifylline (0.30 mg kg-1 min-1 for 1 h and 0.15 mg kg-1 min-1 for the remainder of the 5 h observation period, starting 0.5 h after LAD occlusion) significantly reduced the loss of enzymes from the ischaemic myocardium, prevented any further increase in the ST-segment and restored the platelet count to its control level. There were no significant changes in plasma immunoreactive 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (TXB2), although a tendency for a reduction in TXB2 levels was observed. Pentoxifylline seems to affect, beneficially, the myocardium in this animal model of acute myocardial ischaemia. The reason for this cardioprotective action remains to be elucidated. It is, however, noteworthy that the overall profile of action of pentoxifylline resembles that of PGI2 administration in this model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cathepsin D; Cathepsins; Cats; Coronary Disease; Creatine Kinase; Disease Models, Animal; Electrocardiography; Female; Hemodynamics; Infusions, Parenteral; Male; Myocardium; Pentoxifylline; Platelet Count; Theobromine; Thromboxane B2

Timolol (50 micrograms kg-1), administered intravenously to chloralose-anaesthetized open-chest greyhounds 30 min prior to occlusion of the left anterior descending coronary artery, reduced heart rate and mean arterial blood pressure. This dose caused a 20 fold increase in the dose of isoprenaline required to increase heart rate by 25 beats min-1. During the first 30 min of myocardial ischaemia the number of extrasystoles in the timolol-treated dogs (327 +/- 179) was less than in the control group (888 +/- 168) and none of the dogs that received timolol fibrillated. The haemodynamic changes induced by coronary artery occlusion (decreased cardiac output and stroke volume, increased peripheral vascular resistance) were similar in both control and timolol-treated dogs as were the increases in PCO2 and decreases in PO2 and pH in blood draining from the ischaemic myocardium. Timolol did not alter the release during myocardial ischaemia, of either thromboxane B2 or prostacyclin (measured as 6-keto PGF1 alpha). Reperfusion-induced ventricular fibrillation occurred in 7 out of 8 control dogs and in 5 out of 10 timolol-treated dogs. The overall survival following occlusion and reperfusion was improved by 10% to 50% by timolol.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Blood Gas Analysis; Blood Pressure; Coronary Disease; Coronary Vessels; Dogs; Female; Heart Rate; Hemodynamics; Male; Perfusion; Thromboxane B2; Thromboxanes; Timolol

Previous studies suggested that cigarette smoking 1) inhibits an increase in coronary blood flow that should occur with increased myocardial oxygen demands, and 2) alters thromboxane and prostacyclin production, causing vasoconstriction and platelet aggregation. In 38 smokers (26 men and 12 women, aged 50 +/- 8 years [mean +/- standard deviation] ) with coronary artery disease, systemic and coronary hemodynamic and serologic variables were measured before and after smoking two cigarettes (in 8 to 10 minutes) (21 patients) or 8 to 10 minutes without smoking (17 patients; control group). No variable changed in the control group. Smoking increased (p less than 0.05) heart rate-systolic pressure product, cardiac output and maximal first derivative of left ventricular pressure (dP/dt) without significantly changing the coronary sinus concentrations of thromboxane B2 or 6-keto-prostaglandin F1 alpha (the stable metabolites of thromboxane A2 and prostacyclin, respectively). Smoking did not increase coronary flow in 6 of 11 patients with greater than 70% stenosis of the proximal left anterior descending or circumflex coronary artery, or both, whereas it caused an increase in coronary flow in all 10 patients without proximal stenoses (p = 0.006). To determine if smoking altered the response of coronary flow to increased myocardial oxygen demands, 10 smokers (5 men and 5 women, aged 48 +/- 9 years) underwent atrial pacing for 5 minutes followed 15 minutes later by atrial pacing for 5 minutes during smoking. In the five patients without proximal left coronary artery stenoses, coronary flow increased 26 +/- 29 ml/min with pacing and 45 +/- 21 ml/min with pacing/smoking (p = 0.018).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Pressure; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Disease; Female; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Smoking; Thromboxane B2

To determine thromboxane A2 release in coronary artery disease, we measured its stable metabolite thromboxane B2 by radioimmunoassay in 20 patients. In 15 patients with stable disease (last angina episode greater than 96 hours before study), coronary venous thromboxane B2 concentrations were lower than in aortic blood (mean 109 +/- 36 vs 194 +/- 40 pg/ml, p less than 0.001). In contrast, in five other patients with spontaneous angina, coronary venous thromboxane B2 concentrations were higher than aortic thromboxane B2 concentrations during the angina episode (mean 1716 +/- 316 vs 875 +/- 388 pg/ml, p less than 0.02). Plasma thromboxane B2 levels were in the normal range (mean 175 +/- 35 pg/ml) in patients with stable angina but significantly (p less than 0.02) higher in patients with spontaneous angina. With atrial pacing to the point of chest pain and/or ECG changes in patients with stable coronary artery disease, aortic thromboxane B2 concentrations increased in 10 of 13 patients (mean 283 +/- 70 pg/ml, p less than 0.02). Coronary venous thromboxane B2 concentrations increased in seven patients at peak pacing rates (mean 223 +/- 76 pg/ml) and in three other patients after termination of pacing. These data indicate that release of thromboxane A2 is much greater during spontaneous angina than with pacing stress in patients with coronary artery disease. Thromboxane A2 released during spontaneous or pacing-induced angina may modulate coronary and systemic vascular tone. Enhanced thromboxane A2 activity may either precede or follow myocardial ischemia and could be a factor in the initiation and propagation of the ischemic episode.

