6-ketoprostaglandin-f1-alpha and dazmegrel

Thromboxane A2, a potent vasoconstrictor, is a major metabolite of arachidonic acid in the human kidney. To determine the role of thromboxanes in renal hemodynamics, we administered the new thromboxane inhibitor dazmegrel or placebo to 20 healthy volunteers for 14 days in a double-blind protocol. Dazmegrel reduced urinary thromboxane B2 by an average of 68% and serum thromboxane B2 by 79%, without affecting urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F 1 alpha. Neither p-aminohippurate clearance nor inulin clearance were altered by thromboxane inhibition. Thus it is unlikely that thromboxane A2 plays a major role in the regulation of glomerular function in healthy humans.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Double-Blind Method; Glomerular Filtration Rate; Humans; Imidazoles; Inulin; Kidney; Male; Oxidoreductases; p-Aminohippuric Acid; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Blood Platelets; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Imidazoles; Male; Middle Aged; Oxidoreductases; Random Allocation; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

To investigate the role of thromboxane A(2) in the development of hypertension in the fructose-fed rat, we treated male fructose-fed rats with dazmegrel (a thromboxane synthase inhibitor) and monitored blood pressure, fasting plasma parameters, and insulin sensitivity for 7 weeks. Systolic blood pressure was measured each week using tail plethysmography, and an oral glucose tolerance test was performed at the end of the study to assess insulin sensitivity. Treatment with a 60% fructose diet and dazmegrel (100 mg. kg(-1). d(-1) via oral gavage) was initiated on the same day. Plasma triglyceride levels increased 2-fold in both fructose- and fructose/dazmegrel-treated groups, and plasma insulin levels tended to be higher in these groups, although not significantly. Systolic blood pressure increased significantly throughout the study in the fructose-fed group only (132+/-3 versus 112+/-4 mm Hg in control rats, 118+/-2 mm Hg in control-treated rats, 116+/-2 mm Hg in fructose-treated rats). Both fructose groups demonstrated a higher peak insulin response to oral glucose challenge and had 40% to 60% lower insulin sensitivity index values. The results of this study show that treatment with a thromboxane synthase inhibitor, dazmegrel, can prevent the development of hypertension but does not improve insulin sensitivity or other fructose-induced metabolic impairments. Based on these data, we conclude that the potent vasoconstrictor thromboxane is involved in the link between hyperinsulinemia/insulin resistance and hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Glucose; Blood Pressure; Enzyme Inhibitors; Epoprostenol; Fructose; Hypertension; Imidazoles; Insulin; Rats; Rats, Wistar; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Triglycerides

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Leukotriene Antagonists; Leukotrienes; Lipoxygenase; Masoprocol; Pentoxifylline; Sepsis; Swine; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Toxemia; Tumor Necrosis Factor-alpha

Capsular type-specific polysaccharide is thought to be an important pathogenetic factor in Group B streptococcus (GBS) sepsis. To determine the effects of capsular type-specific polysaccharide on GBS-induced hemodynamic responses, anesthetized infant piglets were infused for 3 h with three related GBS Type lb strains that express different amounts of capsular type-specific polysaccharide. A larger capsule strain and a smaller capsule strain were isolated from an infected infant and its mother, respectively. A capsule-deficient mutant was then made from the larger capsule strain by transposon insertion mutagenesis. The smaller capsule strain and capsule-deficient mutant caused similar elevations in mean pulmonary artery pressure and pulmonary vascular resistance index and reductions in cardiac index. The larger capsule strain caused moderate pulmonary hypertension, but this response was smaller than for the other two GBS strains. Further comparisons in responses between the large capsule strain and its capsule-deficient mutant were then performed using unanesthetized piglets. The mutant caused significantly greater pulmonary hypertension and arterial plasma thromboxane B2 levels than the large capsule strain. The pulmonary hypertension induced by both strains was reversed by dazmegrel, a thromboxane A2 synthase inhibitor. These results suggest that (1) capsular type-specific polysaccharide is not an essential component in the generation of acute hemodynamic responses; (2) expression of large amounts of capsular type-specific polysaccharide on the organism surface partially inhibits GBS-induced pulmonary hypertension; and (3) the inhibition of the pulmonary responses is due to reduced thromboxane A2 release.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Bacterial Capsules; Disease Models, Animal; Drug Evaluation, Preclinical; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Polysaccharides, Bacterial; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Thromboxane-A Synthase

It has been proposed that thromboxane synthetase inhibitors may be of use in the treatment of hypertensive disorders of pregnancy. A patient in whom aspirin did not prevent the development of pre-eclampsia in a previous pregnancy was treated with a thromboxane synthetase inhibitor (dazmegrel, Pfizer) in addition to low-dose aspirin. Increased urinary levels of 6-keto-prostaglandin F1 alpha were found throughout pregnancy, which is consistent with the mode of action. At 17-18 weeks of gestation urinary prostaglandin E2 and F2 alpha levels were increased compared with control pregnancies. These increases in PGE2 and PGF2 alpha production were associated with mid-trimester abortion. In vitro studies were carried out to determine the effects of dazmegrel on platelet eicosanoid production. In whole blood from non-pregnant female volunteers this compound inhibited thromboxane B2 production and significantly enhanced prostaglandin E2 production and slightly increased prostacyclin production, demonstrating a redirection of prostaglandin endoperoxides. This suggested that similar changes in arachidonic acid metabolite production may occur in vivo and in vitro, and that thromboxane synthetase inhibitors should not be used during early pregnancy, since increased production of prostaglandins E2 and F2 alpha may result in preterm labour or abortion.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Platelets; Cells, Cultured; Collagen; Contraindications; Dinoprostone; Eicosanoids; Female; Humans; Imidazoles; Platelet Aggregation; Pregnancy; Thromboxane B2; Thromboxane-A Synthase

