thromboxane-a2 and Coronary-Disease

Multiple factors are involved in thrombus formation and require complex and highly therapeutic strategies. Platelet activation plays a critical role in the genesis of acute coronary syndromes involving not only platelets but also endothelial cells, leucocytes and erythrocytes. Angiotensin II (Ang II) is a vasoconstrictor that could participate in the thrombotic process. Platelets also express Ang II AT1 type receptors on their surface. Losartan is a non-peptidic inhibitor of AT1 receptors. It has been demonstrated that losartan reduced platelet aggregation induced by the thromboxane A2 (TXA2) analogue U46619. This effect was not observed with the losartan metabolite EXP 3174. The effect of losartan was assessed in binding studies in which losartan competitively inhibited the binding of [3H]U46619 to platelets in a dose-dependent manner. Irbesartan also inhibits the TXA2 receptor in platelets, an effect that was not obtained with the active form of candesartan, CV11974, and with valsartan. These results suggest that the structural requirements necessary to antagonize the TXA2/PGH2 platelet receptor may be different from those involved in AT1 receptor antagonism. The in vivo relevance of the in vitro findings has been confirmed by the fact that in vivo administration of losartan decreases P-selectin expression in platelets obtained from stroke-prone spontaneously hypertensive rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Coronary Disease; Coronary Thrombosis; Humans; Losartan; P-Selectin; Platelet Activation; Platelet Aggregation; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Thromboxane; Tetrazoles; Thrombosis; Thromboxane A2; Valine; Valsartan

Prostaglandins (PGI2, PGE2, PGF2 alpha) and thromboxane (TX) A2 are vasoactive, cell membrane-derived lipid mediators that are formed in response to stimulation of vascular smooth muscle cells by a variety of chemical agonists. Different receptor subtypes mediate the contractile and relaxing effects of prostaglandins and TXA2 on coronary vascular smooth muscle: a high-affinity (kD: > or = 1 nM) PGH2/TXA2 receptor mediates the contractile actions of TXA2; a low-affinity (kD 100-200 nM) receptor mediates the contractile actions of other prostaglandins ('primary prostaglandin receptor') and a PGI2 receptor (kD > or = 20 nM) mediates vessel relaxation. These receptors are coupled to intracellular signal transduction pathways via different G-proteins and modify muscle tone by control of cytosolic Cai++. Ca(++)- and ATP-dependent K-channels are regulated by PGI2 (opening) and TXA2 (closure) and are involved in the setting of coronary smooth muscle tone. There is experimental and clinical evidence for enhanced local TXA2 levels, an increased number of platelet TXA2 receptors and a reduced number of PGI2 receptors in acute myocardial infarction. There is also experimental evidence for increased synthesis of PGF2 alpha-receptors in vascular smooth muscle that may mediate smooth muscle proliferation. The interference of both TXA2 and PGI2 with K(+)-channels in coronary arteries may have important implications for coronary vasospasm and ischaemia-related cardiac hypoperfusion.

Topics: Animals; Coronary Disease; Coronary Vessels; Humans; Ion Channels; Muscle, Smooth, Vascular; Prostaglandins; Receptors, Eicosanoid; Signal Transduction; Thromboxane A2

Thromboxane A2 (TXA2), the major cyclooxygenase (COX) product of arachidonic acid (AA), activates platelets and is a potent vasoconstrictor. The functional importance of this eicosanoid has been demonstrated in syndromes of acute coronary ischaemia. The cellular response to this agonist is tightly regulated. The liberation of AA from membrane phospholipids is conventionally thought to be the rate limiting step in TXA2 biosynthesis. However, the discovery of a second, highly regulated COX gene (COX-2) and the demonstration of product-based inactivation of COX and thromboxane synthase suggest a more complex regulation of TXA2 formation. TXA2 signalling is mediated by a G-protein linked receptor (PGH2/TXA2 receptor) which activates phospholipase C (PLC). Pharmacological studies suggest two distinct binding sites on platelets, but receptor heterogeneity has yet to be documented at a molecular level. The PGH2/TXA2 receptors are linked via a pertussis and cholera toxin-insensitive G-protein which has not been fully characterized, but is thought to belong to the Gq class of G-proteins. The diversity of G-protein alpha subunits, and growing evidence suggesting functional roles for the beta-gamma subunit, support a possible dual signalling mechanism of cellular activation. This may be of particular importance in regulating the response to eicosanoids with contrasting actions. A receptor for prostacyclin (PGI2) has not yet been cloned but biochemical studies suggest that it is linked to the activation of adenylate cyclase via Gs. At least three distinct prostaglandin E receptors have been identified. Desensitization of the cellular responses to the activation of TXA2, PGI2 and PGE receptors have been demonstrated and potential phosphorylation sites in their COOH terminal ends may be important in mediating this effect.

Topics: Coronary Disease; Eicosanoids; GTP-Binding Proteins; Humans; Platelet Activation; Receptors, Thromboxane; Signal Transduction; Thromboxane A2

Platelets and their interaction with the vessel wall play a role in atherogenesis and in the formation of the coronary thrombus. Supplementation of the diet with n-3 PUFA shifts the platelet-vessel wall interaction in anti-thrombotic direction in healthy persons and in patients with IHD. This is in part caused by an inhibition of Tx synthesis and also by an increased synthesis of PGI2 and PGI3 in the vessel wall. However, the clinical significance of these findings needs to be elucidated in clinical trials. Large, dense platelets are more reactive than small ones. Platelet size and density are determined at thrombopoiesis. Large, reactive platelets have in states with an increased platelet demand been shown to be produced from large, high-ploidy megakaryocytes. In patients with thrombopoiesis in steady-state an inverse relation between the bleeding time and both the DNA content and the size of the bone marrow megakaryocytes has been demonstrated. The bone marrow megakaryocytes in these patients were larger in men than in women, which may explain the sex difference in bleeding time observed by others. In experimental atherosclerosis changes in megakaryocyte size have been demonstrated. The significance of these changes are still unclear. In a single study stimulation of the platelet-megakaryocyte axis was associated with an acceleration of experimental atherosclerosis. This study suggests that large, high ploidy megakaryocytes may produce a large amount of atherogenic platelets that may be responsible for the increased formation of atheroma in this model. However, due to the complexity of the study design this hypothesis needs verification in other experimental and clinical studies. In patients suffering from an AMI the mean platelet volume is increased. The bleeding time is shortened at the time of infarction in these patients probably due to increased synthesis of TxA2, but an increased production of adrenaline may also be of importance. These large, reactive platelets present in AMI may be a reflection of an altered thrombopoiesis in these patients. It remains to be established whether these changes in platelet reactivity are present before the time of coronary thrombus formation.

Topics: Animals; Arteriosclerosis; Blood Platelets; Coronary Disease; Coronary Thrombosis; Endothelium, Vascular; Epoprostenol; Fatty Acids, Unsaturated; Humans; Megakaryocytes; Platelet Aggregation; Thromboxane A2

We believe that the abrupt conversion from chronic stable to unstable angina and the continuum to acute myocardial infarction may result from myocardial ischemia caused by progressive platelet aggregation and dynamic vasoconstriction themselves caused by local increases in thromboxane and serotonin at sites of coronary artery stenosis and endothelial injury. Platelet aggregation and dynamic coronary artery vasoconstriction probably result from the local accumulation of thromboxane and serotonin and also relative decreases in the local concentrations of endothelially derived vasodilators and inhibitors of platelet aggregation, such as endothelium-derived relaxing factor (EDRF) and prostacyclin. With severe reductions in coronary blood flow caused by these mechanisms, platelet aggregates may increase, and an occlusive thrombus composed of platelets and white and red blood cells in a fibrin mesh may develop. When coronary arteries are occluded or narrowed for a sufficient period of time by these mechanisms, myocardial necrosis, electrical instability, or sudden death may occur. We believe that unstable angina and acute myocardial infarction are a continuum in relation to the process of coronary artery thrombosis and vasoconstriction. When the period of platelet aggregation or dynamic vasoconstriction at sites of endothelial injury and coronary artery stenosis is brief, unstable angina or non-Q-wave infarction may occur. However, when the coronary artery obstruction by these mechanisms is prolonged for several hours. Q-wave myocardial infarction results. Chronic endothelial injury and coronary artery stenosis are probably associated with the accumulation of platelets, white and red blood cells, and a fibrin mesh at the site of stenosis and endothelial injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Disease; Humans; Nitric Oxide; Serotonin; Thrombosis; Thromboxane A2

Serotonin, a weak activator on its own, elicits strong platelet reactions (aggregation, arachidonate metabolization, release reaction) through amplification. Such amplification operates via 5-HT2-serotonergic receptors which are linked to the turnover of polyphosphoinositides and increases of intracellular [Ca2+]i concentrations as signal transducing systems. In experimental animals, selective blockade of 5-HT2-serotonergic receptors eliminates arterial thrombus formation over sites of endothelial injury in stenosed canine coronaries; in combination with a manipulation of TXA2, it prevents coronary thrombotic reocclusion after fibrinolysis with rt-PA, and inhibits drastic platelet activation, elicited by injections of collagen in vivo. These observations suggest that serotonergic amplification substantially contributes to the aggregation of platelets in damaged vessels and offers perspectives for an improved antithrombotic approach.

Topics: Animals; Blood Platelets; Calcium; Coronary Disease; Dogs; Fibrinolysis; Ketanserin; Phosphatidylinositols; Platelet Activation; Platelet Aggregation; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Signal Transduction; Thrombosis; Thromboxane A2

Topics: Aspirin; Coronary Disease; Epoprostenol; Humans; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

Platelet-derived 5-hydroxytryptamine and thromboxane A2 activate vascular smooth muscle cells, blood platelets and myocardial cells, both directly and through mutual amplification. Such an activation triggers: (1) vascular smooth muscle cell mitogenic activity, connective tissue synthetic activity and contractile activity; (2) platelet aggregation, secretion and procoagulant activity; (3) myocardial rhythm disturbances and necrosis. By such mechanisms, these autocoids contribute to arterial vessel wall proliferation, vasospasms and arterial thrombus formation in response to interactions of platelets with a damaged vessel wall, reduce the efficacy of thrombolytic agents and modulate myocardial reperfusion injury. Compounds directed specifically against these autocoids thus may offer possibilities for treating human ischaemic heart disease.

Topics: Arachidonic Acids; Blood Platelets; Cells, Cultured; Coronary Disease; Humans; Muscle, Smooth, Vascular; Receptors, Serotonin; Serotonin; Thromboxane A2

Evidence that combined thromboxane A2 and serotonin blockade may prevent coronary artery thrombosis and the conversion from chronic to acute coronary heart disease syndromes is considered. Available data from clinical and experimental animal studies are consistent with the hypothesis that interference with thromboxane and serotonin's contributions to platelet aggregation and dynamic coronary artery constriction might prevent the conversion from chronic to acute disorders, including the development of unstable angina and myocardial infarction in some patients at risk. Substantial protection preventing the conversion from stable to unstable angina and myocardial infarction may very well require both thromboxane and serotonin receptor antagonists or the combination of a thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist. Future clinical studies should test this hypothesis directly.

Topics: Animals; Coronary Disease; Disease Models, Animal; Humans; Serotonin Antagonists; Thrombosis; Thromboxane A2

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: Animals; Blood Platelets; Coronary Disease; Humans; Thromboxane A2; Vasoconstriction

Topics: Coronary Disease; Humans; Thromboxane A2; Thromboxanes

Topics: Coronary Disease; Epoprostenol; Humans; Myocardium; Norepinephrine; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2

Primary decreases in oxygen delivery to the myocardium associated with important reductions in coronary blood flow are the main mechanism of myocardial necrosis. Endothelial injury at sites of coronary artery stenosis, platelet attachment, and release of humoral mediators, including thromboxane A2 and serotonin, may be major causes of primary reductions in coronary blood flow leading to unstable angina and acute myocardial infarction (MI). Findings of clinical studies are consistent with the hypothesis that platelet aggregation and subsequent increases in thromboxane and serotonin concentrations may play a role in causing acute MI, death, or both in patients with unstable angina. Animal studies suggest that both thromboxane and serotonin are important in initiating or sustaining the cyclic coronary blood flow reductions that occur after severe stenosis and endothelial injury. If the contribution from either of these humoral mediators is eliminated or antagonized, cyclic flow reductions are usually terminated. Beta blocker and/or thrombolytic therapy administered within the first two hours after onset of coronary artery occlusion may limit infarct size and improve segmental ventricular function. When given within six hours of symptoms of MI, thrombolytic therapy may reduce mortality.

Topics: Adrenergic beta-Antagonists; Animals; Coronary Circulation; Coronary Disease; Dogs; Fibrinolytic Agents; Humans; Myocardial Infarction; Myocardium; Oxygen Consumption; Platelet Aggregation; Serotonin; Thromboxane A2; Vascular Resistance

Our current understanding of the physiology of the leukotrienes is far from complete. The abundant supply of synthetic products has directed researchers into examining what the mediators affect rather than the basic mechanism studies of their involvement in disease. It is clear that the peptide leukotrienes possess potent constrictor actions of the microvasculature and can enhance permeability. These actions alone represent a new avenue of interpreting pathologic processes and could lead to alternate means of treating certain diseases in the future. It is of special interest that a consistent action of the leukotrienes is to reduce coronary blood flow, decrease myocardial contractility, and reduce cardiac output without affecting the heart rate. This profile of action is the first indication that a mediator can play a significant role in unstable angina. The main physiologic actions of the leukotrienes in the cardiovascular system are currently believed to be associated with episodes of ischemia and shock. Their relative contribution to the shock states, especially when compared with the actions of other known mediators of shock such as the prostaglandins, thromboxane, angiotensin, serotonin, and histamine, awaits clarification. LTB4 is a proinflammatory mediator that has opened a completely new perspective on the physiologic role of phagocytic cells. Novel therapeutic approaches to inflammatory-related diseases may result from an inhibition of cell chemokinesis, aggregation, and degranulation. The role of LTB4 in the immune system awaits further clarification.

Topics: Animals; Blood Platelets; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cerebrovascular Circulation; Coronary Disease; Coronary Vasospasm; Humans; Leukotriene B4; Lung; Muscle Contraction; Muscle, Smooth, Vascular; Neutrophils; Skin; SRS-A; Thromboxane A2

The overall assessment of eicosanoids in ischemia and shock is complex. Certain prostaglandins, notably PGI2, actually improved survival in shock and ischemic states; however, some, including TxA2, act as mediators, significantly contributing to the pathophysiology of vasospasm and ischemia. This makes the intelligent use of eicosanoid-related drugs very difficult. Broad-based inhibitors (for example, cyclo-oxygenase inhibitors) are not likely to exert significant protective effects because they inhibit beneficial as well as detrimental eicosanoids. More appropriately, the therapy of ischemic disorders should be designed to employ specific agents (for example, TxSI and TxRA) rather than broad-based agents. Preliminary studies already suggest the success of such an approach. Future investigations will focus on the application of potent synthetic modulators or analogues of specific eicosanoids in an attempt to prevent the deleterious effects of eicosanoid mediators of ischemic disorders and to potentiate and prolong the beneficial actions of therapeutic eicosanoids.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Circulation; Coronary Disease; Coronary Vasospasm; Death, Sudden; Diabetic Angiopathies; Eicosanoic Acids; Epoprostenol; Hemodynamics; Humans; Phospholipases A; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Receptors, Cell Surface; Thromboxane A2

Topics: Animals; Arteriosclerosis; Coronary Disease; Epoprostenol; Humans; Hypertension, Pulmonary; Thromboxane A2

Topics: Angina Pectoris, Variant; Catecholamines; Coronary Circulation; Coronary Disease; Coronary Vasospasm; Humans; Myocardial Infarction; Oxygen; Oxygen Consumption; Thromboxane A2

Increased levels of the major metabolites of thromboxane (TxA2) and prostacyclin (PGI2) are found in venous blood draining the ischaemic region of the myocardium of dogs subjected to acute coronary artery occlusion. This suggests that these arachidonic acid derivatives are released under conditions of myocardial ischaemia and may be considered as mediators of some of the consequences of coronary blood flow reduction, including arrhythmogenesis. The present experimental evidence suggests that thromboxane release is detrimental both in the early stages of ischaemia and in reperfusion since the severity of both ischaemia and reperfusion-induced arrhythmias is reduced by selective inhibition of thromboxane synthesis or by thromboxane receptor blockade. Since the local administration of prostacyclin (or iloprost) or the promotion of local prostacyclin production (with nafazatrom) reduces the severity of ischaemia and reperfusion-induced arrhythmias, it is suggested that prostacyclin may act as a local, endogenous antiarrhythmic agent. The conclusion thus far from these experimental studies suggests that the prostacyclin-thromboxane balance is one important factor involved in determining the severity of ischaemia and reperfusion-induced arrhythmias but that the mechanisms have not as yet been clearly defined.

Topics: Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Eicosanoic Acids; Epoprostenol; Humans; Myocardium; Thromboxane A2; Thromboxane-A Synthase

Considerable attention is being given to the interactions that occur among blood platelets, neutrophils, and the vascular endothelium. There is an increasing awareness that the various blood elements interact in the process of thrombus formation and vascular occlusion. In addition, interactions among these cells can lead to the formation and release of vasoactive substances that have the potential to modulate regional blood flow. This review focuses on the coronary vascular bed and an assessment of how cell-cell interactions, under normal physiological conditions as well as in the presence of myocardial injury, may lead to alterations in coronary vascular resistance and myocardial function. Should related events be operative in human clinical states of disease, the circulating elements of the blood may serve as targets in the development of therapeutic interventions to regulate myocardial blood flow.

Topics: Animals; Blood Cells; Coronary Disease; Coronary Thrombosis; Coronary Vessels; Dogs; Endothelium; Free Radicals; Leukocytes; Oxygen; Platelet Activating Factor; Platelet Aggregation; Rabbits; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasodilation; Xanthine Oxidase

The role of platelet and vascular arachidonate metabolism in ischemic heart disease can be derived from direct measurements and/or inhibitor trials. Direct measurements have yielded somewhat conflicting results, largely related to analytical problems and ex vivo platelet activation during blood sampling. On the other hand, inhibitor trials have clearly established the following: 1) thromboxane (TX) A2-dependent platelet activation plays an important role in the dynamic process of coronary thrombosis in unstable angina, 2) TXA2 does not appear to mediate coronary vasospasm, as seen in variant angina, 3) endogenous prostacyclin (PGI2) is not released in response to myocardial ischemia and is unlikely to regulate coronary blood flow, and 4) exogenous PGI2 is of limited therapeutic benefit. The demonstration that low-dose aspirin (0.5-1.0 mg/(kg X day] is a selective inhibitor of TXA2-dependent platelet function provides a conceptual and practical framework for the rational design of future trials. Moreover, the identification of major enzymatic metabolites of TXB2 in plasma (11-dehydro-TXB2) and urine (2,3-dinor-TXB2) and development of appropriate analytical techniques offer the opportunity for better defining the pathophysiological role of TXA2 in humans.

