thromboxane-b2 and Arterial-Occlusive-Diseases

Oxygen infusion is used in complementary medicine for treatment of peripheral occlusive arterial disease. The mechanism of action is unknown. Thus, we determined the effects of oxygen infusion on prostacyclin, thromboxane and nitric oxide synthesis. Twelve patients with peripheral occlusive arterial disease received oxygen 40 ml/d intravenously for 3 weeks. Study parameters, analyzed by gas chromatography-mass spectrometry on day 1, 3, 10, 16, 21: 2,3-dinor-6-oxo-PGF(1alpha), colour invisible 2,3-dinor-TXB2 and nitrate in one-hour-urine before and after oxygen infusion, reflecting prostacyclin, thromboxane and nitric oxide synthesis. Urinary 8-iso-PGF2alpha, indicating oxidative stress, was assessed in one patient. Urinary 2,3-dinor-6-oxo-PGF1alpha rose from baseline more than 4-fold after oxygen infusion. In contrast, urinary 2,3-dinor-TXB2 excretion remained unchanged. Oxygen infusion had no effect on urinary nitrate excretion. Urinary 8-iso-PGF(2alpha) was not influenced by oxygen infusion with and without diclofenac pretreatment. Our data demonstrate a shift of the prostacyclin/thromboxane ratio toward prostacyclin by oxygen infusion. Thus, a mechanism of action is provided and clinical trials with intravenous oxygen find a rational basis.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Arterial Occlusive Diseases; Dinoprost; Epoprostenol; F2-Isoprostanes; Female; Gas Chromatography-Mass Spectrometry; Humans; Infusions, Intravenous; Kinetics; Male; Middle Aged; Nitrates; Oxygen; Thromboxane B2

We evaluated the effectiveness of indobufen administration in reducing neutrophil activation in a clinical model of ischemia-reperfusion. Thirty stable patients with intermittent claudication due to occlusive peripheral arterial disease of the leg were randomly assigned to two groups. Patients in group I were treated with indobufen [200 mg orally twice daily (p.o. b.i.d.) for a week]; patients in group II received a placebo. Both groups of patients were submitted to standardized treadmill exercise until onset of claudication. Plasma levels of thromboxane B2 (TxB2) and 6-keto-prostaglandin F1alpha(6-k-PGF1alpha) neutrophil filterability, and neutrophil activation (by nitro-blue tetrazolium test) were assessed in blood samples from the femoral vein draining the ischemic leg. The values were obtained at rest and 5, 30, and 60 min after onset of claudication. Urinary albumin excretion was measured at rest and 1 h after onset of claudication. Plasma levels of TxB2 and 6-k-PGF1alpha increased significantly in the placebo group 5 min after onset of claudication, whereas only a slight nonsignificant increase was observed in the indobufen-treated group at the same timepoint.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arterial Occlusive Diseases; Cyclooxygenase Inhibitors; Humans; Intermittent Claudication; Isoindoles; Lactic Acid; Middle Aged; Neutrophil Activation; Phenylbutyrates; Platelet Aggregation Inhibitors; Thromboxane B2

The combination of thromboxane synthase inhibition with thromboxane receptor antagonism has been shown to result in a strong inhibition of platelet aggregation and a prolongation of the bleeding time (Gresele et al., J. Clin Invest 1987; 80: 1435-45). Ridogrel is a single molecule that efficiently achieves both inhibitions in human volunteers. The present study was performed in patients with obstructive peripheral arterial disease and elevated plasma beta-thromboglobulin levels. Patients were treated with either 2 x 300 mg ridogrel or 2 x 300 mg placebo per day for 2 1/2 days, according to a double blind randomised parallel design. Plasma beta-thromboglobulin decreased significantly throughout active treatment starting within 2 h after administration; serum and urinary immunoreactive TxB2 levels and urinary 11-dehydro-TxB2 excretion were significantly lower and serum PGE2 and 6-keto-PGF1 alpha levels significantly higher with ridogrel; no changes were observed in the placebo-treated group. In conclusion this study demonstrates a reduction of platelet activation in vivo by ridogrel.