Topics: Adult; Aged; Angina Pectoris; Aorta; Cardiac Catheterization; Cardiac Pacing, Artificial; Coronary Disease; Coronary Vessels; Humans; Male; Middle Aged; Prostaglandins; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Platelets; Coronary Disease; Epinephrine; Humans; Male; Middle Aged; Myocardium; Norepinephrine; Platelet Aggregation; Prostaglandins; Smoking; Thromboxane B2

The hypothesis that exercise-induced myocardial ischemia is associated with abnormal platelet activation and fibrin formation or dissolution was tested in patients with coronary artery disease undergoing upright bicycle stress testing. In vivo platelet activation was assessed by radioimmunoassay of platelet factor 4, beta-thrombo-globulin and thromboxane B2. In vivo fibrin formation was assessed by radioimmunoassay of fibrinopeptide A, and fibrinolysis was assessed by radioimmunoassay of thrombin-increasable fibrinopeptide B which reflects plasmin cleavage of fibrin I. Peripheral venous concentrations of these substances were measured in 10 normal subjects and 13 patients with coronary artery disease at rest and during symptom-limited peak exercise. Platelet factor 4, beta-thromboglobulin and thromboxane B2 concentrations were correlated with rest and exercise catecholamine concentrations to determine if exercise-induced elevation of norepinephrine and epinephrine enhances platelet activation. Left ventricular end-diastolic and end-systolic volumes, ejection fraction and segmental wall motion were measured at rest and during peak exercise by first pass radionuclide angiography. All patients with coronary artery disease had documented exercise-induced myocardial ischemia manifested by angina pectoris, ischemic electrocardiographic changes, left ventricular segmental dyssynergy and a reduction in ejection fraction. Rest and peak exercise plasma concentrations were not significantly different for platelet factor 4, beta-thromboglobulin, thromboxane B2, fibrinopeptide A and thrombin-increasable fibrinopeptide B. Peripheral venous concentrations of norepinephrine and epinephrine increased significantly (p less than 0.001) in both groups of patients. The elevated catecholamine levels did not lead to detectable platelet activation. This study demonstrates that enhanced platelet activation, thromboxane release and fibrin formation or dissolution are not detectable in peripheral venous blood of patients with coronary disease during exercise-induced myocardial ischemia.

Topics: Adult; Aged; Blood Platelets; Blood Proteins; Catecholamines; Coronary Disease; Exercise Test; Fibrin; Fibrinopeptide A; Fibrinopeptide B; Humans; Male; Middle Aged; Physical Exertion; Renin; Thromboxane B2

We used a validated radioimmunoassay to examine plasma thromboxane B2 (TxB2) levels in 6 consecutive vasotonic angina (VA) patients, 14 patients with fixed, occlusive coronary artery (VO) disease and 9 healthy volunteers. In the latter groups, basal TxB2 release was absent. However, all 6 VA patients showed basal release. In one, sustained levels of up to 12 pmol/ml over 2 months of clinical instability were found. Daily aspirin rendered TxB2 undetectable with clinical improvement. In a second patient, angina coincided with up to 14 pmol/ml of TxB2 in peripheral blood, and myocardial infarction produced still further increases. The 14 VO patients were then studied by rapid atrial pacing to detect TxB2 release coinciding with pacing-induced angina and myocardial lactate production. All demonstrated significant occlusive disease (2.5 critical lesions per patient). Blood was taken simultaneously from coronary sinus (CS) and brachial artery (BA) catheters for lactate and TxB2 analysis before, immediately after and 10 min after pacing-induced ischemia. Lactate extraction fell from 29.3 +/- 3.7 per cent to -21.1 +/- 12.8 per cent to -74.3 +/- 20.3 per cent during pacing (all p less than 0.01) but was normal in 10 min (25.1 +/- 3.55). CS TxB2 rose from 18 per cent to 204 per cent of control during pacing but was absent after 10 min. BA TxB2 rose from 40 per cent to 132 per cent of control during and after pacing, but was absent after 10 min (p less than 0.05). In VA, TxB2 is uniquely, continuously present in peripheral blood and levels rise further during symptomatic intervals and myocardial infarction. In VO, even CS TxB2 is absent at rest, and rises less rapidly than in VA, even during pacing-induced ischemia. Although antiplatelet agent will block all TxB2 release even in VO, their clinical potential seems greatest in VA.

Topics: Angina Pectoris; Angina Pectoris, Variant; Arterial Occlusive Diseases; Aspirin; Blood Platelets; Cardiac Pacing, Artificial; Coronary Disease; Coronary Vasospasm; Heparin; Humans; Lactates; Thromboxane B2; Thromboxanes

Topics: Aged; Arachidonic Acids; Blood Platelets; China; Coronary Disease; Female; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Plant Extracts; Plants, Medicinal; Platelet Aggregation; Thromboxane B2; Thromboxanes

The effects of the thromboxane synthetase inhibitor dazoxiben on thrombus formation, platelet aggregation and vascular reactivity have been studied in open-chest anesthetized dogs. Dazoxiben at 4 mg/kg prolonged the time required for occlusive thrombi to form at sites of electrical injury to the left circumflex coronary artery by 3-fold and also decreased venous thromboxane B2 concentrations by 45% within 30 min. The progressive decline in flow observed during thrombogenesis was interrupted by rapid and spontaneous reactive hyperemic responses, the frequency and number of which were diminished by dazoxiben. In vitro platelet aggregation responses to ADP and collagen determined during the course of these experiments also were inhibited to a variable extent. The effect of dazoxiben on coronary vascular responsiveness was examined using an in situ constant pressure perfused coronary vascular bed. Although basal left circumflex coronary blood flow was unaffected by the drug, vasodilation induced by arachidonic acid, but not prostacyclin, was potentiated. The data suggest that dazoxiben possesses in vivo antithrombotic activity due to modification of platelet reactivity and that it can enhance coronary vasodilator responses to exogenously administered arachidonic acid.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Hyperemia; Imidazoles; Male; Oxidoreductases; Platelet Aggregation; Thromboxane B2; Thromboxane-A Synthase; Time Factors; Vasodilation

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

1 Plasma thromboxane levels were obtained from both the coronary sinus and aorta in patients with stable angina pectoris paced to angina, and in unstable angina patients before and after dazoxiben 100 mg. 2 Although there was a wide range of values in the different groups, dazoxiben significantly reduced plasma thromboxane levels in all patients. 3 Dazoxiben had no adverse effect on coronary and systemic haemodynamics, and atrial pacing time to angina was increased from 245 +/- 41 to 308 +/- 48s (P less than 0.01).