Topics: Blood Platelets; Coronary Circulation; Coronary Disease; Coronary Vessels; Drug Evaluation; Epoprostenol; Humans; Prostaglandin Antagonists; Thromboxane A2

Topics: Coronary Disease; Coronary Thrombosis; Epoprostenol; Humans; Myocardial Infarction; Platelet Aggregation; Thromboxane A2; Urokinase-Type Plasminogen Activator

Topics: Animals; Coronary Disease; Dogs; Epoprostenol; Humans; Thromboxane A2

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

Topics: Animals; Blood Coagulation; Coronary Disease; Coronary Vasospasm; Glycoproteins; Humans; Intracranial Embolism and Thrombosis; Muscle, Smooth, Vascular; Myocardial Infarction; Plasminogen Activators; Platelet Adhesiveness; Platelet Aggregation; Protein C; Thrombosis; Thromboxane A2

Topics: Angina Pectoris; Animals; Arterioles; Blood Platelets; Blood Pressure; Coronary Circulation; Coronary Disease; Coronary Vessels; Epoprostenol; Humans; Hyperlipidemias; Microcirculation; Platelet Aggregation; Rheology; Spasm; Stress, Physiological; Stress, Psychological; Thromboxane A2; Vascular Resistance; Vasoconstriction

The dietary fatty acids include saturated and unsaturated fatty acids of the n-9, n-6 and n-3 families. Their quantity and quality are reflected in the plasma lipoproteins. The platelet and endothelial cell lipid composition also is influenced by the dietary fatty acids. These changes have consequences for cellular lipid and prostanoid metabolism and other cellular functions which could be related to the thrombosis mechanism. A high intake of saturated and n-9 unsaturated fatty acids induces changes in plasma, platelets and endothelial cells favouring thrombosis and atherosclerosis. By contrast, both n-6 and n-3 fatty acids give rise to plasma lipoprotein and cellular lipid composition that counteract atherosclerosis and thrombosis. The ideal balance between the various dietary fatty acids is not known. Experimental and epidemiological studies support the recommendation of a low saturated fat intake with supplement of both n-6 and -3 polyunsaturated fatty acids.

Topics: Blood Platelets; Coronary Disease; Dietary Fats; Endothelium; Epoprostenol; Fatty Acids; Humans; Lipids; Thromboxane A2

Topics: Angina Pectoris; Animals; Arachidonic Acids; Coronary Circulation; Coronary Disease; Coronary Vessels; Disease Models, Animal; Epoprostenol; Humans; Leukocytes; Lipoxygenase; Myocardial Infarction; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxane A2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Coronary Disease; Diet, Atherogenic; Myocardial Contraction; Myocardial Infarction; Nucleotides, Cyclic; Prostaglandins; Rabbits; Thiophenes; Thromboxane A2; Ticlopidine

Topics: Angina Pectoris; Angina Pectoris, Variant; Coronary Disease; Coronary Vasospasm; Humans; Prostanoic Acids; Stress, Physiological; Thromboxane A2; Vasoconstriction; Vasodilation

Topics: Angina Pectoris; Angina Pectoris, Variant; Blood Platelets; Coronary Disease; Death, Sudden; Diet; Epoprostenol; Humans; Muscle, Smooth, Vascular; Myocardial Infarction; Platelet Aggregation; Risk; Smoking; Thromboxane A2

Topics: Animals; Coronary Disease; Diabetes Mellitus; Epoprostenol; Humans; Hydronephrosis; Male; Platelet Aggregation; Shock; Thromboxane A2; Thromboxanes; Vasoconstriction

The evidence for a role of the prostaglandin system in myocardial ischemia and its consequences is still fragmentary. We review the factors that alter the relation between thromboxane A2 and prostacyclin production such that vasoconstriction, platelet aggregation, and the tendency toward thrombus formation are increased. Strategies to prevent platelet aggregation by interfering with the production of thromboxane A2 or by stimulation or administration of prostacyclin are currently under investigation in a number of centers. The ubiquity of the prostaglandin system and our incomplete understanding make careful long-term clinical trials and observations essential if we are to be sure that the net effect of these attempts is beneficial.

Topics: Animals; Blood Platelets; Blood Vessels; Coronary Disease; Cyclooxygenase Inhibitors; Epoprostenol; Humans; Phospholipases A; Prostaglandin Antagonists; Prostaglandins; Prostaglandins E; Thromboxane A2; Thromboxane-A Synthase

Topics: Adenosine Diphosphate; Adult; Aged; Angina Pectoris; Aspirin; Blood Platelets; Cerebrovascular Disorders; Coronary Disease; Epinephrine; Epoprostenol; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Adhesiveness; Platelet Aggregation; Propranolol; Thromboxane A2

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

To investigate the effects of electro-acupuncture (EA) combined general anesthesia on myocardial injury of high blood sugar patients with coronary heart disease (CHD) in the perioperative phase.. Recruited were 40 senile patients with glycosylated hemoglobin (HbA1c) more than 6.5%. They were more than 60 years old. They received post-traumatic fracture reduction surgery of four limbs. They were randomly assigned to two groups, Group N (treated by general intravenous anesthesia) and Group D (treated by EA combined with general intravenous anesthesia), 20 in each group. All patients were maintained anesthesia by propofol, fentanyl, and vecuronium. Prior to the induction of anesthesia, patients in Group D received induction of EA at Neiguan (PC6) and Baihui (DU20) for 20 min, which lasted to the end of the surgery. At before intubation (T0), immediately after intubation (T1), 5 min (T2), immediately after extubation (T3), 5 min (T4), 60 min (T5), 180 min (T6), the fast blood glucose (FBG), plasma vasoactive substance TXB2 and 6-K-prostacycline (6-K-PGF1alpha) were detected in the two groups. The glucose coefficient of variation (GluCV) and the ratio of TXB2/6-K-PGF1alpha were calculated. The changes of ST-segment elevation (mV, sampling 1 min after each time point, and the mean calculated) was recorded.. There was no statistical difference in all the tested values between the two groups at T0 (P>0.05). The FBG, ST elevation, and the ratio of TXB2/6-K-PGF1alpha were significantly higher at each time point than at T0 in Group N (P<0.05), while there was no statistical difference in Group D (P>0.05). The ratio of TXB2/6-K-PGF1alpha and ST elevation were significantly higher in Group N than in Group D (P<0.01). The TXB2 and 6-K-PGF1alpha were significantly higher at each time point than at T0 in the two groups (P<0.05). The increment of TXB2 was obviously lower in Group D than in Group N (P<0.05), but the increment of 6-K-PGF1alpha was obviously higher in Group D than in Group N (P<0.05).. EA could reduce the perioperative stress response to the injury of coronary vascular endothelial cells, and improve myocardial ischemia and CHD patients' prognosis by regulating the central nervous system, the cardiovascular active substances, and anti-oxygen free radicals.

Topics: Acupuncture Analgesia; Aged; Anesthesia, General; Blood Glucose; Coronary Disease; Electroacupuncture; Epoprostenol; Female; Glycated Hemoglobin; Humans; Intraoperative Period; Male; Middle Aged; Myocardial Ischemia; Myocardium; Thromboxane A2

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

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

Antithromboxane therapy with aspirin reduces acute procedural complications of coronary angioplasty (PTCA) but has not been shown to prevent restenosis. The effect of chronic aspirin therapy on long-term clinical events after PTCA is unknown, and the utility of more specific antithromboxane agents is uncertain. The goal of this study was to assess the effects of aspirin (a nonselective inhibitor of thromboxane A2 synthesis) and sulotroban (a selective blocker of the thromboxane A2 receptor) on late clinical events and restenosis after PTCA.. Patients (n = 752) were randomly assigned to aspirin (325 mg daily), sulotroban (800 mg QID), or placebo, started within 6 hours before PTCA and continued for 6 months. The primary outcome was clinical failure at 6 months after successful PTCA, defined as (1) death, (2) myocardial infarction, or (3) restenosis associated with recurrent angina or need for repeat revascularization. Neither active treatment differed significantly from placebo in the rate of angiographic restenosis: 39% (73 of 188) in the aspirin-assigned group, 53% (100 of 189) in the sulotroban group, and 43% (85 of 196) in the placebo group. In contrast, aspirin therapy significantly improved clinical outcome in comparison to placebo (P = .046) and sulotroban (P = .006). Clinical failure occurred in 30% (49 of 162) of the aspirin group, 44% (73 of 166) of the sulotroban group, and 41% (71 of 175) of the placebo group. Myocardial infarction was significantly reduced by antithromboxane therapy: 1.2% in the aspirin group, 1.8% in the sulotroban group, and 5.7% in the placebo group (P = .030).. Thromboxane A2 blockade protects against late ischemic events after angioplasty even though angiographic restenosis is not significantly reduced. While both aspirin and sulotroban prevent the occurrence of myocardial infarction, overall clinical outcome appears superior for aspirin compared with sulotroban. Therefore, aspirin should be continued for at least 6 months after coronary angioplasty.

Topics: Angioplasty, Balloon, Coronary; Aspirin; Coronary Angiography; Coronary Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Recurrence; Sulfonamides; Thromboxane A2; Time Factors; Treatment Outcome

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

GR32191B is a novel thromboxane A2-receptor antagonist with potent antiagregational and antivasoconstrictive properties. We have conducted a randomized, double-blind placebo-controlled trial to study its usefulness in restenosis prevention.. Patients received either GR32191B (80 mg orally before angioplasty and 80 mg/day orally for 6 months) or 250 mg i.v. aspirin before angioplasty and placebo for 6 months. Coronary angiograms before angioplasty, after angioplasty, and at 6-month follow-up were quantitatively analyzed. Angioplasty was attempted in 697 patients. For efficacy analysis, quantitative angiography at follow-up was available in 522 compliant patients (261 in each group). Baseline clinical and angiographic parameters did not differ between the two treatment groups. The mean difference in coronary diameter between postangioplasty and follow-up angiogram (primary end point) was -0.31 +/- 0.54 mm in the control group and -0.31 +/- 0.55 mm in the GR32191B group. Clinical events during 6-month follow-up, analyzed on intention-to-treat basis, were ranked according to the highest category on a scale ranging from death (control, six; GR32191B, four) to nonfatal infarction (control, 22; GR32191B, 18), bypass grafting (control, 19; GR32191B, 22) and repeat angioplasty (control, 52; GR32191B, 48). No significant difference in ranking was detected. Six months after angioplasty, 75% of patients in the GR32191B group and 72% of patients in the control group were symptom free.. Long-term thromboxane A2-receptor blockade with GR32191B does not prevent restenosis and does not favorably influence the clinical course after angioplasty.

Topics: Angioplasty, Balloon, Coronary; Aspirin; Biphenyl Compounds; Constriction, Pathologic; Coronary Disease; Double-Blind Method; Female; Follow-Up Studies; Heptanoic Acids; Humans; Male; Middle Aged; Receptors, Prostaglandin; Receptors, Thromboxane; Recurrence; Thromboxane A2

Sixty patients with coronary artery disease (CAD) were investigated in a randomized, placebo-controlled study. Therapeutic dose of diltiazem markedly inhibited the production of whole blood thromboxane A2(TXA2), but had no effect on the production of prostacyclin(PGI2). Both aspirin 20mg/d and diltiazem plus aspirin had marked inhibitive effects on both TXA2 and PGI2. The order of potency of the three regimens in decreasing TXA2/PGI2 ratio was diltiazem plus aspirin greater than diltiazem greater than aspirin. Diltiazem, aspirin and combination of both all decreased significantly serum lipid peroxides level, but had no effect on serum superoxide dismutase concentration. The results indicate that both therapeutic dose of diltiazem and low-dose of aspirin may modulate TXA2/PGI2 balance and inhibit lipid peroxidation in CAD and that the combination of both drugs may result in best therapeutic effect.

Topics: Aged; Aspirin; Coronary Disease; Diltiazem; Epoprostenol; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Superoxide Dismutase; Thromboxane A2

We addressed the hypothesis that platelets are not activated in association with effort-induced myocardial ischemia in stable coronary disease. Seventy-two patients undergoing a diagnostic bicycle exercise test were stratified according to the development of chest pain (yes/no, 33/39) and of exercise-induced ST-segment depression of at least 200 microV in the electrocardiogram (yes/no, 12/60). Noninvasive indexes of platelet activation and of platelet/vessel wall interaction (urinary excretion of the 2,3-dinor-metabolites of thromboxane A2 [Tx-M] and prostacyclin [PGI-M], respectively) were analyzed in samples collected in the basal state and after the test. Basal Tx-M and PGI-M did not differ in patients with (236 +/- 35 and 131 +/- 22 pg/mg creatinine, respectively) and without (185 +/- 16 and 101 +/- 13 pg/mg creatinine, respectively) chest pain, or in those with (178 +/- 45 and 162 +/- 41 pg/mg, respectively) and without (216 +/- 22 and 104 +/- 11 pg/mg, respectively) ST-segment depression during the test. Patients without chest pain or without ST-segment depression moderately increased (p less than 0.05) their urinary Tx-M (by 21% and 13%, respectively) and PGI-M (by 28% and 23%, respectively) after exercise. No significant increases were observed in those developing chest pain or ST depression during exercise. These data indicate that effort-induced myocardial ischemia is not associated with an increase in platelet activation or platelet/vessel wall interaction in patients with stable coronary disease.

Topics: Coronary Disease; Electrocardiography; Epoprostenol; Exercise; Exercise Test; Female; Humans; Male; Middle Aged; Platelet Activation; Thromboxane A2

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

We investigated the contractile response of human coronary microvasculature to thromboxane A-2 (TXA-2), with and without the blockade of TXA-2 receptors or the inhibition of phospholipase-C (PLC) or of protein kinase C-α (PKC-α) in the human coronary microvasculature before and after cardioplegia, followed by reperfusion (CP/Rep). Protein/gene expression and localization of TXA-2 receptors, TXA-2 synthase, PLC, and other TXA-2-related proteins was also examined.. Right atrial tissue was harvested before and after cold blood cardioplegia, followed by about 10 minutes of reperfusion, from 28 patients undergoing cardiac operations. Coronary arterioles (90 to 170 μm in diameter) were dissected from the harvested tissue.. The post-CP/Rep contractile response of coronary arterioles to TXA-2 analog U-46619 was significantly impaired vs pre-CP/Rep (p<0.05). The TXA-2 receptor antagonist SQ-29548 (10(-6) M) prevented the contractile response to U-46619 (p<0.05). Pretreatment with the PLC inhibitor U73122 (10(-6) M) significantly inhibited the U-46619-induced contractile response (p<0.05). Administration of the PKC-α inhibitor safingol failed to affect U-46619-induced contraction. Total protein levels and gene expression of TXA-2 receptors, TXA-2 synthase, PLC-β3, phospho-PLC-β3, PLC-γ1, and phospho-PLC-γ1 were not altered after CP/Rep. Confocal microscopy showed no significant differences in the expression of TXA-2 receptors or PLC-β3 in the microcirculation. TXA-2 receptors and PLC-β3 were both present in smooth muscle and endothelium.. Cardioplegia/Rep decreases the contractile response of human coronary arterioles to TXA-2 soon after cardiac operations. The contractile response to the TXA-2 analog U-46619 is through activation of TXA-2 receptors and PLC.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aged; Arterioles; Coronary Circulation; Coronary Disease; Coronary Vessels; Female; Gene Expression; Heart Arrest, Induced; Humans; Immunoblotting; Male; Microarray Analysis; Microscopy, Confocal; Receptors, Thromboxane A2, Prostaglandin H2; RNA; Thromboxane A2; Thromboxane-A Synthase; Type C Phospholipases; Vasoconstriction

Qi deficiency and blood stasis is traditional Chinese medicine (TCM) syndrome. It leads to many diseases including coronary heart diseases (CHD) and cerebrovascular diseases (CVD). Inflammatory biomarkers and many endothelium-derived vasoactive factors are considered to play pivotal roles in CHD. Buyang Huanwu decoction (BYHWD), a TCM formula, has been recognized as a treatment for CHD with Qi deficiency and blood stasis syndrome and CVD in clinic. The mechanisms of BYHWD effect on CHD with Qi deficiency and blood stasis syndrome are unclear.. The aim is to investigate whether the effects of BYHWD on CHD with Qi deficiency and blood stasis syndrome in rats are associated with the inhibition of CRP, CD40 and vascular endothelial regulators.. The treated groups were lavaged with 25.68, 12.84 and 6.42 g/kg BYHWD respectively once a day for 21 days. The level of C-reactive protein (CRP) in serum and the expression of cluster of differentiation 40 (CD40) in the heart and aorta of rats were detected. Moreover, the levels of thromboxaneA(2) (TXA(2)) and prostacyclin (PGI(2)) in plasma were measured and the levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in serum were detected.. BYHWD (25.68 g/kg) significantly decreased the level of CRP in serum and BYHWD (25.68 and 12.84 g/kg) decreased the expression of CD40 in the heart and aorta (P<0.01). The results also revealed that BYHWD (25.68 g/kg) inhibited the levels of iNOS in serum and TXA(2) in plasma and increased the levels of eNOS in serum and PGI(2) in plasma (P<0.01).. The study shows that the ameliorative effects of BYHWD on CHD with Qi deficiency and blood stasis syndrome in rats are associated with the inhibition of CRP and CD40 and the regulation of endothelium-derived vasoactive factors.

Topics: Animals; C-Reactive Protein; CD40 Antigens; Coronary Disease; Drugs, Chinese Herbal; Epoprostenol; Female; Hemostasis; Medicine, Chinese Traditional; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Qi; Rats; Rats, Sprague-Dawley; Thromboxane A2

Our aim was to analyze the plasma proteome in aspirin (acetylsalicylic acid [ASA])-sensitive and ASA-resistant coronary ischemic patients. Plasma from 19 ASA-sensitive and 19 ASA-resistant patients was analyzed. For the proteomic study, two-dimensional electrophoresis was performed. The expression of one isotype of the fibrinogen gamma chain and three isotypes of haptoglobin was increased in ASA-resistant patients. Three vitamin D binding protein isotypes were increased in ASA-resistant patients. In vitro incubation of vitamin D binding protein (DBP) with blood from healthy volunteers reduced the inhibitory effect of ASA on thromboxane A2 production. DBP may be a new regulator of the inhibitory effect of ASA on platelets.

