thromboxane-b2 and Hemorrhage

Topics: Adenosine Diphosphate; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atherosclerosis; Biomarkers; Biotransformation; Blood Coagulation Tests; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Hemorrhage; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y12; Thrombosis; Thromboxane A2; Thromboxane B2; Ticlopidine; Treatment Failure

Topics: Acute Coronary Syndrome; Administration, Intravenous; Administration, Oral; Adult; Aged; Aspirin; Biomarkers; Blood Platelets; Drug Monitoring; Female; Germany; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Risk Factors; Thromboxane B2; Time Factors; Treatment Outcome

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1), thereby inhibiting platelet function via blockade of thromboxane A2 (TxA2) formation, and COX-2, the enzyme that mediates inflammatory responses. Meloxicam is a relatively COX-2-selective anti-arthritis drug that shows significant TxA2 inhibition, albeit less than traditional NSAIDs. A randomized, double-blind, placebo-controlled trial was conducted in 79 healthy adults to compare the effects of once-daily therapeutic (7.5 mg, 15 mg) and supratherapeutic (30 mg) doses of meloxicam with extended-release indomethacin (Indo-ER 75 mg once daily) on bleeding time, TxA2 formation, and platelet aggregation. The authors measured platelet aggregation to COX-1-dependent (ADP arachidonate) and COX-1-independent (high-dose collagen) agonists, bleeding time, serum TxB2, and clotting times (aPTT and PT) after 8 days' administration and at 3 and 6 hours after steady-state dosing. Meloxicam significantly decreased TxB2 production compared with placebo in a dose-dependent fashion, reaching a peak of 77% inhibition 6 hours after 30 mg meloxicam; Indo-ER blocked TxB2 formation by 96% at the same time point. However, neither acute nor 8 days' administration of meloxicam at any dose caused a significant increase in bleeding time or inhibition of platelet aggregation to any agonist when compared with placebo. By contrast, Indo-ER significantly increased the bleeding time and inhibited platelet aggregation to COX-1-dependent agonists 6 hours after dosing. Clotting times were unaffected by any drug. It was concluded that unlike nonselective NSAIDs, meloxicam's blockade of TxA2 formation (even at supratherapeutic doses) does not reach levels that result in decreased in vivo platelet function, as measured by bleeding time and aggregometry. In this study of healthy subjects, meloxicam did not interfere with platelet-mediated hemostasis.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Bleeding Time; Blood Coagulation; Blood Platelets; Double-Blind Method; Female; Hemorrhage; Humans; Indomethacin; Male; Meloxicam; Middle Aged; Partial Thromboplastin Time; Platelet Aggregation; Platelet Count; Prothrombin Time; Thiazines; Thiazoles; Thromboxane B2

Intravenous acetylsalicylic acid (ASA) and magnesium (Mg) both possess antiplatelet properties and are thus potential inhibitors of the formation of arterial thrombi. Their effect on the dynamic aspects of arterial thrombus formation was investigated following intravenous administration of both substances alone and in combination. A blinded, placebo-controlled, in-vivo study was performed in 71 rats. Thrombus formation was induced by a standardized arteriotomy in the right femoral artery with inversion of the vessel wall during subsequent closure. Thrombus formation was recorded on video tapes and analysed off-line for 30 min. Animals were randomly assigned to one of four groups: 20 mg bolus of ASA followed by 0.3 mmol/h Mg (ASA/Mg group); NaCl followed by 0.3 mmol/h Mg (Mg group); 20 mg bolus of ASA followed by NaCl (ASA group); or NaCl throughout the experiment (control group). In the ASA-treated groups, serum levels of thromboxane B2 were reduced significantly, and the Mg-treated groups reached a serum level of Mg just above 2.0 mmol/l. No significant differences were observed in initial or maximum thrombus area or in mean thrombus area during the study period. In the ASA/Mg group, a trend towards reduced thrombus formation was observed (P = 0.06). In the same group, seven of 22 animals developed an occlusive thrombus (P < 0.01), an unexpected adverse event possibly related to the combined administration of ASA and Mg.

Topics: Animals; Arteriosclerosis; Aspirin; Blood Pressure; Double-Blind Method; Hemorrhage; Magnesium; Male; Rats; Rats, Wistar; Single-Blind Method; Thrombosis; Thromboxane B2

Cardiopulmonary bypass activates and depletes platelets, which may contribute to postoperative bleeding. In addition, activated platelets may be deposited in the coronary vasculature after ischemia and cardioplegia, which may delay recovery of cardiac function and metabolism and may contribute to early bypass graft occlusion. The antiplatelet agent dipyridamole reduces platelet activation and depletion and may decrease postoperative bleeding and transfusion requirements. A prospective randomized trial was conducted in 58 patients undergoing elective coronary bypass operations to compare the effects of oral (19 patients) and intravenous (21 patients) dipyridamole to the results obtained in a control group (18 patients) who received no dipyridamole. Preoperative oral administration of dipyridamole resulted in lower plasma drug concentrations in the early postoperative period than perioperative intravenous administration (p = 0.0001 by analysis of variance). Postoperative arterial platelet counts were highest in the patients receiving intravenous dipyridamole, intermediate in those receiving oral dipyridamole, and lowest in the control group (p = 0.03 by analysis of variance). Postoperative blood loss and blood product transfusions were significantly reduced with both oral and intravenous dipyridamole (p = 0.04 by analysis of variance). Dipyridamole preserved platelets and reduced postoperative bleeding. Intravenous dipyridamole resulted in higher platelet counts than oral dipyridamole and may be required to reduce postoperative bleeding in high-risk patients.