Topics: Adult; Aged; Angina Pectoris; Coronary Circulation; Coronary Disease; Hemodynamics; Humans; Imidazoles; Middle Aged; Myocardium; Oxidoreductases; Platelet Aggregation; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

The plasma concentrations of immunoreactive thromboxane B2 and 6-keto-prostaglandin-F1 alpha were determined in coronary venous blood sampled from open-chested, anaesthetised beagle dogs by local vein catheterisation. Thromboxane levels were high immediately following catheterisation (2.08 +/- 0.75 ng X ml-1, mean +/- SEM, n = 6) and fell over 25 min to 0.48 +/- 0.07 ng X ml-1. Initial trauma of the coronary veins (agitation of the catheter) produced a large but variable increase to 5.13 +/- 2.27 ng X ml-1 (0.1 greater than P greater than 0.05) within 2 min, but arterial trauma (repeated momentary occlusions) produced 0.4 +/- 0.03 ng X ml-1, a value not significantly different from control. After 7 min ischaemia an increase to 0.98 +/- 0.26 ng X ml-1 was detected (P less than 0.05). Reperfusion after 15 min ischaemia caused a fall to 0.43 +/- 0.09 ng X ml-1 at 2 min. In contrast, 6-keto-prostaglandin-F1 alpha levels varied little with trauma but increased to 0.64 +/- 0.14 ng X ml-1 (P less than 0.01) within 2 min ischaemia, remaining elevated. On reperfusion, levels fell to 0.27 +/- 0.06 ng X ml-1 (P less than 0.05) at 2 min, progressively increasing to 0.35 +/- 0.05 ng X ml-1 at 30 min. We conclude that intimal trauma of coronary veins induced thromboxane release and that the physical effects of venous sampling may contribute to apparent thromboxane release from ischaemic muscle. Although transient arterial and venous trauma had no significant effect on 6-keto-prostaglandin-F1 alpha, it is still possible that its release during ischaemia may follow prolonged arterial clamping.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Catheterization; Coronary Disease; Coronary Vessels; Dogs; Female; Indomethacin; Male; Thromboxane B2; Thromboxanes

Thromboxane A2 exerts powerful effects on vascular smooth muscle tone and platelet aggregability. Previous studies have demonstrated increases in transcardiac thromboxane B2 (a stable thromboxane A2 metabolite) in patients with unstable angina and recent chest pain. To determine whether these increases in transcardiac thromboxane B2 are unique to the unstable anginal syndrome or are merely a consequence of ongoing myocardial ischemia, simultaneous ascending aortic and coronary sinus blood samples were obtained for quantitation of thromboxane B2 in 52 patients with a history of chest pain. Provocation was performed with (1) rapid cardiac pacing in 23 patients, (2) cold pressor stress in 19 patients, and (3) sustained isometric exertion in 10 patients. Of the 52 patients, only 5 had a substantial (greater than 3-fold) increase in coronary sinus thromboxane B2 in response to provocation: 1 had unstable angina and chest pain during the previous 48 hours and 4 had a myocardial infarction within the previous 6 weeks. Similarly, only 7 had a greater than 3-fold increase in the coronary sinus/aortic thromboxane B2 ratio in response to provocation: 1 had unstable angina and recent chest pain, 5 had a recent myocardial infarction, and 1 had both of these. There were no other clinical features unique to these patients. The remaining patients with similar diagnoses did not develop a marked increase in coronary sinus thromboxane B2 or the coronary sinus/aortic thromboxane B2 ratio with provocation. None of the 35 patients with stable ischemic heart disease or nonischemic chest pain syndromes had a substantial increase in coronary sinus thromboxane B2 or the coronary sinus/aortic thromboxane B2 ratio (p less than 0.001 for both coronary sinus thromboxane B2 and the coronary sinus/aortic thromboxane B2 ratio in comparison with the 17 patients with recent unstable angina or myocardial infarction). Thus, generous amounts of thromboxane B2 are released into the coronary circulation after provocation in some patients with unstable angina or recent myocardial infarction but not in those with stable ischemic heart disease or nonischemic chest pain syndromes.

Topics: Adult; Aged; Angina Pectoris; Aorta; Cardiac Pacing, Artificial; Cold Temperature; Coronary Disease; Coronary Vessels; Electrocardiography; Female; Humans; Isometric Contraction; Male; Middle Aged; Pain; Thromboxane B2; Thromboxanes

The effect of atrial pacing on intracoronary thromboxane production was investigated in 35 patients with stable (n = 19) or unstable (n = 16) angina. Arterial and coronary sinus thromboxane B2, the stable metabolite of thromboxane A2, myocardial lactate extraction and thermodilution coronary sinus flow were measured before, during and immediately after atrial pacing until the onset of angina. Pacing did not significantly increase coronary sinus thromboxane B2 (rest, 233 +/- 107 pg/ml; pacing, 249 +/- 154 pg/ml; postpacing, 330 +/- 309 pg/ml) (mean +/- standard deviation) despite a moderate increase in arterial thromboxane B2 (rest, 270 +/- 170 pg/ml; pacing, 387 +/- 364 pg/ml; postpacing, 446 +/- 420 pg/ml) (all changes probability [p] less than 0.05). A positive transmyocardial thromboxane B2 gradient, suggesting intracoronary thromboxane A2 production, occurred in only five patients at rest (gradient = 60 +/- 35 pg/ml). During pacing, a transmyocardial thromboxane B2 gradient was not observed despite myocardial lactate production in 18 patients. A postpacing gradient was observed in eight patients (gradient = 284 +/- 349 pg/ml). These gradients were significantly more frequent in patients who produced lactate during pacing (7 of 18) than in patients without lactate production (1 of 17) (p less than 0.05). In patients with and without a postpacing gradient, coronary vascular resistance decreased with pacing and returned to rest levels immediately after pacing, suggesting that a postpacing thromboxane gradient does not significantly alter coronary tone. These data suggest that: 1) pacing-induced angina is usually not associated with substantial intracoronary thromboxane A2 production; 2) in a minority of patients who develop intracoronary thromboxane A2 production, the amount is small and does not produce significant coronary vasoconstriction.