Topics: Aged; Aspirin; Blood Proteins; Coronary Disease; Drug Resistance; Electrophoresis, Gel, Two-Dimensional; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Protein Isoforms; Proteome; Proteomics; Thromboxane A2; Vitamin D-Binding Protein

Topics: Aspirin; Coronary Disease; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Resistance; Humans; Thromboxane A2

Topics: Angioplasty; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Clopidogrel; Coronary Disease; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Eptifibatide; Heparin; Humans; Peptides; Platelet Aggregation Inhibitors; Stents; Thromboxane A2; Ticlopidine; Treatment Outcome

We have previously shown that superoxide anion (O2-) stimulates the release of vasoconstrictor prostanoids and induces a prolonged rise in coronary perfusion pressure (CPP) that persists even after removal of O2-. In this study, we tested the hypothesis that the increased CPP is mediated by activation of TxA2/ PGH2 (TP) receptors and protein kinase C (PKC)-dependent mechanisms. In Langendorff perfused rat hearts, O2- was applied for 15 min and then washed out over a period of 20 min. Application of O2- increased the release of vasoconstrictive (TxA2 and PGF2alpha) and decreased vasodilating (PGI2 and PGE2) prostanoids. Although indomethacin (10 microM), a cyclooxygenase inhibitor, attenuated the rise in CPP during O2- perfusion, the increase was not completely blocked. OKY 046Na (10 microM), a thromboxane synthase inhibitor, had no effect on O2--induced increases in CPP, whereas ONO 3708 (10 microM), a TP receptor antagonist, suppressed this effect. PKC activity was also elevated by more than 50% by O2- perfusion. CPP typically increased throughout the O2- wash-out. This post-O2- vasoconstriction was not inhibited by indomethacin, nitroglycerin or nitrendipine. In contrast, ONO 3708 (10 microM) and two PKC inhibitors, staurosporine (10 nM) and calphostin C (100 nM), completely blocked the rise in CPP, and even elicited vasodilation. PDBu enhanced the post-O2- vasoconstriction. We conclude that O2--induced coronary vasoconstriction is initially mediated by TP receptors, but activation of PKC sustains the response.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium Channel Blockers; Cardiovascular Agents; Coronary Disease; Dinoprost; Enzyme Inhibitors; In Vitro Techniques; Indomethacin; Male; Methacrylates; Naphthalenes; Perfusion; Prostaglandins; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Staurosporine; Superoxides; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

To study pathological significance of circulating thromboxane A2 and prostacyclin in mechanisms of impairment of intrarenal hemodynamics and renal function due to contrast media (CM) in risk group patients and to study protective effects of calcium antagonists in CM nephrotoxicity.. To study plasmic concentrations of TxA2 and prostacyclin, we used radioimmunoassay to measure plasmic TxB2 and 6-keto-prostaglandin F1a in patients with chronic glomerulonephritis (group 1), systemic atherosclerosis and coronary heart disease (group 2). The control group consisted of 23 healthy subjects. Diatrizoate (verografin), a high-osmolar CM, was used (40-60 and 250-400 cc in groups 1 and 2, respectively).. Plasma TxB2 and serum creatinine concentrations were significantly elevated in group 1 after CM infusion compared to the preinfusion period and healthy controls. Plasma 6-keto-prostaglandin F1a in group 1 before CM infusion was lower than in controls after CM infusion. The data in group 2 were similar to those for group 1. Administration of nifedipine before and after introduction of CM prevented a rise in serum creatinine and had beneficial effects on TxA2 and prostacyclin synthesis.. Ionic CM have a renal vasoconstrictive effects mediated by imbalance between vasoconstrictor TxA2 and vasodilator prostacyclin and may be nephrotoxic in risk group patients. The protective effects of calcium antagonists promote normalization of calcium dependent TxA22 and prostacyclin synthesis.

Topics: Adolescent; Adult; Biomarkers; Calcium Channel Blockers; Chronic Disease; Contrast Media; Coronary Disease; Disease Progression; Drug Hypersensitivity; Epoprostenol; Female; Glomerulonephritis; Humans; Kidney; Male; Middle Aged; Renal Circulation; Thromboxane A2

The membrane complex alpha(IIb)beta(3) is the major receptor for fibrinogen and is involved in platelet adhesion and aggregation. Evidence has been presented that the Pl(A2) allele of the beta(3) Pl(A1/A2) gene polymorphism might be an independent risk factor for coronary thrombosis, but the matter is still controversial. We investigated the relationship between this polymorphism and possible alterations of platelet functions in vitro. The platelet adhesion to fibrinogen-coated microplate wells and the aggregation induced by several different agonists were tested in 63 healthy volunteers, among them, 49 subjects with Pl(A1/A1) polymorphism, 12 subjects with Pl(A1/A2) polymorphism and two subjects with (PlA2/A2) polymorphism. Subjects with PlA1/A2 polymorphism or with Pl(A2/A2) polymorphism showed significantly lower platelet responses as compared with Pl(A1/A1) subjects when either arachidonic acid or the thromboxane A(2) analogue, U46619, were used as agonists. In resting condition and after thrombin or ADP stimulation, platelet function was normal in all the subjects. An increased sensitivity to the anti-aggregatory effect of acetylsalicylic acid was observed in platelets from subjects with the Pl(A2) allele. Finally, using a flow-cytometric evaluation and determining the beta-thromboglobulin plasma levels, we did not find any evidence of a Pl(A2) platelet hyper-reactivity ex vivo. Our findings are not consistent with the hypothesis that the purported increase of cardiovascular risk in these subjects may be as a result of platelet hyperactivation. On the contrary, the Pl(A2) allele is associated with a platelet functional deficiency, specifically linked to the activation of the fibrinogen receptor by thromboxane A(2).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Adult; Arachidonic Acid; Aspirin; beta-Thromboglobulin; Blood Platelets; Coronary Disease; Female; Flow Cytometry; Genotype; Humans; Male; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Glycoprotein GPIIb-IIIa Complex; Polymorphism, Genetic; Risk Factors; Statistics, Nonparametric; Thrombin; Thromboxane A2

The aim of this study was to find out the effects of cyclo-oxygenase and thromboxane synthetase inhibitors on right atrial prostacyclin and thromboxane A2 levels.. The study consisted of a total of 50 patients subjected to coronary bypass surgery. These patients were divided into two groups, Group I and Group II each consisting of 25 patients. In Group I patients, the right atrial tissues were studied for effects of indomethacin and U63557A on the prostaglandin levels. In Group II patients, the right atrial tissues were studied for effects of Aspirin and U63557A on the prostaglandin levels.. In Group I patients, the atrial tissues pretreated with indomethacin showed a fall in the levels of 6 keto PGF1 alpha from 153.5 +/- 28.4 pg/0.1 mg to 59.7 +/- 11.6 pg/0.1 mg and of TXB2 from 41.6 +/- 1.2 pg/0.1 mg to 17.2 +/- 3.2 pg/0.1 mg. In the atrial tissues of Group I treated with U63557A the levels of 6 keto PGF1 alpha fell to 145.4 +/- 26.8 pg/0.1 mg and the levels of TXB2 fell to 14.7 +/- 2.8 pg/0.1 mg. In Group II patients, the atrial tissues pretreated with aspirin, showed a fall in the levels of 6 keto PGF1 alpha from 142.1 +/- 2.8 pg/0.1 mg to 17.5 +/- 0.8 pg/0.1 mg. In the atrial tissues pretreated with U63557A, the levels of 6 keto PGF1 alpha fell to 131.2 +/- 2.9 pg/0.1 mg and the levels of TXB2 fell to 14.4 +/- 0.7 pg/0.1 mg.. The study showed that human right atrial tissues are capable of producing TXA2 in addition to prostacyclin. Indomethacin and aspirin by inhibiting generation of cyclic endoperoxides inhibited synthesis of both prostacyclin and TXA2. In contrast a thromboxane synthethase inhibitor U63557A selectively inhibited TXA2 without significant effects on prostacyclin synthesis.

Topics: Aspirin; Benzofurans; Coronary Artery Bypass; Coronary Disease; Culture Techniques; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Heart Atria; Humans; Indomethacin; Prostaglandins; Thromboxane A2; Thromboxane-A Synthase

Coronary artery disease is accelerated in chronic spinal cord injury (SCI). Because prostacyclin (PGI2) may retard atherogenesis through its inhibitory effects on platelet function, the role of PGI2 on SCI platelets was determined. The SCI platelets were neither hypersensitive to aggregating agonists nor resistant to the inhibitory effect of PGI2, but PGI2 failed to inhibit platelet-stimulated thrombin generation and the release of platelet-derived growth factor (PDGF) in SCI. Because thrombin and PDGF are atherogenic mitogens, the generation of these mitogens was investigated. Both the release of PDGF and thrombin generation in SCI platelets were higher when compared with control (n = 12). Treatment of non-SCI platelets with 100 nM PGE1 (a stable probe of PGI2) inhibited the release of the mitogens by 90% (P < 0.001), with no effect on SCI platelets. Scatchard analysis of prostaglandin E1 (PGE1) binding showed a 70% decrease of PGI2 receptors on the SCI platelet surface. Treatment of SCI platelets with insulin or Ca2+ channel blockers restored the PGI2-receptor number and "normalized" the inhibition of PDGF release and thrombin generation by PGI2.

Topics: Adult; Aged; Alprostadil; Blood Platelets; Calcium Channel Blockers; Coronary Disease; Cyclic AMP; Epoprostenol; Humans; Insulin; Middle Aged; Platelet Aggregation; Platelet-Derived Growth Factor; Receptors, Epoprostenol; Receptors, Prostaglandin; Spinal Cord Injuries; Thrombin; Thromboxane A2

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

Topics: Aspirin; Coronary Disease; Epoprostenol; Humans; Platelet Aggregation Inhibitors; Radiotherapy; Salicylates; Thromboxane A2

To elucidate the relationship between Dampness and blood stasis in patients with coronary heart disease (CHD).. One hundred and twenty-eight CHD patients with Phlegm-Dampness Syndrome (PDS) and 69 with blood stasis syndrome (BSS) were chosen and treated by eliminating Dampness and removing blood stasis.. (1) CHD-PDS and -BSS possessed the similar changes on hemorheology, oxygen free radical, blood lipids and vascular active substance. (2) Both of these two methods could alleviate angina (effective rate was 88.3%, 89.9%), improve ischemic S-T segment changes in ECG obviously and reduce consumption of nitroglycerin significantly (P < 0.01), improve abnormal hemorheology obviously (P < 0.001), raise PGI2, SOD obviously (P < 0.01) and lowered TXA2, MDA, ANP, ET and blood lipids significantly (P < 0.001). (3) The two methods could regulate imbalanced state of PGI2/TXA2,SOD/MDA.. CHD-PDS and -BSS had similar pathologic basis or pathologic changes, could eliminate the Dampness also had possessed similar pharmacologic or pharmacodynamic action of removing blood stasis. According to this, the viewpoint of "blood stasis due to Dampness" might be proved from clinical aspect.

Topics: Adult; Aged; Aged, 80 and over; Coronary Disease; Diagnosis, Differential; Drugs, Chinese Herbal; Epoprostenol; Female; Hemorheology; Humans; Male; Malondialdehyde; Medicine, Chinese Traditional; Middle Aged; Superoxide Dismutase; Thromboxane A2

Topics: Animals; Aspirin; Coronary Disease; Epoprostenol; Humans; Radiotherapy; Thromboxane A2

The aim of this study was to trace the possible mechanisms of premature atherosclerosis in its early stages and to expand our knowledge of the genetic structure of an inherited predisposition to coronary heart disease (CHD) by monitoring of TXA2 and PGI2 levels in the children of fathers who have suffered a premature myocardial infarction.. Prostacyclin (PGI2) and thromboxane A2 (TXA2) levels were estimated by radioimmunoassay in 90 children (aged 7-18 years) of fathers who had suffered premature infarction and in both their parents (the 'main' group, n = 191), and in 59 of their healthy contemporaries with no family history of ischaemic events, hypertension, or diabetes, and both their parents (the 'control' group, n = 110).. Sons of early infarction patients presented an average TXA2 level of 158.94 +/- 16.60 pg/ml (versus 86.88 +/- 12.71 pg/ml in the control group, P < 0.001), and daughters presented an average TXA2 level of 230.13 +/- 33.68 pg/ml (versus 69.67 +/- 14.99 pg/ml in the control group, P < 0.001). This hyperproduction was independent of the children's sex and could not be attributed to health problems. A significant increase (two-fold) of PGI2 in the boys but not in the girls of the main group was noted. Daughters of infarction patients had significantly higher levels of TXA2 than PGI2. The wives of early infarction patients presented a significantly higher level of both TXA2 and PGI2 (two and three times the level in the control group, P < 0.02 and P < 0.05, respectively).. Spontaneous TXA2 hyperproduction is intrinsic among children with an inherited propensity for CHD and is strongly determined by genetic factors, which is evident from the structure of in-family phenotypic correlations of PGI2 and TXA2 levels.

Topics: Adolescent; Adult; Child; Coronary Disease; Epoprostenol; Family; Female; Humans; Male; Middle Aged; Phenotype; Risk Factors; Sex Characteristics; Thromboxane A2

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

We investigated the effect of G 619, a dual thromboxane synthase inhibitor and thromboxane A2 (TxA2) receptor antagonist, in pentobarbital-anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase (CPK) activity were studied. MI/R injury significantly reduced survival rate (45%), caused a marked myocardial necrosis, increased serum CPK activity (sham MI/R = 35 +/- 12 U/ml; MI/R = 205 +/- 13 U/ml) and produced an increase in myocardial MPO activity in the area at risk and in the necrotic area (6.3 +/- 0.5 and 6.6 +/- 0.9 U x 10(-3)/g tissue, respectively). The administration of G 619 significantly increased survival rate, lowered the area of necrosis, blunted the increase in serum CPK activity and reduced the increase in MPO activity in both the area at risk and the necrotic area. These data are consistent with an involvement of TxA2 in MI/R injury and suggest that G 619 may represent a novel therapeutic approach to the treatment of acute myocardial infarction.

Topics: Animals; Benzamides; Coronary Disease; Creatine Kinase; Disease Models, Animal; Leukocyte Count; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Neutrophils; Peroxidase; Picolines; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Survival Rate; Thromboxane A2; Thromboxane-A Synthase

The effect of a four weeks oral treatment with 100 mg isosorbide dinitrate (ISDN) daily on platelet function was evaluated in 40 patients (aged 40-65 years) with proven coronary artery disease. Isosorbide dinitrate decreased platelet reactivity to ADP (p less than 0.001), increased platelet sensitivity to PGI2 (p less than 0.01) while the production of TXB2 from exogenous arachidonic acid substrate and from endogenous substrate were both significantly reduced. Circulating platelet aggregates as measured by the Wu-test were markedly reduced (p less than 0.001) but there was little change in the plasma concentration of the platelet proteins beta-thromboglobulin and platelet factor 4. Overall, platelet activation correlated with smoking, hypertension and a family history of coronary artery disease. The reduced platelet activation seen during treatment with isosorbide dinitrate may contribute to the therapeutic benefit seen with this drug in patients with coronary artery disease.

Topics: Adenosine Diphosphate; Adult; Arachidonic Acid; beta-Thromboglobulin; Blood Platelets; Coronary Disease; Drug Interactions; Endothelium, Vascular; Epoprostenol; Female; Humans; Hypertension; Isosorbide Dinitrate; Male; Middle Aged; Platelet Activation; Platelet Aggregation; Platelet Factor 4; Risk Factors; Smoking; Thromboxane A2

The familial correlations of prostacyclin and thromboxane levels were examined in 90 children and adolescents from 70 families with hereditary coronary heart disease and in 56 of the same age from 38 families without hereditary atherosclerosis and their parents. The genetic factors were demonstrated to make a significant contribution to the phenotypic dispersion of prostanoids. The familial predisposition to the disease was ascertained to modify the pattern of familial correlations of prostacyclin and thromboxane levels as compared with no predisposition. The influence of familial and environmental factors was found to be more pronounced in the families of patients with coronary heart disease, and one of the important sequelae is thromboxane hyperproduction in the patients' wives.

Topics: Adolescent; Child; Coronary Disease; Epoprostenol; Female; Humans; Male; Phenotype; Thromboxane A2

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

The aim was to test the hypothesis that thromboxane A2 can cause vasoconstriction of coronary resistance vessels during exercise in hypoperfused regions of myocardium distal to an arterial stenosis.. Eight adult mongrel dogs were studied. Chronically instrumented animals with a left circumflex coronary artery Doppler flow meter, hydraulic occluder, and indwelling catheter underwent treadmill exercise at heart rates of 190-200 beats.min-1. Myocardial blood flow was measured with microspheres during unimpeded arterial inflow and in the presence of a coronary stenosis which decreased distal pressure to 42-45 mm Hg. Measurements were repeated during infusion of the thromboxane A2 analogue, U46619.. When the occluder was partially inflated to produce a stenosis, blood flow in the region perfused by the stenotic artery was 58 (SEM 6)% of flow in the normally perfused region (p less than 0.01). U46619 (0.01 microgram.kg-1.min-1) caused a further 21 (7)% decrease in blood flow in the region perfused by the stenotic artery (p less than 0.05). The vasoconstriction produced by U46619 was uniform across the left ventricular wall from epicardium to endocardium. U46619 did not significantly decrease myocardial blood flow in the absence of a coronary stenosis.. Even during hypoperfusion produced by a flow limiting arterial stenosis, the coronary resistance vessels remain responsive to the vasoconstrictor effect of thromboxane A2. Liberation of thromboxane A2 during platelet activation at the site of a proximal coronary stenosis may worsen myocardial hypoperfusion by causing vasoconstriction of the distal resistance vessels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Dogs; Heart Rate; Microspheres; Physical Exertion; Prostaglandin Endoperoxides, Synthetic; Regional Blood Flow; Thromboxane A2

The goal of this study was to test the hypotheses that endogenous ADP plays an important role in vivo in mediating platelet aggregation and cyclic coronary artery blood flow variations (CFVs) in stenosed and endothelium-injured coronary arteries in an experimental canine model. Anesthetized animals were studied and coronary blood flow velocities monitored by a pulsed Doppler flow probe positioned around the left anterior descending coronary artery. CFVs were established by an external constrictor positioned at sites with injured endothelium. Apyrase, an ADP-removing enzyme, was infused into the left anterior descending coronary artery (0.3-1.8 units/min) 30 minutes or 2 hours after the establishment of CFVs. Complete abolition of CFVs was achieved in 81% (13/16) of dogs with 30-minute CFVs and in 83% (five of six) of dogs with 2-hour CFVs. In other dogs, a potent inhibitor of ADP-induced platelet aggregation, clopidogrel, was administered as a 10 mg/kg i.v. bolus and a 2.5 mg/kg/hr infusion 30 minutes and 3 hours after the establishment of CFVs. This treatment resulted in complete abolition of CFVs in 14 dogs (100%) with either 30-minute or 3-hour CFVs. Epinephrine was infused into some dogs after CFVs had ceased as a result of either apyrase or clopidogrel administration and into some dogs in whom SQ29548, a thromboxane A2 receptor antagonist, had been given when apyrase failed to abolish CFVs. Epinephrine restored CFVs in all dogs treated with apyrase alone, 67% (four of six) of dogs treated with the combination of apyrase and SQ29548, and 29% (two of seven) of dogs treated with clopidogrel. The plasma epinephrine levels required for CFV restoration were 20 times higher than baseline values in dogs receiving apyrase alone, 100 times higher when a combination of apyrase and SQ29548 had been given, and more than 5,000 times higher in dogs receiving clopidogrel. In vitro studies showed that apyrase only inhibited ADP-induced platelet aggregation, whereas clopidogrel not only inhibited ADP-induced platelet aggregation, but also reduced platelet aggregation induced by the thromboxane mimetic U46619 and serotonin. These data suggest that 1) ADP is an important mediator of platelet aggregation and CFVs in vivo and 2) combined inhibition of thromboxane A2 and ADP's effects provides marked protection against CFVs in experimentally stenosed and endothelium-injured canine coronary arteries. These data and our previous observations are consistent with the possibili

Topics: Adenosine Diphosphate; Animals; Apyrase; Bridged Bicyclo Compounds, Heterocyclic; Clopidogrel; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Endothelium, Vascular; Fatty Acids, Unsaturated; Female; Hydrazines; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Serotonin; Thromboxane A2; Ticlopidine

Topics: Aspirin; Combined Modality Therapy; Coronary Artery Bypass; Coronary Disease; Dipyridamole; Drug Therapy, Combination; Epoprostenol; Humans; Phenindione; Postoperative Care; Postoperative Complications; Thromboxane A2; Time Factors

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

The thromboxane-receptor antagonist, SQ 30,741, may be used as adjuvant therapy for thrombolysis and has also been shown to have antiischemic activity that is independent of its thrombolytic activity. Since tissue-type plasminogen activator (t-PA) and SQ 30,741 may be administered simultaneously, we determined whether the antiischemic effects of SQ 30,741 can be potentiated by t-PA. This was accomplished by combining doses of t-PA and SQ 30,741, which alone were not cardioprotective. Anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 minutes and reperfusion for 5 hours. The dogs were treated during reperfusion with a dose of t-PA that caused approximately a 30% reduction in plasma fibrinogen alone or in combination with 1.5 mg/kg + 0.4 mg/kg/hr SQ 30,741, which started 10 minutes after initiation of ischemia. At these doses, neither t-PA nor SQ 30,741 alone significantly reduced infarct size (57% +/- 6%, 50% +/- 10%, 57% +/- 6% of the left ventricular area at risk for vehicle controls, t-PA, and SQ 30,741 respectively); however, combination treatment resulted in a significant reduction in infarct size (37% +/- 5% of the left ventricular area at risk). Higher doses of t-PA and SQ 30,741 alone significantly reduced infarct size. The protective effects of t-PA and SQ 30,741 occurred without altering peripheral hemodynamic status. No differences in collateral or reperfusion blood flow were observed between groups. Thus although SQ 30,741 may act to improve the efficacy of thrombolysis, t-PA may in turn enhance the antiischemic activity of SQ 30,741 or at least reduce the threshold dose.