Topics: Aged; Aged, 80 and over; Arterial Occlusive Diseases; beta-Thromboglobulin; Double-Blind Method; Humans; Pentanoic Acids; Platelet Activation; Platelet Factor 4; Prostaglandins; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase

We studied the effect of nafazatrom on plasma prostacyclin (PGI2) levels, platelet function, and thromboxane B2 (TxB2), and 12-hydroxy-eicosatetraenoic acid (12-HETE) production and clinical improvement in 12 patients with peripheral vascular disease (PVD) by means of a double-blind crossover trial of placebo, 800 or 1600 mg of nafazatrom four times daily for 1 week, with intervening 2-week washout periods. Plasma PGI2 levels were measured as 6-keto-PGF1 alpha by radioimmunoassay. Platelet function ex vivo was measured as collagen and adenosine diphosphate (ADP)-induced platelet aggregation, release of 12-HETE and thromboxane A2 (measured as TxB2), and was determined by high-pressure liquid chromatography (HPLC) and radioimmunoassay, respectively. The plasma 6-keto-PGF1 alpha levels were unaffected by nafazatrom treatment (p greater than 0.25). Nafazatrom treatment had no effect on TxB2 production, but significantly altered the production of the platelet 12-HETE (p less than 0.05). There was a significant association between the changes in 12-HETE production and clinical improvement. These results suggest that the mechanism of action of nafazatrom is in part related to the inhibition of platelet function via the lipoxygenase pathway, independent of PGI2 stimulation.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Aged; Arterial Occlusive Diseases; beta-Thromboglobulin; Blood Platelets; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Epoprostenol; Humans; Hydroxyeicosatetraenoic Acids; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Pyrazoles; Pyrazolones; Random Allocation; Thromboxane B2

To investigate the relationship between syndrome differentiation of traditional Chinese medicine (TCM) and characteristic changes of vascular endothelial function in patients with diabetic arterial occlusion (DAO) of lower extremities.. Forty patients with DAO were selected as trial group. Twenty patients among them were attributed to blood stasis syndrome (group A1), and the others were attributed to syndrome of pathogenic dampness-heat attacking the lower limb (group A2) according to syndrome differentiation type of TCM. Patients with diabetes (group B), arteriosclerosis obliterans (group C) and healthy people (group D) were observed as the control groups, respectively. There were 20 cases in each group. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) were measured by high resolution ultrasound in the 100 subjects and the changes of vascular tension factors were also studied.. The results showed that EDD in group A was reduced significantly as compared with that in the groups B, C and D. The levels of vascular contractile factors such as endothelin-1 (ET-1) and thromboxane B2 (TXB2) in group A were higher than those in the groups B, C and D, while the levels of vascular dilatory factors such as nitric oxide (NO) and 6-keto-prostaglandin F1alpha(6-Keto-PGF1alpha) were declined significantly as compared with those in the groups B and D. Linear correlation analysis showed that EDD was correlated positively with the levels of NO and 6-Keto-PGF1alpha, while the levels of ET-1 and TXB2 had negative correlation with EDD. EDD and EID in group A2 were declined significantly as compared with those in group A1.. Our findings indicate that endothelial dysfunction may play an important role in the pathogenesis of DAO and may be associated with syndrome differentiation of TCM.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Arterial Occlusive Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diagnosis, Differential; Endothelin-1; Endothelium, Vascular; Female; Humans; Lower Extremity; Male; Medicine, Chinese Traditional; Middle Aged; Nitric Oxide; Thromboxane B2

Magnesium (Mg) has been shown to reduce platelet aggregation both in vitro and ex vivo, and this antiplatelet effect may be advantageous in the prevention of arterial thrombosis. Previous animal studies have shown an antithrombotic effect of Mg also in vivo, but mainly with higher Mg concentrations ( approximately 3.0-4.0 mM). The objectives of the present study were to evaluate the antithrombotic effect of (1) intravenous Mg at a lower and clinically more relevant concentration and (2) topically applied Mg. The study comprised 30 male rats, randomly assigned into 3 groups: (1) placebo group, (2) intravenous Mg group, and (3) topical Mg group. A thrombogenic lesion was established by making a standardised arteriotomy in the right femoral artery. The vessel was transilluminated and thrombus formation was visualised dynamically by in vivo microscopy and recorded on videotapes. Thrombus area was measured after ended experiment by computer-assisted image analysis. Intravenously administered Mg, elevating the S-Mg level to 2.2 mmol/L, significantly reduced the mean thrombus area (p<0.05) compared to the control group. Topically applied Mg significantly decreased the maximum thrombus area, without any increase in S-Mg level (p<0.05). The Mg-treated groups showed no increase in bleeding complications. A transient fall in blood pressure was seen in the systemic Mg group, but blood pressures were not significantly different between any of the groups at the end of the experiment. In conclusion, topically as well as intravenously infused Mg reduce arterial thrombus formation in this in vivo rat model without compromising haemostasis.

