thromboxane-a2 and Acute-Disease

Acute rejection of a transplanted organ is characterized by intense inflammation within the graft. Yet, for many years transplant researchers have overlooked the role of classic mediators of inflammation such as prostaglandins and thromboxane (prostanoids) in alloimmune responses. It has been demonstrated that local production of prostanoids within the allograft is increased during an episode of acute rejection and that these molecules are able to interfere with graft function by modulating vascular tone, capillary permeability, and platelet aggregation. Experimental data also suggest that prostanoids may participate in alloimmune responses by directly modulating T lymphocyte and antigen-presenting cell function. In the present paper, we provide a brief overview of the alloimmune response, of prostanoid biology, and discuss the available evidence for the role of prostaglandin E2 and thromboxane A2 in graft rejection.

Topics: Acute Disease; Dinoprostone; Graft Rejection; Humans; Inflammation; Inflammation Mediators; Prostaglandins; Thromboxane A2

Acute massive pulmonary embolism has a high mortality rate. Fatal haemodynamic deterioration is caused by an acute increase in pulmonary vascular resistance. Traditionally, the degree of mechanical obstruction of the pulmonary vasculature by the embolic thrombus is considered to be the major determinant of this increase in right ventricular afterload. However, there is evidence to suggest that another factor plays an important role, since there is a marked discrepancy between the haemodynamic manifestations of acute pulmonary embolism and the degree of mechanical obstruction. Historic studies indicate that this discrepancy is largely explained by pulmonary vasoconstriction caused by vasoactive mediators, released mainly by activated platelets. Thromboxane-A(2) and serotonin are probably the two most important pulmonary vasoconstrictors in this context. Antagonising their effects dramatically increases tolerance to experimental pulmonary embolism in animals. In humans, this concept should eventually find its way into clinical practice. In the future, acute massive pulmonary embolism could be treated with antagonists to pulmonary vasoconstrictors, or with direct pulmonary vasodilators.

Topics: Acute Disease; Animals; Fibrinolytic Agents; Humans; Platelet Activation; Pulmonary Embolism; Serotonin; Serotonin Antagonists; Species Specificity; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasodilator Agents

The causes of ventricular arrhythmias in the acute setting of coronary artery disease (myocardial ischaemia and reperfusion) may be approached using two paradigms. One, the electrophysiological paradigm (disturbance of ionic homeostasis, electrogenesis, and conduction) has not been addressed in detail here. Instead, we have focused on the concept of a chemical paradigm of arrhythmogenesis. Many endogenous chemical substances (derived from the myocardium, nerves, blood plasma, platelets, leucocytes, and endothelium) accumulate in the ischaemic tissue or are produced during reperfusion and many of these have been suggested to modulate ventricular arrhythmias. Some substances may be arrhythmogenic and others may be antiarrhythmic. Together they determine whether or not arrhythmias occur. Potentially arrhythmogenic substances include potassium, catecholamines, cAMP, histamine, 5-HT, lysophosphatidylcholine, palmitylcarnitine, platelet activating factor, prostaglandins, leukotrienes, thromboxane A2, angiotensin II, endothelin, opioids, protons, calcium, and free radicals. We have considered each of these, with the objective of evaluating which are important in arrhythmogenesis in acute ischaemia and reperfusion. Two alternative models of arrhythmogenesis are possible in the context of the chemical paradigm: a series model (where one substance or its effects determines the arrhythmogenicity of another) and a parallel model (where numerous substances operate independently to cause ventricular arrhythmias). It is not yet clear which model is most appropriate; a combination of the two is possible, so a working prototype has been constructed which accommodates both. A set of criteria (hitherto lacking) for establishing whether a substance is sufficient and necessary for arrhythmogenesis is proposed. Some generalisations are given on approaches to establishment of these criteria for putative arrhythmogenic substances. Finally, we have considered how arrhythmogenic drug development may be influenced by using the chemical paradigm as an alternative to the electrophysiological paradigm of arrhythmogenesis.

Topics: Acute Disease; Arrhythmias, Cardiac; Calcium; Endothelins; Free Radicals; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium; Thromboxane A2

Topics: Acute Disease; Animals; Cardiovascular Diseases; Humans; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

Topics: Acute Disease; Adolescent; Adult; Cold Temperature; Double-Blind Method; Female; Fingers; Humans; Imidazoles; Male; Middle Aged; Prospective Studies; Raynaud Disease; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

Topics: Acute Disease; Animals; Drainage; Epoprostenol; Intestinal Mucosa; Microcirculation; Pancreatitis; Paracentesis; Rats; Severity of Illness Index; Thromboxane A2

To investigate changes in the plasma concentrations of cardiac troponin I (CTnI), thromboxane A2 (TXA2), prostaglandin I2 (PGI2) and endothelin-1 (ET-1) in rabbits with massive pulmonary embolism (AMPE) and the impact of nitric oxide inhalation (NOI) on these indices.. A total of 30 Japanese rabbits were used to construct an MPE model and were divided into 3 groups equally (n=10), including an EXP group (undergoing modeling alone), an NOI group (receiving NOI 2 h post-modeling) and a CON group (receiving intravenous physiological saline).. In the model group, plasma concentration of CTnI peaked at 16 h following modeling (0.46±0.10 µg/ml) and significantly decreased following NOI. Plasma levels of TXB2, PGI2 and ET-1 peaked at 12, 16 and 8 h following modeling, respectively, and significantly decreased at different time points (0, 2, 4, 8, 12, 16, 20 and 24 h) following NOI. A significant correlation was observed between the peak plasma CTnI concentration and peak TXB2, 6-keto prostaglandin F1α and ET-1 concentrations in the model and NOI groups.. Increases in plasma TXA2, PGI2 and ET-1 levels causes myocardial damage in a rabbit model of AMPE; however, NOI effectively down regulates the plasma concentration of these molecules to produce a myocardial-protective effect.