Topics: Animals; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Female; Hemodynamics; Male; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Tissue Plasminogen Activator

A study of neurohumoral and functional determinants of the advance of Ischemic heart disease in 39 patients with unstable stenocardia with positive results of loading tests (transesophageal electrocardiostimulation and veloergometry) allowed to reveal a significant reduction of the coronary reserve and regional dysfunction of the myocardium that interrelated with changes of the prostacyclin/thromboxane balance, increase of vasopressin with unchanged angiotensin II value and increased marker of the functional state of thrombocytes--beta-thromboglobulin. These changes may be one of the leading links in the pathogenesis of destabilization.

Topics: Acute Disease; Angiotensin II; beta-Thromboglobulin; Coronary Disease; Epoprostenol; Fibrinopeptide A; Humans; Physical Exertion; Radioimmunoassay; Thromboxane A2; Vasopressins

Platelet-mediated obstruction of stenotic and endothelium-injured coronary arteries may be important in the abrupt progression from chronic stable to unstable coronary heart disease syndromes in patients. Transcardiac accumulation of thromboxane A2 and serotonin has been demonstrated in patients as chronic stable angina is converted to unstable angina. In this study in anesthetized open chest dogs with coronary artery stenosis and endothelial injury, thromboxane A2 and serotonin were shown to be important mediators of intermittent coronary obstruction caused by platelet aggregation and dynamic vasoconstriction. Furthermore, thromboxane A2 synthesis inhibitors and receptor antagonists and serotonin receptor antagonists, singly and together, provided substantial protection against repetitive platelet aggregation and dislodgment in canine models with coronary artery stenosis and endothelial injury even when systemic catecholamine concentrations were markedly elevated. These same observations apply in chronically instrumented, awake, unsedated dogs with coronary artery stenosis and endothelial injury in which recurrent platelet attachment and dislodgment cause cyclic flow alterations that may be prevented by thromboxane A2 synthesis inhibitors and receptor antagonists and serotonin receptor antagonists. Chronically instrumented dogs with coronary stenosis and endothelial injury in which recurrent platelet attachment and dislodgment occurred also developed neointimal proliferation of varying severity within 10 days to 3 weeks; the morphologic appearance of the neointimal proliferation was identical to that found in patients who develop restenosis after coronary angioplasty.

Topics: Animals; Blood Flow Velocity; Chronic Disease; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Endothelium, Vascular; Female; Hemodynamics; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Serotonin; Serotonin Antagonists; Thromboxane A2; Vasoconstriction

This study was designed to test the efficacy of nitroglycerin and diltiazem in inhibiting in vivo platelet aggregation and reducing platelet-mediated vasoconstriction in a canine model of coronary artery stenosis and endothelial injury. Coronary artery diameter was measured in vivo by means of ultrasonic crystals sutured on the left anterior descending coronary artery (LAD) immediately distal to an external constrictor (LAD1), 1 cm below (LAD2), and on the left circumflex coronary artery. Coronary diameter was continuously measured before, during cyclic flow variations (progressive declines in blood flow followed by sudden restorations of flow due to recurrent intracoronary platelet aggregation), during cyclic flow variations and intravenous infusion of nitroglycerin (5 micrograms/kg per min) or diltiazem (15 micrograms/kg per min), and after cyclic flow variations were abolished by administration of LY53857, a serotonin receptor antagonist (n = 7), or SQ29548, a thromboxane A2 receptor antagonist (n = 7). During control cyclic flow variations, at the nadir of coronary flow (6% to 11% of the nonstenosed values), LAD1 cross-sectional area decreased by 43 +/- 8% and 44 +/- 3% in the two groups of dogs subsequently treated with LY53857 and SQ29548, respectively. Neither nitroglycerin nor diltiazem caused changes in cyclic flow variation frequency or severity. Furthermore, neither drug significantly reduced the vasoconstriction associated with cyclic flow variations, whereas they significantly increased circumflex artery cross-sectional area. In contrast, LY53857 and SQ29548 were very effective in abolishing cyclic flow variations and the coronary vasoconstriction related to them. Five additional dogs received an intracoronary infusion of nitroglycerin (21 +/- 5 micrograms/kg per min) and later diltiazem (15 micrograms/kg per min).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Coronary Disease; Coronary Vessels; Diltiazem; Dogs; Endothelium, Vascular; Hemodynamics; Nitroglycerin; Platelet Aggregation; Serotonin; Thromboxane A2; Vasoconstriction

Topics: Coronary Disease; Epoprostenol; Humans; Lipoproteins, HDL; Thromboxane A2

To assess the platelet inhibitory effect of high doses of fish oils and relate it to alterations in eicosanoid synthesis, we used a canine model in which coronary thrombosis, the time to reperfusion induced by recombinant tissue-type plasminogen activator (rt-PA), and the rate of spontaneous reocclusion are sensitive to platelet inhibition. In the animals fed fish oil, the time to rt-PA induced thrombolysis was accelerated (mean, 63 vs. 27 minutes; p less than 0.003). The time to thrombotic occlusion and the rate of reocclusion were unaltered. The ratio of eicosapentaenoic acid (EPA) to arachidonic acid rose in platelet and endothelial cell membranes, whereas serum thromboxane (Tx) B levels fell a mean 86%, and basal excretion of 2,3-dinor-TxB2 (TxA2-M) declined. Basal prostaglandin (PG) I2 formation was unaltered, whereas biosynthesis of EPA-derived TxA3 and PGI3 increased. In control animals, TxA2 formation increased during thrombosis; there was a further, more marked rise during reperfusion. PGI2 formation also increased, probably as a response to platelet-vascular interactions. Stimulated production of both eicosanoids was strikingly suppressed in the animals fed fish oil. Fish oils significantly enhance the efficacy of rt-PA in vivo, albeit to a modest extent. Because the time to reperfusion is highly sensitive to Tx-dependent platelet activation, this effect is likely to reflect the demonstrated suppression of TxA2 biosynthesis by fish oils.

Topics: Animals; Blood Platelets; Coronary Disease; Coronary Thrombosis; Dietary Fats, Unsaturated; Dogs; Epoprostenol; Fish Oils; Male; Membrane Lipids; Phospholipids; Platelet Aggregation Inhibitors; Thromboxane A2; Tissue Plasminogen Activator

Topics: Arachidonic Acids; Aspirin; Coronary Artery Disease; Coronary Disease; Coronary Vasospasm; Cyclooxygenase Inhibitors; Epoprostenol; Humans; Thromboxane A2

We tested the direct effects of thromboxane A2/prostaglandin endoperoxide (TP) receptor agonists and antagonists on ischemic rat hearts to determine if any significant actions of TP may be occurring in a buffer-perfused system (without blood). Buffer-perfused rat hearts were treated with the TP antagonist SQ 30,741 (0.5-1.0 microM) during 15 min of ischemia and 30 min reperfusion. SQ 30,741 had no effect on severity of ischemia. In the same model, the TP receptor agonists U-46619 (0.01-1.0 microM) and SQ 26,655 (0.1 microM) reduced coronary flow and cardiac function both before and after ischemia. The decrease in contractile function appeared to be secondary to flow decrement. Despite the flow effects, U-46619 reduced ischemia-induced lactate dehydrogenase (LDH) release and contracture, indicating some beneficial effects. Measurement of prostacyclin release during reperfusion with and without U-46619 treatment showed that U-46619 significantly increased prostacyclin production. Meclofenamate (5.0 microM) did not reverse the vasoconstrictor and cardiodepressant effects of U-46619 but completely reversed its beneficial effect on LDH release. TP receptor blockade with 1.0 microM SQ 30,741 completely reversed the flow and cardiodepressant effects of SQ 26,655 but did not reverse the beneficial effects of this compound on LDH release. Receptor binding studies using [3H]-SQ 29,548 and [3H]-U-46619 indicated that few if any TP receptors exist in myocytes. In conclusion, TP antagonists are not cardioprotective in this model, but exogenous TP receptor agonists have complex actions in buffer-perfused hearts, some of which are mediated by vascular TP receptors and others which are not.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Circulation; Coronary Disease; Cyclooxygenase Inhibitors; Epoprostenol; Fatty Acids, Monounsaturated; Heart; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Meclofenamic Acid; Myocardium; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred Strains; Thromboxane A2

Intracoronary infusions of activated complement C5a result in myocardial ischemia, contractile dysfunction, and leukocyte accumulation. The hypothesis was tested that the generation of the coronary vasoconstrictors, thromboxane A2 and the 5-lipoxygenase leukotrienes (LTC4 and LTD4), contributes to the C5a-induced decrease in coronary blood flow and contractile function. The left anterior descending coronary artery in anesthetized swine was cannulated and servo pump-perfused with arterial blood at constant pressure and measured flow. Regional subendocardial contractile function was assessed with sonomicrometry. The interventricular vein was cannulated for sampling of coronary venous blood for leukocyte count. The responses in left anterior descending coronary artery blood flow and percent segment shortening to intracoronary infusions of LTC4 (1 microgram), LTD4 (1 microgram), thromboxane agonist U46619 (7.5 micrograms), and C5a (500 ng) were assessed before and after 1) LTD4/LTE4 receptor blockade with leukotriene receptor blocker LY171883 (10 mg/kg i.v.) (n = 5), 2) thromboxane A2/prostaglandin H2 receptor blockade with thromboxane receptor blocker BM13505 (2 mg/kg i.v.) (n = 5), and 3) combined thromboxane and leukotriene receptor blockade (n = 5). In the absence of receptor blockade, intracoronary C5a decreased coronary flow (50-60%) and regional segment function (60-70%) compared with the preinfusion levels. This was accompanied by a fall in coronary venous blood leukocyte levels by 5-6 x 10(6) cells/ml in the absence of alterations in arterial blood leukocyte count. Intracoronary injections of LTD4, LTC4, or U46619 also resulted in prompt decreases in coronary blood flow (50-60%) and segment function (70-80%) from preinfusion levels. Leukotriene receptor blockade with LY171883 abolished these responses to LTD4 and LTC4. Administration of LY171883 also attenuated (p less than 0.05) the myocardial response to C5a; coronary flow and segment function decreased by approximately 28% from preinfusion levels. Thromboxane receptor blockade with BM13505 eliminated the response in coronary flow and segment function to intracoronary U46619. Similar to LY171883, administration of BM13505 blunted (p less than 0.05) the C5a-induced decreases in coronary flow and contractile function, which fell by approximately 20-25% from the preinfusion level. After the combined LTD4/LTE4 receptor and thromboxane A2/prostaglandin H2 receptor blockade, intracoronary C5a resulted in

Topics: Animals; Complement C5a; Coronary Circulation; Coronary Disease; Coronary Vessels; Female; Injections, Intra-Arterial; Leukotrienes; Male; Myocardial Contraction; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Thromboxane; SRS-A; Swine; Thromboxane A2; Thromboxanes; Time Factors

The purpose of this study was to test the hypothesis that combined thromboxane A2 synthetase inhibition and receptor blockade is superior to either action alone in preventing cyclic flow variations in stenosed and endothelially injured canine coronary arteries. Forty-five dogs developed coronary cyclic flow variations after a plastic constrictor was placed around the left anterior descending coronary artery at the site where the endothelium was injured and received different interventions. In Group I, 17 dogs were treated with SQ 29,548, a thromboxane A2-prostaglandin H2 receptor antagonist. In Group II, 11 dogs received dazoxiben, a thromboxane A2 synthetase inhibitor. In Group III, R 68,070, a dual thromboxane A2 synthetase inhibitor and thromboxane A2-prostaglandin H2 receptor antagonist, was administered to 11 dogs. Group IV comprised six dogs that received aspirin before receiving R 68,070. Complete abolition of cyclic flow variations was achieved in 71% of dogs in Group I, 82% in Group II, 100% in Group III (p = 0.06 compared with Group I) and 50% in Group IV (p = 0.03 compared with Group III). Epinephrine was infused into dogs with abolished cyclic flow variations: all dogs in Group I had cyclic flow variations restored, 44% in Group II (p = 0.01 compared with Group I) and 64% in Group III (p = 0.04 compared with Group I). The plasma epinephrine levels required to restore cyclic flow variations were 2.2 +/- 0.5 ng/ml (control 0.04 +/- 0.01) in Group I, 8.7 +/- 4.5 ng/ml (control 0.05 +/- 0.02) in Group II and 7.4 +/- 2.6 ng/ml (control 0.07 +/- 0.02) in Group III.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Dogs; Epinephrine; Epoprostenol; Ergolines; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Male; Pentanoic Acids; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Serotonin Antagonists; Thromboxane A2; Thromboxane-A Synthase

We studied the effects of a novel thromboxane receptor antagonist (+)-S145Na, on the loss of myocardial creatine kinase activity in the rat myocardium after 10 minutes of coronary artery ligation, followed by 24 hours of reperfusion. (+)-S145Na (500 micrograms/kg), or its vehicle, was administered 10 minutes after occlusion (just prior to reperfusion) intravenously. Myocardial creatine kinase activity was significantly reduced in the ischemic areas of hearts obtained from rats receiving vehicle when compared to sham operated control rats. This loss in creatine kinase activity was significantly attenuated in hearts obtained from rats receiving (+)-S145Na. These findings further support the important role of thromboxane A2 in the pathogenesis of reperfusion injury following myocardial ischemia, and that (+)-S145Na may be a useful agent in the treatment of myocardial reperfusion injury.

Topics: Animals; Bridged Bicyclo Compounds; Coronary Disease; Creatine Kinase; Fatty Acids, Monounsaturated; Heart; Male; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

To determine the contribution of thromboxane (Tx) A2 release in reperfusion injury, 17 dogs were subjected to total coronary occlusion for 1 h and reperfusion for 1 h. Eleven dogs were treated with saline, and six were treated with selective TxA2 synthetase inhibitor U63,557A (5 mg/kg iv) 30 min before coronary artery occlusion. In all saline-treated dogs, peak reactive hyperemia after 10-s total coronary artery occlusion was diminished (P less than 0.01) after reperfusion. Myocardial segmental shortening was also reduced (9.8 +/- 1.9 to -6.7 +/- 2.0%, P less than 0.01) in the reperfused region. Reperfusion was associated with 737 +/- 343 premature ventricular contractions (PVCs) per hour. Histology revealed extensive myocardial infiltration and capillary plugging by leukocytes in the reperfused region. Myeloperoxidase, an index of leukocyte infiltration, was also increased (P less than 0.02) in the reperfused region. In the U63,557A-treated animals, serum and plasma TxB2 levels were markedly (P less than 0.02) reduced. Decrease in myocardial shortening fraction was less in U63,557A- than in saline-treated animals (P less than 0.05). The frequency of reperfusion PVCs was also significantly reduced (10 +/- 5 PVCs/h, P less than 0.02 compared with saline-treated dogs). However, peak reactive hyperemia was reduced similar to that in saline-treated dogs. Myocardial infiltration and capillary plugging by leukocytes in the reperfused regions was also similar in the U63,557A- and saline-treated dogs. These results indicate that treatment with U63,557A decreases reperfusion arrhythmias and preserves myocardial function. However, coronary reperfusion-induced deterioration in reactive hyperemia is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Coronary Disease; Dogs; Female; Heart; Hyperemia; Male; Myocardial Reperfusion; Myocardium; Peroxidase; Thromboxane A2; Thromboxane-A Synthase

The authors examined the ratios of blood free polyunsaturated fatty acids (PUFA), such as 20:3n6, 20:4n6, 20:5n3, and 22:6n3, which are substrates and inhibitors of synthesis of thromboxane A2 and prostacyclins that regulate both normal blood fluidity, and platelet adhesion and primary thrombogenesis. The object of the study was plasma from healthy subjects and 4 groups of patients with cardiovascular diseases: 1) large myocardial infarction; 2) resting and exercise-induced angina pectoris; 3) large myocardial infarction; and 4) recurrent myocardial infarction. The levels of plasma free PUFA were measured by gas chromatography. Assessment of the PUFA ratios indicated that the risk for thrombogenesis increased in large and recurrent myocardial infarctions as compared to small myocardial infarction and angina pectoris both by reducing the relative levels of 20:3n6 and, in particular, 20:5n3, substrates of synthesis of only thrombolytics and vasodilators and by more greatly inhibiting the synthesis of prostacyclins than thromboxane with elevated 22:6n3 levels.

Topics: Aged; Aged, 80 and over; Angina Pectoris; Chromatography, Gas; Coronary Disease; Epoprostenol; Fatty Acids, Unsaturated; Female; Humans; Male; Middle Aged; Myocardial Infarction; Recurrence; Thromboxane A2

Topics: Aspirin; Coronary Artery Disease; Coronary Disease; Coronary Thrombosis; Humans; Thromboxane A2

1. Sheep isolated circumflex coronary artery rings were exposed to simulated ischaemia (increased K+ reduced pH, hypoxia, reduced glucose and addition of lactate). Simulated ischaemia caused a transient relaxation lasting approximately 5 min followed by a sustained contraction that was reversible on washing with oxygenated Krebs solution. 2. Haemolysate caused a rise in baseline tension and augmented the ischaemic contraction. 3. The ischaemic contraction was abolished by BW 755C 5 microM and reduced by indomethacin 1 microM, quinacrine 50 microM or the thromboxane A2 antagonist BM 13177 10 microM. The leukotriene D4 antagonist, ICI 198615, had no effect. 4. The ischaemic-induced contraction was enhanced by propranolol 1 microM, methiothepin 1 microM and reduced by ketanserin 1 microM. 5. The ischaemic contraction was markedly inhibited by trypsin (1 mu ml-1) and by verapamil, cromakalim or sodium nitroprusside. 6. The following had no or little effect on the ischaemic contraction: Sar1-Thr8-angiotensin II, mepyramine, atropine, the spin trapping agent PBN or the free radical scavenger dimethylsulphoxide. Superoxide dismutase caused a slight enhancement. 7. The ischaemic-induced contraction was abolished by the simultaneous administration, at subthreshold concentrations, either of two vasodilators (iloprost and adenosine) or of a vasodilator and a vasoconstrictor (iloprost and U46619). 8. The ischaemic relaxation phase was reduced by propranolol and indomethacin, abolished by haemolysate and enhanced by quinacrine or cromakalim. 9. It is concluded that the ischaemic-induced contraction is caused by mediators released from the endothelium including a product of the lipoxygenase pathway. There is also evidence that simulated ischaemia causes the release of noradrenaline and 5-hydroxytryptamine.

