thromboxane-b2 and dazmegrel

The pharmacokinetics of dazmegrel (UK-38,485), a novel selective thromboxane synthase inhibitor, and its effects on in vivo prostanoid formation were studied in a 2 weeks, multiple dose, placebo controlled, double blind trial in man. The drug was well tolerated. After dazmegrel 50-200 mg p.o. peak plasma levels of 0.7-3 mu/ml were reached within 1 hr. Elimination was of first order with a half life of 0.88 +/- 0.17 hr. Platelet count and bleeding time were unchanged by all regimes of dazmegrel used (100 and 200 mg b.i.d.; 50, 100 and 200 mg t.i.d.). Serum thromboxane (TXB2) was more than 95% suppressed one hour after all doses studied, but 200 mg t.i.d. were needed suppress circadian serum TXB2 profiles more than 90% at all times. Urinary excretion of 2,3-dinor-TXB2 (TXA2-M) fell by over 90%. An increase in the excretion of 2,3-dinor-6-keto-PGF1 alpha (PGI2-M), the major metabolite of prostacyclin, was largely transient and fell short of significance at all times. The ratio of TXA2-M to PGI2-M was lowered from about 5.0 to 0.2 and sustained throughout treatment. Dazmegrel selectively blocks in vivo and ex vivo TXA2 formation. Redirection of endoperoxides from total body TXA2 formation into prostacyclin formation is only minor under basal conditions.

Topics: Adult; Double-Blind Method; Epoprostenol; Humans; Imidazoles; Kinetics; Male; Metabolic Clearance Rate; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

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

Albumin excretion rates (AER) were measured in 30 insulin-dependent diabetics during a 16-week double-blind, randomised, placebo-controlled study of the specific thromboxane synthetase inhibitor UK-38,485.6 of 15 subjects in the active group had microalbuminuria (defined as mean pretreatment AER 20-150 micrograms/min); in these patients AER fell from 32 +/- 3 micrograms/min to 11 +/- 1 micrograms/min at 8 weeks and 9 +/- 1 micrograms/min at 16 weeks. The AER rose again (to 29 +/- 8 micrograms/min) within 12 weeks of stopping the drug. There was no significant change in the 10 patients with microalbuminuria who received placebo. There was a strong correlation between change from baseline values and the baseline values themselves in the active, but not in the placebo group, and the change from baseline differed significantly between the two groups. There was no change in glycosylated haemoglobin or mean blood glucose levels during the study. In a separate study UK-38,485 caused significant suppression of thromboxane B2 synthesis in diabetic and non-diabetic subjects.

Topics: Adult; Albuminuria; Clinical Trials as Topic; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Imidazoles; Male; Middle Aged; Oxidoreductases; Thromboxane B2; Thromboxane-A Synthase

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 capacity of glial tumor cells to migrate and diffusely infiltrate normal brain compromises surgical eradication of the disease. Identification of genes associated with invasion may offer novel strategies for anti-invasive therapies. The gene for TXsyn, an enzyme of the arachidonic acid pathway, has been identified by differential mRNA display as being overexpressed in a glioma cell line selected for migration. In this study TXsyn mRNA expression was found in a large panel of glioma cell lines but not in a strain of human astrocytes. Immunohistochemistry demonstrated TXsyn in the parenchyma of glial tumors and in reactive astrocytes, whereas it could not be detected in quiescent astrocytes and oligodendroglia of normal brain. Glioma cell lines showed a wide range of thromboxane B2 formation, the relative expression of which correlated with migration rates of these cells. Migration was effectively blocked by specific inhibitors of TXsyn, such as furegrelate and dazmegrel. Other TXsyn inhibitors and cyclooxygenase inhibitors were less effective. Treatment with specific inhibitors also resulted in a decrease of intercellular adhesion in glioma cells. These data indicate that TXsyn plays a crucial role in the signal transduction of migration in glial tumors and may offer a novel strategy for anti-invasive therapies.