Topics: Administration, Oral; Aspirin; Blood Platelets; Blood Transfusion; Cardiopulmonary Bypass; Dipyridamole; Erythrocyte Count; Female; Hemorrhage; Humans; Infusions, Intravenous; Leukocyte Count; Male; Middle Aged; Platelet Count; Platelet Factor 4; Postoperative Complications; Prospective Studies; Random Allocation; Thromboxane B2

Cardiopulmonary bypass induces platelet activation and dysfunction, which result in platelet deposition and depletion. Reduced platelet numbers and abnormal platelet function may contribute to postoperative bleeding. A membrane oxygenator may preserve platelets and reduce bleeding more than a bubble oxygenator, and the antiplatelet agent dipyridamole may protect platelets intraoperatively and reduce bleeding postoperatively. A prospective randomized trial was performed in 44 patients undergoing elective coronary artery bypass grafting to assess the effects of the membrane oxygenator and dipyridamole on platelet counts, platelet activation products, and postoperative bleeding. Patients who were randomized to receive a bubble oxygenator and no dipyridamole had the lowest postoperative platelet counts, the greatest blood loss, and the most blood products transfused. Platelet counts were highest and blood loss was least in patients randomized to receive a membrane oxygenator and dipyridamole (p less than .05). A bubble oxygenator with dipyridamole and a membrane oxygenator without dipyridamole resulted in intermediate postoperative platelet counts and blood loss. Arterial thromboxane B2 and platelet factor 4 concentrations were elevated on cardiopulmonary bypass in all groups. Both the membrane oxygenator and dipyridamole were independently effective (by multivariate analysis) in preserving platelets. Optimal blood conservation was achieved with a membrane oxygenator and dipyridamole.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Blood; Blood Platelets; Clinical Trials as Topic; Contraceptives, Oral, Combined; Coronary Artery Bypass; Dipyridamole; Hemoglobins; Hemorrhage; Humans; Leukocyte Count; Middle Aged; Oxygenators; Oxygenators, Membrane; Platelet Count; Platelet Factor 4; Postoperative Complications; Prospective Studies; Random Allocation; Thromboxane B2

Topics: Animals; Araliaceae; Blood Coagulation; Coagulants; Endothelin-1; Female; Hemorrhage; Male; Nitric Oxide Synthase Type III; Partial Thromboplastin Time; Prothrombin Time; Rats; Rats, Sprague-Dawley; Thromboxane B2

Ferulic acid (FA) produces protective effects against cardiovascular dysfunctions. However, the mechanisms of FA is still not known. Here we examined the antithrombotic effects of FA and its potential mechanisms. Anticoagulation assays and platelet aggregation was evaluated in vitro and in vivo. Thromboxane B2 (TXB2), cyclic adenosine monophosphate(cAMP), and cyclic guanosine monophosphate (cGMP) was determined using enzyme immunoassay kits. Nitric oxide (NO) production was measured using the Griess reaction. Protein expression was detected by Western blotting analysis. Oral administration of FA prevented death caused by pulmonary thrombosis and prolonged the tail bleeding and clotting time in mice,while, it did not alter the coagulation parameters, including the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). In addition, FA (50-200 µM) dose-dependently inhibited platelet aggregation induced by various platelet agonists, including adenosine diphosphate (ADP), thrombin, collagen, arachidonic acid (AA), and U46619. Further, FA attenuated intracellular Ca(2)(+) mobilization and TXB2 production induced by the platelet agonists. FA increased the levels of cAMP and cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP) while decreased phospho-MAPK (mitogen-activated protein kinase) and phosphodiesterase (PDE) in washed rat platelets, VASP is a substrate of cyclic nucleotide and PDE is an enzyme family responsible for hydrolysis of cAMP/cGMP. These results suggest that antithrombotic activities of FA may be regulated by inhibition of platelet aggregation, rather than through inhibiting the release of thromboplastin or formation of thrombin. The mechanism of this action may involve activation of cAMP and cGMP signaling.