Topics: Administration, Topical; Animals; Arterial Occlusive Diseases; Blood Pressure; Disease Models, Animal; Hemorrhage; Infusions, Intravenous; Magnesium; Male; Rats; Rats, Wistar; Thrombosis; Thromboxane B2

Many researches show that traditional Indonesian diet is good for physical health. The present study examines the antioxidative, anti-inflammatory and antithrombotic potentials of aqueous extract of tempe (fermented soya-beans) and Curcuma domestica in an experimental photochemical thrombogenesis model using rat femoral artery. A total of 15 male Wistar rats weighing 250 g were used, and divided into three groups: control (group-1, n = 5), animals, treated orally with 0.25 ml aqueous extracts of 50 g tempe (fermented soybean cake) once daily for 7 consecutive days (group-2, n = 5) and animals treated orally with 0.25 ml aqueous extracts of 10 g roots of Curcuma domestica once daily for 5 consecutive days (group-3, n = 5). All animals were anesthetized, and Sn-pyrophosphate and Tc99m solutions were injected intravenously for in vivo red cell radioactive labeling. Femoral arterial occlusion was observed, using a gamma camera. Induction of femoral arterial thrombosis was effected following an endothelial injury by free radicals produced by green light-irradiated Rose Bengal (10 mg/kg). The results showed that in the control group arterial total flow occlusion was seen in 15 min of irradiation. The results of MDA absorbency was 0.3700 +/- 1.7 nmol/ml in control group-1, 0.0520 +/- 0.025 in group-2 (significant p < 0.05 in comparison to control group) and 0.2780 +/- 0.027 in group-3 (non-significant). Interleukin-1alpha plasma level was 14.44 +/- 2.3 in control group-1, 8.93 +/- 2.4 in group-2 (significant p < 0.05), and 6.21 +/- 2.5 in group-3 (significant p < 0.05). Plasma thromboxane B2 plasma level was 20.31 +/- 2.4 in control group-1, 14.32 +/- 2.2 in group-2 (significant p < 0.05), and 19.41 +/- 2.1 in group-3 (significant). This study suggests the potential antioxidative, anti-inflammatory and antithrombotic effect that the dietary aqueous extracts has in rat femoral artery.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Arterial Occlusive Diseases; Curcuma; Diet; Disease Models, Animal; Femoral Artery; Fibrinolytic Agents; Indonesia; Interleukin-1; Lipid Peroxidation; Male; Malondialdehyde; Photochemistry; Plant Extracts; Plant Proteins; Polysaccharides; Radionuclide Imaging; Rats; Rats, Wistar; Rose Bengal; Soy Foods; Thiobarbituric Acid Reactive Substances; Thromboxane B2

To investigate the mechanisms responsible for the accelerated radioaerosol transalveolar clearance rates caused by acute balloon occlusion of the pulmonary arterial tree in dogs, the effects of vagal tone (n = 5) and prostaglandins (n = 21) including thromboxane were evaluated. In 15 animals, serial pulmonary arterial and aortic blood samples were acquired to evaluate pertinent metabolic products. Balloon occlusion of a localized arterial territory caused significant acceleration of technetium-99m diethylenetriamine pentaacetic acid (Tc-99m DTPA) clearance in the zone immediately distal to the occlusion (baseline clearance half-time 23.1 +/- 0/7 min versus 19.3 +/- 0.4 min, mean +/- SEM, p < 0.05). Vagotomy had no effect on occlusion-accelerated clearance. However, significant (p < 0.05) normalization did occur in the presence of indomethacin (21.9 +/- 0.4 min) and meclofenamic acid (20.4 +/- 0.5 min). Plasma values of thromboxane rose dramatically (pulmonary blood baseline 119 pg/ml to > 40,000 pg/ml) and transiently immediately after pulmonary vascular occlusion, and this rise was blunted significantly (peak pulmonary thromboxane B2 [TXB2] concentration = 668 pg/ml, p < 0.05) by meclofenamic acid. Significant normalization of local DTPA clearance rates also occurred in the presence of a thromboxane receptor blocker (n = 4), even when blood levels of thromboxane were elevated. Changes in transalveolar DTPA clearance rates after balloon occlusion of pulmonary arteries seem to a significant extent to be thromboxane-mediated.