Topics: Arachidonic Acids; Aspirin; Astrocytes; Benzofurans; Brain Neoplasms; Cell Adhesion; Cell Movement; Enzyme Induction; Enzyme Inhibitors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; GTP-Binding Proteins; Humans; Imidazoles; Indomethacin; Lysine; Models, Biological; Neoplasm Proteins; Neoplastic Stem Cells; Oligodendroglia; Pentanoic Acids; Phenotype; Pyridines; RNA, Messenger; RNA, Neoplasm; Signal Transduction; Thromboxane B2; Thromboxane-A Synthase; Tumor Cells, Cultured

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

To clarify the mechanism of the development of a severe pulmonary hypertensive response to group B streptococcus.. Prospective, randomized controlled trial.. Twelve chronically instrumented and six age-matched uninstrumented newborn piglets.. Six animals received eight injections of group B streptococcus over an 11-day period (control group). Six additional animals (pretreatment group) were given 3 mg/kg of dazmegrel, a thromboxane synthase blocking agent, before each dose of group B streptococcus to prevent the pulmonary hypertensive response and to control for any secondary arterial remodeling.. Hemodynamic measurements, pulmonary arterial morphometry, and thromboxane concentrations were examined in the instrumented animals. Lungs from the uninstrumented piglets were examined to determine morphometric norms for this population. The animals given only group B streptococcus developed a significant pulmonary hypertensive response after five daily doses (+6.8 +/- 2.0 [SEM] mm Hg, p < .05) which became pronounced after eight doses (+13.2 +/- 1.0 mm Hg). Pulmonary hypertension was not observed in the pretreatment group when dazmegrel was given; however, on the final day in this group, dazmegrel was withheld before group B streptococcus dosing and a significant pulmonary hypertensive response was observed (+20 +/- 1.6 mm Hg). The medial thickness of pulmonary arteries was not different between the two groups nor when compared with that of six normal, uninstrumented animals. Plasma thromboxane B2 concentrations were determined from blood samples taken before and after group B streptococcus infusion at the first, seventh and eighth (final) dosing. Thromboxane concentrations increased significantly on days 7 and 8 in the control group (578 +/- 312 to 752 +/- 372 pg/mL, 638 +/- 201 to 1462 +/- 295 pg/mL, respectively) and on day 8 in the pretreatment group (545 +/- 160 to 705 +/- 187 pg/mL).. We conclude that the development of potentiated pulmonary hypertension is not due to pulmonary arterial remodeling, but is associated with increased thromboxane production.

Topics: Analysis of Variance; Animals; Animals, Newborn; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Lung; Prospective Studies; Pulmonary Artery; Random Allocation; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Thromboxane-A Synthase

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

1. Biochemical mechanisms of ischaemia were investigated in rabbit skin flaps subjected to 2 h of primary ischaemia then, 24 h later, to 4 h of secondary ischaemia. During secondary ischaemia, flaps underwent either total ischaemia (arterial and venous blood supply occluded) or partial ischaemia (vein only occluded). Some of these flaps were treated at the time of reperfusion with the free-radical scavenger superoxide dismutase (EC 1.15.1.1) and/or the thromboxane synthetase inhibitor UK-38,485. 2. After 30 min of reperfusion, superoxide dismutase treatment significantly reduced blood thromboxane levels, elevated during ischaemia. Superoxide dismutase also reduced tissue levels of malonyldialdehyde and xanthine oxidase, indicators of free-radical damage, and restored the depleted tissue levels of superoxide dismutase. 3. UK-38,485 treatment failed to significantly alter any of these tissue free-radical parameters, although this agent significantly reduced blood thromboxane levels. 4. Combined superoxide dismutase plus UK-38,485 treatment was not significantly better than either treatment alone with respect to any parameter. 5. Partial ischaemia led to consistently higher levels of tissue free radicals and blood thromboxane than did total ischaemia. Thus partial ischaemia appears to result in greater free-radical damage than total ischaemia. 6. These results are consistent with the hypothesis that thromboxane acts as a mediator for free-radical damage in the ischaemic changes within the flap.