Topics: Acetylcholine; Adenosine; Animals; Arachidonic Acids; Blood Platelets; Coronary Disease; Coronary Vessels; Dinoprostone; Endothelium, Vascular; Enzyme Inhibitors; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Oxygen Consumption; Serotonin; Sheep; Thromboxane A2

The lipoprotein (LP) fractions VLDL, LDL, HDL2 and HDL3 were prepared by ultracentrifugation of plasma from healthy volunteers and from patients with coronary heart disease (CHD). We investigated the capacity of platelets from healthy volunteers and patients with atherosclerosis to generate thromboxane A2 (TXA2) during spontaneous clotting of whole blood under the influence of the lipoprotein fractions. In our experiments the serum concentration of TXB2, reflecting the capacity of platelets to generate TXA2 during clotting, depends on several factors: the type of LP fraction used, the blood used for generation of TXA2, and for the same LP fraction whether it was taken from plasma of healthy volunteers or patients with CHD. VLDL prepared from plasma of healthy volunteers inhibited but VLDL prepared from plasma of patients with CHD enhanced the TXA2 formation of platelets from healthy volunteers (p less than 0.05, resp.). LDL from CHD patients inhibited the TXA2 formation of platelets from atherosclerotic patients (p less than 0.01). The HDL subfractions HDL2 and HDL3 from healthy volunteers inhibited TXA2 formation by platelets from healthy volunteers as well as those from atherosclerotic patients (p less than 0.05; p less than 0.01, respectively). HDL2 from patients with CHD inhibited only the TXA2 formation of platelets from healthy volunteers (p less than 0.01), whereas HDL3 from CHD patients inhibited only the TXA2 formation of platelets from atherosclerotic patients (p less than 0.01).

Topics: Adult; Aged; Arteriosclerosis; Blood Platelets; Cholesterol; Coronary Disease; Humans; Lipoproteins; Middle Aged; Thromboxane A2; Triglycerides

Dynamic changes of the thrombus after its formation due to platelet activation may affect the speed of thrombolysis. In the present study, we wanted to evaluate the role played by thromboxane A2 (TXA2) and serotonin (5HT) in mediating platelet activation during lysis of intracoronary thrombi with human recombinant tissue-type plasminogen activator (t-PA). Coronary thrombi were induced in 26 anesthetized, open-chest dogs by inserting a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Presence of the thrombus was documented for 30 minutes. The dogs were then assigned to one of four groups as follows: group 1 dogs (n = 8), serving as controls, received a bolus of heparin (200 units/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg/min) for up to 90 minutes or until reperfusion was achieved; group 2 dogs (n = 10) received, immediately before heparin and t-PA, an intravenous bolus of SQ29548 (SQ) (0.4 mg/kg, a selective TXA2-receptor antagonist) and LY53857 (LY) (0.2 mg/kg, a selective serotonin S2-receptor antagonist); group 3 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of SQ alone (0.4 mg/kg); and group 4 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of LY alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Disease; Coronary Thrombosis; Dogs; Drug Therapy, Combination; Ergolines; Fatty Acids, Unsaturated; Hydrazines; Myocardial Reperfusion; Platelet Aggregation; Recombinant Proteins; Recurrence; Serotonin; Serotonin Antagonists; Thromboxane A2; Time Factors; Tissue Plasminogen Activator

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

The paper considers the significance of prostacyclin-thromboxane (PGI2/TxA2) balance for cardiovascular performance in health and in angina pectoris and myocardial infarction. The functional interaction between prostacyclin and thromboxane was examined in terms of a number of risk factors for coronary heart disease (CHD), such as ageing, atherosclerosis, arterial hypertension, diabetes mellitus, obesity, hypokinesia, smoking, alcoholism, sex differences, and predisposition to the disease. A unidirectional pattern of changes in the PGI2/TxA2 balance towards TxA2 was found in CHD and in the presence of all the aforementioned risk factors. The paper discusses possible mechanisms responsible for these changes, as well as their contribution to the pathogenesis and prevention of CHD.

Topics: Adult; Aged; Alcoholism; Coronary Disease; Epoprostenol; Female; Humans; Hypertension; Male; Middle Aged; Risk Factors; Smoking; Thromboxane A2

We studied the effects of a thromboxane A2 synthetase inhibitor (RS-5186), a thromboxane A2 antagonist (ONO-3708), a 5-lipoxygenase inhibitor (AA-861) and a peptidoleukotriene antagonist (ONO-1078) on infarct size, polymorphonuclear leukocyte infiltration, gross myocardial hemorrhage and arrhythmias in the canine coronary occlusion (2 hour)-reperfusion model (5 hour). The infarct size and risk area were determined by a double staining technique. Thirty minutes prior to occluding the coronary arteries, dogs were randomly assigned to one of the following five groups: the thromboxane A2 synthetase inhibitor group (n = 11) receiving RS-5186 10 mg/kg i.v., the thromboxane A2 antagonist group (n = 12) receiving continuous intravenous infusion of ONO-3708 1 microgram/kg/min, the lipoxygenase inhibitor group (n = 11) receiving AA-861 3 mg/kg i.v., the peptidoleukotriene antagonist group (n = 11) receiving continuous intravenous infusion of ONO-1078 1 microgram/kg/min and the vehicle control group (n = 15). Except for ONO-3708, all the other drugs reduced the infarct size (RS-5186: 26.3 +/- 2.4% of risk area (mean +/- SEM), AA-861: 21.8 +/- 1.3%, ONO-1078: 22.5 +/- 4.4% vs control: 54.0 +/- 6.4%, p less than 0.01 respectively) as well as reducing the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of infarct size, AA-861: 5.1 +/- 2.4%, ONO-1078: 5.2 +/- 2.5% vs control: 22.3 +/- 3.9%, p less than 0.01 respectively). RS-5186 and AA-861 reduced the intensity of polymorphonuclear leukocyte infiltration into the infarcted area, however, neither ONO-3708 nor ONO-1078 had any significant influence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Benzoquinones; Cardiomyopathies; Chromones; Coronary Disease; Dogs; Hemorrhage; Lipoxygenase Inhibitors; Male; Myocardial Infarction; Myocardium; Neutrophils; Quinones; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

Topics: Animals; Cats; Coronary Disease; Myocardial Reperfusion Injury; Phenylacetates; Platelet Aggregation; Rabbits; Shock; Sulfonamides; Thromboxane A2; Thromboxanes

This study was conducted to determine whether the thromboxane A2 receptor antagonist SQ 30,741 can improve post-ischemic recovery of cardiac function in anesthetized dogs. Saline or SQ 30,741 was infused throughout a 15-min coronary occlusion and 5 hr of reperfusion. Ischemic regional cardiac function was determined using subendocardial ultrasonic crystals. Despite no differences in collateral blood flow or reperfusion flow, SQ 30,741 significantly improved ventricular segmental shortening at all times measured during reperfusion. At 5 hr after the initiation of reperfusion, segmental shortening was 3 +/- 16 and 44 +/- 10% of baseline values for saline and SQ 30,741 groups, respectively. These results implicate thromboxane receptor activation in the pathogenesis of myocardial stunning, and thromboxane antagonists may be useful in mitigating this functional deficit.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Myocardial Reperfusion; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

The use of omega-3 fatty acids to reduce the risks of coronary artery disease is appealing because this product occurs naturally in fish oil. Many questions remain to be answered conclusively, however, including how much omega-3 fatty acid is needed to provide this theoretical protective effect. Suitable trials to determine whether commercially marketed fish oil capsules are of benefit to the general population have not been done. However, increased consumption of seafood seems appropriate even without definitive evidence of its benefits.

Topics: Coronary Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fish Oils; Humans; Thromboxane A2

The effects of thromboxane (Tx)A2 antagonism were examined in a canine model of platelet-dependent coronary occlusion. The novel TxA2 antagonist (3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazo lepropanoic acid (Bay u 3405) was studied to ensure that antithrombotic effects seen in vivo were platelet-mediated and did not reflect unspecific compound effects. Bay u 3405 (1, 3, 10 and 30 mg/kg i.v.) inhibited in vivo platelet aggregation and increased the time to thrombotic vascular occlusion by 2.8 h (p less than 0.05) after 30 mg/kg were given. A dose-dependent reduction of intravascular occlusive thrombus growth occurred: thrombus wet weight decreased from 66 +/- 6 mg in vehicle controls to 42 +/- 6 mg, 25 +/- 5 mg, 18 +/- 3 mg and 6 +/- 2 mg after administration of 1, 3, 10 and 30 mg Bay u 3405 i.v., respectively. Electrocardiographic signs for developing myocardial ischemia were largely prevented by the compound. Collagen-induced platelet aggregation ex vivo was inhibited by over 60% in drug-treated animals. The observed delay of thrombotic coronary occlusion reflected an inhibition of platelet aggregation and protection from coronary vasoconstriction at the site of thrombus formation, most likely mediated through blockade of TxA2 receptors.

Topics: Animals; Blood Pressure; Carbazoles; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Dogs; Electric Stimulation; Female; Fibrinolytic Agents; Heart Rate; Humans; In Vitro Techniques; Male; Myocardial Infarction; Sulfonamides; Thromboxane A2

We have previously shown in anesthetized, open-chest dogs with coronary stenosis and endothelial injury that serotonin and/or thromboxane A2 (TXA2) receptor activation play a major role in the mediation of platelet-dependent, intermittent coronary occlusion. Using a similar model in awake, closed-chest dogs, we tested the following hypotheses: (a) treadmill exercise promotes the development of cyclic flow variations in dogs with coronary stenoses and endothelial injury; (b) ventricular pacing does not induce cyclic flow variations in the same dogs; and (c) TXA2 and/or serotonin are important mediators of exercise-induced cyclic flow variations in this model. The surgical preparation consisted of the application of a hard, flow-limiting constrictor and a Doppler ultrasonic flow probe around the left coronary artery of 11 dogs. Treadmill exercise resulted in the prompt development of cyclic flow variations in all 11 dogs. Ventricular pacing at rates as high as 170 beats/min induced cyclic flow variations in only one of five dogs. Exercise-induced cyclic flow variations were abolished by TXA2 and/or serotonin receptor antagonists in all but one dog. Thus, (a) treadmill exercise promotes the development of cyclic flow variations in dogs with coronary stenoses and endothelial injury; (b) ventricular pacing does not induce cyclic flow variations in most dogs in the same model; and (c) TXA2 and/or serotonin are important mediators of cyclic flow variations in this model.

Topics: Animals; Catecholamines; Coronary Circulation; Coronary Disease; Dogs; Endothelium, Vascular; Female; Hemodynamics; Male; Physical Exertion; Platelet Aggregation; Serotonin; Thromboxane A2; Yohimbine

We compared platelet aggregation and intracellular free calcium concentrations [( Ca2+]i) following stimulation with STA2, an analog of thromboxane A2 between patients with ischemic heart disease (IHD) showing significant stenosis in coronary angiograms and controls. In the presence of extracellular calcium, platelet aggregation and intracellular Ca2+ increase were enhanced by STA2 stimulation in a dose-dependent fashion and were higher in the IHD patients than in the controls. However, in the absence of extracellular calcium, no difference in intracellular Ca2+ increase was observed due to its total dependence on release from intracellular stores. These results suggest that thromboxane A2 increases platelet intracellular Ca2+-inducing aggregation, and this increase and aggregation, which is enhanced by thromboxane A2 in IHD patients, is due to promotion of Ca2+ influx by thromboxane A2. IHD patients appear to have an abnormality in the platelet membrane which may explain such thromboxane A2-dependent increased permeability to Ca2+.

Topics: Adult; Aged; Blood Platelets; Calcium; Cations, Divalent; Coronary Disease; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2

We have shown in anesthetized open-chest dogs that recurrent platelet aggregation at the site of coronary artery stenosis and endothelial injury results in a pattern of cyclical variations in coronary blood flow (CFVs) and that serotonin and thromboxane A2 are important mediators of CFVs. In the present study, we tested the following hypotheses: 1) severe spontaneous reductions in coronary blood flow occur in awake closed-chest dogs with coronary artery stenoses and endothelial injury; 2) there is a progression from CFVs to persistent low coronary blood flow; and 3) serotonin and thromboxane A2 are important mediators of coronary blood flow reductions in this model. In 17 of 20 awake closed-chest unsedated dogs with experimental coronary artery stenoses and endothelial injury, either intermittent CFVs (n = 3), persistent low flow (n = 4), or progression from CFVs to low flow (n = 10) occurred during the first postoperative week. A serotonin receptor antagonist (ketanserin or LY 53857) or a thromboxane synthesis inhibitor (dazoxiben) or receptor antagonist (SQ 29548) abolished platelet-dependent CFVs in 80% of dogs. Thus 1) severe spontaneous reductions in coronary blood flow occur in awake closed-chest unsedated dogs with coronary artery stenoses and endothelial injury; 2) there is a progression from CFVs to persistent low coronary blood flow and final coronary artery occlusion; and 3) serotonin and thromboxane A2 are important mediators of coronary blood flow reductions in this experimental model.

Topics: Anesthesia; Animals; Consciousness; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Endothelium, Vascular; Female; Hemodynamics; Male; Serotonin; Serotonin Antagonists; Thromboxane A2

The role of thromboxane A2 (TXA2) in the control of O2 supply/consumption variables during pacing-induced ischemia was examined using the TXA2 receptor antagonist SQ 29,548. Anesthetized, open-chest dogs were subjected to left anterior descending coronary artery (LAD) stenosis that produced significant epicardial S-T segment elevation (12 mV) only when superimposed on atrial pacing. Regional myocardial blood flow was determined using radioactive microspheres, and O2 consumption was determined by measuring O2 saturation of venous blood draining the ischemic region. The dogs were treated with saline or 0.2 mg/kg + 0.2 mg/kg/hr SQ 29,548, and the effect on ischemia was determined during 5-minute pacing-induced ischemic episodes at 10, 40, and 70 minutes postdrug or saline treatment. SQ 29,548 significantly reduced S-T elevation at 40 and 70 minutes postdrug compared with saline values and at all times measured compared with its paired predrug pace+stenosis values. SQ 29,548 reduced S-T elevation approximately 45% compared with its paired predrug values at 70 minutes. SQ 29,548 resulted in a significantly higher subendocardial-to-subepicardial flow ratio (0.70 +/- 0.10, p less than 0.05) compared with saline-treated animals (0.42 +/- 0.06), with an overall increase of flow to the ischemic region of approximately 40%. This increased flow was matched by a proportional increase in O2 consumption without a change in O2 extraction. The O2 supply/consumption balance was also unchanged by SQ 29,548 implying that despite the increase in blood flow, the ischemic region was still flow-limited.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Disease; Dogs; Drug Evaluation, Preclinical; Electrocardiography; Fatty Acids, Unsaturated; Female; Hemodynamics; Hydrazines; Male; Myocardium; Oxygen Consumption; Thromboxane A2; Time Factors

The effect of the thromboxane A2 (TXA2) receptor antagonist SQ 30,741 on infarct size and myocardial blood flow during coronary occlusion and reperfusion was determined. In anesthetized dogs, the left circumflex coronary artery (LCX) was occluded and after 10 min a continuous infusion of SQ 30,741 (1 mg/kg + 1 mg/kg/h, i.v.) or saline was begun. After 90 min of LCX occlusion, the LCX was reperfused for 5 h and infarct size was then determined. Myocardial blood flows before, during, and after occlusion were determined using radioactive microspheres. SQ 30,741 resulted in a significant decrease in infarct size (34% +/- 6% of left ventricular area at risk) compared to controls (60% +/- 9%). Cardioprotection was also found with SQ 30,741 when infarct size was normalized for both area at risk and predrug collateral flow. The protective effect of SQ 30,741 occurred without an increase in collateral flow. At 1 h postreperfusion, subendocardial flow was significantly higher in SQ 30,741-treated animals (109 +/- 15 ml/min/100 g) compared to controls (71 +/- 16 ml/min/100 g). SQ 30,741, in the dose resulting in infarct size reduction, produced a 95% inhibition of platelet TXA2 receptors throughout the experiment as measured by dose-dependent inhibition of the ex vivo platelet shape change response to U-46,619, a TXA2 mimetic. Thus, a dose of SQ 30,741 that results in TXA2 blockade also results in myocardial salvage without changes in collateral flow.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Platelets; Coronary Circulation; Coronary Disease; Dogs; Female; Hemodynamics; Male; Myocardial Infarction; Myocardial Reperfusion; Oxygen Consumption; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Thromboxane A2

The effect of drugs on eicosanoid production and on the development of atherogenic index was investigated in canine myocardial ischemia. Iloprost, verapamil, the trapidil derivative AR 12463 or 0.9% NaCl solution were administered 60 min after coronary artery ligation in anaesthetized dogs. Both iloprost and AR 12463 reduced the thromboxane A2/prostacyclin (TXA2/PGI2) ratio in coronary sinus plasma in comparison to controls. The atherogenic index was significantly decreased in the iloprost as well as in the AR 12463-treated group in comparison to the control group. Verapamil had no influence on the investigated parameters.