Topics: Animals; Arterial Occlusive Diseases; Catheterization; Dogs; Meclofenamic Acid; Pulmonary Alveoli; Pulmonary Artery; Radiopharmaceuticals; Technetium Tc 99m Pentetate; Thromboxane A2; Thromboxane B2; Thromboxanes

Splanchnic artery occlusion shock was induced in male anaesthetized rats by clamping the splanchnic artery for 45 min. The arteries were then released and survival rate, mean survival time, mean arterial blood pressure, plasma levels of thromboxane B2 and 6-keto-PGF1 alpha, macrophage phagocytosis activity and plasma levels of myocardial depressant factor were evaluated. In addition, the neutrophilic infiltrate was quantified in the ileum and lung using a myeloperoxidase (MPO) assay. Sham splanchnic-artery-occlusion-shocked rats were used as controls. Splanchnic-artery-occlusion-shocked rats died within 93 +/- 7 min, while all sham-shocked animals survived more than 3 h. Splanchnic artery occlusion shock caused changes in mean arterial blood pressure, significantly increased the plasma levels of thromboxane B2 (7.5 +/- 1.3 ng/ml; p < 0.001 vs. sham), 6-keto-PGF1 alpha (8.9 +/- 1.7 ng/ml; p < 0.001 vs. sham) and myocardial depressant factor (114 +/- 11 U/ml), and reduced macrophage phagocytosis. Furthermore, MPO activity was significantly elevated (0.12 +/- 0.03 x 10(-3) and 1.8 +/- 0.5 x 10(-3) U/g protein in the ileum and lung, respectively) 70 min after starting reperfusion. Administration of BAY u3405, a novel thromboxane A2 receptor antagonist (30 mg/kg i.v., 30 min before occlusion), significantly increased survival time (187 +/- 3.7 min) and survival rate, improved mean arterial blood pressure, reduced the plasma levels of myocardial depressant factor (54 +/- 3 U/ml), partially restored macrophage phagocytosis and lowered MPO activity in both the ileum and the lung. Our data are consistent with an involvement of thromboxane A2 in splanchnic artery occlusion shock and suggest that BAY u3405 might be of benefit in low-flow states such as circulatory shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Occlusive Diseases; Blood Pressure; Carbazoles; Macrophages; Male; Myocardial Depressant Factor; Peroxidase; Phagocytosis; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Shock; Splanchnic Circulation; Sulfonamides; Survival Rate; Thromboxane A2; Thromboxane B2

The role of mast cells in pulmonary artery occlusion/reperfusion injury was examined. Lung tissue was obtained from dogs after left pulmonary artery occlusion for 48 h (n = 5) or after similar occlusion followed by 4 h of reperfusion (n = 11). By light microscopy and morphometry, the percentage of mast cells increased 2.4-fold (p < 0.05) in nonoccluded right lungs and 2.9-fold (p < 0.05) in occluded left lungs without reperfusion compared with that in control lungs. After reperfusion, the occluded left lung contained 1.8-fold (p < 0.05) as many mast cells as the nonoccluded right lung and 4.2-fold (p < 0.05) more than that in control lungs. Hydroxyurea did not significantly affect the number of mast cells observed in the right and left lungs after ischemia/reperfusion; 39.8% and 54.4% of the mast cells were degranulated in nonoccluded right lung and occluded left lung preparations, respectively, after left pulmonary artery ischemia/reperfusion (each, p < 0.05 compared with control lungs). The release of eicosanoids into the airways during ischemia/reperfusion injury was also examined. Thromboxane B2 and leukotriene B4 were markedly increased (each, p < 0.05 compared with that in control lungs) in bronchial lavage fluids from both nonoccluded and occluded lungs compared with sham-occluded lungs. Thus, mast cell recruitment and degranulation may play a role in lung ischemia/reperfusion injury.