Topics: Angina Pectoris; Cardiac Catheterization; Cardiac Pacing, Artificial; Coronary Disease; Female; Hemodynamics; Humans; Lactates; Lactic Acid; Male; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxanes

Peripheral plasma concentrations of PF-4 and TxB2 were measured by RIA in 26 patients who underwent exercise stress testing. In group A (n = 15; age 50 +/- 16, mean +/- S.D.) in whom blood sampling was performed by venipuncture, seven patients had a positive stress test associated with an increase in PF-4 concentrations from 3.3 +/- 1.6 ng/ml to 6.9 +/- 3.6 (mean +/- S.D.); six of them demonstrated a greater than 50% increase in PF-4; and only one of eight with a negative stress test had such an increase. In group B (n = 11; 49 +/- 10 yr), patients also underwent postexercise thallium-201 scanning and blood samples were obtained through an intravenous catheter. These patients consistently demonstrated higher PF-4 values (before exercise 7.5 +/- 3.9 ng/ml; after exercise 11.9 +/- 7.1), regardless of the results of the exercise and thallium studies. TxB2 concentrations were unchanged in both groups. To further evaluate the effect of catheter-collected samples on PF-4, five healthy males had serial concurrent blood sampling in opposite arms via both venipuncture and catheter. Although PF-4 concentrations in venipuncture samples were constant, those collected through the catheter increased as a function of time. On the basis of the findings in group A, enhanced platelet activation appears to be associated with exercise-induced ischemia. The observations in group B and the healthy controls indicated that catheter-collection of samples artifactually increased PF-4 concentrations.

Topics: Adult; Aged; Blood Coagulation Factors; Blood Platelets; Blood Specimen Collection; Coronary Disease; Exercise Test; Humans; Middle Aged; Physical Exertion; Platelet Factor 4; Thromboxane B2

The incidence and significance of platelet activation in myocardial ischemia was evaluated by serial measurement of plasma thromboxane B2 (TXB2) and beta thromboglobulin (beta TG) in plasma and urine in 98 patients admitted to a coronary care unit with chest pain. All measurements were normal in the 26 patients with noncardiac chest pain. Mean plasma TXB2 and beta TG concentration, but not urine beta TG, were elevated in the 25 patients with myocardial infarction and the 47 patients with angina. The beta TG levels remained normal in 61% of the patients with angina or infarction. The TXB2 levels were significantly higher in patients with recurrent episodes of angina at rest than in those without ischemic episodes after admission. There was a weak correlation between plasma TXB2 and plasma beta TG (r = 0.20, p less than 0.01) and between plasma and urine beta TG (r = 0.31, p less than 0.01). Results indicate that platelets are frequently activated with myocardial ischemia or infarction. However, the measurement of beta TG and TXB2 is of limited value in detecting or differentiating myocardial ischemia from infarction and therefore lacks clinical value in the management of patients with ischemic heart disease.

Topics: Aged; beta-Thromboglobulin; Blood Platelets; Coronary Disease; Female; Humans; Male; Middle Aged; Thromboxane B2; Thromboxanes

Suppression of platelet function is thought to be a mechanism of propranolol's beneficial action in angina pectoris. To study the effects of propranolol on platelets, we measured plasma beta thromboglobulin and plasma thromboxane B2 (TXB2, stable metabolite of TXA2) levels by radioimmunoassay as indexes of platelet alpha-granule and TXA2 release, respectively. Platelet TXA2 generation in vitro in response to arachidonate and thrombin was also quantitated. Twenty-nine patients with coronary disease -- 15 not taking propranolol (group A) and 14 taking propranolol (group B) -- and 15 normal subjects were studied. Plasma beta-thromboglobulin levels were increased in group A and B patients (mean 63 +/- 8 and 96 +/- 14 ng/ml, respectively) compared with normal subjects (mean 46 +/- 6 ng/ml). Plasma TXB2 levels were similar in group A and B patients and in normal subjects (mean 148 +/- 41, 149 +/- 36 and 216 +/- 39 pg/ml). Arachidonate-induced platelet TXA2 generation was significantly higher in group A patients than in normal subjects (725 +/- 393 vs 82 +/- 25 pg TXB2/10(8) platelets, p less than 0.001). In contrast, platelets from group B patients had very low TXA2 generation (mean 21 +/- 18 pg) compared with platelets from group A patients or normal subjects (p less than 0.001). Similar results were obtained using thrombin. These data show that propranolol therapy does not affect platelet-released beta thromboglobulin or TXA2 at rest, but significantly reduces the capability of platelets to generate TXA2 in vitro. Reduction in platelet TXA2 generation may be an important mechanism of action of propranolol in patients with coronary artery disease.

Topics: Adult; Arachidonic Acids; beta-Thromboglobulin; Blood Platelets; Coronary Disease; Depression, Chemical; Humans; Middle Aged; Propranolol; Prostaglandins; Thrombin; Thromboxane A2; Thromboxane B2

The influence of molsidomin (4 mg i.v.) on platelet function, on the plasma concentrations of 6-oxo-PGF1 alpha, the stable metabolite of prostaglandin I2, and thromboxane B2, the stable metabolite of thromboxine A2 was determined in ten patients with coronary heart disease. Prostaglandin I2 is generated in the vessel wall and is a potent vasodilator and inhibitor of platelet aggregation, whereas thromboxane A2 is a vasoconstrictor and a proaggregatory substance. In addition, in-vitro tests were performed, too. 60 min after bolus injection a decrease of systolic and diastolic blood pressure was observed, whereas heart rate remained nearly constant. Platelet aggregation decreased significantly; the addition of PGI2 in vitro had an additive effect. The plasma concentrations of 6-oxo-PGF1 alpha increased after 60 minutes, whereas thromboxane B2 concentrations remained unchanged. In vitro, SIN1, a metabolite of molsidomin generated in the liver, led to a dose-dependent inhibition of ADP-induced platelet aggregation, whereas molsidomin was nearly inactive. Thus molsidomin shows an inhibition of platelet function besides the known antianginal properties. The vasodilatatory and platelet inhibiting effects of this compound may be due partly to a stimulation of the prostaglandin I2 synthesis in the vessel wall.