Topics: Animals; Free Radical Scavengers; Free Radicals; Imidazoles; Ischemia; Rabbits; Reperfusion Injury; Skin; Surgical Flaps; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Renal vasoconstriction has been implicated as a major contributing factor for the nephrotoxic effects of cyclosporine. In an attempt to assess the relative contribution of thromboxane (Tx), the effects of coadministering CsA with the selective Tx synthetase inhibitor, Dazmegrel (DAZ) (Pfizer, Inc.), were determined. Rats were treated orally with 50 mg/kg of DAZ plus 50 mg/kg of CsA and various indicators of nephrotoxicity and efficacy were assessed. Animals treated with CsA + DAZ had a normalization of renal TxB2 synthesis as compared with animals treated with CsA alone (160 vs. 338 pg/ml). Kidney proximal tubule damage following CsA treatment alone was also reduced in animals coadministered DAZ, as indicated by reduced urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) (9.7 vs. 14.1 U/g creatinine) and by histological examination of kidney sections. However, DAZ did not affect blood levels of CsA nor its efficacious activity in a model of experimental allergic encephalomyelitis (EAE). These studies suggest a major role of elevated thromboxane production in the acute nephrotoxic effects of CsA and demonstrate a reduction in this toxicity by DAZ without altering CsA's efficacious activity.

Topics: Acetylglucosaminidase; Amino Acid Sequence; Animals; Chromatography, Gel; Chromatography, High Pressure Liquid; Creatinine; Cyclosporine; Drug Antagonism; Encephalomyelitis, Autoimmune, Experimental; Imidazoles; Kidney; Kidney Tubules, Proximal; Male; Molecular Sequence Data; Nephrotic Syndrome; Rats; Rats, Inbred F344; Thromboxane B2; Thromboxane-A Synthase; Vasodilator Agents

We studied the formation of cyclo-oxygenase products in a rat model of mesangial cell injury, in order to determine a possible role of prostaglandin E2 (PGE2), prostaglandin I2 (determined as 6-keto-PGF1 alpha and thromboxane A2 (TxA2) in immune-mediated glomerular disease. Selective immune-mediated mesangial cell injury was induced by i.v. administration of a rabbit anti-rat thymocyte antiserum (ATS). Intravenous ATS leads to immune deposits in the mesangium followed by mesangiolysis and the infiltration of polymorphonuclear granulocytes and monocytes. Glomerular TxB2 formation two hours (292 +/- 27 pg/mg/min) and 48 hours (396 +/- 69 pg/mg/min) following antibody was significantly (P less than 0.05) higher compared to animals receiving non-antibody rabbit IgG (TxB2: 2 hr 143 +/- 13; 48 hr 171 +/- 32 pg/mg/min). Treatment with cobra venom factor (CVF) and the reduction of glomerular monocyte infiltration inhibited the increase of glomerular TxB2 formation significantly. Depletion of granulocytes with a rabbit anti-rat granulocyte serum had no effect on glomerular prostanoid formation following ATS. Glomerular PGE2 and 6-keto PGF1 alpha production was not altered following ATS. Inulin clearance in rats with immune-mediated mesangial cell injury was significantly (P less than 0.001) lower at two hours (456 +/- 24 microliters/min/100 g body wt) and 48 hours (433 +/- 54 microliters/min/100 g body wt) compared to their corresponding control animals which were treated with non-antibody IgG (2 hr: 914 +/- 51; 48 hr: 694 +/- 79 microliters/min/100 g body wt).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antilymphocyte Serum; Complement Activation; Dinoprostone; Epoprostenol; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis; Imidazoles; Indomethacin; Male; Rats; Rats, Inbred Lew; Rats, Inbred Strains; T-Lymphocytes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