Topics: Animals; Arterial Occlusive Diseases; Bronchoalveolar Lavage Fluid; Cell Count; Cell Degranulation; Dogs; Hydroxyurea; Leukotriene B4; Lung; Mast Cells; Microscopy, Electron; Pulmonary Artery; Reperfusion Injury; SRS-A; Thromboxane B2; Time Factors

Splanchnic artery occlusion (SAO) shock was induced in anesthetized rats by clamping the celiac trunk and the superior mesenteric artery for 45 min. The arteries were then released and survival rate, mean survival time, mean arterial blood pressure (MAP), plasma levels of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, and the phagocytotic activity of peritoneal macrophages were evaluated. Shocked animals died within 89 +/- 10 min, while all sham-shocked rats survived greater than 3 h. SAO shock produced relevant changes in MAP, significantly increased plasma levels of TxB2 and 6-keto-PFG1 alpha, and decreased peritoneal macrophage phagocytotic activity. The administration of G 619, a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist (50 mg/kg, 15 min before SAO shock) significantly increased survival time (190 +/- 13 min) and survival rate, reduced plasma levels of TxB2, and partially restored the impairment in peritoneal macrophage phagocytosis. Finally, the administration of G 619 had beneficial effects on changes in MAP-induced bay SAO shock. These data further confirm the involvement of TxA2 in SAO shock and suggest that G 619 may have positive effects in low-flow states.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Occlusive Diseases; Benzamides; Blood Pressure; Macrophages; Male; Phagocytosis; Picolines; Radioimmunoassay; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Shock; Splanchnic Circulation; Thromboxane B2; Thromboxane-A Synthase

Splanchnic artery occlusion shock was induced in anesthetized rats by clamping the splanchnic arteries for 45 min. The survival rate, plasma levels of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, serum and peritoneal levels of macrophage tumor necrosis factor (TNF alpha), the phagocytotic and killing activity of peritoneal macrophages and white blood cells count were evaluated. Shocked rats died within 2 h, while all sham-shocked rats survived more than 6 h. Plasma TxB2 and 6-keto-PGF1 alpha levels were increased in rats subjected to splanchnic artery occlusion shock compared to the levels in sham-shocked animals. Serum and peritoneal macrophage TNF alpha levels were undetectable in sham-shocked rats, whereas shocked rats exhibited increased levels of TNF alpha. Moreover, splanchnic artery occlusion shock reduced peritoneal macrophage phagocytotic and killing activity, and also produced severe leukopenia. A specific receptor antagonist of platelet activating factor (PAF), L-652, 731 (an i.v. bolus of 3.2 mg/kg 2 min after removal of the clamps followed, 5 min thereafter, by a continuous infusion of 0.16 mg/kg per min for 30 min) significantly increased the survival rate, lowered plasma TxB2 levels and reduced both serum and macrophage TNF alpha levels in shocked rats. In addition, L-652,731 completely restored macrophage phagocytosis, partially improved macrophage killing and significantly inhibited leukopenia. Finally, the administration of L-652,731 had beneficial effects on the cardiovascular changes induced by splanchnic artery occlusion shock. These findings are consistent with the involvement of PAF in splanchnic artery occlusion shock and indicate that PAF produces shock through direct and indirect (TxB2-mediated and TNF alpha-mediated) actions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Occlusive Diseases; Blood Pressure; Furans; Leukocyte Count; Leukopenia; Macrophages; Male; Phagocytosis; Platelet Activating Factor; Radioimmunoassay; Rats; Rats, Inbred Strains; Shock; Splanchnic Circulation; Thromboxane B2; Tumor Necrosis Factor-alpha

The role of blood platelets in ischemia- and reperfusion-induced arrhythmias and the efficacy of three calcium blocking drugs (verapamil, diltiazem, and nicardipine) in preventing the arrhythmias were investigated. Using anesthetized rats, we measured platelet count (Pc) continuously in vivo with a Technicon autocounter. Thromboxane B2 (TxB2) and 6-keto-PGF1 alpha levels in blood from coronary sinus were determined by radioimmunoassay (RIA). Myocardial ischemia and arrhythmias were monitored from lead I ECG during and after occlusion of the left anterior descending coronary artery (LAD) for 7 min. Ischemia-induced arrhythmias were mainly ventricular ectopic contractions (VECs), whereas reperfusion produced VECs, ventricular tachycardia (VT), and reversible and irreversible ventricular fibrillation (VF). Both ischemia and reperfusion decreased platelet count and increased TxB2 level in blood from the coronary sinus. The effects of the CEBs were determined at two dose levels (0.1 and 0.3 mg/kg). Each calcium entry blocker (CEB), at both dose levels, significantly inhibited ischemia-induced arrhythmias. Verapamil and diltiazem significantly reduced reperfusion-induced VECs, prevented VT and irreversible VF, and reduced the number of animals with reversible VF. Nicardipine in preventing arrhythmias was not very effective at either dose. The CEBs also inhibited both ischemia- and reperfusion-induced decreases in PC with a moderate increase (up to 7%) as compared with levels in sham-operated controls. The CEBs also significantly reduced TxB2 levels in blood from the coronary sinus. These results indicate that ischemia and postischemic reperfusion both induce platelet aggregation in rats. Aggregating platelets release biologically active substances including thromboxane A2 (TxA2) which exacerbates existing ischemia and facilitates generation of arrhythmias. CEBs inhibit platelet aggregation and TxA2 release and enhance PGI2 synthesis, thereby preventing arrhythmias.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Arterial Occlusive Diseases; Blood Platelets; Blood Pressure; Calcium Channel Blockers; Electrocardiography; Heart Rate; Male; Myocardial Reperfusion; Platelet Count; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2