Topics: Animals; Blood Coagulation; Calcium; Cell Adhesion Molecules; Coumaric Acids; Cyclic AMP; Cyclic GMP; Fibrinolytic Agents; Hemorrhage; Intracellular Space; Male; Mice; Microfilament Proteins; Mitogen-Activated Protein Kinases; Nitric Oxide; Phosphoproteins; Phosphoric Diester Hydrolases; Phosphorylation; Rats; Signal Transduction; Superoxides; Thrombosis; Thromboxane B2

Essentials Co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. We determined pathogenic variants in a three-generational pedigree with excessive bleeding. Bleeding occurred with concurrent variants in prostaglandin synthase-1 (PTGS-1) and factor VIII. The PTGS-1 variant was associated with functional defects in the arachidonic acid pathway.. Background Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. Objective We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. Patients/methods Platelet number, size and light transmission aggregometry to multiple agonists were evaluated in pedigree members. Transmission electron microscopy determined platelet morphology and granule content. Thromboxane release studies and light transmission aggregometry in the presence or absence of prostaglandin G

Topics: Adult; Aged; Arachidonic Acid; Child; Cyclooxygenase 1; Factor VIII; Family Health; Female; Gene Frequency; Genetic Variation; Hemorrhage; Humans; Male; Middle Aged; Pedigree; Platelet Aggregation; Platelet Count; Prospective Studies; Prostaglandin-Endoperoxide Synthases; Thromboxane B2; Young Adult

Thromboxane A2 (TXA2) and endothelin-1 (ET-1) have been proposed as the important vasoconstrictors that increase portal venous resistance in paracrine or autocrine fashion. We hypothesized that the hepatic damage following trauma-hemorrhage (T-H) is induced by the impaired hepatic circulation due to the increased production of vasoconstrictors such as ET-1 and TXA2 by the liver. To test this, male Sprague-Dawley rats (n = 6/group) were subjected to trauma (i.e., midline laparotomy) and hemorrhage (35-40 mmHg for 90 min followed by fluid resuscitation) or sham operation. At 2 or 5 h after the end of resuscitation, the liver was isolated and perfused and portal inflow pressure, bile flow, and release of ET-1 and thromboxane B2 (TXB2; a stable metabolite of TXA2) into the perfusate were measured. The level of portal pressure was higher at 5 h following T-H compared with 2 h after T-H and sham. The portal pressure was inversely correlated to the amount of bile production. Furthermore, the bile flow was significantly correlated to the hepatic damage as evidenced by release of lactate dehydrogenase into the perfusate. The level of ET-1 at 5 h following T-H in the perfusate after 30 min of recirculation did not show any difference from sham. However, the levels of TXB2 in the T-H group were significantly higher than those in sham at that interval. These results indicate that the increased release of TXA2 but not ET-1 following T-H might be responsible for producing the increased portal resistance, decreased bile production, and hepatic damage.

Topics: Abdominal Injuries; Alanine Transaminase; Animals; Bile; Endothelin-1; Hemorrhage; Hypertension, Portal; In Vitro Techniques; L-Lactate Dehydrogenase; Liver; Male; Perfusion; Portal Vein; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane B2; Venous Pressure; Wounds, Penetrating

Preoperative bleeding time (BT) does not correlate with postoperative bleeding in patients subjected to surgical procedures. A significant positive correlation has been reported between the BT 2 hours after cardiopulmonary bypass surgery and the nonsurgical blood loss during the first 4 hours after bypass surgery. This study was done to investigate the effect of Hct and platelet count on the BT measurement in normal, healthy men and women.. To assess the relative effect of RBCs and platelets on the BT, 22 healthy male and 7 healthy female volunteers were subjected to the removal of 2 units of RBCs (360 mL), followed by the return of the platelet-rich plasma (PRP) from both units and the infusion of 1000 mL of 0.9-percent NaCl. Four of the men and all seven women received their RBCs 1 hour after their removal. Shed blood levels of thromboxane B(2) (TXB(2)), 6-keto prostaglandin F(1 alpha), and peripheral venous Hct were measured. BTs were measured in 15 men and 13 women before and after a plateletpheresis procedure to collect 3.6 x 10(11) platelets per unit.. The 2-unit RBC apheresis procedure produced a 60-percent increase in the BT associated with a 15-percent reduction in the peripheral venous Hct and a 9-percent reduction in the platelet count. The plateletpheresis procedure produced a 32-percent decrease in the platelet count, no change in peripheral venous Hct, and no change in the BT. After the removal of 2 units of RBCs, the shed blood TXB(2) level decreased significantly. Reinfusion of 2 units of RBCs restored the BT and restored the TXB(2) level to the baseline levels.. The acute reduction in Hct produced a reversible platelet dysfunction manifested by an increase in BT and a decrease in the shed blood TXB(2) level at the template BT site. Return of the RBCs restored both the BT and the shed blood TXB(2) level to normal. The platelet dysfunction observed with the reduction in Hct was due in part to a reduction in shed blood TXB(2) and other, unknown mechanisms.

