thromboxane-a2 and Coronary-Vasospasm

Topics: Autonomic Nervous System; Coronary Vasospasm; Epoprostenol; Humans; Muscle, Smooth, Vascular; Thromboxane A2

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

Injury to the endothelial lining of arteries is an important mechanism in both the early and late stages of the development of atherosclerosis. Platelets can contribute to the early lesions by releasing factors that cause smooth muscle cell migration and proliferation. In the later stages, the formation of large platelet-fibrin thrombi that become organized into the vessel wall contributes to the development of focal atherosclerotic narrowing of arteries. Injury to the vessel wall can also be a factor in causing spasm of coronary arteries, particularly at sites of stenosis. The spasm may cause ischemia, anginal pain, and, in some individuals, ventricular fibrillation and death. In other individuals, the spasm may not cause death but may persist long enough for an occlusive thrombus to form and cause myocardial infarction. The events leading to thrombosis involve not only the release of arachidonic acid and the formation of TXA2, but other pathways that are independent of the arachidonate pathway. In some circumstances thrombin (which causes platelet aggregation and release that are largely independent of the arachidonate pathway and TXA2 formation) is the primary stimulus causing the initiation and growth of the thrombus. The role of products of the arachidonate pathway in causing spasm is not understood. PGI2 produced by the vessel wall could be important in preventing or minimizing coronary artery spasm. The best way to prevent the development of atherosclerosis and its clinical complications is to prevent or minimize injury of the endothelium.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Cell Division; Coronary Vasospasm; Endothelium; Epoprostenol; Humans; Muscle, Smooth, Vascular; Platelet Aggregation; Thrombosis; Thromboxane A2; Vasoconstriction

Topics: Calcium Channel Blockers; Coronary Vasospasm; Electrocardiography; Humans; Thromboxane A2

Topics: Animals; Coronary Circulation; Coronary Vasospasm; Coronary Vessels; Epoprostenol; Models, Biological; Myocardium; Regional Blood Flow; Thromboxane A2; Thromboxanes; Tissue Distribution

Topics: Angina Pectoris, Variant; Animals; Cardiac Catheterization; Coronary Vasospasm; Dogs; Epoprostenol; Ergonovine; Humans; Myocardial Infarction; Nitroglycerin; Platelet Aggregation; Receptors, Adrenergic, alpha; Thromboxane A2

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

Topics: Coronary Vasospasm; Coronary Vessels; Epoprostenol; Humans; Myocardial Infarction; Myocardium; Platelet Aggregation; Thromboxane A2

Topics: Autonomic Nervous System; Calcium; Coronary Circulation; Coronary Vasospasm; Coronary Vessels; Epoprostenol; Histamine; Humans; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandins; Thromboxane A2

The study was undertaken to develop a coronary microvascular spasm model in pigs by repeated epicardial coronary artery endothelial injury.. The pathophysiologic mechanisms responsible for coronary microvascular spasm remain unclear, in large part because a suitable animal model has yet to be found.. Balloon endothelial denudation was done just distal to the site of an implanted Doppler flowmeter in the left anterior descending coronary artery (LAD) every two weeks for a total of four times. Changes in LAD blood flow by intracoronary administration of vasoactive agents were assessed before each denudation.. In the epicardial LAD endothelial denudation pigs, decreases in LAD blood flow caused by acetylcholine were augmented. Before denudation, it was - 15 +/- 4%, and at week 8 (i.e., two weeks after the fourth denudation) it was -100% (i.e., zero flow [p < 0.01]). The LAD flow changes in response to 5-hydroxytryptamine (5-HT) changed from an increase to a decrease, accompanied by medial thickening of microvessels in the LAD perfusion area. These flow responses were observed without significant changes in LAD diameter. In contrast, the LAD blood flow responses to acetylcholine and 5-HT did not change throughout the experiment in pigs given aspirin and a thromboxane A2 (TXA2) synthase inhibitor orally.. This microvascular spasm model indicates that hypersensitivity to vasoactive substances in the microvascular beds as well as microvascular remodeling are brought about partly through TXA2. This model should be useful for examining the pathophysiology and treatment of microvascular angina.