Topics: Acute Disease; Administration, Inhalation; Animals; Bronchodilator Agents; Down-Regulation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Male; Nitric Oxide; Pulmonary Embolism; Rabbits; Random Allocation; Reference Values; Reproducibility of Results; Thromboxane A2; Time Factors; Treatment Outcome; Troponin I

The Wistar-Furth (WF) rat strain is usually used in models of full major histocompatibility complex-mismatched kidney transplantation. Because these rats have been demonstrated to be resistant to several models of chronic kidney disease, the aim of the present study was to investigate their potential resistance to renal ischaemia-reperfusion (I/R) injury compared with another strain, namely Wistar-Hanover (WH) rats. Anaesthetized male WH and WF rats were submitted to I/R by occlusion of the left renal artery and contralateral nephrectomy. Urine, blood and tissue samples were collected at different time points after I/R to evaluate renal function, inflammation and tubular injury, along with determination of nitric oxide synthase (NOS) expression and thromboxane A2 (TxA2 ) production. Post-ischaemic renal function was better preserved in WF than WH rats, as evidenced by reduced levels of creatininaemia, urinary neutrophil gelatinase-associated lipocalin excretion and proteinuria. In addition, WF rats had less intrarenal inflammation than WH rats after I/R injury. These observations were associated with maintenance of neuronal NOS expression, along with lower induction of inducible NOS expression in WF versus WH rats. Moreover, WF rats excreted a significantly lower amount of TxB2 . The results indicate that WF rats are more resistant to an I/R injury than WH rats in terms of renal function and inflammation. These observations are associated with differential regulation of intrarenal NOS expression, as well as a reduction in thromboxane production, which could contribute to a better outcome for the postischaemic kidney in WF rats.

Topics: Acute Disease; Animals; Dinoprostone; Disease Models, Animal; Kidney; Kidney Function Tests; Male; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats, Inbred WF; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Thromboxane A2; Thromboxane B2

The pharmacological target of aspirin is the inhibition of cyclooxygenase-1 (COX1) and thromboxane-A2 (TX) synthesis. Very few data are available on TX assessment in patients with stroke. We studied platelet TX synthesis, COX1-independent platelet reactivity, the influence of platelet-erythrocyte interactions and the potential association between platelet responses and the severity of stroke, evaluated with a clinical score (NIHSS).. We examined 157 aspirin-treated patients with acute stroke or TIA, 128 aspirin-free and 15 aspirin-treated healthy subjects (HS). Collagen-induced TX, platelet recruitment in whole blood and platelets ± erythrocytes (haematocrit 40%) were assessed in patients on daily-aspirin within three days from onset. Arachidonic-acid-, ADP-, thrombin-receptor activating peptide TRAP-, and collagen-induced aggregation were also evaluated.. Partial TX inhibition (<95% inhibition vs aspirin-free controls) was observed in 13% of patients. This was associated with marked increases in COX1-dependent responses (arachidonic-acid- and collagen-induced aggregation and platelet recruitment; P<0.0001) but not with differences in ADP- or TRAP-induced aggregation. Partial TX inhibition was independently associated with severe stroke (NIHSS ≥ 12) at both admission (P<0.05) and discharge (P<0.05). Among patients with fully blocked TX, those with elevated COX1-independent platelet reactivity (mean+2SD of aspirin-treated HS) were most likely to suffer severe stroke (P<0.05). Platelet-erythrocyte interactions enhanced platelet reactivity in these patients by COX1-dependent and -independent mechanisms (P<0.0001).. TX inhibition by aspirin varied across patients. Partial TX inhibition and COX1-independent platelet hyperfunction were associated with more-severe stroke.

Topics: Acute Disease; Aged; Aspirin; Case-Control Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Female; Humans; Ischemic Attack, Transient; Male; Platelet Aggregation; Stroke; Thromboxane A2

Chagas' disease is caused by infection with the parasite Trypanosoma cruzi. We report that infected, but not uninfected, human endothelial cells (ECs) released thromboxane A(2) (TXA(2)). Physical chromatography and liquid chromatography-tandem mass spectrometry revealed that TXA(2) is the predominant eicosanoid present in all life stages of T. cruzi. Parasite-derived TXA(2) accounts for up to 90% of the circulating levels of TXA(2) in infected wild-type mice, and perturbs host physiology. Mice in which the gene for the TXA(2) receptor (TP) has been deleted, exhibited higher mortality and more severe cardiac pathology and parasitism (fourfold) than WT mice after infection. Conversely, deletion of the TXA(2) synthase gene had no effect on survival or disease severity. TP expression on somatic cells, but not cells involved in either acquired or innate immunity, was the primary determinant of disease progression. The higher intracellular parasitism observed in TP-null ECs was ablated upon restoration of TP expression. We conclude that the host response to parasite-derived TXA(2) in T. cruzi infection is possibly an important determinant of mortality and parasitism. A deeper understanding of the role of TXA(2) may result in novel therapeutic targets for a disease with limited treatment options.

Topics: Acute Disease; Animals; Cells, Cultured; Chagas Disease; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction; Thromboxane A2; Trypanosoma cruzi

Acute pancreatitis (AP) is characterized by disturbances of pancreatic microcirculation. It remains unclear whether platelets contribute to these perfusion disturbances. The aim of our study was to investigate platelet activation and function in experimental AP. Acute pancreatitis was induced in rats: (1) control (n=18; Ringer's solution), (2) mild AP (n=18; cerulein), and (3) severe AP (n=18; glycodeoxycholic acid (GDOC)+cerulein). After 12 h, intravital microscopy was performed. Rhodamine-stained platelets were used to investigate velocity and endothelial adhesion in capillaries and venules. In addition, erythrocyte velocity and leukocyte adhesion were evaluated. Serum amylase, thromboxane A2, and histology were evaluated after 24 h in additional animals of each group. Results showed that 24 h after cerulein application, histology exhibited a mild AP, whereas GDOC induced severe necrotizing AP. Intravital microscopy showed significantly more platelet-endothelium interaction, reduced erythrocyte velocity, and increased leukocyte adherence in animals with AP compared to control animals. Thromboxane levels were significantly elevated in all AP animals and correlated with the extent of platelet activation and severity of AP. In conclusion, platelet activation plays an important role in acute, especially necrotizing, pancreatitis. Mainly temporary platelet-endothelium interaction is observed during mild AP, whereas severe AP is characterized by firm adhesion with consecutive coagulatory activation and perfusion failure.

