thromboxane-a2 and Angina--Unstable

Platelet activation occurs episodically in unstable angina, as reflected by enhanced thromboxane metabolite excretion, and most episodes can be suppressed by low-dose aspirin. Biochemical evidence of platelet activation and electrocardiographic evidence of myocardial ischemia are often temporally dissociated, thus suggesting the likely involvement of different triggers. Aspirin is effective in reducing the short-term and long-term risks of myocardial infarction and death by 40-60%, in a dose-independent fashion consistent with the saturability of platelet cyclo-oxygenase inhibition at low doses. Suppression of platelet thromboxane synthesis by aspirin and the blockade of platelet adenosine diphosphate receptors by ticlopidine or clopidogrel appear to have a similar impact on limiting the risk of a thrombotic outcome of plaque fissuring, thereby suggesting combined strategies for future studies.

Topics: Angina, Unstable; Aspirin; Humans; Myocardial Infarction; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane A2; Ticlopidine

Topics: Angina, Unstable; Biomarkers; Creatine Kinase; Creatine Kinase, MB Form; Fibrinopeptide A; Humans; Isoenzymes; Myosin Light Chains; Thromboxane A2; Troponin I; Troponin T

New research about platelet and endothelial functions is allowing us to better understand the pathogenesis of myocardial ischemic episodes in patients with unstable angina, creating new perspectives for the rational utilization of therapies. In patients with unstable angina, the episodes of symptomatic and silent ischemia are caused by repeated reductions of coronary blood flow. They are the result of the mechanical effect of the growing thrombus, which causes intermittent episodes of partial obstruction of the arterial lumen, in association with vasoconstriction at the stenotic site and dependent coronary arterial bed, produced by the cyclic release of platelet derived vasoactive products, namely thromboxane A2 and serotonin. Several studies, many of them in animal models of thrombosis, suggest that serotonin and thromboxane A2 are mediators of platelet aggregation, adynamic obstruction and coronary artery thrombosis. Because they cause coronary cyclic flow reductions, they are implicated in the pathogenesis of myocardial ischemic episodes during unstable angina. Drugs that interfere with the arachidonate pathway, and the 5-HT2-receptor antagonists, have been proven to decrease or abolish coronary cyclic flow variations in animal models and man. However, further studies should be done to test the hypothesis that the association of a 5-HT2-receptor antagonist with aspirin may contribute to decrease myocardial ischemia and prevent coronary occlusion in patients with unstable angina. Continuous Holter monitoring during the first week after admission in the hospital should be a good method to evaluate the eventual efficacy of this new class of drugs in abolishing or decreasing the frequency, intensity and duration of myocardial ischemic episodes in patients with unstable angina. The central role of serotonin in the pathogenesis of thrombotic events, and the presumed preventive effect of ketanserin, were the bases of a national multicenter pilot controlled study designed to evaluate the safety and efficacy of ketanserin plus aspirin in the secondary prevention of patients with unstable angina and non-Q wave myocardial infarction (KATUA Trial).

Topics: Angina, Unstable; Arachidonic Acid; Blood Platelets; Clinical Trials as Topic; Coronary Circulation; Endothelium, Vascular; Humans; Nitric Oxide; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Thromboxane A2

Topics: Angina, Unstable; Aspirin; Coronary Thrombosis; Humans; Myocardial Ischemia; Platelet Activation; Prostaglandins; Thrombolytic Therapy; Thromboxane A2