Topics: Animals; Coronary Vasospasm; Coronary Vessels; Disease Models, Animal; Endocardium; Endothelium, Vascular; Microcirculation; Swine; Thromboxane A2

Susceptibility to drug-induced coronary vasospasm in rhesus monkeys increases after removal of the ovaries and can be normalized by adding back physiological levels of estradiol-17ss (E2) and/or natural progesterone (P) in vivo as reported recently by our group. Furthermore, the reactivity status (Ca2+ and protein kinase C responses) of freshly isolated and primary culture coronary artery vascular muscle cells (VMC) mimic the intact coronary artery responses to 5-HT + U46619. Since coronary reactivity is maintained in the isolated VMC, we hypothesized that the reactivity state inherent in the VMC was modulated directly by ovarian steroids in vitro as in the whole animal. To test this hypothesis, we treated hyperreactive VMC from ovariectomized (ovx) monkeys in vitro with E2 or P and measured VMC reactivity to combined stimulation with 5-HT and U46619, as determined by the amplitude and especially the duration of intracellular Ca2+ signals, as well as protein kinase C (PKC) activation/translocation. VMC were treated for 12 96 h with 3 100 pg/ml E2 (10 365 pM) and/or 0.3 3 ng/ml P (0.95 9.5 nM). Hyperreactive responses to the combination of 5-HT and U46619 in untreated VMC were significantly and dose-dependently reduced by treatment in vitro with physiological levels of either E2 or P for at least 24 h. Both the early transient and late sustained increases in intracellular Ca2+ and PKC translocation were blunted, and the effects of 0.2 nM E2 and 3.2 nM P were specifically antagonized by the receptor blockers ICI 182,780 (200 nM) and RU486 (15 nM), respectively. Antibodies to the estrogen receptor and progesterone receptor labeled nuclei in VMC, which were also positively labeled by a smooth muscle myosin heavy chain monoclonal antibody. These data indicate that natural ovarian steroids directly reduce hyperreactive 5-HT and thromboxane A2-stimulated Ca2+ and PKC responses of coronary artery VMC from surgically menopausal rhesus macaques. We hypothesize that vascular hyperreactivity, which may be a critical factor involved in the increased incidence of coronary artery vasospasm and ischemic heart disease in postmenopausal women, can be normalized by E2 and/or P through direct actions on coronary artery vascular muscle cells.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium Signaling; Coronary Vasospasm; Coronary Vessels; Disease Models, Animal; Disease Susceptibility; Enzyme Activation; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Hormone Antagonists; Hormone Replacement Therapy; Humans; Macaca mulatta; Microscopy, Confocal; Microscopy, Fluorescence; Mifepristone; Muscle Proteins; Muscle, Smooth, Vascular; Ovariectomy; Postmenopause; Progesterone; Protein Kinase C; Receptors, Estrogen; Receptors, Progesterone; Serotonin; Thromboxane A2; Vasoconstriction

We studied the hypothesis that in the absence of vascular pathology, coronary artery vasospasm occurs as a result of local regions of vascular muscle hyperreactivity. We aimed to explore the basis for a functional etiology of those vasospasms not explained on a structural basis.. Ovariectomized rhesus monkeys (Macaca mulatta) without injury or significant vascular disease were stimulated with platelet release products, and angiograms were compared with those from vasospasms induced in human patients.. We used intracoronary (IC) injections of serotonin, thromboxane A2 (U46619), endothelin 1 or angiotensin II in concentrations 3 to 10 times that which reduced coronary artery diameter by 50%.. Although no agent alone caused vasospasm, the combination of pathophysiologic concentrations of serotonin and the stable thromboxane A2 mimetic, U46619, injected through an IC catheter, synergistically caused coronary vasospasm on the second or third challenge in five of seven monkeys. These drug-induced vasospasms were similar to vasospasms induced by mechanical injury followed by serotonin, and to those stimulated in human IC diagnostic tests, as judged by onset, appearance, kinetics and vasodilator reversal.. These studies in ovariectomized monkeys revealed that coronary vasospasm can be stimulated without preexisting vascular pathology, endothelial denudation or injury. Reproducible vasospasm of primate coronary arteries in response to these two endogenous pathophysiologic vasoconstrictors, which are thought to be precipitating stimuli in the etiology of vasospasm, suggests that structure-independent epicardial vasospasm can be an important element in serious cardiac ischemic events, particularly the focal, persistent vasospasms that occur without plaques or injury.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Angiography; Coronary Vasospasm; Coronary Vessels; Female; Macaca mulatta; Male; Muscle, Smooth, Vascular; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Vasoconstrictor Agents