Topics: Acute Disease; Amylases; Animals; Blood Flow Velocity; Blood Platelets; Cell Adhesion; Male; Microcirculation; Pancreas; Pancreatitis; Pancreatitis, Acute Necrotizing; Platelet Activation; Rats; Rats, Wistar; Thromboxane A2

To establish an estimate for the mean pulmonary arterial pressure (mPAP) derived from noninvasive data acquired with magnetic resonance (MR) velocity-encoded sequences.. In seven sedated pigs synchronous catheter-based invasive pressure measurements (IPM) and noninvasive MR were acquired in the main pulmonary artery (MPA) at different severities of pulmonary arterial hypertension (PAH) that were caused by infusion of thromboxane A2 (TxA2). The invasively measured mPAP was correlated with the noninvasive MR velocity data and linear combination equations (LCE) were computed.. Intravenously applied TxA2 induced a dose dependent level of severity of PAH with an mPAP of up to 54 mmHg without systemic effects. The acceleration time (AT) measured with MR demonstrated the best correlation with the mPAP (r(2) = 0.75). The LCE with the highest correlation (R = 0.945, alpha < 0.01) between IPM and MR revealed a mean difference of 0, a SD of s = 4.66 and a maximal difference of 12.2 mmHg using the Bland-Altman analysis.. Applying the identified LCE allowed the estimation of the mPAP in an acute and resistance-based model of PAH with high accuracy using noninvasive MR velocity-encoded sequences.

Topics: Acute Disease; Animals; Blood Flow Velocity; Catheterization; Evaluation Studies as Topic; Hypertension, Pulmonary; Infusions, Intravenous; Magnetic Resonance Spectroscopy; Pressure; Pulmonary Artery; Pulmonary Circulation; Swine; Thromboxane A2

Elevated levels of 11-dehydrothromboxane B2 (11-dehydro-TXB2) excreted in urine have been observed in acute ischemic stroke. This marker of platelet activation has not been investigated in patients with acute spontaneous intracerebral hemorrhage (ICH).. We examined 43 patients with spontaneous ICH and 23 controls. Urinary excretion rates of 11-dehydro-TXB2, 2,3-dinor-thromboxane B2 (2,3 dinor-TXB2) and 2,3-dinor-6-ketoprostaglandin F(1alpha) (2,3-dinor-PGF(1alpha)) during the first week and at 3 months after ICH were compared between patients who had or had not used aspirin and controls.. On admission, ICH patients without aspirin use had significantly higher urinary levels of 11-dehydro-TXB2 (p<0.001), 2,3-dinor-TXB2 (p<0.001) and 2,3-dinor-PGF(1alpha) (p=0.019) than controls. Aspirin users had significantly lower urinary levels of these metabolites than nonusers. The metabolite levels of aspirin users on admission did not significantly differ from those of controls. The differences between aspirin users and nonusers leveled off during the following 3-5 days, however, as the blocking effect of aspirin on the production of TXA2 and PGI2 ceased. Three months after ICH, the metabolite excretion levels in all the patients were similar to those in nonusers of aspirin on admission. On admission, aspirin users had longer bleeding times (p=0.032) than nonusers, but aspirin use did not associate with impaired recovery or hematoma enlargement.. Urinary excretion levels of 11-dehydro-TXB2, 2,3-dinor-TXB2 and 2,3-dinor-PGF1alpha were higher in patients with acute ICH than in controls. The levels in aspirin users were equally low as in controls but rose to the levels of the other patients within a few days. The metabolite levels remained high 3 months after ICH in all patients. Prior use of aspirin did not seem to cause hematoma enlargement.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Aged; Aspirin; Bleeding Time; Blood Coagulation; Cerebral Hemorrhage; Epoprostenol; Female; Humans; Male; Middle Aged; Prospective Studies; Regression Analysis; Thromboxane A2; Thromboxane B2

Ischaemia-reperfusion (IR)-associated microcirculatory changes play a major role in acute post-transplantation pancreatitis. The pathophysiological role of platelets in these events is unknown. The aim of this study was to examine platelet adhesion and function during early reperfusion after pancreatic ischaemia.. Rats were subjected to warm pancreatic ischaemia by cross-clamping of the pancreatic vessels for 1 h. After 1 h of reperfusion, platelet-endothelium interaction was evaluated after platelet separation and staining by fluorescence microscopy. Amylase levels and pancreatic histology were evaluated 24 h after reperfusion. Animals treated according to an identical protocol, but without ischaemia, served as controls.. Mild pancreatitis had developed by 24 h after IR; serum amylase levels were significantly higher than those in control animals. The numbers of adherent platelets in capillaries and venules were significantly increased, and platelet velocity in capillaries was significantly decreased, in the IR group compared with controls. There was significantly more oedema and inflammation in pancreatic tissue after IR.. Warm ischaemia for 1 h followed by reperfusion for 24 h caused mild pancreatitis in this experimental model. The pancreatic microcirculation was characterized by pronounced platelet-endothelium interaction in capillaries and venules. These results suggest that platelet activation may play an important role in acute post-transplantation pancreatitis.