We investigated the roles of eicosanoid mediators in acute systemic anaphylaxis in anesthetized sheep. Sheep were sensitized with dinitrophenylated Ascaris suum extract and were challenged with an intravenous injection of dinitrophenylated bovine serum albumin. During anaphylaxis, cyclooxygenase inhibitors eliminated the elevation of arterial plasma levels of thromboxane B2 and 6-ketoprostaglandin F 1 alpha but markedly elevated the levels of leukotriene E4 in lung lymph without significantly eliminating elevation of plasma levels of histamine. Most of the measured physiological abnormalities accompanying anaphylaxis were aggravated by cyclooxygenase blockade. Enhancement of this anaphylactic mediator response was associated with an accentuated and prolonged increase of airway pressure (P less than 0.05, compared with sensitized, antigen-challenged but otherwise untreated sheep), a more intense hypoxemia (P less than 0.0001), and leukopenia (P less than 0.001), changes that were largely eliminated by pretreating with the sulfidopeptide leukotriene (SPLT) antagonist FPL 55712, suggesting that the SPLTs were important mediators of these responses. In contrast, the prolonged, but less severe, systemic vascular collapse and the reduced pulmonary hypertension induced by cyclooxygenase inhibitors were not influenced by the SPLT antagonist. These results demonstrate that in sheep cyclooxygenase metabolites are mainly involved in the acute, but transient, systemic and pulmonary vascular response of systemic anaphylaxis, whereas SPLTs are primarily implicated in the airway and secondary cardiovascular response. SPLT may act either directly or by potentiating the release of and reactivity to histamine and other mediators. Our data therefore suggest that a combination of cyclooxygenase and lipoxygenase inhibition will be necessary to more effectively protect against the consequences of an anaphylactic reaction.

Topics: 6-Ketoprostaglandin F1 alpha; Anaphylaxis; Animals; Blood Pressure; Chromones; Cyclooxygenase Inhibitors; Dinitrophenols; Female; Histamine Release; Imidazoles; Leukotriene E4; Leukotrienes; Lung; Lymph; Male; Meclofenamic Acid; Prostaglandins; Pulmonary Circulation; Serum Albumin, Bovine; Sheep; SRS-A; Stroke Volume; Thromboxane B2; Thromboxane-A Synthase; Time Factors; Vascular Resistance

The infusion of Group B beta hemolytic streptococci (GBS) in newborn animals generates a dual phase pulmonary hypertensive response. The initial, acute phase responds to cyclooxygenase or thromboxane inhibition, and appears to be thromboxane mediated. The second phase is characterized by a more moderate rise in pulmonary vascular resistance, accompanied by an increase in microvascular permeability. It has been speculated that this phase may be leukotriene mediated. In an attempt to clarify this, we have studied and compared the effects of the thromboxane synthetase inhibitor, Dazmegrel (DAZ), and the combined cyclooxygenase/lipoxygenase inhibitor, BW755C, on the cardiopulmonary hemodynamics of the secondary phase of GBS induced pulmonary hypertension in newborn piglets. Ten piglets were infused with GBS, and all animals developed a significant increase in pulmonary artery pressure (to 39 +/- 5 and 36 +/- 5 mmHg for DAZ and BW755C animals respectively). After one hour of GBS, either DAZ or BW755C was administered. Data were collected for another two hours following drug administration. GBS infusion was continued throughout. Both DAZ and BW755C were associated with transient, acute reductions in pulmonary artery pressure (to 22 +/- 5 and 22 +/- 8 mmHg, respectively). However, after 60 minutes, PAP again began to rise in both groups (PAP 30 +/- 5 and 30 +/- 11 mmHg respectively by 240 minutes). There were no differences between the groups at any time. These data do not support a significant role for lipoxygenase products in mediating the secondary phase of septic pulmonary hypertension.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Cyclooxygenase Inhibitors; Heart Rate; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Lipoxygenase Inhibitors; Pyrazoles; Swine; Thromboxane B2; Thromboxane-A Synthase; Time Factors

