thromboxane-a2 and Necrosis

Heterogeneity in response to aspirin (ASA) treatment, or "aspirin resistance," could be of importance in patients with ST-segment elevation myocardial infarction (STEMI). Decreased effects of ASA in platelets could be due to partial inhibition of cyclo-oxygenase-1 (COX-1) or to COX-1-independent mechanisms. We evaluated the effect of ASA treatment in patients with STEMI for (1) platelet thromboxane A(2) (TXA(2)) synthesis, (2) platelet recruitment elicited by TXA(2)-dependent and -independent mechanisms, and (3) a possible association of these aspects of platelet reactivity with serum markers of myonecrosis. We studied 62 ASA-treated patients within 48 hours of onset of the acute event and 69 ASA-free and 10 ASA-treated controls. TXA(2) synthesis and platelet recruitment (fluid-phase proaggregate activity of cell-free releasate) were assessed after collagen stimulation (1 micro g/ml) of whole blood. Partial inhibition of TXA(2) by ASA was found in 21 patients (34%). This was associated with significant increases in troponin T, creatine kinase-MB mass, creatine kinase, and recruiting activity versus 41 patients with blocked TXA(2) production. This was independent of fibrinolysis, and platelet COX-2 expression was not augmented. TXA(2) blockade was achieved after subsequent daily treatments or platelet incubation with ASA in vitro, suggesting lower sensitivity of COX-1 to ASA. In addition, 28 patients (45%) had an abnormally increased recruiting activity despite TXA(2) blockade, which was also associated with increased myonecrosis. In conclusion, ASA resistance, elicited by TXA(2)-dependent and TXA(2)-independent mechanisms, was prevalent in patients with STEMI. This study describes, for the first time, the association of partial platelet TXA(2) inhibition with myonecrosis.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Case-Control Studies; Drug Resistance; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Necrosis; Platelet Aggregation; Platelet Aggregation Inhibitors; Severity of Illness Index; Thromboxane A2

Free radical-induced peroxidation is an important factor in the genesis of hypoxic-ischemic encephalopathy, including that of the preterm infant. Isoprostanes are major peroxidation products. Since microvascular dysfunction seems to contribute to ischemic encephalopathies, we studied the cytotoxicity of 8-iso-prostaglandin F2alpha (PGF2alpha) on cerebral microvascular cells.. Microvascular endothelial, astroglial, and smooth muscle cells from newborn brain were cultured. The cytotoxicity of 8-iso-PGF2alpha on these cells was determined by MTT assays and lactate dehydrogenase (LDH) release, propidium iodide incorporation, and DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]). In addition, effects of intraventricular injections of 8-iso-PGF2alpha and possible involvement of thromboxane in 8-iso-PGF2alpha-induced cytotoxicity were determined.. 8-Iso-PGF2alpha induced time- and concentration-dependent endothelial cell death (EC50=0.1 nmol/L) but exerted little effect on smooth muscle and astroglial cells; endothelial cell death seemed mostly of oncotic nature (propidium iodide incorporation and LDH release). Cell death was associated with increased endothelial thromboxane A2 (TXA2) formation and was prevented by TXA2 synthase inhibitors (CGS12970 and U63557A); TXA2 mimetics U46619 and I-BOP also caused endothelial cell death. Intraventricular injection of 8-iso-PGF2alpha induced periventricular damage, which was attenuated by CGS12970 pretreatment.. These data disclose a novel action of 8-iso-PGF2alpha involving TXA2 in oxidant stress-induced cerebral microvascular injury and brain damage.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Cell Death; Cell Survival; Cells, Cultured; Dinoprost; Dinoprostone; DNA Fragmentation; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; F2-Isoprostanes; In Vitro Techniques; Injections, Intraventricular; Isoprostanes; L-Lactate Dehydrogenase; Microcirculation; Muscle, Smooth, Vascular; Necrosis; Rats; Rats, Sprague-Dawley; Swine; Thromboxane A2; Thromboxane-A Synthase