The formation of the proischemic and prothrombotic thromboxane A2 (TXA2) and of its functional antagonist prostacyclin is increased in patients with unstable angina and myocardial infarction. Therefore, pharmacological interventions aim at an inhibition of the synthesis or action of TXA2 without interference with the desirable effects of prostacyclin. Clinical studies currently evaluate low-dose aspirin, thromboxane synthase inhibitors, TXA2/PGH2 receptor antagonists, and a combination of the latter two principles of action. The major advantages and disadvantages of these drugs are: 1. Aspirin irreversibly inhibits TXA2 and PGH2 synthesis in platelets, but also reduces the formation of the platelet-inhibiting PGD2 and prostacyclin--even under a low-dose regimen. 2. Thromboxane synthase inhibitors increase the formation of PGD2 and prostacyclin, but also enhance the accumulation of the potent platelet agonist PGH2. 3. Competitive TXA2/PGH2 receptor antagonists selectively inhibit the action of TXA2 and PGH2 and do not interfere with the eicosanoid metabolism, but their inhibitory effect can be overcome by very high local TXA2 or PGH2 concentrations. 4. Non-competitive TXA2/PGH2 receptor antagonists do not share this drawback. Therefore, they might combine the advantage of aspirin to exert an irreversible inhibition with the specificity of a TXA2/PGH2 receptor antagonist. However, these antagonists are in the stage of experimental studies. 5. The most potent of the clinically available principles of a platelet inhibition is the combination of a thromboxane synthase inhibitor with a competitive TXA2/PGH2 receptor antagonist. Agents that combine both principles of action in one compound are also under clinical investigation.

Topics: Angina, Unstable; Animals; Aspirin; Humans; Myocardial Infarction; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Thromboxane-A Synthase

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: Angina Pectoris; Angina, Unstable; Animals; Coronary Vessels; Humans; Leukocytes; Platelet Activation; Thromboxane A2; Vasoconstriction

Platelets contain three types of secretory organelles: the dense granules, the alpha granules, and the lysosomes. Most of the proteins secreted from platelets are stored in the alpha granules, whereas the dense granules contain substances such as adenine nucleotides, serotonin, Ca++, and inorganic pyrophosphate types as well as a heparatinase. Three of the secreted alpha granule proteins have been measured by radioimmunoassay and it has been suggested that levels of these proteins in patient plasmas provide an index of in vivo platelet activation and secretion. These three are beta-thromboglobulin, platelet factor 4, and thrombospondin. In this chapter the chemistry of these proteins will be considered briefly, as will their clearance from the circulation, and then the clinical studies will be reviewed critically. Since radioimmunoassays were developed for these proteins (the first was reported in 1975), there has been a profusion of reports on levels of one or another of these proteins in a wide range of disease states, and these reports have indicated secreted platelet protein levels ranging from normal to grossly elevated in a given disease state. Possible reasons for such variability will be discussed.

Topics: Angina, Unstable; Beta-Globulins; beta-Thromboglobulin; Blood Platelets; Catecholamines; Catheterization; Cerebrovascular Disorders; Coronary Disease; Coronary Vessels; Cytoplasmic Granules; Exercise Test; Female; Humans; Hyperlipidemias; Hypertension; Kidney Diseases; Myocardial Infarction; Platelet Factor 4; Pregnancy; Renal Dialysis; Thromboxane A2

Topics: Angina Pectoris; Angina, Unstable; Arachidonic Acid; Arachidonic Acids; Coronary Disease; Epoprostenol; Humans; Myocardium; Platelet Aggregation; Thromboxane A2

Unstable angina is associated with enhanced lipid peroxidation and reduced antioxidant defenses. We have previously reported aspirin failure in the suppression of enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation in this setting. We tested the hypothesis that the in vivo formation of the F(2)-isoprostane 8-iso-prostaglandin (PG)F(2alpha), a bioactive product of arachidonic acid peroxidation, is enhanced in unstable angina and contributes to aspirin-insensitive TX biosynthesis.. Urine samples were obtained from patients with unstable angina (n=32), stable angina (n=32), or variant angina (n=4) and from 40 healthy subjects for the measurement of immunoreactive 8-iso-PGF(2alpha) and 11-dehydro-TXB(2). 8-Iso-PGF(2alpha) excretion was significantly higher in patients with unstable angina (339+/-122 pg/mg creatinine) than in matched patients with stable angina (236+/-83 pg/mg creatinine, P:=0.001) and control subjects (192+/-71 pg/mg creatinine, P:<0.0001). In patients with unstable angina, 8-iso-PGF(2alpha) was linearly correlated with 11-dehydro-TXB(2) excretion (rho=0.721, P:<0.0001) and inversely correlated with plasma vitamin E (rho=-0.710, P:=0. 004). Spontaneous myocardial ischemia in patients with variant angina or ischemia elicited by a stress test in patients with stable angina was not accompanied by any change in 8-iso-PGF(2alpha) excretion, thus excluding a role of ischemia per se in the induction of increased F(2)-isoprostane production.. These findings establish a putative biochemical link between increased oxidant stress and aspirin-insensitive TX biosynthesis in patients with unstable angina and provide a rationale for dose-finding studies of antioxidants in this setting.

