thromboxane-b2 and Coronary-Thrombosis

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

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

To evaluate effects of diltiazem on platelet hyper-reactivity in situations associated with endothelial injury and their possible relationship to cytosolic calcium concentration.. Blood samples were collected at seven time points from 35 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) who received combined diltiazem and aspirin/ticlopidine therapy or aspirin/ticlopidine therapy alone. Platelet expression of glycoprotein IIb/IIIa and P-selectin, production of thromboxane B(2), and cytosolic calcium concentration were measured, respectively, by whole blood flow cytometry, radioimmunoassay, and fluorospectrophotometry. The effects of diltiazem of different concentrations on expression of glycoprotein IIb/IIIa and P-selectin were also studied in vitro in blood samples from patients with chronic stable angina.. Of the two treatments, aspirin/ticlopidine therapy did not prevent an acute increase of expression of glycoprotein IIb/IIIa and P-selectin and plasma thromboxane B(2) five minutes and 10 minutes after first inflation and 10 minutes after PTCA, whereas combined diltiazem and aspirin/ticlopidine therapy had a significant inhibitory effect. In the group receiving aspirin/ticlopidine therapy, there was a short term increase of platelet [Ca(2+)](i) immediately after PTCA which was significantly reduced by diltiazem treatment. Expression of glycoprotein IIb/IIIa and P-selectin was significantly inhibited in vitro by diltiazem in the concentration of 200 ng/ml or higher, but not 50 ng/ml.. Combined diltiazem and aspirin/ticlopidine therapy significantly inhibited platelet activation that continued in the presence of conventional aspirin/ticlopidine treatment. Antiplatelet effects of diltiazem were probably a consequence of reduction of platelet [Ca(2+)](i) and may only be achieved in higher than therapeutic concentrations.

Topics: Aged; Angioplasty, Balloon, Coronary; Aspirin; Blood Platelets; Calcium; Calcium Channel Blockers; Coronary Thrombosis; Cytosol; Diltiazem; Drug Therapy, Combination; Female; Humans; Male; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thromboxane B2; Ticlopidine

RGD-containing peptides and other antagonists of the platelet glycoprotein (GP) IIb/IIIa may induce a high-affinity binding site for fibrinogen and the expression of novel epitopes, called ligand-induced binding sites (LIBS). The functional relevance of LIBS expression in a canine model of coronary thrombolysis induced by tissue-type plasminogen activator (t-PA) was examined. Ro43-5054 (N-[N-[N-(p-amidinobenzoyl)-b-alanyl]-l-a-aspartyl]-3-phenyl-l- alanine) and Ro44-9883 ([1-(N-(p-amidinobenzoyl)-l-tyrosyl)-4-piperidinyl)oxy]acetic acid), antagonists of the GP IIb/IIIa receptor, were administered in increasing doses of 2 to 10 microg/kg/min, beginning 30 min before the infusion of t-PA. LIBS expression was determined by the binding of the monoclonal antibody, D3GP3, to platelets on exposure to Ro43-5054, Ro44-9883 and t-PA. Ro43-5054 was shown to induce LIBS, whereas Ro44-9883 and t-PA did not. Both drugs abolished platelet aggregation in response to U46619 and ADP ex vivo. Reocclusion was prevented with both Ro43-5054 and Ro44-9883, but neither drug altered reperfusion times (49 +/- 8 and 55 +/- 39 min). Both drugs increased the rate of bleeding compared with t-PA alone, but there was no difference in hemostasis between the two drugs. To determine whether the drugs differed in their effect on platelet activation in vivo, urinary 2,3-dinor-thromboxane (TX) B2, a major metabolite of TXB2, was determined by gas chromatography-mass spectrometry. After reperfusion, the urinary 2,3-dinor-TXB2 increased in the Ro43-5054-treated group, similar to control groups (32 +/- 8 and 37 +/- 9 ng/mg creatinine). This increase was blunted in the Ro44-9883-treated group (9 +/- 3 ng/mg creatinine). GP IIb/IIIa antagonists that do not induce LIBS result in a greater suppression of platelet activity but not in any discernible functional benefit in vivo.

Topics: Acetates; Animals; Binding Sites; Blood Platelets; Coronary Thrombosis; Dogs; Fibrinolytic Agents; Hemorrhage; Oligopeptides; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Reperfusion Injury; Thromboxane B2; Tissue Plasminogen Activator; Tyrosine

The antiplatelet and antithrombotic activities of LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) a novel thromboxane A2 (TXA2) receptor antagonist were examined after intravenous administration. The correlation between LCB 2853 plasma concentration and ex vivo inhibition of arachidonic acid-induced aggregation was observed in rats, for 4 h, as long as LCB 2853 was detected in plasma by HPLC analysis. Pharmacokinetic parameters were determined. The antithrombotic activity was tested in arterial and venous thrombosis models. In dog coronary stenosis, LCB 2853 shown a very high efficacy (ED50 = 7.2 micrograms/kg), whereas acetylsalicylic acid (ASA) was only active at 3.2 mg/kg and ticlopidine was ineffective at 12.8 mg/kg. In rat venous thrombosis induced by combination of venous injury and blood stasis, perfused LCB 2853 decreased the weight of thrombi in a dose related manner (ED50 = 220 micrograms/kg/min). In a comparative study, at 250 micrograms/kg/min, ticlopidine was less potent and ASA failed to show any protection. The potent immediate efficacy of LCB 2853 and the advantageous comparisons with ASA (which was ineffective in some models) or ticlopidine (which needs metabolization lag time) observed in many models suggest that this compound may have beneficial effects in patients with TXA2-associated disturbances.