Topics: Animals; Antihypertensive Agents; Arteriosclerosis; Biomarkers; Coronary Disease; Dogs; Epoprostenol; Female; Iloprost; Male; Pyrimidines; Reference Values; Thromboxane A2; Trapidil

Topics: Adult; Coronary Disease; Epoprostenol; Exercise Test; Female; Humans; Male; Middle Aged; Thromboxane A2

Human recombinant tissue-type plasminogen activator (rt-PA) has been shown to be an effective and safe agent for coronary thrombolysis in patients with acute myocardial infarction. However, thrombolysis is associated with a high rate of acute reocclusion after discontinuation of rt-PA. The goals of the present study were to assess whether reocclusion after thrombolysis is caused by intracoronary platelet aggregation and to determine the role of thromboxane A2 (TxA2) and serotonin (5HT) in mediating this phenomenon. Accordingly, coronary thrombosis was induced in anesthetized, open-chest dogs by insertion of a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Thrombolysis was achieved with rt-PA (0.05 mg/kg bolus + micrograms/kg/min infusion) in 23 +/- 3 min. rt-PA was then discontinued and each animal received a bolus of heparin (150 U/kg) every hour. Reperfusion was followed by repeated cycles of gradual occlusions followed by spontaneous restorations of blood flow (cyclic flow variations, CFVs) before a persistent occlusion recurred. In control dogs (n = 6), heparin alone did not prevent CFVs and reocclusion time was 25 +/- 4 min. Administration of an intravenous bolus of 0.2 +/- 0.06 mg/kg SQ29548, a TxA2/prostaglandin H2-receptor antagonist, and an intravenous bolus of 0.2 +/- 0.04 mg/kg ketanserin, a 5HT2-receptor antagonist, completely abolished CFVs in six of six dogs and reocclusion time was greater than 158 +/- 14 min (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Dogs; Fatty Acids, Unsaturated; Hydrazines; Ketanserin; Platelet Aggregation; Recombinant Proteins; Recurrence; Serotonin; Thromboxane A2; Tissue Plasminogen Activator

The purpose of this investigation was to examine the potential beneficial effect of the selective endoperoxide/thromboxane A2 (TxA2) receptor antagonist, sulotroban (BM 13.177), on tissue type plasminogen activator (tPA)-induced coronary thrombolysis in the dog. A stenosis that eliminated reactive hyperemic capacity was placed on the circumflex coronary artery and an occlusive thrombus was produced by electrical injury to the intimal surface of the artery. Upon occlusion, sodium heparin was administered (300 U/kg i.v.) followed by 100 U/kg i.v. every hour thereafter. All dogs received i.v. tPA 60 min after the formation of the occlusive thrombus at a dose of 10 micrograms/kg/min for up to 90 min, if necessary, to elicit reperfusion. Thrombolysis was demonstrated in all dogs by restoration of coronary blood flow. Dogs were randomized to one of three groups. Group I consisted of 24 animals that received vehicle infusion along with tPA. Group II consisted of 10 animals that received sulotroban at a bolus dose of 1 mg/kg i.v. followed by 1 mg/kg/hr i.v. administered simultaneously with tPA. Group III consisted of 11 animals that received sulotroban at a bolus of 10 mg/kg i.v. followed by 10 mg/kg/hr i.v. administered simultaneously with tPA. Infusions of either vehicle or sulotroban were continued for 2 hr, post-thrombolysis. tPA was infused for at least 30 min, after which infusion of tPA was terminated upon achieving a reperfusion level of coronary blood flow equivalent to 50% or greater than control blood flow. All animals occluded spontaneously to electrolytic stimulation between 32 and 62 min. tPA-induced thrombolysis occurred in Group I vehicle-infused animals at 32 +/- 5 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Dogs; Drug Therapy, Combination; Female; Fibrinolytic Agents; Male; Platelet Aggregation Inhibitors; Sulfonamides; Thromboxane A2; Tissue Plasminogen Activator

Circulatory blood corpuscles have enzymes catalyzing arachidonic acid. Platelets have cyclo-oxygenase system which produce highly vasoconstrictive and thrombogenic thromboxane A2 (TXA2). Neutrophils have another type of arachidonate metabolism system, lipoxygenase enzymes, which produce hydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT), mediating inflammatory reactions. These arachidonate metabolites were found to play important roles in the evolution of myocardial ischemia. Thromboxane B2 (TXB2) a stable metabolite of TXA2, was elevated in peripheral blood of patients with angina pectoris. This elevation of TXB2 was supposed to be derived from platelet activation in coronary circulation due to altered production of TXA2 and prostacyclin (PGI2). Augmentation of TXA2 was also observed in patients with acute myocardial infarction. TXA2 synthetase inhibitors decreased plasma levels of TXB2 in these patients accompanied by attenuation of infarct size. Neutrophils were found to accumulate in ischemic myocardium and were augmented at reperfusion phase especially at interface between infarcted and risk zone. These infiltrated neutrophils may also provide deleterious effects on myocardial cells by producing lipoxygenase metabolites. In fact, a chemotactic and vasoconstrictive lipoxygenase product, 12-HETE, was produced selectively in ischemic myocardial tissue of an occlusion-reperfusion model. During evolution of myocardial cell damage, platelets and neutrophils, accumulated in ischemic tissue, may contribute to the exacerbation of microcirculatory disorders by producing vasoactive prostanoids, leading to expansion of myocardial necrosis. We should gain insights into these cellular interactions through arachidonate metabolism under normal and catastrophic conditions of coronary circulation.

Topics: Arachidonic Acids; Coronary Circulation; Coronary Disease; Humans; Lipoxygenase; Prostanoic Acids; Thromboxane A2; Thromboxane-A Synthase

Topics: Adult; Aged; Angina Pectoris; Anticoagulants; Cinnamates; Coronary Disease; Coumaric Acids; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Thromboxane A2

Effects of the administration of a thromboxane A2 (TXA2) analogue (STA2), a leukotriene C4 (LTC4), and a leukotriene D4 (LTD4) on regional myocardial blood flow (RMBF) and hemodynamics were studied in anesthetized, open-chest dogs. The blocking ability of a recently synthesized TXA2 selective antagonist, ONO-3708, and a peptidoleukotriene-selective antagonist, ONO-1078, was also investigated. RMBF was measured continuously in three areas: the left anterior descending coronary artery (LAD) area, the circumflex artery (Cx) area, and the area between LAD and Cx. STA2, LTC4, and LTD4 caused a significant dose-dependent reduction of the RMBF in the LAD area. The peak percentage decrease in RMBF followed by a 10 micrograms dose of STA2, 1 micrograms dose of LTC4, and 1 micrograms dose of LTD4 is 38.6% +/- 3.0%, 39.0% +/- 3.1%, and 36.2% +/- 2.4%, respectively. ED50 for the action of LTC4, LTD4, and STA2 on RMBF is 3, 3, and 50 micrograms, respectively. Pretreatment with the newly developed TXA2 antagonist, ONO-3708 (1 micrograms/kg/min for 10 min), completely inhibited the RMBF reduction induced by STA2 (10 micrograms). Pretreatment with the peptidoleukotriene antagonist, ONO-1078 (1 mg), inhibited the RMBF reduction induced by LTC4 or LTD4 (0.3-3 micrograms). Following pretreatment with a 1 mg dose of ONO-1078, the peak percentage decrease of RMBF caused by a 1 micrograms dose of LTC4 and LTD4 was reduced to 21.1% +/- 2.3% and 19.8% +/- 3.1%, respectively. However, the LTC4 (1 micrograms)-induced reduction of the RMBF was not affected by pretreatment with a TXA2 antagonist, ONO-3708, or an inhibitor of the endogenous production of TXA2, OKY-046.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Flow Velocity; Chromones; Coronary Circulation; Coronary Disease; Dogs; Male; Methacrylates; SRS-A; Thromboxane A2; Thromboxane-A Synthase

Topics: Animals; Antithrombins; Arginine; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Dogs; Fatty Acids, Unsaturated; Female; Heparin; Hydrazines; Ketanserin; Male; Pipecolic Acids; Platelet Aggregation; Sulfonamides; Thrombin; Thromboxane A2

Topics: Animals; Coronary Disease; Coronary Thrombosis; Endothelium, Vascular; Epoprostenol; Fibrinolytic Agents; Humans; Myocardial Infarction; Platelet Aggregation; Rabbits; Thromboxane A2; Thromboxane-A Synthase; Vasodilation

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

The effects of the new thromboxane A2 (TXA2) synthetase inhibitor sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b]thiophene)carboxylate (RS-5186), 10 mg/kg i.v., on infarct size, polymorphonuclear leukocytes (PMNs) infiltration, gross myocardial hemorrhage and ventricular arrhythmias were studied using a canine coronary occlusion (2 h)-reperfusion (5 h) model. Infarct size (IS) and risk area (RA) were determined by a dual staining technique. 60 min before coronary occlusion dogs were randomly assigned to either the RS-5186 treated group (n = 11) or the control group (n = 15). RS-5186 reduced infarct size (RS-5186: 26.3 +/- 2.4% of RA (mean +/- SEM) vs control: 50.7 +/- 5.9%, p less than 0.01), and also reduced the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of IS vs control: 22.4 +/- 4.0%, p less than 0.01). The drug also decreased the intensity of PMNs infiltration into the infarcted area (p less than 0.05). However, RS-5186 had no significant influence on the incidence of ventricular arrhythmias. These results suggest that the new thromboxane A2 synthetase inhibitor RS-5186 might be useful in salvaging ischemic myocardium.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Coronary Vessels; Dogs; Hemodynamics; In Vitro Techniques; Male; Neutrophils; Risk Factors; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

This study was designed to determine the effect of sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b] thiophene)carboxylate (RS-5186), a new thromboxane A2 (TXA2) synthetase inhibitor, on mitochondrial function and lysosomal integrity in ischemic myocardium. 17 anesthetized mongrel dogs were divided into 2 groups. In the control group (n = 11), the left anterior descending arteries (LAD) of the dogs were occluded for 2 h and physiological saline was infused until the end of the experiment. In the RS-5186 treated group (n = 6), 25 min prior to LAD occlusion, RS-5186, 10 mg/kg, was injected for 10 min. 2 h after occlusion, mitochondria were prepared from both ischemic and non-ischemic areas, which were confirmed by Evans' blue dye, and mitochondrial function (respiratory control index: RCI, and the rate of oxygen consumption in state III respiration: St.III O2) was measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both ischemic and non-ischemic areas was also performed, and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase: NAG, beta-glucuronidase: beta-gluc) of each fraction were measured. 2-h LAD occlusion induced a significant greater decrease in mitochondrial function from the ischemic area of the control group (RCI: 2.80 +/- 0.45, St.III O2: 133.5 +/- 35.6 natoms/mg protein/min) compared with those from the non-ischemic area (RCI: 4.49 +/- 0.46, St.III O2: 344.0 +/- 31.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Coronary Disease; Dogs; Female; Heart Rate; In Vitro Techniques; Lysosomes; Male; Mitochondria, Heart; Oxygen Consumption; Thiophenes; Thromboxane A2; Thromboxane-A Synthase; Time Factors

Thromboxane A2 and cysteinyl leukotrienes are highly effective microvessel constrictors in normally perfused myocardium. Their release during acute coronary thrombosis might augment myocardial underperfusion. The constrictor action of these substances could be modified substantially, however, by concomitant myocardial ischemia. We compared the effects of the two eicosanoid constrictors in normally perfused and ischemic myocardium of 24 open-chest, pentobarbital-anesthetized pigs. Left anterior descending coronary flow was measured after intracoronary bolus injections of the stable thromboxane A2 analog U46619 (1-10 micrograms) or leukotriene D4 (LTD4, 1-10 micrograms). Each dose was given before and during myocardial ischemia induced by a snare adjusted to produce 63 +/- 2% decrease in coronary flow for 10 min. Marked dose-independent inhibition of eicosanoid-induced coronary flow decrease occurred during ischemia. With 10 micrograms U46619, coronary flow decrease in the unoccluded state (25 +/- 2 from 55 +/- 4 ml/min pretreatment baseline) was virtually eliminated during snare occlusion (1 +/- 1 from 21 +/- 3 ml/min pretreatment baseline, P less than 0.001). Similar results occurred with LTD4. Distal coronary pressure during ischemia indicated a lack of microvessel responsiveness to the eicosanoids rather than a buffering of resistance change by the snare. U46619 and LTD4 did induce transient, small reductions in regional shortening fraction during ischemia. Our data suggest that eicosanoid-induced constriction of myocardial resistance vessels is not a likely complication of acute coronary thrombosis. However, eicosanoids could depress residual contractility in moderately ischemic regions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Circulation; Coronary Disease; Eicosanoic Acids; Female; Male; Prostaglandin Endoperoxides, Synthetic; SRS-A; Swine; Thromboxane A2; Vasoconstriction

Modification of the thromboxane: prostacyclin ratio alters the severity of reperfusion arrhythmias and postischemic damage in long-term, irreversibly injured myocardium. In this study, the effects of the thromboxane synthetase inhibitor dazmegrel and the thromboxane receptor antagonist BM 13.505 on myocardial postischemic functional recovery and preservation of tissue adenine nucleotides was examined after a 15-minute episode of ischemia followed by 3 hours of reperfusion (myocardial stunning). Dazmegrel (3 or 8 mg/kg) or BM 13.505 (10 mg/kg) was given 15 minutes before coronary occlusion and compared with a control group in barbital-anesthetized dogs. Regional segment shortening (percent segment shortening, sonomicrometry), regional myocardial blood flow (microspheres), and coronary venous eicosanoid and high-energy phosphate levels (biopsies after 3 hours of reperfusion) were measured. Areas at risk, regional myocardial blood flow, and regional segment shortening during coronary occlusion were similar in all groups. Dazmegrel (3 mg/kg) attenuated the decrease in endocardial and midmyocardial adenosine 5'-triphosphate, and both doses significantly improved regional segment shortening during reperfusion. Coronary venous thromboxane levels were significantly decreased throughout the experiment in both dazmegrel-treated groups, and thromboxane levels were significantly elevated in the control group 3 hours after reperfusion. Prostacyclin, measured in the form of its main metabolite, 6-keto-prostaglandin F1 alpha, did not change significantly in the control group throughout the experiment, but it was markedly increased in dazmegrel groups throughout reperfusion, particularly in the dazmegrel group receiving 3 mg/kg. BM 13.505 exerted no beneficial effects on postischemic function or metabolism. In conclusion, after a reversible ischemic insult, postischemic recovery of function and metabolic status was not enhanced by preocclusion treatment with a thromboxane receptor blocker, and thus, the beneficial effects of thromboxane synthesis inhibition on postischemic abnormalities was not due to a reduction in thromboxane but was the result of endoperoxide shunting and a subsequent increase in prostacyclin. Therefore, thromboxane does not appear to be an important mediator of reversible ischemia-reperfusion damage.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Energy Metabolism; Female; Heart; Hemodynamics; Imidazoles; Male; Myocardial Contraction; Phenylacetates; Phosphates; Prostaglandins; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

We have reported previously that thromboxane A2 (TXA2) and serotonin (5-HT, 5-hydroxytryptamine) are important mediators of cyclic flow variations (CFVs) in a canine model of coronary artery stenosis and endothelial injury. The present study tested the hypothesis that a TXA2 receptor antagonist is more effective in reducing intracoronary platelet deposition at sites of endothelial injury and severe stenosis than a 5-HT2 receptor antagonist. CFVs developed after placing a plastic constrictor around the left anterior descending coronary artery (LAD) in 51 of 56 dogs. Autologous platelets labeled with 111In were injected in 48 animals. Ten control dogs (group 1A) were killed after CFVs were observed for 1 hour at the nadir of coronary blood flow. Five dogs (group 1B) did not develop CFVs after placement of the constrictor. CFVs were abolished with SQ 28668 (2.75 +/- 0.36 mg/kg, group 2) and SQ 29548 (0.45 +/- 0.1 mg/kg, group 3), two different TXA2 and PGH2 receptor antagonists, in eight of 10 and six of seven dogs, respectively. In eight of 10 dogs (group 4), CFVs were abolished with ketanserin (0.66 +/- 0.12 mg/kg), a 5-HT2 receptor antagonist. In group 2, 3, and 4 dogs, the respective drugs were given so that the minimal dose required to abolished CFVs was administered. In six of six dogs (group 5), a higher dose of ketanserin (i.e., 1.5 mg/kg) was used to abolish CFVs. At death, intracoronary platelet deposition was evaluated by calculating the LAD platelet accumulation ratio (111In activity in the LAD/111In activity in the circumflex coronary artery) in 43 dogs and, in 22 dogs, by microscopic examination of the LAD. A marked LAD platelet accumulation ratio was found in group 1A dogs at the stenotic site and in segments immediately distal to it. The LAD platelet accumulation ratio was significantly reduced by both the low and the high doses of ketanserin compared with group 1A dogs (p less than 0.001). However, the two TXA2 receptor antagonists further reduced the LAD platelet accumulation ratio compared with ketanserin-treated animals (p less than 0.01). Microscopic examination confirmed these findings. We conclude that SQ 28668 and SQ 29548, two different TXA2 receptor antagonists, reduce residual intracoronary platelet deposition associated with CFVs in this canine model more effectively than ketanserin, a 5-HT2 receptor antagonist.

Topics: Animals; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Coronary Disease; Coronary Vessels; Dogs; Fatty Acids, Unsaturated; Female; Hemodynamics; Hydrazines; Male; Platelet Aggregation; Receptors, Serotonin; Serotonin Antagonists; Thromboxane A2

Topics: Acrylates; Animals; Coronary Disease; Dogs; In Vitro Techniques; Methacrylates; Mitochondria, Heart; Oxygen Consumption; Thromboxane A2; Thromboxane-A Synthase

Topics: Coronary Circulation; Coronary Disease; Fibrinolytic Agents; Humans; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction and has a direct cytolytic effect, thromboxane receptor antagonists would be expected to be beneficial in acute myocardial ischemia. A new thromboxane A2 receptor antagonist, AH-23,848, was studied in a cat model of acute myocardial ischemia. Myocardial ischemia was induced by ligation of the left anterior descending (LAD) coronary artery. Thirty minutes later, AH-23,848 or vehicle was given as a bolus (1 mg.kg-1) followed by a continuous infusion (1 mg.kg-1.h-1). AH-23,848 effectively reduced the S-T segment elevation while vehicle treated cats showed an increase. From direct myocardial biopsies, it was also seen that AH-23,848 prevented the loss of creatine kinase (CK) activity from the ischemic myocardium. Furthermore, the loss of amino-nitrogen compounds was also significantly reduced (p less than 0.05) by treatment with the receptor antagonist. This protective effect was not due to an indirect reduction of myocardial oxygen demand since blood pressure, heart rate or their product was unaltered by AH-23,848 administration. Moreover, the specificity of AH-23,848 to thromboxane receptors was confirmed in isolated cat coronary arteries and in cat platelets. These experiments demonstrate that blockade of the thromboxane receptor by AH-23,848 is an effective means of preventing acute myocardial ischemic damage in the cat, and thus thromboxane A2 plays a role in propagating the extension of ischemic damage during acute myocardial ischemia.

Topics: Acute Disease; Animals; Biphenyl Compounds; Cats; Coronary Disease; Coronary Vessels; Creatine Kinase; Electrocardiography; Free Radicals; Hemodynamics; In Vitro Techniques; Male; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Vasoconstriction

Topics: Aspirin; Coronary Disease; Epoprostenol; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Adult; Angina Pectoris; Coronary Disease; Humans; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2

To observe platelet TXA2 synthesizing activities in acute myocardial infarction (AMI, 38 cases) and effort angina (EA, 23 cases), radioimmunoassay was used to measure the amount of synthesized TXB2 at 5 min after an addition of arachidonic acid or thrombin to the platelet suspension. The amount of TXB2 in AMI patients did not show a significant difference from that of 13 healthy controls. However, there were significant changes during the time course of AMI. It increased in the super acute phase within the first 12 hrs from the onset of AMI. The activity decreased in 4 days, increased again in 10 days and then gradually recovered to the normal value. Platelet aggregation was elevated immediately after the onset of AMI and recovered during the time course. A significant negative correlation was observed between aggregation and TXA2 production in AMI, but not in the healthy controls, suggesting that platelets with hyper TXA2 synthesizing activity are consumed selectively in AMI. In EA, activity increased after treadmill exercise. Under ticlopidine-treatment, activity was depressed, and these patients were able to tolerate a longer exercise time than before ticlopidine. Since the pressure rate products did not change under treatment, changes in microcirculation such as the appearance of platelet aggregates may be important in the occurrence of anginal attacks.