Topics: Angina, Unstable; Antioxidants; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprost; Dose-Response Relationship, Drug; Drug Resistance; F2-Isoprostanes; Humans; Isoenzymes; Male; Membrane Proteins; Middle Aged; Oxidative Stress; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Time Factors

We have previously reported aspirin failure in suppressing enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation during the acute phase of unstable angina. The recent discovery of a second prostaglandin H synthase (PGHS-2), inducible in response to inflammatory or mitogenic stimuli, prompted us to reexamine TXA2 biosynthesis in unstable angina as modified by two cyclooxygenase inhibitors differentially affecting PGHS-2 despite a comparable impact on platelet PGHS-1.. We randomized 20 patients (15 men and 5 women aged 59+/-10 years) with unstable angina to short-term treatment with aspirin (320 mg/d) or indobufen (200 mg BID) and collected 6 to 18 consecutive urine samples. Urinary 11-dehydro-TXB2 was extracted and measured by a previously validated radioimmunoassay as a reflection of in vivo TXA2 biosynthesis. Metabolite excretion averaged 102 pg/mg creatinine (median value; n=76) in the aspirin group and 55 pg/mg creatinine (median value; n=99) in the indobufen group (P<.001). There were 16 samples (21%) with 11-dehydro-TXB2 excretion >200 pg/mg creatinine among patients treated with aspirin versus 6 such samples (6%) among those treated with indobufen (P<.001). In vitro and ex vivo studies in healthy subjects demonstrated the capacity of indobufen to largely suppress monocyte PGHS-2 activity at therapeutic plasma concentrations. In contrast, aspirin could only inhibit monocyte PGHS-2 transiently at very high concentrations.. We conclude that in unstable angina, episodes of aspirin-insensitive TXA2 biosynthesis may reflect extraplatelet sources, possibly expressing the inducible PGHS in response to a local inflammatory milieu, and a selective PGHS-2 inhibitor would be an ideal tool to test the clinical relevance of this novel pathway of arachidonic acid metabolism in this setting.

Topics: Aged; Angina, Unstable; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Humans; Isoenzymes; Isoindoles; Male; Membrane Proteins; Middle Aged; Phenylbutyrates; Prostaglandin-Endoperoxide Synthases; Reference Values; Thromboxane A2; Thromboxane B2

The role of thromboxane A2 (TxA2) in unstable angina has not yet been defined. TxA2 receptor antagonists may be of value in studying this role.. To investigate whether TxA2 has a pathogenetic effect on the occurrence of myocardial ischemia and from what source TxA2 originates, we studied TxA2 formation by unstimulated monocytes from patients with unstable angina (n = 40), stable effort angina (n = 20), and controls (n = 20). We also compared the effects of picotamide (1200 mg/day), a TxA2-synthase inhibitor and TxA2-receptor antagonist, with those of aspirin (325 mg/day) on myocardial ischemia and TxA2 formation by monocytes and platelets. The double-blind randomized study was performed on patients with unstable angina on continuous Holter monitoring.. In the presence of autologous lymphocytes, unstimulated monocytes from patients with unstable angina formed significantly (P < 0.001) more TxA2 than those from controls or from patients with effort angina. Although TxA2 formation by circulating monocytes and platelets was inhibited to a greater degree by aspirin than by picotamide (88 +/- 6 and 98 +/- 2%, respectively, versus 65 +/- 2 and 74 +/- 1%, P < 0.001), aspirin failed to affect the occurrence of myocardial ischemia whereas picotamide significantly (P < 0.001) reduced the number of anginal attacks (84.8%), silent ischemic episodes (64.2%), and overall duration of ischemia (69.8%), in comparison to the run-in period.. These results indicate that TxA2 formed by monocytes contributes to the pathogenesis of myocardial ischemia in unstable angina. TxA2 formation occurs mainly in extravascular spaces, probably within the coronary vascular wall. Picotamide appears to control myocardial ischemia effectively in patients with unstable angina.