Platelet aggregation (PA), platelet thromboxane B2 (TXB2) generation and 14C 5-hydroxytryptamine (5HT) release were studied in 13 patients with unstable angina, and compared to 14 patients with stable angina and 16 healthy controls. A typical pattern, distinct in 4 aspects from stable angina patients or controls, was observed in the unstable angina patients. ADP or collagen induced shape change was 3-4 times greater, the extent of epinephrine induced PA was nil or very low, the extent of collagen induced 14C 5HT release was also reduced while collagen induced platelet TXB2 generation was increased in spite of a reduced extent of PA. The extent of ADP or collagen induced PA was also significantly reduced. These results indicate a platelet membrane abnormality occurring presumably during contact of the circulating platelets with a non-occlusive thrombus observed at sites of ruptured plaques in unstable angina patients. Since also the pattern (20-30% overlap with control values) was distinct from that of stable angina patients, it might indicate an active thrombotic process. Plasma beta-thromboglobulin (beta TG) and TXB2 levels and serum TXB2 generation were also studied in the cardiac patients and controls and in another 10 patients with advanced peripheral occlusive arterial disease (POAD). Plasma beta TG and TXB2 levels were slightly elevated in the unstable angina patients and markedly elevated in the POAD patients. Serum TXB2 generation was, however, elevated in the stable angina patients (p less than 0.002) and more so in the unstable angina patients (p less than 0.001) compared to controls or to POAD patients. This was presumably mediated through enhanced thrombin generation. These results suggest that the measured plasma beta TG variable in the unstable angina patients is not useful in the assessment of in vivo platelet activation. It is presumably reflecting the sum of local enhanced platelet activation (at sites of ruptured plaques) and of reduced function of the "defective" circulating platelets. The ability of the platelets of unstable angina patients to generate large amounts of TXB2 if occurring in vivo might induce an intense coronary vasospasm.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Arterial Occlusive Diseases; beta-Thromboglobulin; Blood Platelets; Humans; Middle Aged; Platelet Aggregation; Serotonin; Thromboxane B2

An in vitro model of platelet adhesion, the annular perfusion chamber, was utilized to test the effects of Interleukin 1 on vascular thrombogenicity for platelets. De-endothelialized, everted human umbilical arteries were placed in cell culture media with or without Interleukin 1. The arteries were later perfused with citrated human blood and then fixed. Platelet adhesion and aggregate formation on artery segments was quantified by blinded morphometric analysis. A monolayer of contact platelets was seen on control artery segments, but arteries exposed to 100 Units/ml Interleukin 1 for 2-20 hours had increased numbers and size of platelet aggregates. Ultrastructurally, intact endothelial cells were not present on any segment. Both prostacyclin and thromboxane were released by vascular cells in the artery segments, but the quantity and ratio of these eicosanoids was not altered by artery exposure to Interleukin 1. Arterial thrombogenicity is modulated by non-endothelial vascular cells in response to Interleukin 1, and this does not appear to be mediated by changes in vascular production of thromboxane or prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Arterial Occlusive Diseases; Humans; In Vitro Techniques; Interleukin-1; Perfusion; Platelet Aggregation; Thrombosis; Thromboxane B2; Umbilical Arteries

An open study was carried out in 14 patients with peripheral arterial disease to investigate the effects of prolonged therapy with picotamide on platelet activity. Patients received daily oral doses of 900 mg picotamide for 1 month, 600 mg per day during the second month and 300 mg per day from the third to the sixth month of the study. Measurements were made before and during therapy of blood coagulation parameters and factors influencing platelet function, i.e. plasma beta-thromboglobulin and serum thromboxane B2. The results showed that there were no significant variations in platelet count, prothrombin time, partially activated thromboplastin time, presence and amount of fibrinogen in blood, and antithrombin III. Examination for fibrinogen degradation products was constantly negative and unaltered during therapy. Although plasma beta-thromboglobulin values did not vary significantly, there was a significant and progressive reduction throughout treatment in serum levels of thromboxane B2.