The effects of thromboxane A2 (TXA2)/prostaglandin endoperoxide receptor blockade on myocardial infarct size and cardiac dynamics were determined in a canine model of 24 h acute myocardial infarction. Anesthetized open-chest dogs were subjected to left anterior descending (LAD) coronary artery occlusion. Twenty minutes post-occlusion the dogs were given i.v. saline (0.9% NaCl solution) (n = 12) or the TXA2 receptor antagonist SQ 29548 (0.2 mg/kg i.v. loading dose +0.2 mg/kg/h i.v. for 4 h) (n = 10). SQ 29548 treatment resulted in a significant (P < 0.01) reduction in infarct size. Heart rate (HR) and systolic blood pressure (SAP) were not markedly affected by the drug. The sharp rise in the left ventricular end diastolic pressure (LVEDP) in the saline-treated animals was significantly lowered by SQ 29548 treatment and the correction of this variable was maintained till 24 h post-occlusion. The lowered maximal rate of rise of left ventricular pressure (LVdP/dt max) in the saline-treated animals was corrected albeit non-significantly by the drug treatment. Thus, SQ 29548 treatment resulted in a significant salvage of myocardial tissue and marked alterations in left ventricular dynamics. The study suggests a deleterious role for thromboxane A2 in ischemia; indicating that TXA2 blockade may have potential as a mode of therapy for ischemic heart disease.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Fatty Acids, Unsaturated; Female; Heart Rate; Hemodynamics; Hydrazines; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Receptors, Thromboxane; Thromboxane A2

Ischemic necrosis resulting from vasospasm is a common complication in skin flap surgery, and serotonin released by traumatized platelets is likely to play an important role in the pathogenesis of skin vasospasm in flap surgery. We studied the pathogenic role of serotonin and its pharmacologic intervention thereof in skin flap ischemic necrosis in pigs. We observed that serotonin caused a concentration-dependent (10(-8)-10(-5) M) increase in perfusion pressure in isolated perfused pig skin flaps. This vasoconstrictive effect of serotonin was blocked by S1C/2-serotonergic receptor antagonists LY53857 (10(-5) M) and ketanserin (10(-5) M), but not by an alpha 1-adrenoceptor antagonist (prazosin 10(-5) M), or a thromboxane A2 (TxA2)/endoperoxide receptor antagonist (SQ30741 10(-5) M). The vasoconstrictive effect of serotonin was more pronounced (p < 0.05) in the presence of an endothelium-derived nitric oxide (NO) synthesis inhibitor [N omega-monomethyl-L-arginine (L-NA) or NG-nitro-L-arginine (L-NMMA) 10(-5) M] but not a cyclooxygenase inhibitor (indomethacin 10(-5) M). In in vivo studies, serotonin infusion (5 micrograms/kg/min intravenously, i.v.) significantly (p < 0.05) decreased pig random pattern skin flap capillary blood flow. This in vivo vascular effect was also completely blocked in pigs pretreated with LY53857 (0.4 mg/kg i.v.). In a separate experiment without serotonin infusion, i.v. prazosin (2-8 micrograms/kg), dazmegrel (2-6 mg/kg), or SQ30741 (2-4 mg/kg) had no significant effect on skin flap capillary blood flow as compared with control. On the other hand, i.v. sergolexole or LY53857 significantly (p < 0.05) increased skin flap capillary blood flow in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic alpha-Antagonists; Animals; Arginine; Dose-Response Relationship, Drug; Ergolines; In Vitro Techniques; Ischemia; Ketanserin; Necrosis; omega-N-Methylarginine; Prostaglandin H2; Prostaglandins H; Regional Blood Flow; Serotonin; Serotonin Antagonists; Skin; Surgical Flaps; Swine; Thromboxane A2; Vasoconstriction

Adrenergic cardiac and aortic lesion was reproduced by using intramuscularly a stress-necrogenic epinephrine dose of 2 mg/kg. Following 24 hours, the levels of malonic dialdehyde (MDA) as a TxA2 marker, were measured in the platelets. The antiaggregability of the aortic wall where PGI2 is synthesized was also examined. The adrenergic lesion was found to impair the platelet function-vascular wall balance, creating the condition for enhancing spontaneous platelet aggregation. This led to 50% death of experimental "lowland" rats. The short-term high-altitude adaptation failed to substantially modify the death rates in adrenergic lesion, though the platelets showed a 30% decrease in MDA generation. The combination of high-altitude adaptation and the calcium antagonist finoptin completely prevented the stress-induced increase in the platelet generation of MDA, a TxA2 marker, which was followed by a drastic reduction (16.6% versus 50%) in sudden death cases among the rats during adrenergic cardiac and aortic lesion.