Topics: Adult; Analysis of Variance; Anemia; Bleeding Time; Blood Component Removal; Erythrocyte Transfusion; Female; Hematocrit; Hemorrhage; Humans; Male; Platelet Count; Plateletpheresis; 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

RGD-containing peptides and other antagonists of the platelet glycoprotein (GP) IIb/IIIa may induce a high-affinity binding site for fibrinogen and the expression of novel epitopes, called ligand-induced binding sites (LIBS). The functional relevance of LIBS expression in a canine model of coronary thrombolysis induced by tissue-type plasminogen activator (t-PA) was examined. Ro43-5054 (N-[N-[N-(p-amidinobenzoyl)-b-alanyl]-l-a-aspartyl]-3-phenyl-l- alanine) and Ro44-9883 ([1-(N-(p-amidinobenzoyl)-l-tyrosyl)-4-piperidinyl)oxy]acetic acid), antagonists of the GP IIb/IIIa receptor, were administered in increasing doses of 2 to 10 microg/kg/min, beginning 30 min before the infusion of t-PA. LIBS expression was determined by the binding of the monoclonal antibody, D3GP3, to platelets on exposure to Ro43-5054, Ro44-9883 and t-PA. Ro43-5054 was shown to induce LIBS, whereas Ro44-9883 and t-PA did not. Both drugs abolished platelet aggregation in response to U46619 and ADP ex vivo. Reocclusion was prevented with both Ro43-5054 and Ro44-9883, but neither drug altered reperfusion times (49 +/- 8 and 55 +/- 39 min). Both drugs increased the rate of bleeding compared with t-PA alone, but there was no difference in hemostasis between the two drugs. To determine whether the drugs differed in their effect on platelet activation in vivo, urinary 2,3-dinor-thromboxane (TX) B2, a major metabolite of TXB2, was determined by gas chromatography-mass spectrometry. After reperfusion, the urinary 2,3-dinor-TXB2 increased in the Ro43-5054-treated group, similar to control groups (32 +/- 8 and 37 +/- 9 ng/mg creatinine). This increase was blunted in the Ro44-9883-treated group (9 +/- 3 ng/mg creatinine). GP IIb/IIIa antagonists that do not induce LIBS result in a greater suppression of platelet activity but not in any discernible functional benefit in vivo.

Topics: Acetates; Animals; Binding Sites; Blood Platelets; Coronary Thrombosis; Dogs; Fibrinolytic Agents; Hemorrhage; Oligopeptides; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Reperfusion Injury; Thromboxane B2; Tissue Plasminogen Activator; Tyrosine

This study examines the hypothesis that long-term resuscitation with hyperalimentation (TPN) following acute hemorrhage/reperfusion (H/R) injury stimulates renal release of PGE2. Male Sprague-Dawley rats were anesthetized and subjected to sham or hemorrhage to 30 mmHg for 30 min followed by reperfusion. All rats were placed on TPN for 5 days, then underwent laparotomy for in vivo renal artery and aortic blood flow for 60 min. The kidney was perfused in vitro with Krebs-Henseleit buffer at 3 ml/min (pH 7.4, 37 degrees C) and venous effluent was collected for analysis of PGE2, 6-keto-PGF1 alpha and thromboxane B2 by EIA. Hemorrhage/reperfusion followed by TPN for 5 days increased renal PGE2 2-fold and decreased in vivo renal artery blood flow by 50% compared to the sham group. Hemorrhage/reperfusion followed by TPN did not alter release of the other eicosanoids measured. These data suggest that the kidney has a limited capacity to maintain renal blood flow by increasing release of PGE2 when the animal is subjected to long-term resuscitation with TPN following mild hemorrhage/reperfusion injury.

Topics: Animals; Dinoprostone; Eicosanoids; Hemorrhage; Kidney; Male; Models, Biological; Parenteral Nutrition, Total; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion Injury; Resuscitation; Thromboxane B2; Time Factors; Vasodilator Agents

Left ventricular assist devices (LVADs) have provided a new therapeutic option for patients with end-stage heart failure. Despite advances in device design, there remains an apparent bleeding diathesis, which leads to increased transfusion requirements and reoperative rates. The purpose of our study was to examine the abnormalities that might contribute to these clinical sequelae.. To separate the effects of cardiopulmonary bypass (CPB), eight patients undergoing coronary revascularization (CABG) were compared with seven LVAD (TCI HeartMate) recipients intraoperatively and 2 hours postoperatively. We evaluated several well-characterized indexes of platelet activation: platelet count, platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), and thromboxane B2 (TXB2). We also measured activation of thrombin: thrombin-antithrombin III (TAT), prothrombin fragment 1 + 2 (F1 + 2), and fibrinopeptide A (FPA) as well as markers of fibrinolysis: plasmin-alpha 2-antiplasmin (PAP) and D-dimer. Patterns of intraoperative platelet adhesion and activation were not statistically different in the CABG control and LVAD groups. In the immediate postoperative period, however, there was significant release of PF4 and beta-TG and generation of TXB2. Compared with the CABG controls (TAT, 26 +/- 8 micrograms/L; F1 + 2, 4 +/- 1 nmol/L; mean +/- SEM), there was a significant increase in TAT (380 +/- 112 micrograms/L) and F1 + 2 (23 +/- 4 nmol/L) in LVAD patients 2 hours after surgery. Furthermore, a sharp rise in FPA was noted 20 minutes after LVAD initiation (CABG, 8 +/- 4 ng/mL; LVAD, 235 +/- 63 ng/mL; P < .05). A concomitant increase in both PAP (CABG, 987 +/- 129 micrograms/L; LVAD 3456 +/- 721 micrograms/L; P < .05) and D-dimer (CABG, 1678 +/- 416 ng/mL; LVAD, 15243 +/- 4682 ng/mL; P < .05) was observed.. The additive effects of CPB and LVAD lead to platelet activation as well as elevation of markers of in vivo thrombin generation, fibrinogen cleavage, and fibrinolytic activity. The etiology of these findings may be secondary to the LVAD surface, flow characteristics, and/or operative procedure. Nevertheless, platelet alterations and exaggerated activation of the coagulation and fibrinolytic systems may contribute to the clinically observed hemostatic defect.