Topics: Adolescent; Adult; Aged; Angina Pectoris; Blood Platelets; Coronary Disease; Female; Humans; Male; Middle Aged; Myocardial Infarction; Physical Exertion; Platelet Aggregation; Thromboxane A2; Ticlopidine; Time Factors

We have reported previously that thromboxane A2/prostaglandin (PG)H2 and serotonin independently mediate the occurrence of cyclic flow variations (CFVs) in a canine preparation of severe coronary artery narrowing. This may be due to an effect of these substances on platelets and/or the vascular wall. We tested the hypothesis that there is a cooperative effect between thromboxane A2/PGH2 and serotonin receptor stimulation in the development of CFVs in this animal preparation. After placement of a hard plastic cylindrical constrictor around the left anterior descending coronary artery, CFVs develop and are characterized by repetitive cycles of declines in coronary blood flow and abrupt increases in flow. In a control group of dogs, CFV frequency (cycles/hour) and severity (lowest coronary blood flow just before its restoration) did not change significantly over a 3 hr interval. In a second group of dogs, CFVs were established after constrictor placement, abolished with the serotonin (5HT2) receptor antagonist ketanserin, and reestablished by the continuous infusion of serotonin into the left atrium. Serotonin-induced CFVs were then abolished with a thromboxane A2/PGH2 receptor antagonist, SQ29,548, or a thromboxane synthetase inhibitor, dazoxiben (UK37,248). The relative specificity of the respective antagonists, SQ29,548 and ketanserin, was determined in canine platelets and rat aortic vascular strips. No significant cross-reactivity between ketanserin and SQ29,548 was found. Thus, the data obtained in these studies demonstrate a cooperative interaction between thromboxane A2/PGH2 and serotonin S2 receptors that contributes to the development of CFVs in this experimental preparation.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Drug Antagonism; Epinephrine; Hemodynamics; In Vitro Techniques; Ketanserin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Rats; Receptors, Prostaglandin; Receptors, Serotonin; Thromboxane A2

To determine if differences exist in the degree of ischemic damage and in postischemic recovery when different coronary arteries are occluded and reperfused, 40 barbital-anesthetized dogs were subjected to brief 15-minute periods of coronary artery occlusion followed by 3 hours of reperfusion ("stunned" myocardium) of the left anterior descending (LAD) or the left circumflex (LCX) coronary arteries. Myocardial segment shortening (%SS) in the subendocardium of nonischemic and ischemic reperfused areas was measured by sonomicrometry, and regional myocardial blood flow was measured by radioactive microspheres. Transmural tissue biopsies were taken at the end of reperfusion for the measurement of adenine nucleotides and total tissue water content. Arterial and local coronary venous blood samples were collected during preocclusion, during occlusion, and at 30 and 180 minutes of reperfusion for determination of blood oxygen content and oxygen consumption in the ischemic area. During occlusion, subendocardial blood flow (LAD flow = 0.11 +/- 0.02; LCX flow = 0.15 +/- 0.04 ml/min/gm), myocardial oxygen consumption (LAD = 2.4 +/- 0.7; LCX = 2.7 +/- 0.7 ml/min/100 gm), and areas of the left ventricle at risk (LAD = 27.4 +/- 2.3%; LCX = 32.4 +/- 2.4) were similar in both groups, thus indicating equivalent degrees of ischemia. There were no differences between groups in hemodynamics throughout the experiment or in the loss of myocardial high-energy phosphates or increase in total tissue water in the ischemic reperfused area at 3 hours of reperfusion. There was a significantly greater loss (p less than 0.05) of systolic wall function during LAD versus LCX occlusion and a greater recovery of segment function from 5 minutes throughout 1 hour of reperfusion after LCX occlusion (p less than 0.05), with no difference in %SS at 2 and 3 hours following reperfusion. Thus, although similar changes occurred in blood flow, metabolite parameters, tissue edema, wall function, and overall hemodynamics when either the LAD or LCX perfusion territories were occluded and reperfused, the loss of systolic wall function and recovery of segment shortening were more variable after regional stunning of the LCX perfusion bed. These data suggest that evaluation of pharmacologic or surgical interventions to improve postischemic functional recovery may be more reliably performed when the LAD coronary artery is the vessel occluded.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Female; Hemodynamics; Male; Myocardium; Perfusion; Thromboxane A2

Blood pressure, heart rate and ECG were monitored continuously and coronary venous blood samples assayed for thromboxane B2. Arterio-coronary venous lactic acid differences were estimated. In anaesthetized sheep, 60 sec occlusions of the left circumflex coronary artery caused hypotension with little change in heart rate. Five minute occlusions produced similar changes accompanied by cardiac arrhythmias and a larger fall in blood pressure. In conscious sheep heart rate rose and blood pressure was maintained. ECG and lactic acid changes indicated severe myocardial ischaemia but not change in thromboxane release was detected. The apparent lack of involvement of thromboxane may reflect a relative inability of sheep platelets to produce this substance or a failure to provide an adequate stimulus for synthesis.

Topics: Anesthesia; Animals; Blood Pressure; Coronary Disease; Electrocardiography; Female; Heart Rate; Hemodynamics; Lactates; Lactic Acid; Myocardium; Sheep; Thromboxane A2; Time Factors

The electrical stimulation model of thrombus formation was tested on rabbit carotid artery and adapted to sheep left circumflex coronary artery (LCCA). LCCA blood flow, mean arterial pressure (MAP), heart rate (HR) and ECG were monitored continuously and arterial and coronary venous blood samples were taken for radioimmunoassay of thromboxane B2. Stimulation of the LCCA mimicked acute myocardial infarction; reduction in LCCA blood flow preceded a fall in MAP and appearance of ECG abnormalities. Thromboxane B2 levels rose by 126% 35 min after stimulation. These findings support the proposal by other authors that thromboxane plays an important role in the pathogenesis of acute myocardial infarction.

Topics: Anesthesia; Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Coronary Vessels; Electric Stimulation; Electrocardiography; Electrodes; Heart Rate; Rabbits; Sheep; Thromboxane A2; Time Factors

If myocardial ischemia always results from an imbalance between the needs and supplies in oxygen of the myocardium cells, the physiopathology of this process seems today infinitely more complex than the mere diminution or interruption of the output in a coronary artery. The extension of atheromatous lesions, the platelets aggregation, thrombosis, the coronary spasm, the release of products from the arachidonic cascade, the reactivity of the vascular endothelium, the profibrinolytic activity of the tissues are many of the intricate factors inducing myocardial ischemia. Cellular alterations, of which some are triggered by the release of oxygenated free radicals, lead then to an irreversible necrosis. The medications used until now in the treatment of angina are oxygen scavengers and research goes on in this direction with vaso-dilators beta-blockers, prolonged action nitro-compounds (nicorandil) or nitro-compounds with an action reinforced by N-acetyl-cysteine, bradycardiac derivates of alinidine and the new calcium antagonists dihydropyridine. However, the new physiopathological concepts of ischemia have opened new directions for the research: products which modify the arachidonic cascade by increase of synthesis or release of PGI2 (nafazatrom, defibrotide), by inhibition of TXA2 synthesis or blocking of TXA2 receptors, and similar products of PGI2 (iloprost); thrombolytic agents more specific of thrombin (PTA) or fibrinolysis activators (defibrotide), and anticoagulants with extended action; chelating agents of oxygenated free radicals (peroxide dismutase, catalase, peroxidase) or xanthine oxidase inhibitors; platelets anti-aggregates like ticlopidine which blocks the platelets receptors to fibrinogen, or inhibitors of the synthesis of pro-aggregating agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Antagonists; Animals; Calcium Channel Blockers; Cardiovascular Agents; Chelating Agents; Coronary Disease; Coronary Vasospasm; Epoprostenol; Fibrinolytic Agents; Humans; Nitrites; Platelet Aggregation; Thromboxane A2

In order to elucidate the role of endogenous thromboxane A2 in myocardial ischaemia, cats were subjected to 5 h of permanent occlusion of the left anterior descending coronary artery (LAD) and treated with the thromboxane receptor antagonist BM 13.177 (5 mg kg-1 h-1, i.v.). In comparison with vehicle-treated LAD-occluded cats, BM 13.177 significantly attenuated the loss of creatine phosphokinase-specific activity from the ischaemic myocardium and antagonized the ischaemia-induced rise in the ST-segment of the electrocardiogram. BM 13.177 at the dose used did not reduce plasma thromboxane levels or ischaemia-induced platelet aggregate formation but considerably antagonized thromboxane-dependent platelet secretion ex vivo. The study demonstrates some beneficial effects of selective blockade of thromboxane receptors on biochemical and electrophysiological parameters of acute myocardial ischaemia.

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Cats; Coronary Disease; Creatine Kinase; Electrocardiography; Fibrinolytic Agents; Heart Rate; Hemodynamics; Myocardium; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Time Factors

We tested the hypothesis that thromboxane A2 and thromboxane A2/PGH2 receptor occupation are important in mediating cyclical reductions in coronary blood flow (CFVs) in concentrically narrowed canine coronary arteries. Two potent and selective thromboxane A2/PGH2 receptor antagonists, SQ29,548 and SQ28,668 eliminated CFVs and restored a normal pattern of blood flow through the severely narrowed vessels in 77 and 75% of the dogs, respectively. CFVs were eliminated within several minutes of an intravenous bolus injection of SQ29,548 or SQ28,688. A continuous infusion of SQ29,548 (0.2 mg/kg X min) prevented the recurrence of CFVs throughout the duration of its infusion. Left atrial infusion of the thromboxane A2 mimetic, U46619, restored CFVs in 5 of 8 SQ29,548-treated and in 5 of 7 SQ28,668-treated dogs. Circulating concentrations of the stable metabolites of TxA2 and PGI2, TxB2 and 6-keto-PGF1 alpha, respectively, were unaffected by administration of SQ29,548. However, stenosed vascular segments of the left anterior descending coronary artery (LAD) of SQ29,548-treated dogs produced significantly less thromboxane A2 than comparable segments from untreated dogs. Morphologic studies showed that stenosed coronary arteries in which CFVs had been abolished by either SQ29,548 or SQ28,668 had relatively few adherent platelets, whereas comparable coronary segments removed from untreated animals had relatively large, platelet-rich mural thrombi. SQ29,548 did not alter the synthesis of TxB2 by platelets. 6-keto-PGF1 alpha concentrations in the stenosed LAD and nonstenosed circumflex coronary arteries were not altered by SQ29,548 administration. These data suggest that the thromboxane A2/PGH2 receptor antagonists, SQ29,548 and SQ28,688, inhibit cyclic reductions in coronary blood flow in this model by preventing the accumulation of platelets at the site of a critical coronary arterial stenosis. The data also suggest that TxA2 is important in mediating the interaction between platelets and the constricted coronary artery that is responsible for the development and maintenance of CFVs in this experimental model.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Epoprostenol; Hemodynamics; Male; Microscopy, Electron, Scanning; Prostaglandin Endoperoxides, Synthetic; Prostaglandins H; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Thromboxanes

This study was performed to examine potential protective effects of UK 38.485, an inhibitor of thromboxane synthetase, in canine myocardium stressed by transient ischemia. On anesthetized open-chest mongrel-dogs (n = 9) repeated ischemia (3 min) was produced by proximal, intermittent occlusion of the left anterior descending artery. A total of 18 occlusions after 3 mg UK 38.485/kg body wt. and 12 occlusions after 5 mg UK 38.485/kg body wt. were compared to a total of 24 occlusions under control conditions. In each experiment, 2-3 control occlusions and 3-4 therapy occlusions were performed. The drug was applied i.v. in a dose of 3 or 5 mg/body wt. 30 min before the first therapy occlusion. In both groups, hemodynamics and energetics did not significantly change as compared to control. The efficiency of the drug in protecting ischemically stressed myocardium was examined by (a) quantification of oxygen debt and oxygen repayment in the occlusion and reperfusion periods and (b) the amounts of inorganic phosphate, lactate, and potassium released in the first minute of reperfusion. Compared to control occlusions, premedication with either 3 or 5 mg UK 38.485 led to a significantly reduced oxygen debt combined with a significant decrease of the release of inorganic phosphate, lactate, and potassium. The protective effect is suggested to be mainly due to enhanced flow to ischemic areas. Data obtained in this study suggest protective effects of the compound in the preservation of myocardium in transient ischemia and attest to the concept that thromboxane A2 may aggravate the metabolic and energetic situation of myocardium in circumstances with reduced oxygen supply.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Energy Metabolism; Hemodynamics; Imidazoles; Myocardium; Oxygen Consumption; Thromboxane A2; Thromboxane-A Synthase

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

Elevated oestradiol (E2) levels may be a risk factor for ischaemic heart disease in men, although the mechanisms for the elevation of oestrogen and for its adverse effects remain unclear. We have studied 100 Caucasian males undergoing elective coronary angiography for ischaemic chest pain and measured serum oestradiol, a profile of haemostatic tests, extent of coronary artery disease and evidence of previous myocardial infarction in order to assess any relationships which could explain the effect of elevated serum oestradiol levels. Levels were significantly higher in men with a history of myocardial infarction compared to those without (p less than 0.01), but were unrelated to the extent of coronary disease or to the haemostatic tests. These results suggest that the association of oestradiol with coronary events relates to myocardial infarction, not to atherogenesis, and is not due to any currently measurable alterations of haemostasis. Current beta-adrenoceptor blocker treatment was associated with lower oestradiol and thromboxane B2 concentrations (both, p = 0.06). These incidental findings suggest that further studies of the effects of beta-blockade on oestradiol and thromboxane metabolism are indicated.

Topics: Adrenergic beta-Antagonists; Arteriosclerosis; Coronary Disease; Estradiol; Hemostasis; Humans; Male; Middle Aged; Myocardial Infarction; Risk; Thromboxane A2

Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction, and has a direct cytolytic effect, thromboxane receptor antagonism would be expected to be beneficial in acute myocardial ischemia. Thirty minutes after ligation of the left anterior descending coronary artery (LAD) in anesthetized cats, the TxA2 receptor antagonist BM-13,177 or its vehicle was given as a bolus injection at 20 mg/kg, followed by continuous infusion of 20 mg/kg/hr for 4.5 hours. ST segment elevation declined significantly (p less than 0.02) after BM-13,177 treatment, suggesting a reduction in cellular ischemia. The loss in myocardial creatine kinase (CK) activity and in free amino-nitrogen concentration in the ischemic area was also significantly reduced (p less than 0.01). No significant changes in blood pressure or heart rate were seen with BM-13,177 during myocardial ischemia or in nonischemic control cats. Blood levels of BM-13,177 were sufficient to inhibit ex vivo platelet aggregation induced by the prostaglandin endoperoxide analog, U-46,619. Data from isolated cat coronary arteries suggest that BM-13, 177 antagonizes the thromboxane/endoperoxide receptor in coronary vascular smooth muscle. These experiments indicate that TxA2 plays a significant role in propagating the extension of ischemic damage, and that thromboxane receptor antagonism is an effective means of reducing the damage provoked by TxA2 in acute myocardial ischemia.

Topics: Animals; Blood Pressure; Cats; Coronary Disease; Creatine Kinase; Heart Rate; Myocardium; Pancreas; Platelet Aggregation; Proteins; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

The relationship between the antithrombotic and antiplatelet effects of aspirin is complex, since aspirin influences other systems that protect against thrombosis as well as inhibiting platelet function. We investigated possible cumulative effects of low-dose aspirin on vascular production of prostacyclin in patients with documented atherosclerotic cardiovascular disease. Candidates for coronary artery vein graft bypass ingested 20 mg of aspirin daily during the week before surgery, and platelet aggregation, platelet formation of thromboxane A2 (TXA2), aortic and saphenous vein production of prostacyclin (PGI2), and hemostatic status were measured at the time of the bypass surgery. Low-dose aspirin markedly inhibited platelet aggregation responses and reduced TXA2 generation by greater than 90%, effects similar to those observed with much higher doses of aspirin. Both aortic and saphenous vein production of PGI2 were inhibited by 50% compared with PGI2 produced by vascular tissues of control subjects who received no aspirin preoperatively (51 +/- 10 pg 6-keto-PGF1 alpha/mg aortic wet weight [mean +/- SEM] in aspirin-treated subjects vs 130 +/- 16 pg/mg in control subjects, and 71 +/- 8 pg/mg saphenous vein wet weight vs 131 +/- 17 pg/mg). Blood loss at surgery was not significantly increased by preoperative low-dose aspirin as measured by chest tube drainage (754 +/- 229 ml in aspirin-treated subjects vs 645 +/- 271 ml in control subjects), hematocrit nadir (31.2 +/- 1.9% vs 31.8 +/- 1.7%), or transfusions (2.2 +/- 1.3 units of red blood cells vs 2.2 +/- 1.7 units).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Blood Platelets; Blood Vessels; Coronary Disease; Epoprostenol; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxanes

Topics: Animals; Coronary Disease; Dogs; Epoprostenol; In Vitro Techniques; Kinetics; Perfusion; Thromboxane A2; Thromboxanes

Topics: Arachidonic Acids; Coronary Disease; Epoprostenol; Humans; Platelet Aggregation; Thromboxane A2

The effects of 3-dimethylamino 5-(2',6'-dichlorobenzylidene) 6-methyl (4H)-pyridazine (PC 89) on the biosynthesis of PG I2 and TX A2 using horse aorta and horse platelet microsomes as sources of enzymes and arachidonic acid as substrate, were investigated. PC 89 (1.10(-6) M- 1.10(-3) M) dose-dependently - enhanced the biosynthesis of PG I2: the AD50 was 6.8 X 10(-6) M +/- 1.2 X 10(-9) M, the Vmax did not vary significantly with concentrations: PC 89 increased the affinity of enzyme for substrate - but inhibited TX A2 biosynthesis (ID50 = 3.31 X 10(-3) M +/- 4.8 X 10(-7) M): this inhibiting action was not of competitive type. Owing to this dual activity of preventing TX A2 formation and stimulating PG I2 biosynthesis, PC 89 could be a valuable drug for myocardial ischemia and atherosclerosis therapeutics.

Topics: Animals; Aorta; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Coronary Disease; Epoprostenol; Horses; In Vitro Techniques; Kinetics; Microsomes; Pyridazines; Thromboxane A2; Thromboxanes

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

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: Blood Platelets; Coronary Disease; Epoprostenol; Humans; Sympathetic Nervous System; Thromboxane A2; Thromboxanes

Weanling swine were fed for 6 months high fat diets containing as fat source, a high oleic acid safflower oil, lard, or a partially hydrogenated soybean oil blended with soybean oil. The extent of atherosclerosis in left coronary arteries and the ability of vascular components to synthesize eicosanoids important for blood clotting were determined. There was no significant difference (p greater than 0.05) in the extent of atherosclerosis or the synthesis of thromboxane A2. Significant effects were observed on serum cholesterol, which was elevated in the lard fed group, serum triacylglycerol, which was highest in the safflower oil group, and prostacyclin synthesis, which was depressed in both the lard and hydrogenated soybean oil diets compared to the safflower oil diet. No unique effect on the development of heart disease appears to be attributable to hydrogenated fats. The hydrogenated fat was similar to lard in decreasing prostacyclin synthesis, suggesting that the saturation of dietary fatty acids may be a contributory factor in the development of heart disease, through its effect on thrombotic processes.