Impaired contralateral kidney (CLK) function is important in the maintenance of hypertension in the two-kidney, one-clip (2K, 1C) Goldblatt rat model. Since glomerular filtration rate (GFR) is influenced by the products of arachidonic acid metabolism, we investigated the potential role of eicosanoids as mediators of impaired CLK pressure-volume regulation. At 4 wk following right renal artery clipping, GFR of hypertensive rats was significantly reduced. This decrease was due to the fixed reduction in GFR of the clipped kidney and failure of the CLK to increase its GFR. Thromboxane (Tx) production by isolated perfused CLK was significantly elevated, whereas prostacyclin production remained unchanged. Furthermore, CLK GFR was inversely proportional to Tx production. Treatment of 4-wk hypertensive animals with either the Tx synthase inhibitor UK-38,485 or the Tx receptor antagonist GR 32191 produced a significant increase in CLK GFR. In addition, treatment with either the Tx synthase inhibitor or the Tx receptor antagonist significantly reduced systemic blood pressure. Thus, in this 2K, 1C model of hypertension, increased renal Tx production prevents functional hypertrophy of the contralateral kidney. As a result, CLK pressure-volume regulation is impaired and systemic hypertension is maintained. Furthermore, Tx antagonists restore CLK function and acutely lower systemic blood pressure. Therefore, increased renal Tx production by the CLK appears to be an important mediator of hypertension in the 2K, 1C model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Biphenyl Compounds; Blood Pressure; Glomerular Filtration Rate; Heptanoic Acids; Hypertension, Renovascular; Imidazoles; Kidney; Male; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Reference Values; Regional Blood Flow; Renal Circulation; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Thromboxane A2 production is increased early after burn. We studied the effect of inhibiting thromboxane synthetase, using dazmegrel, on postburn hemodynamic stability and edema formation, the latter monitored by burn tissue lymph flow. Dazmegrel (3.4 mg/kg) was given to six anesthetized sheep, and a 40% of total-body-surface third-degree burn was produced. Lactated Ringer's solution was infused at a rate to restore filling pressures during a 12-hour study period. Data were compared to burn alone (n = 8), anesthesia alone (n = 6), and dazmegrel alone (n = 5) groups. The latter two groups showed no physiologic changes. Dazmegrel pretreatment prevented increased thromboxane A2, measured as thromboxane B2, but resulted in a significant increase in plasma prostacyclin, measured as 6-keto-PGF1 alpha. In addition, a marked vasodilatation and decrease in systemic vascular resistance were noted, as well as a 30% increase in fluid requirements and an increase in lymph flow compared with burn alone. The increase in prostacyclin more than likely accentuated the burn-induced permeability change. Of interest was that oxygen consumption was better maintained with dazmegrel postburn, even with the relative hypovolemia, indicating that postburn vasoconstriction impairs adequate O2 delivery to tissues and that thromboxane synthetase inhibition attenuates this process.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Flow Velocity; Blood Volume; Burns; Cardiac Output; Disease Models, Animal; Edema; Hemodynamics; Imidazoles; Lymph; Oxygen Consumption; Sheep; Skin Diseases; Thromboxane-A Synthase; Vascular Resistance; Vasodilation

13 newborn piglets with group-B-beta-hemolytic-streptococci (GBS)-induced pulmonary hypertension were assigned to receive either placebo (group 1) or Dazmegrel, a thromboxane synthetase inhibitor (group 2). All piglets with pulmonary hypertension had increased thromboxane B2 (TxB2) and 6-keto PGF1 alpha levels. With continued GBS infusion, the placebo group demonstrated a continued elevation of pulmonary artery pressure (PAP) and of TxB2. The Dazmegrel piglets, however, despite continued GBS infusion, demonstrated a selective decrease in PAP associated with a significant decrease in TxB2 levels and stability of systemic pressure and cardiac output. These data demonstrate that thromboxane synthetase inhibition is effective therapeutically in selectively reducing PAP.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Epoprostenol; Hypertension, Pulmonary; Imidazoles; Radioimmunoassay; Streptococcal Infections; Swine; Thromboxane B2; Thromboxane-A Synthase

We tested the hypothesis that prostaglandins (PGs) and thromboxane (Tx) A2 are important mediators of the hemodynamic derangements occurring in a rabbit model of hyperdynamic endotoxicosis. Rabbits were injected with either normal saline (NS) or Escherichia coli lipopolysaccharide (LPS; 1-3 micrograms/kg) and studied 6 hr later. Cardiac index (CI) and regional blood flow were determined using thermodilution and radioactive microspheres, respectively. Systemic and regional hemodynamics were determined before and 40 min after administering indomethacin (cyclo-oxygenase inhibitor; 5 mg/kg), UK38485 (Tx synthetase inhibitor; 10 mg/kg), or NS. LPS increased CI (P = .0024) and decreased mean arterial pressure (P = .0031) and systemic vascular resistance index (P = .0001). LPS increased flow to the heart and small intestine and decreased flow to the hepatic artery and pancreas. The systemic and regional hemodynamic effects of indomethacin were similar in NS- and LPS-treated rabbits. UK38485 decreased perfusion of skeletal muscle and diaphragm in both endotoxemic and control animals. This agent increased splenic perfusion only in NS-treated rabbits. Plasma levels of 6-keto PGF1 alpha (PGI2 metabolite) were typically undetectable in both NS- and LPS-treated rabbits. These data do not support the hypothesis that PG's or TxA2 are major determinants of the hemodynamic perturbations that occur in this endotoxicosis model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase Inhibitors; Disease Models, Animal; Endotoxins; Escherichia coli; Hemodynamics; Imidazoles; Indomethacin; Lipopolysaccharides; Male; Prostaglandins; Rabbits; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase

We have recently reported that infusion of stoichiometrically equal quantities of acid and base (neutral acid-base infusion) in the cat resulted in rapid, shallow breathing and in pulmonary hypertension (Orr et al., 1987). To investigate the mechanisms involved in these effects, we have measured in the anesthetized cat thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha, the stable metabolites of TXA2 and PGI2, in blood as well as cardiorespiratory parameters in response to neutral acid-base infusion. The first acid-base infusion prompted right ventricular blood pressure (Prv) to rise from 30 to a peak of about 55 mm Hg, with a concomitant rise in the right ventricular TXB2 level from below detection level to over 500 pg/ml. The second or third infusion evoked no (or small) rises in Prv and TXB2, individual values of Prv and TXB2 being tightly correlated. After blockade of TX synthesis by Dazmegrel, no changes were observed even at the first acid-base infusion in either Prv or TXB2. The TXA2 mimetic, U 46,619, caused Prv to rise with no change in TXB2, and this effect was repeatable. Increases were also observed in ventilation, particularly in respiratory rate. We conclude that acid exposure of blood stimulates TX synthesis and release from platelets, which in turn leads to pulmonary hypertension and to hyperventilation. The fact that these effects cannot be repeated within the same animal is due to a lack in TX release but not to a loss of responsiveness of the TX receptors in the lung.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cats; Female; Hydrochloric Acid; Imidazoles; Infusions, Intravenous; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Respiration; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

To determine the role of eicosanoids in hypoxic pulmonary vasoconstriction, we studied 42 isolated, blood-perfused lamb lungs during normoxia and hypoxia. We used the lung micropuncture technique to measure microvascular pressures in 20- to 80-micron diameter arterioles and venules and estimated segmental vascular resistance. In separate experiments, lungs were untreated or treated with either indomethacin (a cyclooxygenase inhibitor), Dazmegrel (a thromboxane synthetase inhibitor), SQ 29548 (a thromboxane receptor blocker), FPL 57231 (a leukotriene receptor blocker), or U 60257 (a 5'lipoxygenase inhibitor). In control untreated lungs both pulmonary arteries and veins constricted during hypoxia. Addition of indomethacin, Dazmegrel, or SQ 29548 to the perfusate resulted in abolition of venous constriction during hypoxia but enhancement of arterial constriction. FPL 57231 or U 60257 resulted in complete abolition of the pulmonary hypoxic vasoconstrictor response. Our results indicate that during hypoxia, leukotrienes mediate arterial and venous constriction with thromboxane A2 being necessary for venous constriction. We conclude that the interaction between 5'lipoxygenase and cyclooxygenase products of arachidonic acid results in the characteristic pulmonary hypoxic vasoconstrictor response in isolated, perfused lamb lungs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Chromones; Epoprostenol; Hypoxia; Imidazoles; In Vitro Techniques; Indomethacin; Lipoxygenase; Lung; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pulmonary Circulation; Receptors, Leukotriene; Receptors, Prostaglandin; Sheep; SRS-A; Thromboxane B2; Thromboxanes; Vasoconstriction

The direct and indirect actions of two active components of slow-reacting substance of anaphylaxis, leukotrienes C4 (LTC4) and D4 (LTD4), were studied in chronically instrumented unanesthetized sheep. Intravenous injection of 3 micrograms of LTD4 caused immediate marked pulmonary arterial hypertension which returned to baseline in 6.5 +/- 1.0 min. Dynamic compliance of the lungs (Cdyn) and left atrial (PLA) and aortic (Paorta) blood pressure fell concomitantly with the increases in pulmonary artery pressure (PPA). PLA and Paorta then increased above baseline and heart rate deceased significantly. LTD4 caused only small increases in lung lymph flow but did increase lung lymph concentrations of thromboxane B2. Lung lymph concentrations of 6-keto-prostaglandin F1 alpha did not increase following LTD4 infusion. The increase in PPA after 3-micrograms injections of LTD4 was greater than that caused by 10-micrograms injections of prostaglandin H2-analog. Injections of 10-30 micrograms of LTC4 caused only minor increases in PPA but did cause bradycardia and delayed increases in PLA and Paorta. The cyclooxygenase inhibitors meclofenamate and ibuprofen inhibited the increases in PPA caused by LTD4 but not the later bradycardia or increases in PLA and Paorta. The thromboxane synthetase inhibitor UK-38485 attenuated the early increase in PPA and moderated the later increases in PLA and Paorta and bradycardia caused by LTD4 injection. The response of unanesthetized sheep to LTD4 is mediated, at least in part, indirectly by stimulation of the cyclooxygenase pathway of arachidonate metabolism.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthesia; Animals; Arachidonate 5-Lipoxygenase; Blood Pressure; Female; Hypertension, Pulmonary; Ibuprofen; Imidazoles; Lung; Lung Compliance; Lymph; Male; Meclofenamic Acid; Prostaglandin-Endoperoxide Synthases; Pulmonary Wedge Pressure; Sheep; SRS-A; Thromboxane B2; Thromboxane-A Synthase