Cellular mechanisms of protection against drug-stimulated coronary vasospasm were studied by multiweek estrogen plus progesterone (P) vs. medroxy-progesterone acetate (MPA) treatments by measuring intracellular Ca2+ and protein kinase C (PKC) signals. Ovariectomized monkeys (OVX) were treated by slow-release implants with either P or MPA for 4 wk added to estradiol-17 beta (E2) begun 2 wk earlier. A third group received E2 for 2 wk and withdrawal of E2 (W; no steroid treatment) during the last 4 wk. OVX coronary artery vascular muscle cells (VMC) in primary culture conditions were labeled by the fluorescent indicators, fluo 3 and hypericin, respectively, to study intracellular Ca2+ and PKC mechanisms of coronary artery hyperre-activity, using digital analysis of single VMC by photon-counting camera. Stimulation by 10 microM serotonin and 100 nM U-46619 (thromboxane A2 mimetic) caused Ca2+ increases (2-5 min) and no PKC activation in VMC from five P-treated monkeys but prolonged (> or = 30 min) increases in both Ca2+ and PKC signals in VMC from six MPA-treated monkeys or seven W-treated monkeys; these P vs. MPA (or W) differences were maintained > or = 14 days. We hypothesize that hyperreactivity in VMC from MPA- or W-treated monkeys results from accelerated prolonged Ca2+ release, with concomitant PKC activation, and that MPA (but not P) negates the coronary vasospasm protective effect of E2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium; Cells, Cultured; Coronary Vasospasm; Coronary Vessels; Drug Combinations; Estrogens; Female; Macaca mulatta; Medroxyprogesterone Acetate; Muscle, Smooth, Vascular; Ovariectomy; Progesterone; Progesterone Congeners; Prostaglandin Endoperoxides, Synthetic; Protein Kinase C; Serotonin; Thromboxane A2; Tissue Distribution; Vasoconstrictor Agents

Satisfactory results were obtained with the radial artery used as a conduit for coronary artery bypass. However, spasm of this conduit was observed. Human radial and internal mammary artery ring segments were studied in organ chambers. Potassium chloride, norepinephrine, serotonin and thromboxane A2 mimetic were used to obtain dose-response curves, permitting assessment of force of contraction and sensitivity. The radial artery presents stronger contractions than the internal mammary artery. The two vessels have equal sensitivity to the vasoconstrictors used. These data emphasize the hyperreactivity of the radial artery and the need for prevention of vasospasm when this vessel is used as a conduit for coronary artery bypass.

Topics: Acetylcholine; Aged; Coronary Artery Bypass; Coronary Vasospasm; Female; Humans; In Vitro Techniques; Internal Mammary-Coronary Artery Anastomosis; Male; Mammary Arteries; Middle Aged; Norepinephrine; Radial Artery; Serotonin; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Reperfusion of the ischemic myocardium is a cornerstone of current therapy for acute coronary syndromes. Experiments show that reperfusion is associated with injury to the coronary artery. Such injury may manifest as augmented vasospasm or impaired vasodilation, and in this study we assessed whether such coronary responses to serotonin do occur.. Left anterior descending arteries (LAD) were occluded in 12 open-chested dogs for 1 h, then reperfused for 1 h. Vasoreactivity to serotonin was measured in isolated rings from the LAD and circumflex arteries (Cx), both at basal resting tension and after preconstriction with U-46619. Endothelium was removed in half of the rings.. In the basal state, LAD rings displayed increased initial constriction and decreased dilation in response to serotonin (maximum dilation: LAD, -4.5 +/- 1.7% versus Cx, -7.6 +/- 1.4%, P < 0.05). With endothelium removed, peak constrictions of the LAD and Cx were significantly augmented, and LAD dilations remained slightly impaired compared with the Cx. After U-46619, dilation in response to serotonin was impaired in the LAD compared with Cx rings (maximum dilation: LAD, -18.3 +/- 11.4% versus Cx, -44.0 +/- 8.4 LAD, P < 0.05). Endothelium removal diminished, but did not abolish, this relationship. De-endothelialized Cx, but not LAD, rings displayed slightly impaired dilations in response to serotonin compared with their respective controls.. After ischemia-reperfusion, coronary arteries respond to serotonin with enhanced constriction and impaired dilation. Changes in both the endothelium and the smooth muscle may determine these responses to serotonin.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Vasospasm; Coronary Vessels; Dogs; Endothelium, Vascular; Male; Muscle, Smooth, Vascular; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Serotonin; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