Topics: Adolescent; Adult; Aged; Blood Coagulation; Cardiopulmonary Bypass; Female; Fibrinolysis; Heart-Assist Devices; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Platelet Factor 4; Thrombin; Thromboxane B2

Like indomethacin, BW755C, diphenhydramine and methysergide, 2-phenyl-4-quinolone (YT-1) suppressed the polymyxin B-induced hind-paw edema. This inhibitory effect of YT-1 was also demonstrated in adrenalectomized mice. YT-1 inhibited the antidromic stimulation of saphenous nerve-induced plasma leakage in dorsal paw skin and reduced the volume of plasma exudation in PCA reaction. Bradykinin-, substance P- and compound 48/80-induced mouse ear edema was suppressed by YT-1 in a dose-dependent manner. In isolated rat peritoneal mast cells, YT-1 produced a dose-dependent inhibition of bradykinin-, substance P- and compound 48/80-induced histamine and beta-glucuronidase release. YT-1 also reduced the TXB2 formation from PMN leukocytes with IC50 2.0 +/- 0.5 microM, however with little effect on LTB4 formation. Histamine- and serotonin-induced plasma exudation in ear edema were reduced by YT-1. Moreover, the maximal response of ileum contraction caused by histamine and serotonin were also suppressed by YT-1 in a dose-dependent manner. In compound 48/80-pretreatment mice, YT-1 failed to suppress the bradykinin- and substance P-induced ear edema to a significantly greater extent than diphenhydramine combined with methysergide did. These results indicate that the inhibitory effect of YT-1 on local edema formation is not through the release of steroid hormones from adrenal gland, and is probably by suppressing the release of chemical mediators from mast cells, inhibition of prostaglandins formation, and noncompetitive but selective protection of the vasculature against the histamine- and serotonin-induced plasma extravasation.

Topics: Animals; Ear Diseases; Edema; Guinea Pigs; Hemorrhage; Hindlimb; Histamine; Ileum; In Vitro Techniques; Leukotriene B4; Mast Cells; Mice; Mice, Inbred ICR; Muscle Contraction; p-Methoxy-N-methylphenethylamine; Quinolones; Rats; Rats, Sprague-Dawley; Serotonin; Skin; Thromboxane B2

The role of endogenous splanchnic eicosanoids in mediating splanchnic vasoconstriction induced by the leukotriene C4 (LTC4) was examined during mild hemorrhage/reperfusion injury. Male Sprague-Dawley rats were anesthetized and subjected to sham or acute hemorrhage for 30 minutes, to 30 mm Hg, followed by blood reperfusion (SK+R). The superior mesenteric artery was cannulated and removed with its end-organ intestine (SV+SI preparation) and perfused in vitro with oxygenated Krebs-Henseleit buffer. Perfusion pressure was constantly recorded. Net SV+SI release of 6-keto-PGF1 alpha, PGE2 and thromboxane B2 were analyzed by enzyme immunoassay after LTC4 stimulation. Leukotriene C4 increased perfusion pressure and decreased the ratio of 6-keto-PGF1 alpha to thromboxane release (but not PGE2 to thromboxane B2) in the sham group. Hemorrhage/reperfusion increased perfusion pressure and decreased the ratio of 6-keto-PGF1 alpha to thromboxane B2. Mild hemorrhage/reperfusion increased LTC4-induced splanchnic vasoconstriction in part by decreasing the release ratio of endogenous splanchnic PGI2 to thromboxane B2.

Topics: Analysis of Variance; Animals; Hemorrhage; Immunoenzyme Techniques; Leukotriene C4; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Splanchnic Circulation; Thromboxane B2; Vasoconstriction