Thromboxane A2 may play a major role in circulatory shock. In some species, thromboxane synthetase inhibitors have a beneficial effect on shock induced by endotoxin, trauma, sepsis and administration of arachidonate. In some shock models, however, results with thromboxane synthetase inhibitors have been conflicting. The effect of UK-38,485, a selective thromboxane inhibitor, was evaluated in ponies injected with endotoxin intraperitoneally. Four groups of ponies were used to compare the effects of endotoxin alone, UK-38,485 alone, treatment with UK-38,485 before endotoxin challenge and treatment with UK-38,485 after endotoxin challenge. Haematological, metabolic, eicosanoid and clinical responses in each group were evaluated. The results indicated that UK-38,485 is an effective inhibitor of thromboxane A2 generation following endotoxin challenge. Prostacyclin values were elevated compared with baseline in ponies administered UK-38,485 and endotoxin. However, prostacyclin values were not significantly different from those of ponies receiving endotoxin alone. Furthermore, UK-38,485 failed to attenuate the haematological, metabolic and clinical manifestations commonly seen in the pony after endotoxin challenge.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Female; Horses; Imidazoles; Male; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Reduction of renal mass in the rat results in an increased glomerular prostaglandin (PG) and thromboxane (TX) formation that modulates renal hemodynamics. To evaluate whether dietary protein intake could exert effects on renal PG and TX formation after reduction of approximately 70% of renal mass, rats with remnant kidneys were placed on either a high-protein (HP) or a low-protein (LP) diet. After 2 wk on the diet, proteinuria, glomerular filtration rate (GFR), urinary PGE2 excretion, and glomerular PGE2, 6-keto PGF1 alpha, and TxB2 biosynthesis were significantly greater in the rats on HP diets. Two-wk administration of the thromboxane synthesis inhibitor UK 38485 reduced renal TxB2 formation by approximately 70%. In addition, chronic UK 38485 treatment significantly inhibited papillary PGE2 production. Neither chronic nor bolus administration of UK 38485 had an effect on proteinuria or GFR in rats on HP diets. Chronic UK 38485 treatment, however, reduced GFR and proteinuria in rats on LP diets. The bolus administration of UK 38485 did not alter GFR in animals receiving a LP diet. The cyclooxygenase inhibitor indomethacin reduced GFR only in rats on HP diets. The data demonstrate that HP intake stimulates renal prostanoid formation. The increased prostaglandin formation on HP intake modulates GFR in these rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Body Weight; Dietary Proteins; Dinoprostone; Imidazoles; Indomethacin; Inulin; Kidney Glomerulus; Organ Size; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2

Alterations in local prostacyclin and thromboxane synthesis could mediate the changes in vascular perfusion and platelet deposition in acutely rejecting renal allografts and prostaglandin E2 (PGE2) has been implicated in the regulation of the immune response. 6-Keto-prostaglandin F1 alpha (6 KetoPGF1 alpha), thromboxane B2 (TxB2) (the stable degradation products of prostacyclin and thromboxane A2 [TxA2], respectively) and PGE2 were measured in incubates of cortical slices taken from rat renal allografts or isografts one to seven days after transplantation. 6 KetoPGF1 alpha and TxB2 synthesis was also measured in incubates of blood vessels supplying and transplanted with the kidney in these animals. During the phase of cellular rejection (3-5 days), TxB2 synthesis was selectively elevated in allografted renal cortex, renal artery, renal vein, and abdominal aorta in comparison with isografted tissues. There was also a small but significant rise in cortical PGE2 synthesis at this time, but vascular and cortical 6 KetoPGF1 alpha production remained unchanged. Renal infarction, occurring 7 days after transplantation, was accompanied by a nonspecific rise in the synthesis of all three prostaglandins by renal cortical slices. Increased tissue TxA2 synthesis may contribute to local thrombosis and decreased graft perfusion during acute rejection, thereby potentiating graft destruction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Blood Vessels; Creatinine; Graft Rejection; Imidazoles; Indomethacin; Kidney; Kidney Cortex; Kidney Transplantation; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

Pretreatment with the thromboxane synthase inhibitor OKY-046 but not the cyclo-oxygenase inhibitor ibuprofen protects against ischemia-induced acute tubular necrosis. However, ibuprofen together with the vasodilating agent prostaglandin E1 is protective. This suggests that a high prostaglandin to thromboxane ratio is the major factor operative in preventing tubular necrosis, the subject of this study. Rats that had unilateral nephrectomy (n = 60) with the exception of rats that had sham operations (n = 8) underwent 45 minutes of left renal pedicle clamping. Thirty minutes before the operation, the rats received either a saline solution or a thromboxane synthase inhibitor that was given intravenously. The inhibitors OKY-046 (2 milligrams per kilogram, n = 10), UK38485 (1 milligram per kilogram, n = 9) and U63357A (10 milligrams per kilogram, n = 10) were given as a single bolus while the inhibitor CGS13080 (0.1 milligram per kilogram, n = 9, and 1.0 milligram per kilogram, n = 7) was given by constant infusion and continued for 60 minutes after reperfusion. With saline solution therapy, five minutes after reperfusion, thromboxane B2 increased from 154 to 2,537 picograms per milliliter (p less than 0.00001) and 6-keto-prostaglandin F1 alpha increased from 51 to 266 picograms per milliliter (p less than 0.004). At 24 hours, the creatinine level increased from 0.5 to 2.8 milligrams per deciliter (p less than 0.00001). Only OKY-046 yielded a creatinine level at 24 hours of 1.2 milligrams per deciliter, a value lower than that for those in the saline solution control group (p less than 0.002). Furthermore, OKY-046 led to the highest prostaglandin to thromboxane ratio (p less than 0.035). The five other ratios which occurred after drug therapy were inversely related to the decrease in the creatinine value (r = -0.93, p less than 0.02). Histologically, OKY-046 was the only thromboxane synthase inhibitor to prevent acute tubular necrosis (p less than 0.05). Results show that a high prostaglandin to thromboxane ratio protects against acute tubular necrosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Benzofurans; Creatinine; Evaluation Studies as Topic; Ibuprofen; Imidazoles; Ischemia; Kidney; Kidney Tubular Necrosis, Acute; Male; Methacrylates; Pyridines; Rats; Thromboxane B2; Thromboxane-A Synthase