Topics: Aged; Aged, 80 and over; Arterial Occlusive Diseases; beta-Thromboglobulin; Female; Humans; Male; Middle Aged; Phthalic Acids; Platelet Aggregation; Thromboxane B2

Topics: Adult; Arterial Occlusive Diseases; Aspirin; Dose-Response Relationship, Drug; Female; Humans; Male; Platelet Aggregation; Thromboxane B2

In order to test the influence of coronary artery obstruction on cardiac prostaglandin metabolism during surgically induced cardioplegia (CP), we have measured transcardiac veno-arterial gradients of prostacyclin and thromboxane A2 (TXA A2) during experimental canine cardiopulmonary bypass. Cardiac arrest was induced by infusion of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 meq) crystalloid CP solution into the aortic root with (group I) and without (group II) occlusion of the left anterior descending artery (LAD). After 30 minutes of cardioplegic arrest the LAD occlusion in group I was released and a second set of CP infusion was applied in both groups. Transcardiac gradients were obtained 5 seconds after onset of the first and second CP washouts. Significant prostacyclin and TXA A2 gradients were observed at both times. Prostacyclin gradients did not differ between group I and group II. In contrast, TXA A2 gradients were significantly higher during the second CP washout in group I as compared to the unoccluded group (group I 918 +/- 221, group II 244 +/- 144 pg/ml, p less than 0.05). The results of our study suggest that cardiac TXA A2 metabolism during cardioplegic arrest is increased distal to a coronary artery obstruction. Cardiac TXA A2 production might contribute to the increased ischemic myocardial injury observed in this setting.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Occlusive Diseases; Cardiopulmonary Bypass; Coronary Vessels; Dogs; Female; Heart Arrest, Induced; Male; Platelet Count; Thromboxane B2

Plasma beta-thromboglobulin (beta TG) and thromboxane B2 (TXB2) level, platelet aggregation (PA) in platelet rich plasma, platelet survival time using 111Indium radiolabelled platelets and platelet sensitivity to prostacyclin (PGI2) were measured in chronic obstructive arterial disease (COAD) patients. Severity of the disease was assessed by the ankle pressure index using Doppler auscultation. Platelet survival time was shorter, plasma beta TG and TXB2 and the rate and extent of PA induced by ADP or 1-epinephrine (but not collagen) were greater in the patients than in controls. Beta TG was inversly correlated with the pressure index and positively with TXB2 indicating increased platelet TXA2 synthesis. Platelet sensitivity to PGI2 was similar in the patients and controls. These results indicate increased platelet consumption and enhanced in vivo platelet activation and PA in COAD. The enhanced activation correlates with the severity of the disease and the activated platelets presumably synthesize increased amounts of TXA2. It is therefore concluded that platelets might be involved in the pathogenesis of COAD. The normal platelet sensitivity to PGI2 suggests that the administration of the compound may improve the abnormal platelet function in COAD patients and may attenuate the progression of the disease.

Topics: Adenosine Diphosphate; Aged; Arterial Occlusive Diseases; beta-Thromboglobulin; Blood Platelets; Cell Survival; Epinephrine; Epoprostenol; Female; Humans; In Vitro Techniques; Male; Middle Aged; Platelet Aggregation; Thromboxane B2; Thromboxanes