Topics: Animals; Chromatography, High Pressure Liquid; Coronary Thrombosis; Dogs; Female; Fibrinolytic Agents; Injections, Intravenous; Male; Phenylacetates; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Receptors, Thromboxane; Sulfonamides; Thrombophlebitis; Thromboxane B2

The combination of thromboxane (TX) synthase inhibition and prostaglandin (PG) H2/TXA2 receptor antagonism yields enhanced antithrombotic effects as compared with either intervention alone. However, it is not known whether the enhancing effect of TX synthase inhibition is expressed also in the presence of complete blockade of PGH2/TXA2 receptors. Thus we evaluated the antithrombotic effects of increasing doses of the PGH2/TXA2 receptor antagonist L 670596 alone and in combination with a dose of the TX synthase inhibitor FCE 22178 causing > 95% inhibition of platelet TXB2 production. In the dog model of electrically induced coronary thrombosis, occlusion time in control animals (n = 14) averaged 72 +/- 29 min. L 670596 alone dose-dependently antagonized platelet PGH2/TXA2 receptors and prolonged occlusion time. The addition of FCE 22178 displaced the dose-occlusion time relation of L 670596 in a parallel fashion without modifying receptor occupancy. In the rabbit model of copper coil-induced carotid artery thrombosis, occlusion was very rapid (14 +/- 4 min) in control animals (n = 17) and was not modified by either aspirin or FCE 22178. L 670596 caused a dose-related receptor blockade and prolongation of occlusion time. The association with FCE 22178 enhanced significantly the antithrombotic effect of L 670596 at all doses. We conclude that the full therapeutic potential of PGH2/TXA2 receptor antagonism is expressed at > 90% platelet receptor occupancy. The additive effect of TX synthase inhibition suggests that conversion of PGH2 to platelet-inhibitor and vasodilator prostaglandins might be of therapeutic importance, irrespective of the extent of PGH2/TXA2 receptor blockade.

Topics: Animals; Carbazoles; Carotid Artery Thrombosis; Copper; Coronary Thrombosis; Disease Models, Animal; Dogs; Evaluation Studies as Topic; Imidazoles; Male; Naphthalenes; Platelet Aggregation; Prostaglandin H2; Prostaglandins H; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Various antiplatelet agents were examined for their effectiveness as adjuncts to thrombolytic therapy in a canine model of thrombin-induced coronary thrombosis. Aspirin (5 mg/kg i.v. bolus), CGS 15435A (thromboxane synthase inhibitor (TxSI), 0.1 mg/kg i.v. bolus +0.04 mg/kg per h) and BM 13.505 (thromboxane receptor antagonist (TxRA), 0.5 mg/kg i.v. bolus +0.2 mg/kg per h) administered concurrently with streptokinase (750,000 units/h) were examined for their effects on reperfusion and reocclusion, as were a combination therapy with CGS 15435A + BM 13.505 or the dual TxRA/TxSI inhibitor, CGS 22652 (1 mg/kg i.v. bolus +0.4 mg/kg per h). All dogs received heparin (150 U/kg bolus + 50 U/kg per h) throughout the experimental protocol. Survival analysis at reperfusion indicated that thrombolysis was significantly improved in dogs treated with CGS 15435A, BM 13.505, CGS 15435A+BM 13.505 or CGS 22652 over that of vehicle-treated animals. Both dual inhibitor groups and the BM 13.505 group were significantly different from aspirin. Aspirin-treated dogs were not different from vehicle. Otherwise, all treatments differed from the vehicle-treated group at reocclusion. Time and incidence of reocclusion for CGS 22652 was significantly improved over that of BM 13.505. Residual thrombus weight was significantly reduced in the CGS 22652-treated and BM 13.505 + CGS 15435A-treated animals. These findings demonstrate that streptokinase-induced thrombolysis is accompanied by TxA2/prostaglandin H2 synthesis and platelet activation and suggest a role for platelet activation during reocclusion following clot lysis. These studies also show it is possible to combine the beneficial effects of both a TxRA and TxSI into a single chemical entity, CGS 22652, which, when administered as adjunctive therapy to streptokinase, results in an apparent synergistic antithrombotic effect.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Caprylates; Coronary Circulation; Coronary Thrombosis; Dinoprostone; Dogs; Hemodynamics; Indoles; Male; Myocardial Reperfusion; Phenylacetates; Platelet Activation; Platelet Aggregation Inhibitors; Pyridines; Receptors, Thromboxane; Streptokinase; Sulfonamides; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