In a previous study, we demonstrated that a non-toxic concentration of phorbol myristate acetate (PMA) produced edema in isolated rat lungs which were coperfused with neutrophils (PMN). In this study, we examined whether prostaglandins or thromboxane were responsible for increases in pressure and/or edema in this preparation. In lungs perfused with PMA (14 ng/ml) and PMN (1 X 10(8], significantly greater amounts of thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were produced than in controls. Relative lung weights and increases in perfusion pressure correlated with concentrations of TxB2 and 6-keto-PGF1 alpha that were produced. Indomethacin (10 microM) or Dazmegrel (10 microM) retarded the increase in perfusion pressure and prevented the increase in relative lung weight induced by PMA and PMN. When lungs were perfused with a high concentration of PMA (57 ng/ml) in the absence of added PMN, lungs also become edematous. Compared to controls, concentrations of TxB2 and 6-keto-PGF1 alpha were elevated in media collected from this preparation. As with lungs perfused with PMN and PMA, increases in pressure and relative weights of lungs perfused with PMA (57 ng/ml) correlated with the concentrations of TxB2 that were detected in perfusion media. Although indomethacin (10 microM) and Dazmegrel (50 microM) retarded the increase in perfusion pressure in this preparation, they only partially attenuated the increase in lung weight. These results suggest that, depending on the concentration, PMA can produce lung injury via different mechanisms. Thromboxane does not seem to be required for the genesis of edema induced by a high concentration of PMA in the absence of perfused neutrophils; however, it appears to play an obligatory role in the pathogenesis of edema induced by a low concentration of PMA in the presence of PMN.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Imidazoles; Indomethacin; Lung; Male; Neutrophils; Organ Size; Perfusion; Pressure; Pulmonary Edema; Rats; Rats, Inbred Strains; Tetradecanoylphorbol Acetate; Thromboxane B2; Thromboxane-A Synthase

Two cyclooxygenase inhibitors (flunixin meglumine and phenylbutazone) and a selective thromboxane synthetase inhibitor were assessed in the management of experimental equine endotoxemia. Drugs or saline solution were administered to 16 horses 15 minutes before administration of a sublethal dose of endotoxin (Escherichia coli 055:B5). Plasma concentrations of thromboxane B2 (TxB2), prostacyclin (6-keto PGF1 alpha), plasma lactate, and hematologic values and clinical appearance were monitored for 3 hours after endotoxin administration. Pretreatment with flunixin meglumine (1 mg/kg of body weight) prevented most of the endotoxin-induced changes and correlated with a significant decrease in plasma TxB2 and 6-keto PGF1 alpha concentrations, compared with concentrations in nontreated horses (ie, pretreated with saline solution). Pretreatment with phenylbutazone (2 mg/kg) attenuated the effects of endotoxin and was associated with a brief, early, significant increase in plasma TxB2 concentrations, but not in plasma 6-keto PGF1 alpha concentrations. Pretreatment with the thromboxane synthetase inhibitor did not appear to clinically benefit the horses involved; however, arachidonic acid metabolism was redirected to prostacyclin production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Clonixin; Endotoxins; Escherichia coli; Horses; Imidazoles; Lactates; Male; Nicotinic Acids; Phenylbutazone; Thromboxane B2; Thromboxane-A Synthase

The purpose of this study was to compare the effects of dazoxiben (DAZ), UK 38,485 (UK) and aspirin (ASA) in the prevention of thrombotic sudden death in rabbits. In anesthetized male rabbits, sudden death was produced by intravenous administration of 0.75 mg/kg arachidonic acid (AA). AA increased plasma TxB2 levels from 0.20 +/- 0.10 ng/ml to 8.75 +/- 1.79 ng/ml and produced a 42% reduction in the number of circulating platelets. Death occurred in all animals within 5 minutes. Administration of DAZ (8.6 mumole/kg) 15 min before AA prevented the increase in plasma TxB2, the thrombocytopenia and sudden death while pretreatment with DAZ 2 hr before AA did not. The administration of UK (8.6 mumole/kg) 15 min. 4 hrs or 8 hrs before AA resulted in 100%, 67% and 33% survival, respectively. ASA (110 mumole/kg) administered 2 or 24 hrs before AA inhibited the increase in plasma TxB2 and prevented the fall in platelet counts. All animals pretreated with ASA survived. These data demonstrate that DAZ and UK have only a short to moderate duration of action in preventing AA-induced increases in plasma Tx levels and thrombocytopenia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Imidazoles; Male; Rabbits; Thrombocytopenia; Thrombosis; Thromboxane B2; Time Factors