To determine the effect of 1.5 MAC of two volatile anesthetics (halothane and isoflurane) on platelet-induced contraction of canine coronary artery, isolated, denuded coronary rings were suspended between two stirrups, placed into organ chambers filled with an oxygenated Krebs-Ringer solution, and connected to an isometric force transducer. Human platelets were obtained from healthy donors and introduced into the organ chambers in increasing amounts to reach 20,50 and, 70 x 10(9) platelets/L. The tension generated in both the control and anesthetic-treated rings was recorded; only halothane reduced the tension induced by platelet activation in the organ chambers. In some experiments, aliquots of Krebs-Ringer solution were taken to determine the amount of 5-HT and TB2 released by 70 x 10(9) human platelets in the presence and absence of the anesthetics. Only halothane reduced TA2 production by the activated platelets. Finally, the contractile response of isolated denuded canine coronary artery rings to U46619, a thromboxane analog, was measured in the presence and absence of the anesthetics. Neither halothane nor isoflurane attenuated the response. In another series of experiments, in vitro platelet aggregation was induced by epinephrine, collagen, ADP, or arachidonic acid in the presence or absence of 1.5 MAC isoflurane or halothane. Both anesthetics significantly reduced the aggregation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Platelets; Coronary Vasospasm; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Female; Halothane; Humans; Isoflurane; Male; Muscle, Smooth, Vascular; Platelet Activation; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Serotonin; Thromboxane A2; Thromboxane B2; Vasoconstriction; Vasoconstrictor Agents; Vasomotor System

The involvement of endothelin, an important endogenous vascular constrictor, and prostanoids in coronary vasospasm was evaluated in 14 patients with and 12 patients without coronary vasospasm who had normal coronary angiograms. Coronary vasospasm was defined as a total or subtotal occlusion or diffuse and intense constriction of the left coronary artery provoked by intracoronary acetylcholine administration and associated with electrocardiographic ischemic ST-segment shifts. Blood samples were taken from the left coronary ostium and the coronary sinus before and during coronary spasm. The blood concentrations of endothelin, 6-keto-PGF1 alpha, and thromboxane B2 were measured. Patients with and without coronary vasospasm demonstrated no significant changes in endothelin and thromboxane B2 concentrations in the coronary sinus blood, or in the difference between left coronary ostium and coronary sinus blood. Patients with coronary vasospasm had 6-keto-PGF1 alpha concentrations in the coronary sinus before and during coronary vasospasm of 133.6 +/- 32.5 and 179.4 +/- 46.7 pg/ml, respectively (p < 0.05), and the differences between coronary sinus and coronary ostium concentrations were -25.7 +/- 29.5 and 41.6 +/- 22.6 pg/ml, respectively (p < 0.05). Patients without coronary vasospasm showed no significant changes in 6-keto-PGF1 alpha concentration. Endothelin and thromboxane A2 are not involved in coronary vasospasm, while prostacyclin concentration rises during coronary vasospasm provoked by acetylcholine.

Topics: Acetylcholine; Adult; Aged; Coronary Vasospasm; Endothelins; Epoprostenol; Female; Humans; Male; Middle Aged; Thromboxane A2

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

To clarify the role of thromboxane A2 (TXA2) in evoking coronary spasm, we compared coronary arterial spasticity induced by ergonovine maleate (EM) with coronary sinus thromboxane B2 (TXB2: a stable catabolite of TXA2) in 34 patients with documented variant angina and 11 patients with chest pain syndrome (CPS). We also examined the effect of OKY-1581 (8 mg/kg, i.v.), a TXA2 synthetase inhibitor, on the coronary arterial spasticity of these patients. When blood samples were taken from coronary sinus just before EM test, all patients with variant angina exhibiting markedly augmented TXB2 levels (424 +/- 138 pg/ml), had positive EM test results, while CPS exhibiting lower TXB2 levels (223 +/- 38 pg/ml), had negative EM test. We found that the amounts of EM needed to induce coronary spasm were inversely correlated with TXB2 levels in coronary sinus. In 7 out of these 8 patients, OKY-1581 was found to attenuate the increased spasticity with reduction of coronary sinus TXB2 levels. In 3 patients, an EM rechallenge at symptomatically quiescent stage resulted in negative test with augmented TXB2 levels being markedly decreased. These findings indicate that increased TXA2 in circulating plasma is closely correlated with the hypersensitivity of coronary arteries to EM in patients with variant angina, suggesting a possible role of augmented TXA2 production in the enhancement of coronary vascular spasticity.