The effects of Y-20811, a selective inhibitor of thromboxane A2 (TXA2) synthetase, on blood flow and local levels of immunoreactive thromboxane B2 (i-TXB2) and 6-keto prostaglandin F1 alpha (i-6-keto PGF1 alpha) in the coronary artery were investigated in the canine model of coronary thrombosis. Thrombosis was induced by applying an electric current to the intraluminal surface of the coronary artery. The plasma levels of i-TXB2 and i-6-keto PGF1 alpha were measured distal to the electrode. In the control group, coronary blood flow decreased and finally stopped 207 +/- 53 min (mean +/- S.E.M., n = 5) after the start of current application. The level of i-TXB2 rose before the coronary occlusion. Coronary blood flow did not change significantly in the Y-20811-treated group (1 mg/kg i.v.). The level of i-TXB2 decreased and remained significantly lower than that in the control group. The level of i-6-keto PGF1 alpha tended to increase slightly in the Y-20811-treated, but not in the control group. The weight of the thrombus in the Y-20811-treated group was significantly less than that in the control group (P less than 0.01). These results suggest that Y-20811 prevents coronary thrombosis by the inhibition of TXA2 production around the electrically injured lumen of the coronary artery.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Thrombosis; Disease Models, Animal; Dogs; Electric Stimulation; Imidazoles; Male; Thromboxane B2; Thromboxane-A Synthase

Topics: Aspirin; Coronary Thrombosis; Cross-Sectional Studies; Humans; Intracranial Embolism and Thrombosis; Platelet Activation; Risk Factors; Thromboxane A2; 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

The levels of thromboxane B2, prostaglandin 6-keto F1 alpha (PG F1 alpha), thrombocytic factor IV (TF IV), and beta-thromboglobulin (beta-TG) were measured in 66 patients with postinfarction cardiosclerosis concurrent with acute recurrent myocardial infarction or unstable angina pectoris. There was a substantial increase in thromboxane B2 activity and a less significant elevation of PG F1 alpha, as well as a rise of TF IV and beta-TG. Circulatory insufficiency, cardiac aneurysm, intracardiac thrombi were accompanied by much more severe abnormalities in the above-mentioned parameters.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Blood Coagulation; Coronary Thrombosis; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Platelet Factor 4; Recurrence; Thromboxane B2

Platelet behavior was compared in two groups of patients with unstable angina: 13 patients with rest pain and ST depression on the electrocardiogram (the intermediate coronary syndrome), 14 patients with progressive angina without rest pain, and 20 healthy controls. Both patient groups had hyperaggregating platelets when compared with the controls (p less than 0.01). Platelet aggregation was measured ex vivo in the presence of arachidonic acid. Serum thromboxane B2, plasma beta-thromboglobulin, and platelet factor 4 were all temporarily increased in the group with intermediate coronary syndrome (p less than 0.01), whereas measurements in patients with progressive angina were not significantly different from the controls. Thus, patients with the intermediate coronary syndrome, who have a high frequency of suboccluding coronary artery thrombus and a very serious prognosis, had severely altered platelet behavior in contrast to patients with progressive angina.

Topics: Angina Pectoris; Angina, Unstable; beta-Thromboglobulin; Coronary Thrombosis; Electrocardiography; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Factor 4; Prognosis; 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

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

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

An experimental model of acute myocardial infarction is presented. Intracoronary thrombus was precipitated by a mock ruptured atheromatous plaque, which is a cholesterol-collagen mixture, protruding into the stenosed left anterior descending coronary artery. Twenty-five dogs, divided into two groups, were studied: a control group of 15 dogs and a treated group of 10 dogs. Intracoronary thrombus was precipitated by the mock atheromatous plaque in 13 of 15 control animals. Myocardial infarction was induced in 10 and sudden death in two. Coronary blood flow decreased gradually or cyclically to end in myocardial infarction. The model was utilized to investigate the effects of a thromboxane synthetase inhibitor, OKY-046, on 10 additional animals. OKY-046 could significantly decrease the incidence of occlusive thrombus formation and myocardial infarction when administered intravenously during coronary blood flow reduction (3 of 10 in the treated group vs 12 of 15 in the control group, p less than 0.02). Thromboxane B2 was significantly elevated in the coronary venous blood during reduction of the coronary blood flow, while thromboxane B2 was reduced and 6-ketoprostaglandin F1 alpha increased during OKY-046 administration. The reduction in thromboxane A2 production associated with increased prostacyclin appeared to be the major mechanism of the interruption of the thrombus formation by OKY-046.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Thrombosis; Dogs; Epoprostenol; Female; Male; Methacrylates; Myocardial Infarction; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

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