Topics: Angina Pectoris; Blood Pressure; Coronary Disease; Epoprostenol; Female; Humans; Male; Molsidomine; Muscle, Smooth, Vascular; Oxadiazoles; Platelet Aggregation; Prostaglandins F; Sydnones; Thromboxane A2; Thromboxane B2

Topics: Adult; Blood Platelets; Coronary Disease; Female; Flurbiprofen; Humans; Male; Middle Aged; Platelet Factor 4; Propionates; Prostaglandins F; Thromboxane B2

To investigate the pathophysiology of ischemic heart disease (IHD), tourniquet ischemia on the upper limb was one and change in platelet aggregation, plasma 6-keto-PGF1 alpha concentrations and plasma thromboxane B2 (TXB2) concentrations were studied. At rest, platelet aggregability and plasma TXB2 concentrations were significantly increased in IHD patients compared with those in normal subjects (p less than 0.001 and p less than 0.001, respectively). In normal subjects, platelet aggregability, plasma 6-keto-PGF1 alpha concentrations and plasma TXB2 concentrations rose significantly during ischemia (p less than 0.05, p less than 0.02 and p less than 0.05, respectively). In addition, plasma 6-keto-PGF1 alpha concentrations were significantly lower in IHD patients than in normal subjects during ischemia (p less than 0.005), though there was no significant change in the level of either group at rest. These results suggest that increase in prostacyclin synthesis in normal subjects during tourniquet ischemia may be a defense mechanism to maintain the balance between prostacyclin and thromboxane A2 (TXA2) and to prevent platelet aggregation induced by the procedure. Increase in platelet aggregation and TXA2 generation in IHD patients at rest indicates a close correlation between IHD and platelet reactivity. Tourniquet ischemia induced a significant increase in prostacyclin generation in normal subjects but not in IHD patients, which suggests the production of prostacyclin was impaired in IHD patients during ischemia. A marked different was obvious in prostacyclin and TXA2 generation between IHD patients and normal subjects, and this difference may play an important role in the pathogenesis of IHD.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arm; Blood Circulation; Coronary Disease; Female; Humans; Ischemia; Male; Middle Aged; Platelet Aggregation; Thromboxane B2; Thromboxanes; Tourniquets

Topics: Adult; Blood Platelets; Coronary Disease; Female; Flurbiprofen; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Factor 4; Propionates; Thrombin; Thromboxane B2

Abnormalities of thromboxane (TXA2)-prostacyclin (PGI2) balance have been described in patients with coronary artery disease. Whether these abnormalities precede or follow an acute coronary event is debated. We report a patient in whom spontaneous acute right coronary artery occlusion was observed during coronary angiography. Measurements of arachidonic acid metabolites demonstrated imbalance in TXA2-PGI2 equilibrium preceding coronary occlusion. Marked increase in TXA2 in coronary sinus but not in the aortic blood suggested intracoronary release. Absence of PGI2 in the coronary venous blood at baseline and during tachycardia stress was evidence for failure of atherosclerotic coronary vessels to generate PGI2.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Coronary Disease; Humans; Male; Platelet Count; Prostaglandins; Radiography; Thromboxane B2; Thromboxanes

Nonpulsatile cardiopulmonary bypass, in patients with coronary artery disease, produces a significant increase in thromboxane, a potent platelet aggregant and putative coronary vasoconstrictor. Pulsatile flow may decrease the incidence of perioperative infarction and the hormonal stress response to bypass. This study assessed the effect of pulsatile blood flow on plasma thromboxane and prostacyclin profiles during cardiopulmonary bypass by serial measurement of their stable metabolites, thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Two groups of eight patients each were studied before, during, and after cardiopulmonary bypass. Eight patients had routine (nonpulsatile) bypass and eight had pulsatile flow. In the nonpulsatile group, the TxB2 concentration significantly increased during bypass (65 +/- 39 to 1,224 +/- 306 pg/ml, p less than 0.01) and rapidly returned to control. Prostacyclin also rose (53 +/- 20 to 613 +/- 132 pg/ml, p less than 0.01). In the pulsatile group, TxB2 rose during bypass (53 +/- 18 to 693 +/- 130 pg/ml, p less than 0.01), but peak concentration was significantly lower than in the nonpulsatile group (1,224 +/- 306 versus 693 +/- 130 pg/ml, p less than 0.05). Prostacyclin rose sharply during cardiopulmonary bypass in the pulsatile group (53 +/- 22 to 1,033 +/- 136 pg/ml, p less than 0.01) and was higher than in the nonpulsatile group (1,033 +/- 136 versus 325 +/- 33 pg/ml, p less than 0.01). There were no intragroup differences of plasma hemoglobin, hematocrit, or platelet count. These data demonstrate that pulsatile flow significantly alters prostacyclin and thromboxane profiles during cardiopulmonary bypass and favors production of the coronary vasodilator and platelet disaggregant prostacyclin. This may be an important factor in some of the clinical advantages previously reported with this modality.

Topics: 6-Ketoprostaglandin F1 alpha; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Hematocrit; Humans; Platelet Count; Thromboxane A2; Thromboxane B2; Thromboxanes

Attempts were made to demonstrate release of vasoactive substances from the heart during coronary occlusion (for 60 min) and reperfusion (for 60 min), and to clarify the pathophysiological significance of them. Vasoactive substances were detected by superfusion of rabbit aortic and dog coronary arterial strips with great coronary venous blood. Plasma thromboxane (TX) B2 was radioimmunologically assayed. Gradually developing, sustained contraction of both vascular strips was noted during coronary occlusion and reperfusion, while a transient contraction in rabbit aortic and relaxation in dog coronary arterial strips were seen immediately after reperfusion. The TXB2 released into the great coronary venous blood significantly increased during occlusion and reperfusion. Indomethacin treatment of the dog abolished the sustained contraction of both vascular strips and TXB2 release. The transient contraction of rabbit aorta after reperfusion was inhibited by phenoxybenzamine. Reactive hyperaemia following a 60 min occlusion was significantly depressed, as compared with that following 30 s to 30 min occlusion, and the depression was alleviated by indomethacin and imidazole. These results suggest that catecholamine(s) and TXA2 are released during coronary occlusion and reperfusion, and that the latter might be responsible for the coronary circulatory failure during reperfusion of irreversibly damaged myocardium.