Topics: Acute Disease; Animals; Blood Platelets; Constriction; Endothelin-1; Male; Pancreas; Pancreatitis; Platelet Adhesiveness; Rats; Rats, Wistar; Reperfusion Injury; Thromboxane A2

Trypanosoma cruzi induces inflammatory reactions in several tissues. The production of prostaglandin F2alpha, 6-keto-prostaglandin F1alpha and thromboxane B2, known to regulate the immune response and to participate in inflammatory reactions, was studied in mice experimentally infected with T. cruzi. The generation of nitric oxide (NO), which could be regulated by cyclooxygenase metabolites, was also evaluated. In the acute infection the extension of inflammatory infiltrates in skeletal muscle as well as the circulating levels of cyclooxygenase metabolites and NO were higher in resistant C3H mice than in susceptible BALB/c mice. In addition, the spontaneous release of NO by spleen cells increased earlier in the C3H mouse strain. In the chronic infections, the tissue inflammatory reaction was still prominent in both groups of mice, but a moderate increase of thromboxane B2 concentration and in NO released by spleen cells was observed only in C3H mice. This comparative study shows that these mediators could be mainly related to protective mechanisms in the acute phase, but seem not to be involved in its maintenance in the chronic T. cruzi infections.

Topics: Acute Disease; Animals; Chagas Disease; Chronic Disease; Dinoprostone; Disease Susceptibility; Epoprostenol; Inflammation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Muscle, Skeletal; Nitric Oxide; Prostaglandin-Endoperoxide Synthases; Species Specificity; Spleen; Thromboxane A2; Thromboxane B2

Epidemiological studies link acute infection of the respiratory tract to a transient increased risk of acute myocardial infarction. The underlying mechanisms remain unknown. We hypothesized that vasoactive mediators produced by inflammatory cells in the lungs and drained in the coronary circulation may trigger acute myocardial ischemia. To test this hypothesis we used an experimental model in the rabbit. Injection of the bacterial-derived peptide N-formyl-Met-Leu-Phe (or N-formyl-Methionyl-Leucyl-Phenylalanine)(fMLP) in the jugular vein induced massive recruitment of both polymorphonuclear leukocytes (PMN) and platelets in the microcirculation of the lungs, accompanied by rapid and marked increase of leukotriene B4, cysteinyl leukotrienes and thromboxane (Tx) A2 in the aortic blood. In all animals, fMLP evoked ischemic electrocardiographic changes: within the first minute of infusion a profound depression of the ST segment and inversion of the T wave were observed. Mean aortic pressure and heart rate fell to 64.0 +/- 6.9 and 83.5 +/- 3.1% of the basal levels at 3 and 10 min, respectively. All these alterations were transient. Aspirin, prevented electrocardiographic ischemic changes, reverted bradycardia and hypotension but did not significantly modify either PMN or platelet recruitment nor leukotriene synthesis. Ridogrel, a Tx-synthase and receptor inhibitor, prevented ECG alterations and bradycardia, but did not prevent and even worsened hypotension; it blocked platelet, but not PMN, sequestration. Pretreatment of animals with intravenous high dose of aspirin prevented ridogrel-dependent hypotension and platelet inhibition, suggesting that PGI2 contributes to the effects of Tx-synthase and receptor inhibitor. In hypercholesterolemic rabbits, ECG alterations persisted longer than in normal controls. In summary, our results indicate that acute activation of PMN and platelets in the lungs provokes transient myocardial ischemia, in normal animals that is exacerbated in hypercholesterolemic rabbits. TxA2 appears to be the major mediator of this phenomenon. Moreover the data suggest that a balance between TxA2 and PGI2 plays a pivotal role in platelet activation and recruitment in our model.

Topics: Acute Disease; Animals; Arteriosclerosis; Disease Models, Animal; Electrocardiography; Epoprostenol; Inflammation Mediators; Male; Myocardial Ischemia; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activation; Pneumonia; Rabbits; Thromboxane A2

The effects of endothelin 1 (ET-1) on hemodynamics and acute liver damage were studied using perfused livers of rats treated with D-galactosamine. In control liver perfused in situ with constant pressure, infusion of ET-1 into the portal vein at a concentration of 0.1 nmol/L decreased the flow rate without a significant leakage of lactate dehydrogenase (LDH) or aspartate transaminase (AST) into the effluent. In contrast, in similarly perfused liver 24 hours after treatment with D-galactosamine (800 mg/kg intraperitoneally), ET-1 caused rapid and remarkable increases in the leakage of LDH and AST from the liver accompanied by the reduction of perfusion flow to the extent similar to that observed in control livers. In addition, ET-1 decreased oxygen uptake and bile secretion in galactosamine-treated livers. The potentiating effects of ET-1 on enzyme leakage were also observed under constant flow conditions. Moreover, infusion of the thromboxane A2 analogue at a concentration of 10 nmol/L decreased the flow rate markedly, yet the rapid increases in enzyme leakage were not observed. Infusion of ET-3 induced the responses of flow reduction and the potentiation of rapid enzyme leakage similar to those obtained with ET-1. Neither the endothelin A-receptor antagonist BQ485 nor the endothelin B-receptor antagonist BQ788 could inhibit the acute liver damage caused by ET-1; instead they exaggerated its effects. The combination of both antagonists together, however, almost completely suppressed the flow reduction and the potentiation of enzyme leakage caused by ET-1. These results indicate that ET-1 is capable of aggravating acute liver damage not merely through reduction of the flow rate but through direct action on liver cells. They also suggest that both the endothelin A and endothelin B receptors are involved in this action of ET-1.