Topics: Adult; Aged; Angina Pectoris, Variant; Coronary Circulation; Coronary Vasospasm; Ergonovine; Female; Humans; Male; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Diffuse coronary artery vasoconstriction was provoked in the rabbit by a stable thromboxane A2 analogue, STA2 (9,11-epithio-11,12-methano thromboxane A2). Injection of 25 micrograms.kg-1 STA2 into the left main trunk caused complete occlusion of the left anterior descending artery and narrowing of the left circumflex artery. Two minutes after injection, however, the diameter of the coronary artery returned to the control value (n = 10). The right coronary artery was also temporarily occluded by an injection of 25 micrograms.kg-1 STA2. Left ventricular end diastolic pressure increased significantly, and ST segment elevation of the electrocardiogram occurred during vasoconstriction. The angiographic findings showed that the vasoconstriction in the coronary artery induced by STA2 was similar to the diffuse vasoconstriction seen clinically. Induction of the vasoconstriction by STA2 was prevented by the preadministration of 25 micrograms.kg-1 of either a calcium antagonist, diltiazem, or a thromboxane A2 receptor antagonist, ONO 3708 (n = 10). The relation of the calcium movement to this vasoconstriction was studied in vitro using the isolated left circumflex artery in the rabbit. STA2 (50 micrograms.litre-1 to 0.5 mg.litre-1) produced a concentration dependent contraction of helical strips of left circumflex artery. Diltiazem (50-100 g.litre-1) suppressed this contraction dose dependently. ONO 3708 (10 micrograms.litre-1 to 1 mg.litre-1) caused a significant rightward and downward shift of the dose-response curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium; Coronary Angiography; Coronary Vasospasm; Diltiazem; Dose-Response Relationship, Drug; Rabbits; Thromboxane A2

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

Studies have been conducted on isolated segments of the left circumflex coronary artery of the dog to gain information on the mechanism or mechanisms of vasospasm. Coronary arteries contain both postjunctional alpha 1- and beta 1-adrenoceptors, and both are accessible to norepinephrine released from the sympathetic nerves. However, owing to the dominance of the beta 1-adrenoceptors, sympathetic stimulation causes relaxation of the vascular smooth muscle. In the primary branches of the circumflex artery, only beta 1-adrenoceptors are present. In patients with spasm of the coronary arteries, blockade of the beta 1-adrenoceptors may aggravate the spasm by permitting the unopposed constrictor action of the sympathetic nerves on the alpha 1-adrenoceptors on these vessels. The blood platelets contain substances, including 5-hydroxytryptamine (serotonin) and thromboxane A2, which can cause constriction of vascular smooth muscle. These substances are released whenever platelets aggregate. The normal endothelium, by forming and releasing prostacyclin, inhibits platelet aggregation. In addition, in response to platelet products, the normal endothelium forms one or more inhibitory substances that cause relaxation of the underlying smooth muscle. Also, if any thrombin is formed, this also causes an endothelium-mediated relaxation of the artery. Patients with coronary artery spasm usually have morphologic changes in the artery at the site of the spasm. Thus, platelets can aggregate at the site and the resultant release of serotonin and thromboxane A2, acting directly on the smooth muscle, causes constriction of the artery. Hypoxia of the myocardium follows and this augments the constriction.

Topics: Adenosine Diphosphate; Animals; Coronary Vasospasm; Dinoprost; Dogs; Endothelium; Epoprostenol; Heart; Humans; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandins F; Receptors, Adrenergic; Serotonin; Swine; Swine, Miniature; Sympathetic Nervous System; Thromboxane A2

This chapter documents the significance of TXA2 and PGI2 in the pathologic events associated with active coronary artery disease. We suggest that altered metabolism of these prostanoids may result in disintegration of platelet and vascular wall reactivities accompanying coronary spasm or intravascular thrombosis associated with myocardial cell necrosis. Further studies should be carried out to determine if coronary circulatory disorders and subsequent myocardial cell injury can be affected by disintegration of the lipoxygenase system that plays a pivotal role in maintaining homeostasis in vascular endothelium and blood components.