Topics: Animals; Biological Assay; Blood Pressure; Catecholamines; Coronary Circulation; Coronary Disease; Dogs; Female; Heart Rate; Male; Muscle Contraction; Muscle, Smooth, Vascular; Myocardium; Perfusion; Rabbits; Thromboxane A2; Thromboxane B2; Thromboxanes

Various cardiovascular drugs such as nitrates and propranolol, used in the treatment of coronary artery disease have been shown to have an antiplatelet effect. We have studied the in vitro effects of two antiarrhythmic drugs, verapamil and disopyramide, and have shown their inhibitory effect on platelet function. Verapamil, a calcium channel blocker, inhibited the second phase of platelet aggregation induced by adenosine diphosphate (*ADP) and inhibited aggregation induced by collagen. Disopyramide similarly inhibited the second phase of platelet aggregation caused by ADP and aggregation induced by collagen. Either drug in synergism with propranolol inhibited ADP or collagen-induced platelet aggregation. Disopyramide at high concentrations inhibited arachidonic acid whereas verapamil was without effect. Verapamil, but not disopyramide, inhibited aggregated induced by the ionophore A23187.

Topics: Adenosine Triphosphate; Arachidonic Acids; Blood Platelets; Coronary Disease; Disopyramide; Humans; Platelet Aggregation; Propranolol; Pyridines; Thromboxane B2; Verapamil

Thromboxane A2 may play a role in coronary arterial spasm, unstable angina, myocardial infarction, cardiac arrhythmias, and sudden death. Although previous studies have examined peripheral, aortic, and coronary sinus concentrations of its stable metabolite, thromboxane B2 (TxB2), it is unknown, first, if blood sampling through long catheters alters the concentration of TxB2 and second, if peripheral levels of this prostanoid reflect its intracoronary production and release. In order to answer these questions, paired blood samples were obtained through an 18-gauge needle and a No. 7 or 8 French 110 to 125 cm catheter from the arterial (14 patients) and venous (16 patients) circulations; in addition, coronary sinus and peripheral venous samples were obtained in 16 patients and aortic samples were obtained in 14 of these patients. All samples were analyzed to TxB2 by radioimmunoassay. Blood sampling through long catheters did not systematically alter the concentrations of arterial TxB2 (needle, 85.5 +/- 67.5 pg/ml [mean +/- SD]; catheter, 62.3 +/- 40.9 pg/ml; p = 0.20) or venous TxB2 (needle, 182.5 +/- 170.5 pg/ml; catheter, 521.4 +/- 1536.0 pg/ml; p = 0.39). Peripheral venous TxB2 levels did not correlate with TxB2 levels in coronary sinus (r = 0.01) or the TxB2 coronary sinus/aortic ratios (r = 0.21). Thus blood sampling through long catheters across the coronary bed is both a reliable and necessary method for assessing intracoronary TxB2 production in patients with ischemic heart disease.

Topics: Adult; Aged; Aorta; Arteries; Blood Chemical Analysis; Blood Specimen Collection; Catheterization; Coronary Disease; Female; Humans; Male; Methods; Middle Aged; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Thromboxanes

Thromboxane A2 (TxA2), released by aggregating platelets, has been proposed as a potential mediator of coronary vasospasm. We studied six patients with variant angina, a clinical syndrome due to coronary vasospasm, and one patient with frequent recurrent episodes of transient ST-segment depression at rest in whom the spasm was demonstrated angiographically. All patients underwent continuous ECG monitoring for 2 days before and 2 days after a single, low, i.v. dose of aspirin (2 mg/kg), which reduced TxB2 (the stable metabolite of TxA2) to less than 3% of the control values. There were 129 transient ischemic episodes during control and 146 after aspirin, when platelet TxB2 was reduced to negligible levels. The duration, severity and incidence of symptomatic episodes were not significantly affected by TxA2 blockade. We conclude that platelet TxA2 is probably not responsible for the initiation of coronary vasospasm.

Topics: Adult; Aspirin; Coronary Disease; Coronary Vasospasm; Electrocardiography; Humans; Male; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxanes

In our ongoing studies of the interrelationship between platelets and the vascular wall we found that an accurate estimate could be made of the clinical condition and more effective therapy prescribed when we monitored alterations in the plasma levels of TXB2. For this purpose we devised a radioimmunoassay with I125-TXB2-Tyramide. Patients with ischemic heart disorders, cerebral apoplexy, diabetes mellitus, Buerger's disease, Takayasu disease etc., all had statistically high levels of TXB2 as compared with healthy controls. In particular, patients with myocardial infarction, cerebral thrombosis and/or hemorrhage all revealed increases in levels of TXB2 and these levels increased in parallel with a worsening of the clinical condition, and there was always a re-increase in TXB2 level before a recurrence of an attack. As plasma TXB2 levels clearly reflect thrombogenic disorders, the assessment of these levels on a routine basis, enables a more accurate diagnosis, an indication of possible recurrences, and more effective chemotherapy and rehabilitation.

Topics: Adolescent; Adult; Arteriosclerosis; Arteriosclerosis Obliterans; Child; Chromatography, Gel; Circadian Rhythm; Coronary Disease; Diabetes Mellitus; Dinoprost; Female; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Prostaglandins F; Takayasu Arteritis; Thromboangiitis Obliterans; Thromboxane B2; Thromboxanes

Current concepts of atherogenesis, based on animal models, suggest a role for platelets in the development of atherosclerotic lesions, possibly through the release of alpha granule constituents. Platelets may also contribute to the development of vascular spasm through thromboxane A2 production. Platelet activation in the coronary circulation in patients with coronary artery disease (CAD) should occur if these hypotheses apply clinically. We measured aortic and coronary sinus plasma levels of the platelet alpha granule constituent beta-thromboglobulin (B-TG) and thromboxane B2 (TX B2) by radioimmunoassay in 15 patients with severe atherosclerotic CAD, seven patients with angiographically normal coronaries, and five patients undergoing evaluation for coronary artery spasm (CAS). Compared with the controls, CAD patients had significantly greater transmyocardial release of B-TG (11.1 +/- 8.1 ng/ml, mean +/- SEM vs 62.5 17.2, p less than 0.05 by rank sum test); TX B2 gradients showed a similar trend but the difference was not statistically significant (-0.08 +/- 0.03 ng/ml vs 0.22 +/- 0.02, 0.05 less than p less than 0.10). Three of the five patients studied developed CAS which was associated with acute elevation in coronary sinus TX B2; the two non-CAS patients with drug provocation had undetectable coronary sinus TX B2. We conclude that abnormal platelet activation takes place in the coronary circulation of CAD patients, and that production of acute myocardial ischemia by CAS occurs with increased coronary sinus TX B2.