Topics: Adaptation, Physiological; Altitude; Animals; Aorta, Abdominal; Disease Models, Animal; Epinephrine; Epoprostenol; Male; Myocardium; Necrosis; Platelet Aggregation; Rats; Thromboxane A2; Verapamil

The thromboxane A2 (TXA2) plasma level in kappa-carrageenin (KC)-induced acronecrosis in the rat tail has been studied. TXB2 as stable metabolite of TXA2 was determined by a radioimmunoassay (RIA). 30 min after KC i.v. injection, the increase in the plasma TXB2 level was highest in Barby:Wistar rats but not in Halle:Wistar rats. Lambda-carrageenin (LC) increased the TXB2 levels in both strains of Wistar rats, although it did not induce acronecrosis. Drugs inhibiting TXB2 formation, namely dexamethasone, acetylsalicylic acid, Hoe 944, R 68070 or chlorpromazine, had only a small effect on acronecrosis frequency. Heparin inhibited TXB2 formation and acronecrosis frequency while the serotonin antagonist cyproheptadine decreased only the acronecrosis frequency but caused no change in TXB2 plasma level. These data demonstrate that the kappa-carrageenin-induced acronecrosis is followed by an increased formation of TXA2 in rats.

Topics: Animals; Aspirin; Carrageenan; Chlorpromazine; Dexamethasone; Heparin; Imidazoles; Naphthalenes; Necrosis; Pentanoic Acids; Pyridines; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2

The effects of alterations in platelet activity on arrhythmias, haemodynamics and extent of necrosis during coronary ligation for 30 min were assessed in rabbits. Reduction of platelet counts to less than 1% of control by intravenous injection of platelet antiserum (1 ml kg-1 i.v.) reduced the volume of necrosed tissue from 23 +/- 2% to 15 +/- 1%, P less than 0.01 (expressed as % of total LV) and attenuated the hypotensive effect of ischaemia. Pretreatment with the platelet activating factor (PAF) antagonist BN 52021 also attenuated the hypotension and necrosis caused by coronary ligation 23 +/- 2% vs 14 +/- 1%, P less than 0.01. Pretreatment with the thromboxane antagonist CGS 13080 attenuated the hypotensive response to ischaemia but had only a very small effect on the area of necrosis. Administration of PAF at 10 min following coronary ligation markedly increased the volume of necrosed tissue 36 +/- 2%, P less than 0.01 and caused VF and haemodynamic collapse in 10 out of 12 animals. Pretreatment with platelet antiserum or the PAF antagonist BN 52021 reversed this effect of PAF. Pretreatment with CGS 13080 attenuated the marked hypotensive effect of PAF but failed to reverse its necrotic or arrhythmogenic effects. These findings indicate that platelet activation contributes to the necrosis and hypotension following coronary ligation and that platelet-activating factor may contribute to this. The ameliorating effects of platelet antiserum or BN 52021 support the concept that inhibition of platelet activity may have a useful role in the treatment of acute myocardial infarction.

Topics: Animals; Arrhythmias, Cardiac; Blood Platelets; Diterpenes; Ginkgolides; Hypotension; Imidazoles; Immune Sera; Lactones; Myocardial Infarction; Necrosis; Platelet Activating Factor; Platelet Activation; Pyridines; Rabbits; Thromboxane A2; Thromboxane-A Synthase

The role of thromboxane A2 (TXA2) in myocardial necrosis during coronary occlusion and reperfusion was investigated by using a new long-acting TXA2 synthetase inhibitor, DP1904. A rabbit coronary branch was occluded for 30 min and then reperfused for 72h. Infarct size and area at risk were determined histologically and by fluorescent particles, respectively, for 4 groups; a saline receiving control group (C group), a DP1904 treated group (DP group), a heparin treated group (H group), and a DP1904 plus heparin treated group (DP-H group). The H group and DP-H group were included to examine the influence of heparinization on the effect of DP1904. In the DP and DP-H groups, 10 mg/kg of DP1904 was injected i.v. 2h before coronary occlusion, as well as 24 and 48h after reperfusion. This dose of DP1904 (10 mg/kg i.v.) was able to inhibit serum thromboxane B2 formation ex vivo to 1.1% of the control level 2h after its administration, and to 39.5% at 24h, in the rabbit (n = 5). The H and DP-H groups received 1000 units of heparin i.v. 3 min prior to coronary occlusion. The size of the area at risk, heart rate, blood pressure, and rate-pressure products were comparable between the 4 groups. Mortality was not significantly different in any group. Myocardial infarct size as the percentage of area at risk was 43.6 +/- 3.9% in C group (n = 10), 41.1 +/- 4.4% in DP group (n = 9), 47.8 +/- 3.0% in H group (n = 13), and 44.7 +/- 4.0% in DP-H group (n = 10), which were not significantly different. These findings suggest that TXA2 does not contribute directly to myocardial necrosis during coronary occlusion and reperfusion in the rabbit.

Topics: Animals; Constriction; Coronary Vessels; Disease Models, Animal; Heparin; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Necrosis; Rabbits; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane-A Synthase

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

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

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

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

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