Topics: Aged; Angina Pectoris; Angina, Unstable; Aspirin; Double-Blind Method; Female; Follow-Up Studies; Humans; Leukocytes, Mononuclear; Lymphocytes; Male; Middle Aged; Myocardial Ischemia; Phthalic Acids; Placebos; Platelet Aggregation Inhibitors; Prospective Studies; Thromboxane A2

Episodic platelet activation has been shown to occur in unstable angina, and aspirin should have an important therapeutic role in the management of these patients. The response to aspirin alone or to aspirin in combination with vasodilators such as heparin and beta-blockers has been assessed in 41 patients with unstable angina. Therapy was added sequentially in the event of recurrence of transient myocardial ischemia. Patients were randomly assigned to two groups. Group 1 (21 patients) received an intravenous infusion of isosorbide dinitrate and oral diltiazem, and group 2 (20 patients) received intravenous aspirin (60 mg the first day and 20 mg on successive days). This dose of aspirin reduced serum thromboxane B2 from 160 +/- 88 ng/ml (mean +/- SD) to undetectable values (less than 6 ng/ml, p less than 0.01). If episodes of ischemic ST segment shift continued, the therapy of group 1 was added to that of group 2 or vice versa; if further ST segment changes were documented, intravenous heparin and oral beta-blockers were added; if episodes of myocardial ischemia persisted, urgent coronary arteriography and myocardial revascularization were performed. Nine patients in group 1 and six in group 2 (p = 0.8) had no further episodes of myocardial ischemia on their initial therapy; 12 additional patients had no further episodes when taking combined therapy of aspirin and vasodilators. Thus, the administration of aspirin alone was not superior to coronary dilators; 30% of all patients continued to have episodes of myocardial ischemia or had a myocardial infarction develop when heparin and beta-blockers were added. Myocardial infarction occurred in one patient on vasodilator therapy alone, in two on combined therapy, and in two on full therapy. These results suggest that in some patients, the stimulus to coronary thrombosis and vasoconstriction occasionally becomes so strong that it cannot be inhibited by certain antagonist drugs. The unstable tendency to continuation of ischemia or evolution to myocardial infarction is not related to the severity of the persisting stenosis. Those patients not promptly responding to combined therapy immediately from admission should have early coronary angiography and aggressive treatment.

Topics: Angina Pectoris; Angina, Unstable; Aspirin; Diltiazem; Drug Therapy, Combination; Electrocardiography; Exercise Test; Female; Humans; Isosorbide Dinitrate; Male; Middle Aged; Platelet Aggregation; Randomized Controlled Trials as Topic; Thromboxane A2; Thromboxane B2

Topics: Angina, Unstable; Blood Platelets; Heparin, Low-Molecular-Weight; Humans; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

The current study was designed to investigate the number and affinity of platelet thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptors in patients with unstable angina and, if any, the role played by the increased thrombin formation that is a common finding in these patients. Measurements taken during active unstable angina but not those taken during inactive angina showed an increase number (p < 0.001), without changes in affinity, of platelet TxA2/PGH2 receptors, evaluated as the binding capacity of iodine 125-PTA-OH, a stable TxA2 analogue. Moreover patients with active angina had higher plasma concentrations of fibrinopeptide A (FPA) (p < 0.0001), which were significantly related to the number of platelet TxA2/PGH2 receptors (r = 0.76; p < 0.01). Heparin infusion but not aspirin treatment promptly normalized the number of TxA2/PGH2 receptors and significantly reduced plasma FPA concentrations. In an in-vitro study thrombin in a concentration similar to that found in vivo significantly increased the number of platelet TxA2/PGH2 receptors (p < 0.01), whereas heparin did not affect TxA2/PGH2 receptors. These results have important therapeutic implications and indicate the preferential use of heparin rather than aspirin during the acute phase of unstable angina.