Topics: Angina Pectoris; Angina Pectoris, Variant; beta-Thromboglobulin; Blood Platelets; Catheterization; Coronary Angiography; Coronary Disease; Humans; Thromboxane B2

Endogenous modulators of platelet aggregability and vascular tone may play a part in coronary-artery disease. We therefore measured the release of prostaglandins and thromboxane into the coronary circulation in patients with various kinds of cardiac disease. Simultaneous coronary-sinus (CS) and ascending-aortic (AO) blood samples were obtained from 60 patients for measurement of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, a prostaglandin I2 metabolite) and of thromboxane B2 (TxB2). Samples from 45 of these patients were also tested for prostaglandin E2 (PGE2) and lactate. Patients with unstable angina pectoris who reported chest pain within 24 hours of study had higher TxB2 CS/AO ratios (5.8 +/- 2.8, mean +/- S.D.) than patients whose most recent anginal pain was more than 96 hours before study (1.3 +/- 0.6; P less than 0.05), than those with nonischemic chest pain (1.2 +/- 0.4; P less than 0.05), or with valvular or congenital nonischemic heart disease (1.2 +/- 0.6; P less than 0.05). Those whose most recent anginal pain occurred 24 to 96 hours before study were distributed bimodally: the majority had low TxB2 CS/AO ratios (range, 0.5 to 2.1) like the patients in the three aforementioned groups, whereas a few had markedly elevated values (range, 10.5 to 46.6). The 6-keto-PGF1 alpha and PGE2 CS/AO ratios and myocardial lactate extraction were not significantly different among the five groups. These data suggest that local thromboxane release is associated with recent episodes of angina in patients with unstable angina pectoris, but whether this release is a cause or an effect is not yet known.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angina Pectoris; Coronary Circulation; Coronary Disease; Female; Humans; Lactates; Male; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane B2; Thromboxanes

Trapidil inhibited the aggregation of rat platelets and the contraction of the isolated aortic strip of rabbit mainly caused by thromboxane A2, and the thromboxane A2 biosynthesis in rabbit platelets. The drug also reduced ischemic changes in ECG, the incidence of myocardial infarction, histopathological changes and a decrease in serum high density lipoprotein cholesterol, and inhibited an increase in plasma thromboxane B2 and a decrease in plasma 6-keto-prostaglandin F1 alpha content in the animals with an experimental ischemic heart injury caused by the injection of thromboxane A2 into the coronary artery. These findings suggest that trapidil is a new type of a therapeutic agent for ischemic heart disease which not only dilates the coronary artery but also inhibits the actions and biosynthesis of thromboxane A2 and may promote the biosynthesis of prostaglandin I2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Cholesterol; Coronary Disease; Lipoproteins, HDL; Muscle Contraction; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandins F; Pyrimidines; Rabbits; Rats; Thromboxane A2; Thromboxane B2; Thromboxanes; Trapidil

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Coronary Vessels; Disease Models, Animal; Dogs; Heart; Prostaglandins F; Thromboxane B2; Thromboxanes

Topics: Arteriosclerosis; Aspirin; Coronary Circulation; Coronary Disease; Coronary Vessels; Dipyridamole; Humans; Platelet Aggregation; Propranolol; Tachycardia; Thromboxane B2; Thromboxanes

The combined cellular membrane stabilizing and prostaglandin-inhibiting agent, naproxen, administered either 30 minutes before or after left coronary occlusion, induced significant preservation of the acutely ischemic experimental animal myocardium. A consistent extent of myocardial protection was provided as measured by ST segment elevation, plasma accumulation of CK activity, tissue CK activities, and amino-nitrogen concentrations, and ultrastructural integrity. Protection did not appear to be via hemodynamic mechanisms since naproxen neither altered pressure-rate product nor decreased coronary resistance. While the degree that inhibition of platelet thromboxane A2 generation contributes to these salutary results requires clarification due to possible simultaneous decrease of coronary endothelial PGI2 formation, the present study emphasizes the value of the concomitant special lysosomal and cellular stabilizing actions of naproxen. In contrast to acetylsalicylic acid, meclofenamate, and indomethacin which do not effect such benefit in the same experimental conditions, our results indicate that naproxen resembles the nonsteroidal anti-inflammatory agents which also possess membrane stabilizing properties, such as ibuprofen and flurbiprofen, and protects ischemic myocardium in similar adverse circumstances.

Topics: Animals; Anti-Inflammatory Agents; Arterial Occlusive Diseases; Cats; Cell Membrane; Coronary Disease; Creatine Kinase; Lysosomes; Male; Naproxen; Platelet Aggregation; Thromboxane B2; Thromboxanes

Acute coronary artery occlusion in anaesthetized open-chest greyhounds led to early release of thromboxane B2 (TxB2) into venous blood draining the ischaemic region. No release occurred from the remainder of the left ventricular wall (coronary sinus sampling). TxB2 release and ventricular ectopic activity were positively correlated (r = 0.863) 2 min post-occlusion. Aspirin (3 mg/kg i.v.) suppressed both local TxB2 release and ectopic activity and prevented ventricular fibrillation. It is suggested that TxB2 release is a factor contributing to early post-infarction arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Aspirin; Coronary Disease; Dogs; Myocardium; Thromboxane B2; Thromboxanes

Topics: Adult; Aged; Angina Pectoris; Angina Pectoris, Variant; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Disease; Coronary Vasospasm; Female; Humans; Male; Middle Aged; Thromboxane B2; Thromboxanes

Topics: Angina Pectoris; Arachidonic Acids; Aspirin; Constriction, Pathologic; Coronary Disease; Dietary Fats; Epoprostenol; Fatty Acids, Unsaturated; Fish Oils; Humans; Platelet Aggregation; Risk; Thromboxane B2