Several studies have reported that prostanoids are involved in many of the physiopathological mechanisms underlying acute pancreatitis but their precise role in this disease remains to be established. The objective of this work is to evaluate the variation of local tissue production of prostanoids and lipoxygenase metabolites of arachidonic acid in acute pancreas inflammation induced by intraductal administration of 3.5% sodium taurocholate (0.1 ml/100 mg body weight) in rats. Pancreatic tissue levels of leukotriene B4 (LTB4), 15 hydroxyeicosatetraenoic acid (15-HETE), 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) were determined by HPLC-RIA techniques at 5 and 60 minutes after induction of acute pancreatitis (AP). Prostanoids increased significantly at 5 minutes and LTB4 and 15-HETE at 60 minutes. These data confirm that the prostanoid imbalance could be considered as an early specific response of the pancreas to the inflammatory events characteristic of induced AP while the altered levels of the lipoxygenase products (LTB4 and 15-HETE) would be more of a nonspecific organ response associated to the high cellular infiltration rate and necrosis observed in the late phases of acute pancreatitis.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Dinoprostone; Hemorrhage; Hydroxyeicosatetraenoic Acids; Kinetics; Leukotriene B4; Lipoxygenase; Male; Pancreas; Pancreatitis; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Taurocholic Acid; Thromboxane B2

The effect of cycloheximide on increased splanchnic prostacyclin release following acute hemorrhage was studied in the rat. Male Sprague-Dawley rats were anesthetized and subjected to acute hemorrhage to 30 mm Hg for 30 min (shock) or sham shock. The superior mesenteric artery was cannulated and removed with its end organ intestine (SV + SI preparation) and perfused in vitro with oxygenated Krebs-Henseleit buffer. Cycloheximide was infused in half of the sham and acute hemorrhage SV + SI preparations at 50 micrograms/ml. Venous effluent from all groups were analyzed for prostanoid release by radioimmunoassay. The SV + SI released 10-fold more 6-keto-prostaglandin (PG) F1 alpha than PGE2 and thromboxane. Acute hemorrhage increased SV + SI release of 6-keto-PGF1 alpha 3-fold compared to sham. Cycloheximide abolished the increased 6-keto-PGF1 alpha following acute hemorrhage but not the basal release in the sham group. Indomethacin decreased PG synthesis in all groups by 90%. Sham PG release was dependent on a stable pool of cyclooxygenase with a long half-life and was not affected by cycloheximide treatment. Acute hemorrhage stimulated a rapid induction of enzymes (cyclooxygenase, prostacyclin synthase) responsible for prostacyclin synthesis and release which were dependent on de novo protein synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cycloheximide; Dinoprostone; Epoprostenol; Hemorrhage; Indomethacin; Male; Prostaglandin-Endoperoxide Synthases; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Splanchnic Circulation; Thromboxane B2

Guinea pigs were intravenously injected with icterhemorrhagiae serogroup Lai serovar strain 017 leptospirosis to model the pulmonary diffuse hemorrhage (PDH) in leptospirosis. Thirty-eight hours after the injection, the jugular arteries were catheterized to collect blood sample. The plasma was prepared for radioimmunoassay of TXB2 and 6-keto-PGF1a, the stable metabolites of TXA2 and PGI2 respectively. The plasma level of TXB2 in the experimental group, 107.15 +/- 41.65 pg/ml (n = 7), almost doubled that of the control, 54.05 +/- 12.93 pg/ml (n = 7), with significant difference (P less than 0.01); meanwhile, no significant difference was observed of 6-keto-PGF1a, 67.97 +/- 16.89 pg/ml (n = 6) vs. 98.06 +/- 40.63 pg/ml (n = 9) with P greater than 0.1. The fact that TXA2 causes vasoconstriction and increases vessel permeability suggests that TXA2 elevation should play a role in the mechanism of PDH in leptospirosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Epoprostenol; Guinea Pigs; Hemorrhage; Lung Diseases; Thromboxane B2; Weil Disease

The safety of the combination of heparin and ridogrel therapy and its antiplatelet efficacy was examined in the setting of percutaneous transluminal coronary angioplasty (PTCA). In 32 patients without known aspirin intake for 10 days before PTCA, therapy with ridogrel (300-mg intravenous bolus) was begun just before PTCA and continued orally at a dose of 300 mg twice daily until discharge. Heparin was administered as a 10,000 IU bolus dose before PTCA and followed by an intravenous infusion at a rate of 1,000 IU/hour for 24 hours. Bleeding problems at the arterial entry site occurred in 13 patients, which required a blood transfusion in only 2 patients. One patient underwent emergency bypass surgery without specific problems of hemostasis. Ridogrel virtually eliminated thromboxane B2 from the serum (29,990 +/- 6,555 pg/0.1 ml before vs 63 +/- 7 pg/0.1 ml at 2 hours after ridogrel), with a concomitant increase in serum 6-keto-prostaglandin F1 alpha (511 +/- 34 pg/0.1 ml before vs 1,190 +/- 146 pg/0.1 ml at 24 hours after ridogrel). There were no acute reocclusions in the ridogrel-treated patients, whereas acute reocclusions occurred in 5.6% of the patients taking the standard aspirin + heparin regimen during the same period. Furthermore, at 6-month clinical follow-up patients treated with ridogrel compared favorably with those receiving standard treatment.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Angioplasty, Balloon, Coronary; Coronary Disease; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Male; Middle Aged; Pentanoic Acids; Pilot Projects; Pyridines; Radiography; Recurrence; Salicylates; Thromboxane B2; Thromboxane-A Synthase