Topics: Adipose Tissue; Animals; Blood Platelets; Coronary Disease; Dietary Fats; Eicosanoic Acids; Epoprostenol; Fatty Acids; Isomerism; Male; Myocardium; Swine; Thromboxane A2

Topics: Animals; Aspirin; Coronary Disease; Diet; Dogs; Epoprostenol; Humans; Male; Platelet Aggregation; Risk; Thromboxane A2

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

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

Topics: Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cardiovascular Diseases; Coronary Disease; Eicosanoic Acids; Endothelium; Heart Failure; Humans; Leukocytes; Lipoxygenase; Muscle, Smooth, Vascular; Myocardial Infarction; Myocarditis; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thrombosis; Thromboxane A2

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

Under physiologic conditions the tone of the epicardial coronary arteries plays a minimal role in the regulation and distribution of myocardial blood flow. However, under pathophysiologic conditions, especially in coronary heart disease, even small changes in tone may play an eminent role. A uniform mechanism for the induction of excessive coronary constriction and spasm is as yet not recognizable. It is probably a multifactorial event in which different, variable factors add to or potentiate each other. This constriction or spasm inducing chain can with certainty only be interrupted at one of its last links: prevention of an excessive activation of the smooth vascular contractile apparatus through a reduction of the activating calcium influx (calcium antagonists) or through an increase of the intracellular cGMP-content with nitrates (through a not yet identified relaxation procedure). In this brief review constriction-inducing or -potentiating factors are discussed in context with the "dynamic stenosis:" alpha-adrenergic and parasympathetic mechanisms, serotonin, histamine, prostanoids and leukotrienes, finally changes of endothelial factors. Under experimental conditions these factors may bring about a more or less pronounced coronary constriction. In animal experiments it is only possible in mini-pigs with experimental coronary atheromatosis or sclerosis (in combination with experimental endothelial damage) to induce spasm-like constrictions of the large epicardial arteries using histamine or serotonin. Under a variety of clinical conditions the importance of these factors for the induction of dynamic coronary stenoses was shown to be of potential significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angina Pectoris; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Endothelium; Histamine; Humans; Muscle Tonus; Muscle, Smooth, Vascular; Myocardium; Oxygen Consumption; Receptors, Adrenergic; Receptors, Serotonin; Serotonin; Thromboxane A2; Vascular Resistance; Vasoconstriction

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: Arteriosclerosis; Cardiovascular Diseases; Coronary Disease; Fibrinolytic Agents; Humans; Platelet Adhesiveness; Platelet Aggregation; Prostaglandins; Risk; Thromboxane A2

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Circulation; Coronary Disease; Dogs; Heart; Indomethacin; Kinetics; Lactates; Lactic Acid; Methacrylates; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes

Topics: Arteriosclerosis; Blood Platelets; Coronary Disease; Dietary Fats; Epoprostenol; Humans; Myocardial Infarction; Prostaglandins; Thrombosis; Thromboxane A2

Alterations in platelet-generated thromboxane A2 (TXA2) and vessel wall-generated prostacyclin (PGI2) have been associated with myocardial ischemia. To examine TXA2-PGI2 equilibrium at rest and during exercise stress, we studied 13 normal subjects and 15 coronary artery disease patients. Plasma TXB2 and 6-keto-PGF1 alpha were measured as stable metabolites of TXA2 and PGI2, respectively, by radioimmunoassay. In normal subjects, plasma TXB2 levels increased 24% during exercise from 135 +/- 30 to 168 +/- 42 pg/ml (p = NS). Plasma 6-keto-PGF1 alpha levels increased 224% from 54 +/- 17 to 175 +/- 57 pg/ml (p less than 0.05). In coronary artery disease patients, although resting plasma TXB2 levels (mean 136 +/- 43 pg/ml) were comparable to levels in normal subjects, a greater increase (82%) occurred during exercise (mean 248 +/- 70 pg/ml; p less than 0.02 compared to resting levels). Resting plasma 6-keto-PGF1 alpha levels (mean 94 +/- 28 pg/ml) were also similar to normal subjects but increased only by 43% during exercise (mean 134 +/- 53 pg/ml; p = NS compared to resting levels). These data suggest that: in normal subjects TXA2 and PGI2 increase during exercise, PGI2 increasing more than TXA2, and although coronary disease patients have resting TXA2 and PGI2 levels in the normal range, TXA2 levels increase more than PGI2 levels during exercise. These observations may have a bearing on the mechanism of exercise-induced angina pectoris in certain coronary artery disease patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Platelets; Blood Pressure; Blood Vessels; Coronary Disease; Epoprostenol; Heart Rate; Humans; Middle Aged; Physical Exertion; Prostaglandins; Thromboxane A2; Thromboxanes

Topics: Aged; Aspirin; Blood Platelets; Cerebral Infarction; Coronary Disease; Dipyridamole; Epoprostenol; Fatty Acids; Female; Humans; Male; Middle Aged; Phospholipids; Thromboxane A2; Thromboxanes; Trapidil

Molsidomine is able to restore a better balance between myocardial oxygen supply and demand during myocardial ischaemia, by inducing a prolonged decrease in the left ventricular wall pressure, by reducing the venous return to the heart and by dilating the large coronary trunks. Molsidomine is also able to redistribute the coronary blood towards the deep sub-endocardial layers during a transient or permanent coronary occlusion, by complex changes in the metabolic autoregulation, by dilatation of the transmural coronary arteries and by reduction of the extravascular compression forces. Finally, by inhibiting platelet aggregation and by a possible action thromboxane A2/prostacyclin synthesis, molsidomine exerts a real anti-thrombotic effect which helps reduce ventricular arrhythmia, improve segmental contractility and reduce the size of the post-stenotic infarct.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Epoprostenol; Molsidomine; Oxadiazoles; Oxygen Consumption; Platelet Aggregation; Sydnones; Thromboxane A2

After a brief survey of the already well known functions of tromboxane and prostacyclin both in physiological and pathological conditions, the data found in the literature on the therapeutical use of prostacyclin are discussed. The positive results obtained in the treatment of arteriosclerosis obliterans of the lower limbs, of Raynaud's syndrome, of ischaemic stroke and of ischaemic heart diseases, together with the very modest side effects of prostacyclin, suggest to continue with prostacyclin therapy even if its mechanism of action is not yet clear.

Topics: Arachidonic Acid; Arachidonic Acids; Arteriosclerosis Obliterans; Cardiovascular Diseases; Cerebrovascular Disorders; Coronary Disease; Cytochrome P-450 Enzyme System; Epoprostenol; Humans; Intramolecular Oxidoreductases; Raynaud Disease; Thromboxane A2

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

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

Topics: Aged; Coronary Disease; Coronary Vasospasm; Coronary Vessels; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2

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

Topics: Adult; Aged; Animals; Benzopyrans; Catechin; Coronary Disease; Humans; In Vitro Techniques; Male; Middle Aged; Platelet Aggregation; Rabbits; Thromboxane A2; Vasoconstriction

Topics: Adult; Animals; Blood Platelets; Cardiovascular Diseases; Coronary Disease; Diet; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Female; Fish Oils; Fish Products; Humans; Male; Platelet Aggregation; Rabbits; Thromboxane A2

Topics: Adenylyl Cyclases; Animals; Blood Platelets; Coronary Disease; Cyclic AMP; Humans; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Platelet Aggregation; Thromboxane A2

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: Coronary Circulation; Coronary Disease; Epoprostenol; Humans; Prostaglandins; Thromboxane A2; 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

Topics: Arteriosclerosis; Aspirin; Blood Platelets; Coronary Disease; Dipyridamole; Epoprostenol; Hemostasis; Humans; Propranolol; Prostaglandin Antagonists; Risk; Sulfinpyrazone; Thromboxane A2

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

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

We have shown that platelets of diabetic patients (D) with coronary artery disease (CAD) produce more thromboxane A2 (TXA2) compared to normal subjects (N), when induced to aggregate with arachidonic acid. The purpose of this investigation was to determine: 1) whether TXA2 biosynthesis in platelets of D without exogenous substrate is increased, 2) whether platelets of D without CAD produce more TXA2 than N and 3) to compare platelet TXA2 biosynthesis in D with those angiographically diagnosed as having CAD but without D. TXB2 (stable metabolite of TXA2) was measured by RIA in platelets of 100 volunteer subjects: 24 D without other clinical complications, 10 D with retinopathy or nephropathy, 7 D with CAD, 30 CAD without D and 11 had D and hypertension. Eighteen subjects had no D, CAD or hypertension. TXA2 synthesis in platelets, stimulated to aggregate with both endogenous and exogenous substrate was higher in all patient classes studied as compared to normal subjects. Plasma triglyceride concentration was higher in diabetics as compared to controls while total cholesterol as well as platelet phospholipid fatty acid distributions were similar in all groups of subjects indicating a similar substrate concentration for TXA2 biosynthesis. It is concluded that platelets of D and CAD with or without D have greater sensitivity to aggregation which might be due to the increased thromboxane synthetase system at one or more sites.

Topics: Blood Platelets; Coronary Disease; Diabetes Complications; Diabetes Mellitus; Humans; Lipids; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxanes

The potential therapeutic value of the chemically stable carbacyclin analog ZK 36 374 was studied in acute myocardial ischemia (MI). In anesthetized cats, the left anterior descending coronary artery was ligated and 30 min later an i.v. infusion of ZK 36 374 (0.18 microgram/kg X min) on vehicle was initiated and continued for 4.5 hr. ZK 36 374 reduced the ST-segment elevation at 2 to 5 hr (P less than .01) when compared to vehicle-treated MI cats. ZK 36 374 completely prevented the loss of CK specific activities and the decrease in percentage of bound cathepsin D in the infarcted area of the myocardium (P less than .01), but had no influences on any of these parameters in shamoperated animals. In addition, ZK 36 374 reversed the MI-induced decrease in circulating platelet count toward the preinfarction levels, probably by dispersion of circulating platelet aggregates. ZK 36 374 prevented the ischemia-induced loss of myocardial catecholamines from adrenergic nerve terminals. ZK 36 374, at 0.18 microgram/kg X min, exerted a maximum antiplatelet effect, whereas a significant decrease in arterial blood pressure was seen at 1.79 microgram/kg X min (-30-40%). This indicates a considerable dissociation between antiplatelet and blood pressure-lowering activities of ZK 36 374 in this model. The data demonstrate a significant protective effect of ZK 36 374 in acute MI that might be associated with its platelet-stabilizing, antiadrenergic and myocardial cytoprotective activities.

Topics: Animals; Blood Pressure; Catecholamines; Cathepsin D; Cathepsins; Cats; Coronary Disease; Creatine Kinase; Electrocardiography; Epoprostenol; Female; Hemodynamics; Iloprost; Male; Myocardium; Platelet Count; Prostaglandins; Prostaglandins, Synthetic; Thromboxane A2

In 98 patients with ischemic heart disease (IHD), independent of their clinical status (previous myocardial infarction, spontaneous angina or effort angina), a hypercoagulable state (indicated by significant elevation of fibrinopeptide A plasma level) and an increased platelet biologic activity were observed. Moreover, plasma fibrinopeptide A concentration and platelet aggregation were remarkably higher in patients with frequently occurring spontaneous clinical manifestations (active disease) than in IHD patients with relatively quiescent symptoms. Abnormalities of blood clotting and platelet changes were not significantly altered by the presence of severity of coronary angiographic fixed obstruction in IHD. Multiple regression analysis indicated that hypercoagulability and increased platelet biologic activity were not a consequence of differences in risk factor patterns in IHD patients compared to control subjects.

Topics: beta-Thromboglobulin; Blood Coagulation; Blood Platelets; Coronary Disease; Female; Fibrinogen; Fibrinopeptide A; Hemostasis; Humans; Male; Middle Aged; Platelet Aggregation; Risk; Thromboxane A2; 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

In vitro experiments indicate that thromboxane A2 (TA2) is a potent platelet aggregator and vascular constrictor. However, it is unclear what roles these specific actions may contribute in the pathophysiology of myocardial ischemia. Carbocyclic thromboxane A2 (CTA2), a TA2 analog, constrict isolated perfused cat coronary arteries, but does not aggregate platelets, and thus appeared useful to clarify these separate actions of TA2. In anesthetized cats, radioactive labeled microspheres were injected into the left atrium for measurement of cardiac output and tissue blood flows. Compared to control measurements, CTA2 infusion (4.8 microgram.kg-1.min-1 for 10 min) significantly decreased cardiac output from 347 to 16 ml.min-1 to 248 +/- 16 ml.min-1 (p less than 0.025). Furthermore, CTA2 also significantly reduced blood flow to the left ventricle by 33 +/- 7%, but did not alter heart rate or MABP in the intact cat. In cats subjected to left anterior descending coronary artery occlusion, infusion of CTA2 (1 microgram.min-1 for 120 minutes) 30 min after ligation resulted in a significantly reduced myocardial cellular integrity as measured by myocardial creatine kinase activity (p less than 0.01) or percent bound myocardial cathepsin D (p less than 0.01). Thus, these data suggest that activation of vascular thromboxane receptors as well as direct cellular damage may play a role in the pathophysiology of myocardial ischemia.

Topics: Animals; Blood Pressure; Cardiac Output; Cathepsin D; Cathepsins; Cats; Coronary Disease; Coronary Vessels; Creatine Kinase; Heart Rate; Male; Regional Blood Flow; Thromboxane A2; Thromboxanes; Vasoconstrictor Agents

Topics: Adenosine Diphosphate; Animals; Blood Platelets; Blood Vessels; Coronary Disease; Diet; Disease Models, Animal; Endothelium; Fatty Acids; Humans; Hyperlipoproteinemia Type II; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Thrombosis; Thromboxane A2

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

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

Topics: Coronary Disease; Coronary Vessels; Humans; Spasm; Thromboxane A2; Thromboxanes

Fluribiprofen, a non steroidal anti-inflammatory agent, was studied in anesthetized cats subjected to acute myocardial ischemia. Flurbiprofen was given at 0.25, 1 or 4 mg/kg bolus intravenously at 0.5 hours and again at 2.5 hours. Assessment of ischemic myocardial preservation was appraised by measurement of S-T segment elevation, and plasma and cardiac tissue creatine phosphokinase (CK) specific activity. Plasma thromboxane B2 (TB2) concentrations measured by specific radioimmunoassay for TB2, and arachidonic-induced platelet aggregation were also assessed. All three doses of flurbiprofen prevented both the increase to plasma TB2 concentrations occuring in MI (p less than 0.05) at 2, 3 and 4 hours) and platelet aggregation induced by arachidonic acid. However, flurbiprofen at either 0.25 or 4 mg/kg failed to prevent the increase in the S-T segment, the increase in plasma CK activity and failed to maintain myocardial CK values in the ischemic region. At 1 mg/kg, flurbiprofen returned S-T segment to normal values and preserved myocardial CK activities but only slightly prevented the increase in plasma CK activity. These data suggest that the low and high dose of flurbiprofen showed no protection during acute myocardial ischemia, while the intermediate dose was effective. The reason for the narrow range of myocardial preservation is not clear.

Topics: Acute Disease; Animals; Blood Pressure; Cats; Cell Membrane; Coronary Disease; Creatine Kinase; Electrocardiography; Flurbiprofen; Heart; Heart Rate; Ibuprofen; Lysosomes; Male; Oxygenases; Platelet Aggregation; Propionates; Thromboxane A2; Vascular Resistance

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: Animals; Coronary Disease; Dose-Response Relationship, Drug; Electrocardiography; Hypotension; Myocardium; Necrosis; Phthalazines; Prostaglandins H; Rabbits; Thromboxane A2; Thromboxanes

A reduced oxygen supply to the heart causes coronary vasodilatation in the first instance. But if the hypoxia is severe or prolonged, the dilatation passes off and coronary vasospasm develops leading to a vicious circle with a further reduction of myocardial oxygenation. The spasm is associated with increased outflow of prostaglandin (PG)-like material and can be prevented or reversed by inhibitors of PG synthesis such as indomethacin or antagonists of PG action such as chloroquine. The spasm does not appear to be caused by thromboxane (TX) A2 since selective inhibitors of TXA2 synthesis enhance the hypoxic spasm and by themselves can cause spasm even in oxygenated hearts. The mechanism may be related to loss of negative feedback control of the PG pathway by TXA2. Oxygen may enhance TXA2 production and reduce formation of vasoconstrictor PGs, while smoking, because of the formation of carboxyhaemoglobin, may have the opposite effect. Oestradiol and testosterone do not influence the hypoxic spasm but progesterone at physiological concentrations blocks it completely. Progesterone may be the protective female hormone and the increased susceptibility to myocardial infarction in women on oral contraceptives may be related to reduced formation of endogenous progesterone.. The role of coronary vasospasm in many heart attacks has been reported. The paper presents a quite different mechanism, overproduction of prostaglandins (PGs), as the major factor in producing both the spasm and disorders of the rhythm which often accompany it. Coronary vasodilatation is caused by a reduced oxygen supply to the heart. If the hypoxia is severe or prolonged, coronary vasospasm results, leading to a further reduction of myocardial oxygenation. Increased outflow of PG-like material is related with the spasm, which can be prevented or reversed by infusion of inhibitors of PG synthesis (e.g., indomethacin) or of antagonists of PG action (chloroquine). The mechanism of the spasm may be associated with loss of negative feedback control of PG pathway by TXA2 (thromboxane). Oxygen may stimulate TXA2 production and reduce formation of vasoconstrictor PGs; the opposite effect is achieved with smoking due to formation of carboxyhaemoglobin. Estradiol and testosterone have no effect on hypoxic spasms; progesterone at physiological concentration blocks it entirely. Increased susceptibility to myocardial infarction of women on oral contraceptives is associated with reduced formation of endogenous progesterone, possibly the protective female hormone.

Topics: Coronary Circulation; Coronary Disease; Estradiol; Female; Humans; Hypoxia; Progesterone; Prostaglandins; Smoking; Testosterone; Thromboxane A2; Thromboxanes

Topics: Adult; Arachidonic Acids; Aspirin; Blood Platelets; Coronary Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Malonates; Malondialdehyde; Middle Aged; Myocardial Infarction; Platelet Aggregation; Thromboxane A2; Thromboxanes

How an acute ischemic attack is induced in a patient with coronary atherosclerosis is unknown and we carried out studies using thromboxane A2 (TXA2) to determine if acute myocardial ischemia and necrosis could be induced in rabbits. TXA2 was perfused through the coronary artery for 5 seconds by means of a Swan-Ganz catheter through the right common carotid artery. Significant serial changes of ST-T on ECG and hypotension were observed from 1 minute to more than 1 day after the perfusion in all 22 rabbits. The TXA2 that was composed of both aggregated platelets and prostaglandin H2 induced the same response, and such was dose dependent. The inactivated TXA2 was without effect. Seventeen of the experimental rabbits were autopsied. Histological studies of the hearts showed focal myocardial ischemia and necrosis in all rabbits except one autopsided 10 minutes after the perfusion. TXA2 is apparently capable of inducing acute myocardial ischemia and necrosis.

Topics: Acute Disease; Animals; Blood Pressure; Coronary Disease; Dose-Response Relationship, Drug; Electrocardiography; Heart Ventricles; Myocardium; Necrosis; Rabbits; Thromboxane A2; Thromboxanes