Eicosanoid synthesis was studied in a model of in situ glomerulonephritis (gn) in the rat. Unilateral gn was induced by perfusion of left kidneys with 200 micrograms cationized human IgG followed by intravenous (i.v.) autologous anti-human IgG antiserum. Rats developed proteinuria in the first 24 hours and hypercellular gn with leukocyte infiltration in the left kidney. Synthesis of thromboxane B2 (TXB2), prostaglandin E2 (PGE2) and 6-ketoprostaglandin F 1 alpha(6-keto-PGF 1 alpha) was measured at 6, 12, 18 and 24 hours in isolated glomeruli by radioimmunoassay. In nephritic glomeruli there was a nine-fold rise in TXB2 at six hours (5.35 ng/mg glomerular protein) when compared to control (0.6 ng/mg). TXB2 was still elevated at 24 hours (2.7 +/- 1 ng/mg; control 0.7 +/- 0.2 ng/mg). There were no consistent changes in PGE2 or 6-keto-PGF 1 alpha. No changes were found in right kidneys of nephritic or control rats. Treatment of nephritic rats with a selective thromboxane synthetase inhibitor, dazmegrel (20 mg/kg 8 hourly intraperitoneally), suppressed glomerular TXB2 at 24 hours. TXB2 was also inhibited in right (non-nephritic) kidneys and serum. Dazmegrel did not inhibit proteinuria or glomerular hypercellularity. We conclude there is a major increase in glomerular TXB2 in this model which does not play an essential role in the development of proteinuria or cellular infiltration.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Glomerulonephritis; Imidazoles; Kidney Glomerulus; Prostaglandins E; Radioimmunoassay; Rats; Rats, Inbred Lew; Thromboxane B2; Thromboxane-A Synthase

The efficacy of three agents which alter the metabolism of arachidonic acid was investigated in normal, conscious horses. A dose response evaluation was made of flunixin meglumine and phenylbutazone, two cyclo-oxygenase inhibitors, and of a selective thromboxane synthetase inhibitor, UK-38,485. Radioimmunoassay of thromboxane B2 (TxB2) and 6-keto prostaglandin F1 alpha (PGF1 alpha) was used to assess the concentrations of thromboxane A2 (TxA2) and prostacyclin (PGI2) respectively, in serum. Flunixin was the most potent inhibitor of serum TxB2 and 6-keto PGF1 alpha production. UK-38,485 also decreased serum TxB2 generation while significantly increasing serum 6-keto PGF1 alpha levels, thus confirming its selectivity as a thromboxane synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Clonixin; Epoprostenol; Horses; Imidazoles; Male; Nicotinic Acids; Orchiectomy; Phenylbutazone; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Four major prostanoids (6-keto-PGF1 alpha, PGE2, PGF2 alpha and TXB2) were measured by specific radioimmunoassays in the outputs from human umbilical vessels perfused in vitro. As evaluated by scanning electron microscopy (SEM) only few blood platelets were attached to the vessel wall. After an initial flush with decreasing concentrations of all four prostanoids, a stable stage was reached, lasting for 4-5 hours. During this stage the production could be inhibited by indomethacin and only slightly stimulated with arachidonic acid. The TXA2 synthetase inhibitor UK 38485 depressed the TXB2 production, while only slightly affecting the other three prostanoids at very high concentrations. The arteries produced relatively more 6-keto-PGF1 alpha than did the vein.

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprost; Dinoprostone; Humans; Imidazoles; Immunologic Techniques; In Vitro Techniques; Indomethacin; Prostaglandins; Prostaglandins E; Prostaglandins F; Radioimmunoassay; Thromboxane B2; Umbilical Arteries; Umbilical Veins

The purpose of this study was to determine the role of thromboxane and prostacyclin in modulating pulmonary hemodynamics during maximal cardiopulmonary stress in the healthy lung. We studied 11 yearling sheep in paired studies during progressive maximal treadmill exercise with and without meclofenamate (n = 5), ibuprofen (n = 6), or UK38485 (n = 2). We also studied five sheep during hypoxia and hypoxic exercise, and six sheep during prolonged steady-state treadmill exercise for 45-60 min with and without drug treatment. We measured the metabolites of thromboxane A2 (thromboxane B2, TxB2) and prostacyclin (6-ketoprostaglandin F1 alpha, 6-keto-PGF1 alpha) in blood plasma and lung lymph in each protocol. We found that progressive exercise significantly reduced pulmonary vascular resistance but that cyclooxygenase or thromboxane synthesis blockade did not alter the change. Plasma TxB2 rose minimally but significantly during maximal exercise, but 6-keto-PGF1 alpha did not change. During continuous hypoxia, exercise reduced pulmonary vascular resistance nearly to base-line levels, but the degree of reduction was also unchanged by drug treatment. There were also no significant changes in lymph or plasma TxB2 or 6-keto-PGF1 alpha during 45-60 min of continuous moderate exercise. We conclude that neither TxB2 nor prostacyclin modulate pulmonary hemodynamics in the normal lung during maximal exercise, prolonged moderate exercise, or exercise-induced reductions in vascular resistance during hypoxia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cardiac Output; Epoprostenol; Hemodynamics; Hypoxia; Ibuprofen; Imidazoles; Lung; Lymph; Meclofenamic Acid; Physical Exertion; Pulmonary Artery; Sheep; Thromboxane A2; Vascular Resistance