Topics: Acute Disease; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Galactosamine; Hemodynamics; L-Lactate Dehydrogenase; Liver; Liver Circulation; Liver Diseases; Male; Perfusion; Rats; Rats, Sprague-Dawley; Thromboxane A2

To evaluate whether thromboxane A2 participates in the ischemia-reperfusion injury associated with acute compartmental syndrome (ACS) and if by using a cyclooxygenase inhibitor this can be either reduced or abolished.. To assess the role of thromboxane A2 in ACS, a tourniquet was applied for 2 hours to the hind limb of 12 dogs. Group 1 (n = 6) served as controls while group 2 (n = 6) was pretreated with lysine-acetyl-salicylate (Lysoprim). Blood thromboxane B2 levels and intracompartmental pressures were assayed prior to inflation of the tourniquet and at 5 minutes, 90 minutes, and 24, 72, and 144 hours after deflation.. Five minutes after deflation, the compartmental pressure increased from 11.2 +/- 2.2 mm Hg to 16.1 +/- 3.3 mm Hg and 17 +/- 2.2 mm Hg (mean +/- SD) in groups 2 and 1, respectively. At 90 minutes and 24 hours, pressures were 17.1 +/- 3.3 mm Hg and 23.2 +/- 3.3 mm Hg (P<.01) and 15.3 +/- 2.6 mm Hg and 25.2 +/- 1.8 mm Hg (mean +/- SD) (P<.001), respectively, in groups 2 and 1. A similar effect, although of a lesser magnitude, was observed in the counterlateral limb. Thromboxane B2 levels increased from a mean (+/- SD) of 46 +/- 5.5 pg/0.1 mL to 132 +/- 7.5 pg/0.1 mL at 90 minutes in group 1, while remaining unchanged in group 2.. Thromboxane A2 plays a major role in the ischemia-reperfusion injury of acute compartmental syndrome. By using a cyclooxygenase inhibitor both the levels of thromboxane and the compartmental pressures can be reduced.

Topics: Acute Disease; Animals; Compartment Syndromes; Dogs; Reperfusion Injury; Thromboxane A2

The local and systemic release of thromboxane A2, prostaglandin I2, leukotriene B4 (LTB4), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and interleukin-8 (IL-8) were studied before and after operation in 29 patients with acute and 22 with chronic posttraumatic osteomyelitis. Twenty patients without osteomyelitis, who underwent operations for fractures of the lower extremities, served as controls. Blood and tissue samples from the osteomyelitic and control groups were collected under defined conditions and mediators were determined by radioimmunoassay (thromboxane B2, 6-keto-prostaglandin F1 alpha, LTB4) or by enzyme-linked immunosorbent assay (TNF-alpha, IL-1 beta, and IL-8). In addition, common parameters (leukocyte count, C-reactive protein, temperature) were measured. The best correlation with acute disease activity was given by TNF-alpha, IL-6, IL-8, and LTB4. Plasma levels of these mediators in acute osteomyelitis were significantly increased compared to chronic osteomyelitis and to controls, respectively. Tissue samples from osteomyelitic focus showed significantly increased levels for IL-8, IL-6, TNF-alpha, IL-1 beta, and LTB4 in acute osteomyelitis, whereas the values for TxB2 and 6-keto-prostaglandin F1 alpha were only slightly increased compared to the chronic osteomyelitis group. This study describes the local and systemic liberation of various mediators in acute and chronic posttraumatic osteomyelitis in detail for the first time and provides data for pre- and postoperative monitoring of disease activity and demonstrates new pathogenetic and therapeutic aspects of bone modulation in osteomyelitis.

Topics: Acute Disease; Adult; Case-Control Studies; Chronic Disease; Cytokines; Eicosanoids; Epoprostenol; Female; Fractures, Bone; Humans; Interleukin-6; Interleukin-8; Leukotriene B4; Male; Middle Aged; Osteomyelitis; Thromboxane A2

Systemic prostacyclin and thromboxane A2 production in rat experimental acute pancreatitis has been evaluated by measuring the urinary excretion of the 2,3-dinor 6-keto prostaglandin F1 alpha and 2,3-dinor thromboxane B2, respectively. Acute pancreatitis was induced by intraductal administration of 4.5% sodium taurocholate (0.1 ml/100 mg body weight) and intravenous cerulein perfusion (5 micrograms/kg/hr) for 6 hr, respectively. Urinary excretion of 2,3-dinor 6-keto prostaglandin F1 alpha and 2,3-dinor thromboxane B2 were much more important in sodium taurocholate- than in cerulein-induced acute pancreatitis. These data confirm an altered prostacyclin and thromboxane metabolism occurring in experimental acute pancreatitis. Phospholipase A2 activity and the effect of gabexate mesilate on the arachidonate metabolism were also evaluated.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Amylases; Animals; Ceruletide; Epoprostenol; Gabexate; Lipase; Male; Pancreatitis; Phospholipases A; Phospholipases A2; Rats; Rats, Sprague-Dawley; Taurocholic Acid; Thromboxane A2; Thromboxane B2

The principal causes of failure of a pancreas transplant are rejection and vascular thrombosis. There is an unusually high attrition rate for pancreas transplants, but study models have been difficult to develop. In a rat model that allows study of acute rejection to the exclusion of nonspecific effects of transplant surgery on the pancreas, in vitro synthesis of prostacyclin (PGI2) and thromboxane A2 (TXA2) by transplanted pancreas and the blood vessels transplanted with it was measured using an RIA for their stable hydrolysis products 6-keto-prostaglandin F1 alpha and thromboxane B2 (TXB2). TXB2 synthesis was significantly greater in allotransplanted pancreas than isotransplanted pancreas from the 5th day after transplantation. Rejection was complete in the allografted group 7-9 days after transplantation. 6-Keto-prostaglandin F1 alpha synthesis was similar in the pancreas for both allografts and isografts. Similar changes were seen in aorta, celiac artery, superior mesenteric artery, and portal vein transplanted with the pancreas. In the transplanted aorta, TXB2 was significantly greater in the allograft group from the third posttransplant day. A group of CsA-treated allografts sampled after 9 days had transplanted pancreatic parenchymal and vascular prostanoid synthesis in the isograft range. The changes in PGI2 and TXA2 synthesis that accompany cellular rejection may mediate vascular failure in rejecting pancreas transplants, and changes in PGI2 and TXA2 synthesis in blood vessels transplanted with the pancreas could promote early vascular thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Aorta; Celiac Artery; Cyclosporine; Epoprostenol; Graft Rejection; Male; Mesenteric Artery, Superior; Pancreas; Pancreas Transplantation; Rats; Rats, Inbred Strains; Thrombosis; Thromboxane A2; Thromboxane B2; Transplantation, Homologous; Transplantation, Isogeneic; Vena Cava, Inferior