Topics: Coronary Vasospasm; Epoprostenol; Humans; Myocardial Infarction; Thrombosis; Thromboxane A2

Topics: Animals; Coronary Vasospasm; Disease Models, Animal; Rabbits; Thromboxane A2

Topics: Animals; Coronary Vasospasm; Coronary Vessels; Dogs; Ergonovine; In Vitro Techniques; Potassium; Prostaglandins; Thromboxane A2

Topics: Animals; Arteriosclerosis; Coronary Vasospasm; Disease Models, Animal; Epoprostenol; Histamine; Indomethacin; Swine; Swine, Miniature; Thromboxane A2

To elucidate the contribution of prostanoids in coronary spasm, plasma levels of thromboxane B2 (TXB2) and 6-keto PGF1 alpha at the coronary sinus and ascending aorta in 21 patients with variant angina were measured, as compared with findings in 20 with effort angina and 13 subjects with normal coronaries. In the coronary sinus blood, plasma TXB2 in patients with effort angina exhibited statistically significant high levels, as compared with data in the controls. On the contrary, the data obtained from patients with variant angina were not statistically significant. However, eight patients whose coronary angiogram revealed more than 50% of coronary stenoses had statistically significant high levels of TXB2 and other patients with normal coronaries or less than 50% of narrowing showed almost the same levels of TXB2 as the controls. In contrast to TXB2, the plasma levels of 6-keto PGF1 alpha in patients with variant angina were very low in both groups with variant angina. These data suggest that high levels of TXB2 observed in patients with atherosclerotic coronaries may be an accelerating factor while low levels of prostacyclin may be an essential factor leading to spasm. HLA analysis of 23 patients with variant angina was performed to search for genetic factors, under the hypothesis that such may contribute to the low levels in prostacyclin. This preliminary study revealed statistically significant high frequencies of Bw52 and B-40 in the patients, as compared with frequencies among 152 normal Japanese. Genetic studies are ongoing in our clinic.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Angina Pectoris; Angina Pectoris, Variant; Coronary Vasospasm; Electrocardiography; Female; Histocompatibility Antigens Class II; HLA Antigens; Humans; Male; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxanes

The role of prostanoids in a swine model of coronary artery spasm was examined. Eighteen miniature pigs underwent endothelial denudation of the left coronary artery (left circumflex branch in 14 pigs and left anterior descending branch in 4 pigs) followed by high cholesterol feeding. Three months after the denudation, when coronary artery spasm was repeatedly provoked along the denuded portion of the coronary artery by histamine, the vasoconstrictive effect of thromboxane A2 and the preventive effects of indomethacin and prostacyclin against histamine-induced coronary artery spasm were examined. Intracoronary administration of thiothromboxane A2, 200 micrograms, a stable thromboxane A2 analog, failed to provoke coronary artery spasm (seven of seven cases) but nonselectively constricted the coronary artery by 33%. Intravenous administration of indomethacin, 2 mg/kg, or continuous intravenous infusion of prostacyclin, 50 ng/kg per min, failed to prevent histamine-induced coronary artery spasm (four of four and eight of eight cases, respectively), yet the spasm was all but prevented by intravenous pretreatment with diphenhydramine at a dose of 1 mg/kg. Thus, in this swine model, prostanoids may not play a primary role in the occurrence of coronary artery spasm.

Topics: Animals; Arteriosclerosis; Body Weight; Cholesterol; Coronary Vasospasm; Disease Models, Animal; Epoprostenol; Histamine; Indomethacin; Male; Prostaglandins; Swine; Swine, Miniature; Thromboxane A2

Coronary artery spasm was virtually unknown not long ago, but the intense, ongoing interest it has generated in the past decade has produced a number of specific diagnostic techniques and therapeutic approaches, as well as considerable insight into mechanisms of coronary vascular tone and various coronary syndromes. There is growing evidence that coronary artery spasm is involved in unstable angina, stable angina, myocardial infarction, and sudden death. It is by no means a benign process and is associated with significant morbidity or mortality if misdiagnosed or untreated. It seems clear that what started as a mere clinical curiosity involving a minority of patients with the so-called Prinzmetal's variant angina is snowballing into a major arena for research, diagnosis, and treatment in the field of ischemic coronary artery disease.

Topics: Arrhythmias, Cardiac; Calcium; Calcium Channel Blockers; Coronary Vasospasm; Death, Sudden; Electrocardiography; Humans; Prostaglandins; Thromboxane A2

A 57 year old white woman is reported who developed a myocardial infarction during an attack of allergic asthma and was subsequently found to have a normal coronary arteriogram. The literature on myocardial ischemia and infarction associated with structurally normal coronary arteries is reviewed with particular reference to prostaglandin production, histamine release, platelet activation and the induction of coronary vasospasm. A hypothesis is constructed to explain asthma induced myocardial infarction in terms of interrelated pathogenetic mechanisms.

Topics: Asthma; Coronary Angiography; Coronary Vasospasm; Electrocardiography; Epoprostenol; Female; Histamine Release; Humans; Middle Aged; Myocardial Infarction; Platelet Aggregation; Thromboxane A2

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

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