Clinical and animal data suggest that the pathogenesis of CO poisoning extends beyond the inhibition of hemoglobin function, but no mechanism has been identified. Evidence of neurological compromise, particularly loss of consciousness, has been implicated as a marker for increased mortality and morbidity in clinical reports. Experiments were carried out with rats to assess whether CO exposure may cause brain lipid peroxidation. With the use of two methods, measurement of conjugated dienes and thiobarbituric acid reactivity, brain lipid peroxidation could be documented as a result of exposure to CO at a concentration sufficient to cause unconsciousness. Products of lipid peroxidation were increased by 75% over the base-line values 90 min after CO exposure. Unconsciousness was associated with a brief period of hypotension, so brief that in itself it caused no apparent insult. Lipid peroxidation occurred only after the animals were returned to CO-free air, and there was no direct correlation with the carboxyhemoglobin level. This work may provide an explanation for a number of currently poorly understood clinical observations regarding CO poisoning.

Topics: Animals; Brain; Carbon Monoxide Poisoning; Carboxyhemoglobin; Cardiovascular System; Disease Models, Animal; Hemorrhage; Hypotension; Lipid Peroxidation; Male; Rats; Rats, Inbred Strains; Thromboxane B2

The effects of lysine vasopressin (LVP) on pial arteriolar diameter and cortical periarachnoid fluid prostanoid concentrations were investigated in newborn pigs. Chloralose-anesthetized piglets were equipped with closed cranial windows over the parietal cortex for observation of pial arterioles and collection of cerebrospinal fluid (CSF) passing over the cerebral surface. Prostanoids in the CSF were determined by radioimmunoassay. LVP (10-1,000 microU/ml) elicited concentration-dependent increases in pial arteriolar diameter associated with increased levels of 6-keto-prostaglandin (PG)F1 alpha, PGE2, thromboxane B2, and PGF2 alpha. LVP-induced pial arteriolar dilation was unchanged after intravenous indomethacin (5 mg/kg). Conversely, LVP constricts pial arterioles previously dilated by physiological (hemorrhagic hypotension) and pharmacological (topically applied PGE2 or isoproterenol) intervention. This constriction is potentiated by indomethacin. Vascular and biochemical changes elicited by LVP were blocked by intravenous [1-(beta-mercapto-beta beta-cyclopentamethylene propionic acid),2,(O-methyl)-Tyr-AVP] (5 micrograms/kg), a putative V1 receptor antagonist, whereas vascular effects of norepinephrine and U46619, a thromboxane A2 mimic, were unchanged. Therefore, the degree of vascular tone appears to influence responses of the newborn pig cerebral circulation to LVP.

Topics: Animals; Animals, Newborn; Arginine Vasopressin; Arterioles; Blood Pressure; Hemorrhage; Hypotension; Isoproterenol; Lypressin; Pia Mater; Prostaglandins; Swine; Thromboxane B2; Vasoconstriction; Vasodilation

Changes in the production of proaggregatory (thromboxane A2 and prostaglandin E2) and antiaggregatory (prostacyclin) prostaglandins by blood platelets, macrophages and endothelial cells during acute African swine fever caused by both a highly virulent virus and a less virulent virus were studied. No impairment in thromboxane A2 release by either platelets or macrophages could be detected but prostacyclin production by the endothelium was impaired. There was also a significant increase in prostaglandin E2 release by macrophages at the time when thrombocytopenia was most marked. However, the early event that causes primary aggregation remains obscure.

Topics: African Swine Fever; Animals; Arachidonic Acids; Blood Coagulation; Blood Platelets; Dinoprostone; Endothelium; Hematocrit; Hemorrhage; Macrophages; Platelet Aggregation; Platelet Function Tests; Prostaglandins E; Swine; Swine Diseases; Thrombocytopenia; Thromboxane B2

To study the role of the vasodilatory, antiaggregatory prostacyclin (PGI2) and its endogenous antagonist thromboxane A2 (TxA2) in acute pancreatitis, we measured serum thromboxane B2 (TxB2, which indicates platelet TxA2 production) and plasma 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, which indicates systemic PGI2 production) from sequential blood samples in trypsin and taurocholate induced acute canine hemorrhagic pancreatitis (AHP). In addition the effect of a prostaglandin synthesis inhibitor, ibuprofen, was studied and systemic (MAP) and pulmonary artery pressure (MPAP) were recorded for 4.5 hr. The animals were divided into a sham-operated group, an AHP group, an ibuprofen prophylaxis group, and an ibuprofen therapy group. In the sham group the parameters remained stable throughout the experiment. In the AHP group MAP decreased steadily and 6-keto-PGF1 alpha rose significantly from 80.0 +/- 7.8 to 956.0 +/- 287.0 pg/ml (P less than 0.001), whereas serum TxB2 and MPAP remained unchanged. Ibuprofen prophylaxis eliminated the initial fall in MAP and the rise of 6-keto-PGF1 alpha. Ibuprofen therapy normalized the initially decreased MAP and depressed the level of 6-keto-PGF1 alpha. We conclude that PGI2 may at least partly mediate the initial hypotension in canine AHP, whereas platelet TxA2 production obviously has a negligible role in the development of hemodynamic changes in AHP.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Blood Pressure; Dogs; Epoprostenol; Hemorrhage; Ibuprofen; Pancreatitis; Thromboxane B2