Vasoconstriction during acute renal allograft rejection may be regulated by increased formation of vasoactive prostanoids. To address this hypothesis we investigated the biosynthesis of thromboxane (Tx)A2, a potent vasoconstrictor and platelet agonist, of prostacyclin (PGI2), a vasodilator and platelet antagonist, and of prostaglandin (PG)E2, a mediator of salt and water excretion, in nine children with 12 acute rejection episodes, prospectively during the first 7 weeks after renal transplantation. We used physicochemical analysis of stable urinary prostanoid index metabolites. Rejection crises were associated with an increase in TxB2 excretion from baseline median 9.2 (range 1.9-18.6) ng/h/1.73 m2 to 21.2 (range 10.0-133.0) ng/h/1.73 m2 (P < 0.005) during acute rejection episodes. Methylprednisolone pulse therapy resulted in a partial reduction, but not normalization of TxB2 excretion. Urinary 2,3-dinor-TxB2 was slightly stimulated during allograft rejection, urinary 11-dehydro-TxB2 did not change significantly. Renal PGI2 and PGE2 biosynthesis remained essentially unchanged. In contrast to acute graft rejection, patients with chronic graft rejection and those with stable graft function on different immunosuppressive regimens with or without cyclosporin A did not present stimulated renal TxA2 formation. Increased renal TxA2 formation in acute renal allograft rejection is likely to mediate vasoconstriction and potentiate the loss of renal blood flow and glomerular filtration rate, in the absence of an adequate response of the renoprotective prostanoids PGI2 and PGE2.

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Creatinine; Cyclosporine; Female; Graft Rejection; Humans; Kidney Transplantation; Male; Middle Aged; Prostaglandins; Thromboxane A2; Thromboxane B2; Transplantation, Homologous

It is shown that in patients with cerebral circulatory disorders, the prostacyclin -thromboxane balance is replaced toward the latter one. As a result of nifedipine administration part of the test subjects demonstrate a rise of the content of prostacyclin and a decline of the concentration of thromboxane. This effect of nifedipine is ascertained to be in a good agreement with its action on blood inflow to the brain and platelet aggregation. It is concluded that the efficacy of nifedipine can be raised if it is combined with the drugs that enhance the synthesis of prostacyclins in the body.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Aged; Cerebral Infarction; Cerebrovascular Circulation; Epoprostenol; Humans; Intracranial Arteriosclerosis; Middle Aged; Nifedipine; Thromboxane A2

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

Thromboxane A2 is a potent bronchial smooth muscle spasmogen in vitro, and it has been implicated in airway inflammation and in the genesis of bronchial hyperresponsiveness in asthma. We have examined the urinary excretion of a variety of products derived from thromboxane A2 (thromboxane B2, 2,3-dinor, and 11-dehydro-thromboxane B2) and prostacyclin (6-oxo-PGF1 alpha and 2,3-dinor-6-oxo-PGF1 alpha) using gas chromatography-mass spectrometry in patients admitted acutely to hospital with severe asthma and in atopic volunteers after bronchial antigen challenge. Urinary excretion of all thromboxane-derived products was markedly increased in a number of patients with severe acute asthma compared with that in a nonsmoking control population, in some cases approaching those previously described in myocardial infarction: TXB2, 31.6 +/- 12.0 versus 6.5 +/- 0.9; 2,3-dinor-TXB2, 79.0 +/- 19.2 versus 29.5 +/- 2.7; and 11-dehydro-TXB2, 234.3 +/- 65.3 versus 25.0 +/- 2.1 ng/mmol creatinine (p less than 0.001). Urinary prostacyclin-derived products were also significantly raised in acute asthma. In contrast, after inhaled allergen challenge in atopic volunteers, which caused significant bronchoconstriction, urinary excretion of thromboxane-derived products was not significantly elevated: TXB2, 5.6 +/- 1.1 versus 5.7 +/- 1.0; 2,3-dinor-TXB2, 41.2 +/- 12.5 versus 28.5 +/- 6.9; and 11-dehydro-TXB2, 69.8 +/- 17.6 versus 39.7 +/- 11.2 ng/mmol creatinine. In a separate experiment, less than 2% of exogenously administered TXB2 to the airway appeared as urinary thromboxane-derived products, suggesting that production of greater than or equal to 1 microgram of TXA2 in vivo would be required to increase urinary thromboxane excretion twofold.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Adult; Aged; Allergens; Asthma; Bronchial Provocation Tests; Female; Humans; Male; Middle Aged; Prostaglandins; Thromboxane A2

Plasma thromboxane concentrations were found to be significantly elevated in acute necrotizing pancreatitis in rats, whereas prostaglandin I2 levels were not. The significance of these alterations was investigated. Pancreatitis was induced by injecting 5% sodium taurocholate into the pancreatic duct. Iloprost (ZK 36374, a stable analog of prostaglandin I2, 25 ng/kg body weight) decreased the mortality rate from 100% to 50%. When treatment with iloprost was combined with simultaneous administration of either Sibelium (flunarizine R 14,950, 0.2 mg/kg body weight) or dazmegrel (UK 38,485, 50 mg/kg body weight) an additional decrease in the mortality rate was recorded. Dazmegrel is a selective thromboxane A2 synthetase inhibitor and flunarizine (a calcium entry blocker) also inhibits the effects of elevated thromboxane A2 levels. With flunarizine and iloprost the mortality rate was 40% (P less than 0.05); with dazmegrel and iloprost it was 10% (P less than 0.01). The results of the present study suggest that thromboxane A2 and prostaglandin I2 play a role in the course of acute necrotizing pancreatitis.