Topics: Aged; Angina Pectoris; Angina, Unstable; Aspirin; Blood Platelets; Dose-Response Relationship, Drug; Fibrinopeptide A; Heparin; Humans; Middle Aged; Physical Exertion; Platelet Activation; Prostaglandins H; Radioligand Assay; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thrombin; Thromboxane A2

STUDY OBJECTIVE - The objective was to measure platelet function in vivo (as cutaneous bleeding time), the role of catecholamines, and the effect of inhibiting thromboxane synthesis on bleeding time, in patients with myocardial infarction, unstable angina, and non-cardiac chest pain. DESIGN - Haemotological variables and plasma catecholamines were compared between patient diagnostic groups using the Kruskal-Wallis test, Conover's multiple comparison test, and Wilcoxon paired rank sum test. PATIENTS - 49 patients entered the study and 45 were assigned to three groups: myocardial infarction (n = 26), unstable angina (n = 9), and non-coronary chest pain (control) (n = 10). There were no significant differences between groups for age or sex. Patients with myocardial infarction smoked more than others. MEASUREMENTS and RESULTS - Compared to the controls, bleeding time in patients with myocardial infarction was shortened, while in unstable angina it was normal. Plasma adrenaline and noradrenaline concentrations were higher in the myocardial infarction group than in the unstable angina and control groups, but were not correlated with bleeding time. Bleeding time was remeasured 2 h after ingestion of 300 mg aspirin and increased in all subjects, especially in those with myocardial infarction, but it remained significantly shorter in the infarct group than in the comparison groups. Plasma adrenaline was inversely correlated with the bleeding time after aspirin in the infarct group. CONCLUSIONS - The shortened bleeding time may be an indicator of an increased prethrombotic tendency present in patients with myocardial infarction but not in those with unstable angina. The effect appears to be mediated by both thromboxane A2 and adrenaline.

Topics: Aged; Angina Pectoris; Angina, Unstable; Aspirin; Bleeding Time; Blood Platelets; Chest Pain; Epinephrine; Female; Humans; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Thromboxane A2

Thromboxane A2 (TxA2) generation and 1-14C arachidonic acid (AA) metabolism by platelets (stimulated with thrombin) were studied in vitro in 16 patients with unstable angina both during the acute and chronic inactive phase of the angina. Eight patients with stable effort angina and 21 controls were also investigated. In acute unstable angina 1-14C AA metabolism was significantly increased through cyclooxygenase pathway resulting in a higher selective TxA2 generation than in stable effort angina and in controls (p less than 0.01). No differences were found between patients with stable effort angina and controls. The alterations in AA metabolism were no longer found when patients reverted to the inactive phase of angina. TxA2 generation by platelets was independent of the number of the daily ischemic attacks (r = 0.17, ns) in patients with unstable angina. Present results indicate that an altered intraplatelet AA metabolism leading to the increased TxA2 synthesis occurs simultaneously with the conversion of angina from the chronic to the acute phase.

Topics: Acute Disease; Angina Pectoris; Angina, Unstable; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Female; Humans; In Vitro Techniques; Male; Middle Aged; Thromboxane A2

Topics: Angina Pectoris; Angina, Unstable; Blood Platelets; Coronary Vessels; Endoscopy; Epoprostenol; Humans; Thromboxane A2

Pathological and clinical studies have suggested that platelets have a role in the pathogenesis of unstable angina and myocardial infarction. However, the relation of platelet activation to episodic ischemia in patients with unstable angina is unknown. We assessed the biosynthesis of thromboxane and prostacyclin as indexes of platelet activation in patients with stable and unstable coronary disease by physicochemical analysis of metabolites in plasma and urine. Prostacyclin biosynthesis was markedly elevated in patients with acute myocardial infarction and correlated with plasma creatine kinase (r = 0.795; P less than 0.001). The largest rise in thromboxane synthesis was observed in patients with unstable angina, in whom 84 percent of the episodes of chest pain were associated with phasic increases in the excretion of thromboxane and prostacyclin metabolites. However, 50 percent of such increases were not associated with chest pain, possibly reflecting silent myocardial ischemia. These data indicate that platelet activation occurs during spontaneous ischemia in patients with unstable angina. The increment in prostacyclin biosynthesis during such episodes may be a compensatory response of vascular endothelium that limits the degree or effects of platelet activation. If so, biochemically selective inhibition of the synthesis or action of thromboxane A2 would be desirable in the treatment of unstable angina. In contrast, thromboxane inhibitors or antagonists would not be expected to be effective in patients with chronic stable angina, in whom there was no increase in the formation of thromboxane A2.