Prostacyclin (PGI2), a potent vasodilator with complex effects on the mesenteric circulation, has been found to be elevated in the hemorrhagic ascitic fluid of pigs with hemorrhagic pancreatitis. This investigation was designed to determine if blockage of PGI2 significantly reduces the volume and/or toxicity of hemorrhagic ascitic fluid associated with hemorrhagic pancreatitis in pigs. Fifteen pigs were studied: five received corticosteroids, five received ibuprofen, and five were untreated. The relative toxicity of the hemorrhagic ascitic fluid was assessed by intraperitoneal injections of the fluid from pigs into mice.. (1) hemorrhagic pancreatitis was associated with high levels of PGI2 in blood 15 times and in hemorrhagic ascitic fluid 25 times that of baseline; (2) steroids and ibuprofen blocked PGI2 production (p less than 0.05); (3) neither steroids nor ibuprofen, even when administered as pretreatment, decreased ascites formation; and (4) the mortality rate in mice was significantly reduced (p less than 0.05) in the ibuprofen-treated group as compared with the untreated and steroid-treated groups.. PGI2 does not play a significant role in the volume of ascites formation. There was an absence of toxicity in the hemorrhagic ascitic fluid of the ibuprofen-treated group.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Ascitic Fluid; Biological Assay; Electrolytes; Epoprostenol; Female; Hemorrhage; Hydrogen-Ion Concentration; Ibuprofen; Methylprednisolone; Mice; Osmolar Concentration; Pancreatitis; Swine; Thromboxane B2

The effect of haemorrhagic hypotension on the levels of prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-keto prostaglandin F1 alpha (6-keto-PGF1 alpha) in cortical tissue of rats was studied. Lightly anesthetized rats were subjected to steady-state hypotension for 15 min, with a mean arterial blood pressure of 80, 60, and 40 mm Hg, and compared to a control group of normotensive rats. No significant change was found in the levels of PGE2 and TXB2. The level of 6-keto-PGF1 alpha increased from 7.8 +/- 0.9 to 14.1 +/- 1.9 pg/mg protein (p less than 0.02) at 80 mm Hg. Our findings suggest that prostacyclin, which is a potent vasodilator, might play a role in setting the lower limit of the autoregulation range.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Gas Analysis; Brain; Dinoprostone; Epoprostenol; Hemorrhage; Homeostasis; Hypotension; Male; Prostaglandins E; Rats; Thromboxane B2

The 'Simplate' technique for measuring skin bleeding time was adapted to quantify thromboxane A2 in the emerging blood as the stable degradation product thromboxane B2 in twelve Swedish and ten English volunteers. During the bleeding time thromboxane B2 concentrations increased, but as the rate of blood loss fell the rate of production of thromboxane A2 was constant. The English subjects had shorter bleeding times and produced more thromboxane A2 than the Swedish subjects. When the Swedish subjects were grouped according to bleeding times those with the shortest had more thromboxane A2 than those with longer bleeding times. Clotting venous blood in vitro produced much more thromboxane A2 than bleeding-time blood and there was no correlation with bleeding time. Determination of the capacity of clotting blood to form thromboxane A2 is therefore irrelevant to in-vivo haemostasis. Acetylsalicylic acid greatly diminished the appearance of thromboxane A2 in the bleeding time and prevented the increase of thromboxane A2 concentration with time.

Topics: Adenosine Diphosphate; Adult; Aspirin; Bleeding Time; England; Hemorrhage; Hemostasis; Humans; Male; Platelet Aggregation; Platelet Function Tests; Skin; Sweden; Thromboxane A2; Thromboxane B2; Thromboxanes

The effect of aspirin on perioperative blood loss was studied in 52 patients undergoing unplanned operation. Twenty-two of 52 patients were found to have taken aspirin prior to operation. Five others were suspected of having taken aspirin or some aspirin-like drug prior to operation. All patients who remembered taking aspirin preoperatively had significantly decreased platelet thromboxane B2 levels caused by aspirin inhibition of platelet arachidonic acid metabolism. Eight of 22 patients who took aspirin had abnormal template bleeding times. No significant increase occurred in the perioperative blood loss of patients who had taken aspirin. Neither the aspirin induced decrease in thromboxane B2 levels nor the increase in template bleeding times was associated with an increased perioperative blood loss. We concluded that aspirin is commonly used prior to unplanned operations but that preoperative aspirin usage does not result in increased perioperative blood loss in patients with normal platelet counts and with normal coagulation factors. These results suggest that there is no need to delay operation in this group of patients because of recent aspirin ingestion.

Topics: Arachidonic Acids; Aspirin; Bleeding Time; Blood Coagulation; Blood Platelets; Hemorrhage; Humans; Intraoperative Period; Surgical Procedures, Operative; Thromboxane B2; Time Factors