Topics: Acute Disease; Animals; Epoprostenol; Flunarizine; Iloprost; Imidazoles; Male; Necrosis; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Thromboxane A2; Vasodilator Agents

In Wistar male rats, 1-h acute immobilization stress resulted in the increased plasma adrenalin, noradrenaline and dopamine in approximately 13, 8 and 23 times, respectively. Plasma PGF2 alpha increased in 3.5 times while PGE remained unchanged; this resulted in the decreased PGE/PGF2 alpha relation in 2.8 times. The PGI2/TXA2 relation also decreased in 1.5 times due to a more pronounced growth of TXA2 than that of PGI2. In rats adapted to the repeated stress (12 sessions), the plasma catecholamine level was higher than that in control but 2-3 fold lower than in unadapted rats after acute single stress. In this situation, PGE was increased by 70% as compared to the control. This is why PGE/PGF2 alpha relation was similar to the control whereas the level of PGF2 alpha increased. PGI2 increased by 53% and TXA2--in two times as compared to the control. In these rats, acute stress induced neither plasma catecholamine enhancement nor PGE/PGF2 alpha relation decrease in comparison with the initial levels; the TXA2 content was increased but it was by 33% less than that in unadapted rats exposed to such stress. One can suggest that the decreased activation of adrenergic system respondent to acute stress in unadapted rats is associated with the increase in plasma PGE and PGI2 which are known to limit the catecholamine release from adrenergic terminals and their harmful effects.

Topics: Acute Disease; Adaptation, Physiological; Animals; Catecholamines; Dinoprost; Dopamine; Epinephrine; Epoprostenol; Immobilization; Male; Norepinephrine; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Stress, Physiological; Thromboxane A2

The purpose of this study was to examine the effects and mechanisms of the selective thromboxane synthesis inhibitor CGS-12970 (3-methyl-2[3 pyridyl]-1-indoleoctanoic acid) on renal allograft function and eicosanoid production. Kidneys were transplanted between nonimmunosuppressed outbred mongrel dogs and renal allograft function, renal eicosanoid production and histologic signs of rejection were monitored. In the untreated animals, renal allograft blood flow and allograft glomerular filtration rate declined steadily over the 5-day observation period compared to animals with nonrejecting autotransplanted kidneys. However, renal blood flow and glomerular filtration rate of renal allografts from animals receiving the selective thromboxane synthesis inhibitor CGS-12970 (3 mg/kg p.o. b.i.d.) were significantly higher compared to nontreated allograft animals. Histologic examination of renal allografts harvested 5 days after transplantation revealed rejection with mononuclear infiltration in both the untreated and the CGS-12970-treated animals. In untreated dogs, renal allograft tissue production of thromboxane B2 (TXB2) Prostaglandin E2 (PGE2) and 6-Keto PG F1 alpha (6-K-PGF1 alpha) was significantly elevated 5 days after transplantation compared to normal renal tissue. In animals treated with CGS-12970, renal allograft tissue production of TXB2, PGE2 and 6-K-PGF1 alpha was significantly lower than the untreated allografts and was not different from normal kidneys. In-vitro dose-response experiments revealed that CGS-12970 nonselectively inhibited renal allograft tissue TXB2 and 6-K-PGF1 alpha production in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Animals; Dogs; Glomerular Filtration Rate; Graft Rejection; Kidney Transplantation; Prostaglandins; Pyridines; Renal Circulation; Thromboxane A2; Thromboxane-A Synthase; Transplantation, Homologous

Macrophages isolated from liver granulomas of mice infected with Schistosoma mansoni for 8 or 20 wk synthesize predominantly thromboxane A2 with smaller amounts of the PGE2 and PGI2. There is no physiologic production of leukotrienes, as determined by RIA and HPLC. Thromboxane A2 is the predominant arachidonic acid metabolite whether the cells are stimulated by a phagocytic stimuli such as zymosan or the exogenous substrates arachidonic acid and PGH2. These data indicate that the predominant arachidonate enzymatic activity in these cells is thromboxane synthase.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Acute Disease; Animals; Arachidonic Acid; Arachidonic Acids; Chronic Disease; Granuloma; Hydroxyeicosatetraenoic Acids; Liver Diseases; Macrophage Activation; Macrophages; Mice; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Schistosomiasis mansoni; SRS-A; Thromboxane A2; Thromboxane-A Synthase

We investigated the role of prostacyclin (PGI2) and thromboxane A2 (TxA2), as evidenced by changes in their stable metabolites, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), in the pathophysiology of acute bacteremic gram-negative pneumonia. Three groups of dogs were inoculated endotracheally: Group I (n = 5) with sterile broth, and Groups II (n = 5) and III (n = 10) with Pseudomonas aeruginosa. Gas exchange, hemodynamics, and plasma prostaglandins were measured before inoculation and hourly thereafter for 5 h in Groups I and II but only once in Group III, 5 h after inoculation. All animals were then killed, and the extent of pneumonia was assessed by lung wet weight and measurement of the percentage of cardiac output (CO) perfusing pneumonic lung using radionuclide-labeled microspheres. None of these measurements changed significantly in Group I, but all dogs in Groups II and III developed severe pneumonia. In Group II, mean arterial oxygen tension fell from 575 +/- 17 to 237 +/- 59 mm Hg (FIO2 = 1.0), with an increase in pulmonary shunt from 6 +/- 2% to 24 +/- 6%. Although TxB2 levels did not change, plasma 6-keto-PGF1 alpha rose progressively as pneumonia developed from baseline levels (less than 100 pg/ml) to a peak level of 890 +/- 114 pg/ml 5 h after inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Animals; Dogs; Epoprostenol; Hemodynamics; Pneumonia; Pseudomonas Infections; Pulmonary Circulation; Sepsis; Thromboxane A2