Topics: 6-Ketoprostaglandin F1 alpha; Angina Pectoris; Angina, Unstable; Blood Platelets; Epoprostenol; Humans; Myocardial Infarction; Thromboxane A2; Thromboxane B2

We examined platelet aggregation and plasma levels of thromboxane B2, a stable metabolite of thromboxane A2, in patients with unstable angina and correlated these platelet indices with the response to antianginal conventional therapy such as isosorbide dinitrate and calcium channel blocker. Eight of 36 patients exhibited anginal attacks more than 5 times/week in spite of the therapy, designated refractory unstable angina, associated with augmented platelet aggregation induced by arachidonate (0.3 mM, 71 +/- 3%, mean +/- SEM) and collagen (2 micrograms/ml, 72 +/- 5%), and elevated plasma levels of thromboxane B2 (350 +/- 19 pg/ml). In the remainder of the patients whose anginal attacks were effectively subsided by the therapy, platelet aggregation was much lower (arachidonate: 34 +/- 9%, collagen: 31 +/- 8%, p less than 0.01) and plasma levels of thromboxane B2 were also lower (295 +/- 12 pg/ml, p less than 0.05). To evaluate the effect of selective thromboxane A2 blockade on clinical findings and platelet reactivity in refractory unstable angina, OKY-046 (600 mg/day, p.o.) was administered to another 14 patients with refractory unstable angina in addition to the conventional therapy. We found that platelet aggregation induced by arachidonate (71 +/- 4%) and collagen 65 +/- 8%) was markedly reduced (44 +/- 7% and 24 +/- 3%, respectively, p less than 0.01) and plasma levels of thromboxane B2 (358 +/- 31 pg/ml) and thromboxane B2 production in serum (29 +/- 5 ng/ml) were also significantly reduced after OKY-046 treatment (262 +/- 21 pg/ml, p less than 0.05, and 1.4 +/- 0.2 ng/ml, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angina Pectoris; Angina, Unstable; Calcium Channel Blockers; Female; Humans; Isosorbide Dinitrate; Male; Methacrylates; Middle Aged; Platelet Aggregation; Thromboxane A2

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

Thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 (TXA2), was measured in the coronary sinus and in aortic blood before and after cold pressor test (CPT) in 21 patients suffering from ischemic heart disease (7 affected by stable effort angina and 14 by unstable angina) and in 12 patients not suffering from myocardial ischemia (control group) during coronary angiography. Aspirin (10 mg/kg intravenously) was administered before catheterization in order to prevent platelet and leukocyte TXA2 formation. Control subjects and patients with effort angina had TXB2 resting levels lower than unstable angina patients without a transcardiac gradient which, on the contrary, was found in unstable angina patients. Only in these patients CPT resulted in a significant TXB2 increase more marked in the coronary sinus (from 50.0 +/- 18.9 pg/ml to 73.0 +/- 35.1 pg/ml, p less than 0.001) than in the aorta (from 33.4 +/- 17.1 pg/ml to 42.6 +/- 24.0 pg/ml, p less than 0.05), so that the transcardiac TXB2 gradient significantly increased. In all but two unstable angina patients, TXB2 elevation was not associated with a fall of cardiac lactate extraction. The resting and CPT-induced TXB2 gradients were unrelated to the presence and severity of coronary angiographic lesions. These results indicate that unstable angina patients show an abnormal cardiocoronary capacity to synthesize TXA2, which seems not to be elicited by the occurrence of myocardial ischemia.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Aorta; Cold Temperature; Coronary Angiography; Coronary Vessels; Female; Humans; Lactates; Male; Middle Aged; Sympathetic Nervous System; Thromboxane A2; Thromboxane B2; Thromboxanes

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

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

Topics: Angina Pectoris; Angina, Unstable; Epoprostenol; Humans; Male; Middle Aged; Prognosis; Thromboxane A2