Mice transplanted with NC carcinoma were treated with the thromboxane synthetase inhibitor dazmegrel (UK38485) or with nafazatrom (BAY G 6575), a compound that is reported to increase prostacyclin formation. Some experiments included the cytotoxic drugs methotrexate and melphalan. The tumours were excised under anaesthesia on day 14 or day 21 after transplantation, and weighed; some were extracted for prostanoids which were measured by radioimmunoassay. Mouse survival time was determined up to day 121, and cancer spread was determined by postmortem examination. The survival was increased by methotrexate and melphalan but not by the other drugs. Nafazatrom-treated mice tended to have lighter tumours. Although dazmegrel reduced the formation of thromboxane B2 during clotting of blood from normal mice, it did not affect the tumour yields of prostanoids. Nafazatrom had no effect on serum or tumour prostanoids. There were no obvious effects of the treatments on the recurrence of tumour in the excision scar, lung metastasis or spread to lymph nodes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antineoplastic Agents; Female; Imidazoles; Mammary Neoplasms, Experimental; Mice; Prostaglandins E; Pyrazoles; Pyrazolones; Thromboxane B2; Thromboxane-A Synthase

The phospholipid platelet-activating factor (PAF) stimulates platelet aggregation and coronary vasoconstriction. In this study we determined whether PAF alters coronary flow patterns in vivo in a canine preparation with concentric coronary artery stenosis. This preparation is characterized by cyclic flow variations in coronary blood flow associated with transient platelet aggregation at the site of the coronary constriction. Thirty-nine male mongrel dogs were used in three protocols. In protocol 1, PAF (10(-9) or 10(-8) mol/min) was infused into the coronary artery proximal to the stenosis to determine (1) whether PAF induces cyclic flow variations and (2) whether PAF has an effect on systemic hemodynamics. Cyclic flow variations were induced in three of six dogs; in these animals, mean arterial pressure decreased by 5.5% and 42.1% 10 min after infusion of the lower and higher dose of PAF. In protocol 2, cyclic flow variations were abolished with either the thromboxane synthetase inhibitor UK38485 (mean dose 2.2 mg/kg iv), the serotonin antagonist ketanserin (0.5 mg/kg iv), or the alpha 2-adrenergic antagonist yohimbine (2 mg/kg iv). Subsequent administration of PAF restored the frequency of cyclic flow variations to the preantagonist levels. Thromboxane (Tx) B2 and 6-keto-PGF1 alpha, the stable metabolites of TxA2 and prostacyclin, respectively, were measured in blood obtained distal to the coronary stenosis. TxB2 levels increased substantially during cyclic flow variations and were returned to control values with the thromboxane synthetase inhibitor UK38485. Infusion of PAF subsequently restored cyclic flow variations without altering coronary arterial coronary arterial TxB2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic alpha-Antagonists; Animals; Arteriosclerosis; Coronary Circulation; Coronary Disease; Dogs; Hemodynamics; Imidazoles; Male; Platelet Activating Factor; Platelet Aggregation; Serotonin Antagonists; Thromboxane B2

The rabbit epigastric free flap was used to investigate the effect of prostacyclin and drugs modifying its synthesis in vivo on microvascular blood flow. Prostacyclin and its analogue carbacyclin caused an increase in flow with a maximal twofold increase at approximately 6.5 and 250 ng/ml, respectively, in the flap. Thromboxane synthetase inhibitors such as dazoxiben hydrochloride, UK-38,485, 7-IHA, and imidazole (up to 7 X 10(-4) M in the flap) as well as the prostaglandins 6-oxo-PGF1 alpha and PGE2 (up to 3.7 and 9.2 ng/ml, respectively, in the flap) all failed to modify the control flow rate in the cutaneous microcirculation. It is concluded that the vasodilatory properties of prostacyclin and carbacyclin, together with their known platelet antiaggregatory properties, warrant further study in problem areas of microsurgery such as flap ischemia. The use of thromboxane synthetase inhibitors had no demonstrable effect on the normal flap, and their effect on the ischemic flap remains to be investigated.

Topics: 6-Ketoprostaglandin F1 alpha; Abdominal Muscles; Animals; Blood Flow Velocity; Blood Pressure; Cyclooxygenase Inhibitors; Epoprostenol; Imidazoles; Indomethacin; Microcirculation; Platelet Aggregation; Pyrazoles; Pyrazolones; Rabbits; Regional Blood Flow; Surgical Flaps; Thromboxane-A Synthase; Vasoconstriction; Vasodilation