The possible role of thromboxane A2 (TXA2) in acute necrotizing pancreatitis (ANP) was investigated in rats. After ANP was induced by injecting sodium taurocholate (5% w/v) into the pancreatic duct, the thromboxane B2 (TXB2) levels in plasma increased significantly. The effects of indomethacin, a general blocker of prostaglandin synthesis, on survival time and on plasma TXB2 levels were compared with those of dazoxiben, a more specific blocker of TXA2 synthesis, and Flunarizine, a calcium entry blocker known to inhibit the effects of TXA2. In a test group without any treatment, all animals died within 30 h of ANP induction. Although TXB2 levels were lowered by the administration of indomethacin, dazoxiben, and Flunarizine, survival times were not significantly altered. Indomethacin pretreatment had no beneficial effect, whereas 30% and 40% of the animals survived for 36 h after treatment with Flunarizine and dazoxiben, respectively. The results of the present study indicate that inhibition of TXA2 synthesis alone does not dramatically alter survival time. However, a potential role for other arachidonate metabolites in ANP cannot be ruled out by this study.

Topics: Acute Disease; Animals; Flunarizine; Imidazoles; Indomethacin; Male; Necrosis; Pancreatitis; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2

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

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

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

This study investigated the interaction of plasma levels of circulating prostaglandins and activated complement in clinical acute respiratory failure (ARDS). Fifty patients at risk for ARDS were followed up for up to ten days. Arterial blood gases and plasma levels of complement components C3a and C5a, thromboxane B2 (TxB), and prostaglandin 6-keto-F1 alpha (PGI) and granulocyte aggregation (GA) were measured daily. Seventeen patients (34%) developed ARDS, with mortality of 41% vs 23% for patients without ARDS. Compared with patients without ARDS, the ARDS group had significantly increased plasma C3a (1,130 +/- 750 vs 636 +/- 368 ng/mL) and granulocyte aggregation (48 +/- 10 vs 17 +/- 4 percentage of the maximum light transmission [% max T]). Plasma C5a, TxB, or PGI did not change significantly with or without ARDS. No measured variable was significantly associated with mortality. Regression analysis revealed significant correlations between GA, TxB, PGI, and arterial oxygenation. Plasma C3a and GA are increased in ARDS, suggesting systemic complement activation. A complex series of interactions between the prostaglandins, complement, and GA appears to be involved in ARDS.

Topics: Acute Disease; Adolescent; Adult; Aged; Cell Aggregation; Complement Activation; Complement C3; Complement C3a; Complement C5; Complement C5a; Epoprostenol; Female; Granulocytes; Humans; Male; Middle Aged; Oxygen; Prospective Studies; Radioimmunoassay; Regression Analysis; Respiratory Distress Syndrome; Thromboxane A2

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

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

Prostaglandin plasma levels are elevated in patients with transient myocardial ischemia. We measured 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane (B2(TXB2) in venous blood of 32 patients with myocardial infarction on the first, third, and seventh days. TXB2 and 6-keto-PGF1 alpha levels in these patients (up to 117 +/- 237 pg/ml and 96 +/- 105 pg/ml mean +/- SD, respectively) differed significantly from levels in normal control subjects (10 +/- 12 pg/ml and 4 +/- 7 pg/ml mean +/- SD, respectively) (p less than 0.01). Prostaglandin values remained elevated from day 1 through day 7. In most patients, 6-keto-PGF1 alpha levels prevailed over those of TXB2. In a subgroup suffering from cardiac arrhythmias, the ratio of 6-keto-PGF1 alpha/TXB2 was inverse. It is concluded that prostaglandin generation is increased for at least 7 days after myocardial infarction. A disturbed ratio of 6-keto-PGF1 alpha/TXB2 in favor of the latter might be associated with cardiac arrhythmias in myocardial infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Adult; Aged; Arrhythmias, Cardiac; Epoprostenol; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prostaglandins; Thromboxane A2; Thromboxane B2

Isolated glomeruli, glomerular epithelial cells and mesangial cells contain the cyclooxygenase enzyme that converts arachidonic acid to prostaglandin (PG)-endoperoxides. Biologically active metabolites of the latter include PGE2, PGF2 alpha, PGI2 and Thromboxane (TX) A2. These substances modulate renal cortical functions, i.e. renin release, renal blood flow (RBF) and glomerular filtration rate. Acute glomerular injury (nephrotoxic serum nephritis) augments glomerular production of PGs and TXA2. Thromboxane A2 reduces glomerular function and inhibition of TXA2 synthesis preserves GFR and RBF in this disease model. Patients with chronic glomerulonephritis have a lower urinary excretion of 6-Keto-PGF1 alpha (the stable hydrolysis product of the vasodilator PGI2). In these patients, inhibition of PGI2 synthesis by a cyclooxygenase inhibitor leads to reductions in GFR and RBF inversely related to the basal urinary excretion of 6-Keto-PGF1 alpha. These findings suggest that in both acute and chronic glomerulonephritis, arachidonate metabolites may serve as pathophysiologic mediators of changes in glomerular function.

Topics: Acute Disease; Animals; Arachidonic Acids; Chronic Disease; Disease Models, Animal; Glomerulonephritis; Humans; Kidney Cortex; Kidney Glomerulus; Prostaglandins; Thromboxane A2

Topics: Acute Disease; Animals; Blood Pressure; Cardiac Output; Dogs; Femoral Artery; Heart; Lung; Prostaglandins F; Pulmonary Artery; Pulmonary Embolism; Thromboxane A2; Thromboxanes

Topics: Acute Disease; Animals; Dogs; Prostaglandins F; Respiratory Insufficiency; 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

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