We have previously shown that there is an acute increase in anastomotic bronchial blood flow (Qbr) after pulmonary arterial obstruction in dogs. We examined the role of arachidonic acid metabolites in mediating this increase. The left lower lobe (LLL) was isolated and perfused (zone 2) with autologous blood in open-chested anesthetized dogs (n = 19). Qbr was measured from the amount of blood that overflowed from the closed vascular circuit of the suspended LLL and changes in its weight. In the control animals, there was a prompt and significant increase in Qbr following pulmonary arterial obstruction. Pretreatment with indomethacin (n = 6) or sodium salicylate (n = 4) almost completely blocked this rise in Qbr. Following pulmonary arterial occlusion, there was a rise in both thromboxane and a prostacyclin metabolite (6-keto-PGF1 alpha) in the blood of the pulmonary circulation of the LLL, although the 6-keto-PGF1 alpha rose relatively more. Pretreatment with indomethacin caused a fall in both thromboxane and prostacyclin levels (n = 3), which no longer rose after pulmonary arterial occlusion. These findings suggested that the balance of the vasodilator (prostacyclin) and vasoconstrictor (thromboxane) prostaglandins may play an important role in mediating the rise in Qbr that follows pulmonary arterial obstruction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Occlusive Diseases; Arteriovenous Anastomosis; Aspirin; Bronchi; Dogs; Indomethacin; Pulmonary Artery; Regional Blood Flow; Thromboxane B2

We used a validated radioimmunoassay to examine plasma thromboxane B2 (TxB2) levels in 6 consecutive vasotonic angina (VA) patients, 14 patients with fixed, occlusive coronary artery (VO) disease and 9 healthy volunteers. In the latter groups, basal TxB2 release was absent. However, all 6 VA patients showed basal release. In one, sustained levels of up to 12 pmol/ml over 2 months of clinical instability were found. Daily aspirin rendered TxB2 undetectable with clinical improvement. In a second patient, angina coincided with up to 14 pmol/ml of TxB2 in peripheral blood, and myocardial infarction produced still further increases. The 14 VO patients were then studied by rapid atrial pacing to detect TxB2 release coinciding with pacing-induced angina and myocardial lactate production. All demonstrated significant occlusive disease (2.5 critical lesions per patient). Blood was taken simultaneously from coronary sinus (CS) and brachial artery (BA) catheters for lactate and TxB2 analysis before, immediately after and 10 min after pacing-induced ischemia. Lactate extraction fell from 29.3 +/- 3.7 per cent to -21.1 +/- 12.8 per cent to -74.3 +/- 20.3 per cent during pacing (all p less than 0.01) but was normal in 10 min (25.1 +/- 3.55). CS TxB2 rose from 18 per cent to 204 per cent of control during pacing but was absent after 10 min. BA TxB2 rose from 40 per cent to 132 per cent of control during and after pacing, but was absent after 10 min (p less than 0.05). In VA, TxB2 is uniquely, continuously present in peripheral blood and levels rise further during symptomatic intervals and myocardial infarction. In VO, even CS TxB2 is absent at rest, and rises less rapidly than in VA, even during pacing-induced ischemia. Although antiplatelet agent will block all TxB2 release even in VO, their clinical potential seems greatest in VA.

Topics: Angina Pectoris; Angina Pectoris, Variant; Arterial Occlusive Diseases; Aspirin; Blood Platelets; Cardiac Pacing, Artificial; Coronary Disease; Coronary Vasospasm; Heparin; Humans; Lactates; Thromboxane B2; Thromboxanes

The combined cellular membrane stabilizing and prostaglandin-inhibiting agent, naproxen, administered either 30 minutes before or after left coronary occlusion, induced significant preservation of the acutely ischemic experimental animal myocardium. A consistent extent of myocardial protection was provided as measured by ST segment elevation, plasma accumulation of CK activity, tissue CK activities, and amino-nitrogen concentrations, and ultrastructural integrity. Protection did not appear to be via hemodynamic mechanisms since naproxen neither altered pressure-rate product nor decreased coronary resistance. While the degree that inhibition of platelet thromboxane A2 generation contributes to these salutary results requires clarification due to possible simultaneous decrease of coronary endothelial PGI2 formation, the present study emphasizes the value of the concomitant special lysosomal and cellular stabilizing actions of naproxen. In contrast to acetylsalicylic acid, meclofenamate, and indomethacin which do not effect such benefit in the same experimental conditions, our results indicate that naproxen resembles the nonsteroidal anti-inflammatory agents which also possess membrane stabilizing properties, such as ibuprofen and flurbiprofen, and protects ischemic myocardium in similar adverse circumstances.

Topics: Animals; Anti-Inflammatory Agents; Arterial Occlusive Diseases; Cats; Cell Membrane; Coronary Disease; Creatine Kinase; Lysosomes; Male; Naproxen; Platelet Aggregation; Thromboxane B2; Thromboxanes