Pinane thromboxane A2 (PTA2), a thromboxane A2 analog has been shown to antagonize the vasoconstriction and platelet aggregation induced by thromboxane A2, in addition to specifically inhibiting thromboxane synthetase. Because thromboxane A2 generation would be detrimental in acute myocardial ischemia (MI) by both decreasing coronary blood flow and increasing platelet aggregation, inhibition of thromboxane production and action may be beneficial in myocardial ischemia. In pentobarbital-anesthetized cats, the left anterior descending coronary artery was ligated, and PTA2 (0.5 mumol . kg-1 . h-1) or a Na2CO3 vehicle was infused 30 min post-MI for 270 min. Compared to vehicle-treated MI cats, PTA2 prevented the increase in plasma thromboxane levels seen at 2 through 5 h (P less than 0.005 at 2 through 5 h) and prevented the large increase in plasma CK activities at 4 and 5 h (P less than 0.025). In addition, PTA2 treatment abolished the differences in myocardial CK activities between ischemic and nonischemic regions and prevented the decrease in percent-bound cathepsin D in the ischemic region. Moreover, ECG analysis revealed a decreased incidence of premature beats in PTA2-treated MI cats as compared to MI-vehicle cats. In summary, these data indicate that PTA2 protects the ischemic myocardium and provide further evidence that inhibition of thromboxane formation, in addition to antagonism of its activity, is beneficial during the early stages of acute myocardial ischemia.

Topics: Animals; Blood Pressure; Cathepsins; Cats; Coronary Disease; Creatine Kinase; Electrocardiography; Heart; Heart Rate; Male; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Adult; Aged; Angina Pectoris; Blood Pressure; Brachial Artery; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Disease; Coronary Vessels; Female; Heart Rate; Humans; Lactates; Male; Middle Aged; Radioimmunoassay; Thromboxane B2; Thromboxanes; Time Factors; Vasoconstrictor Agents

Increases in endogenous free fatty acids (FFA) induced by several stimuli are associated with increases in platelet aggregates and platelet factor 4 in man. To determine if thromboxane (TxB) release is also an associated event, we measured plasma FFA and TxB2 levels before and 5 min after bolus injection of 2,500 U of heparin prior to coronary arteriography in 27 patients with angina. Significant increases in FFA occurred in all patients (p less than 0.02) and those with critical lesions (p less than 0.01), while TxB2 levels also rose (p less than 0.02, p less than 0.05, respectively). However, linear regression showed increases in FFA and TxB2 were independent. The observed TxB2 release may be due to lipolysis-induced exposure of vascular collagen or direct inhibition of platelet adenylate cyclase by heparin.

Topics: Aged; Angina Pectoris; Angiocardiography; Coronary Disease; Fatty Acids, Nonesterified; Female; Heparin; Humans; Male; Middle Aged; Prostaglandins; Thromboxane B2; Thromboxanes

The effects of thromboxane (Tx) inhibition or arachidonic acid (AA) infusion were studied in anesthetized cats during acute myocardial ischemia (MI). AA (7.2 mg kg-1 h-1) or imidazole (25 mg kg-1 h-1) infusions were initiated 30 min after occlusion of the left anterior descending coronary artery. Assessment of the degree of protection of the ischemic myocardium was made by measurement of S-T segment elevation, plasma and myocardial creatine phosphokinase (CPK) activities, and myocardial amino-nitrogen content. Assessment of Tx inhibition was performed by radioimmunoassay. Administration of imidazole inhibited the sevenfold increase in plasma thromboxane B2 (TxB2) levels occurring in MI (p less than 0.001 at 2-5 h), markedly decreased S-T segment elevations at 2-k h (p less than 0.025), significantly prevented the elevation in plasma CPK (p less than 0.05, at 4 and 5 h), the increase in TxB2 post-MI, significantly decreased (p less than 0.025) S-T segment evaluations at 2-5 h, caused a decrease in plasmaCPK levels (p less than 0.05 at 5 h), but did not prevent loss of myocardial CPK or amino-nitrogen. In summary, the administration of imidazole resulted in significant protection of the myocardium in all indices of ischemic damage measured, while AA infusion resulted in only a partial protection. The mechanism of the imidazole protection of ischemic myocardial tissue appears to be via inhibition of Tx synthesis althoug we cannot exclude a hemodynamic or cytoprotective mechanism. These results suggest that specific inhibition of Tx formation is beneficial during acute MI.

Topics: Animals; Arachidonic Acids; Cats; Coronary Disease; Creatine Kinase; Imidazoles; In Vitro Techniques; Liver; Lysosomes; Male; Myocardial Contraction; Myocardium; Thromboxane A2; Thromboxane B2; Thromboxanes

To examine plasma levels of vasoconstrictive prostanoid (thromboxane A2) in patients with coronary artery disease, amounts of its product, thromboxane B2, in acidic lipid extracts from plasma were determined by a radioimmunoassay. Peripheral venous samples were obtained in 14 normal subjects and 12 patients with coronary artery disease, and simultaneous aortic and coronary sinus blood samples were obtained at rest, during pacing, and after pacing in eight cases who were subjected to atrial pacing stress test. Mean thromboxane B2 levels in peripheral venous blood in 14 normal subjects were found to be 243 +/- 96 pg/ml. Of nine cases with angina pectoris on effort (angiographically documented severe coronary artery stenosis), five exhibited increased thromboxane B2 levels in peripheral plasma. Three cases of a variant form of angina pectoris exhibited pronounced increases in peripheral thromboxane B2 levels. Of eight cases subjected to atrial pacing stress test, three exhibited marked increases in thromboxane B2 levels in coronary sinus effluent at peak pacing, two of which were accompanied by typical anginal pain during the test. These findings suggest that increased thromboxane A2 production may be associated with altered thromboxane metabolism. This may occur because of altered interactions between functions of vascular wall and blood platelets within coronary circulation in patients with coronary artery disease.

Topics: Angina Pectoris; Angina Pectoris, Variant; Cardiac Pacing, Artificial; Coronary Disease; Humans; Male; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Adult; Angina Pectoris; Angina Pectoris, Variant; Coronary Disease; Female; Humans; Male; Middle Aged; Radioimmunoassay; Rest; Thromboxane B2; Thromboxanes