GBS (Group B Hemolytic Streptococci) cause pulmonary hypertension with associated neutropenia. We investigated whether there is a correlation between the neutropenia of sepsis and GBS-induced pulmonary vasoconstriction, through study of the effects of inhibiting pulmonary vasoconstriction on the neutropenia of GBS in newborn piglets. Fifteen piglets were infused with GBS. After one hour, animals were given either a thromboxane inhibitor (DAZ), a combined cyclooxygenase/lipoxygenase inhibitor, BW755C, or placebo. With GBS infusion, WBC and PMN counts dropped steadily, from similar baselines, to 2250 +/- 570, 3300 +/- 500 and 5400 +/- 1100 cells/mm3 respectively (p less than 0.05; DAZ and BW vs. placebo). PMN's dropped similarly to 710 +/- 320, 2390 + 1240 and 3130 +/- 1050 cells/mm3 respectively (p less than 0.05; DAZ vs. BW and placebo). The drop in WBC's predominantly resulted from proportional decreases in PMN's (DAZ: r = 0.98; BW: r = 0.88; placebo r = 0.93). Compared to GBS alone, DAZ reduced pulmonary vasoconstriction, but exacerbated the granulocytopenia. BW755C similarly reduced pulmonary hypertension: however, it ameliorated the exacerbation of GBS induced neutropenia described above. These data imply that there is no direct correlation between GBS induced granulocytopenia and pulmonary hypertension.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Animals, Newborn; Blood Pressure; Cyclooxygenase Inhibitors; Hypertension, Pulmonary; Imidazoles; Leukocyte Count; Lipoxygenase Inhibitors; Neutropenia; Neutrophils; Pulmonary Artery; Streptococcus agalactiae; Swine; Thromboxane B2; Vasoconstriction

The effect of platelet activating factor (PAF) on the generation of cyclo-oxygenase-derived arachidonic acid metabolites was examined on purified eosinophils harvested from the peritoneal cavity of male guinea pigs. PAF produced a concentration-dependent increase in the amount of immunoreactive thromboxane B2 (TXB2) and PGE1/E2 released from these inflammatory cells at a relative molar ratio of 30:1. The EC50 of PAF was 20 to 40 nM and maximum stimulation (4.5-fold) of both prostanoids occurred at 1 microM PAF. The ability of PAF to generate TXA2 was rapid (t 1/2 = 9 s), transient (40 s), noncytotoxic, and noncompetitively antagonized by the PAF-receptor blocking drug, WEB 2086. On an equimolar (100 nM) basis, PAF was significantly more effective than C5a, fMLP, and PMA at stimulating TXB2 release but markedly less potent than the calcium ionophore, calcimycin. Pretreatment of eosinophils with the cyclo-oxygenase inhibitor flurbiprofen (8 microM for 5 min) abolished the ability of PAF to promote both TXB2 and PGE1/E2 release. Likewise, dazmegrel (50 microM for 5 min), a selective inhibitor of thromboxane synthetase, abolished PAF-stimulated TXB2 release but markedly augmented the elaboration of PGE1/E2. Inhibition of cyclo-oxygenase with flurbiprofen affected neither the ability of PAF to elevate the intracellular calcium ion concentration (measured by fura-2 fluorescence) nor its appetency to generate superoxide anions at any PAF concentration examined. It is concluded that activation of guinea pig eosinophils by PAF is receptor-mediated and independent of the concomitant generation of cyclo-oxygenase-derived excitatory prostanoids. Inasmuch as TXA2 may contribute to the pathogenesis of bronchial hyperreactivity, then these data implicate the eosinophil as a potential source of this lipid mediator.

Topics: Animals; Azepines; Calcimycin; Calcium; Complement C5a; Cyclooxygenase Inhibitors; Enzyme Activation; Eosinophils; Flurbiprofen; Guinea Pigs; Imidazoles; In Vitro Techniques; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activating Factor; Platelet Membrane Glycoproteins; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Superoxides; Tetradecanoylphorbol Acetate; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Triazines; Triazoles

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

Urinary TXB2 excretion and the release of TXB2 from vascular and renal cortical tissues are increased in rats with severe AII-salt hypertension. Treatment with an inhibitor of TXA2 synthesis did not change the blood pressure of normotensive or of AII-salt hypertensive rats. Treatment with SQ29,548, a TXA2 receptor antagonist, caused reduction of blood pressure and renal vascular resistance in AII-salt hypertensive but not in normotensive rats. We conclude that the SQ29,548-induced lowering of blood pressure and renal vascular resistance in AII-salt hypertensive rats is the result of blockade of the vascular actions of one or more pressor eicosanoids including TXA2 and the prostaglandin endoperoxides. A corollary of this conclusion is that pressor eicosanoids may be contributory factors in the pathogenesis of severe AII-salt hypertension in rats.

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; In Vitro Techniques; Kidney; Kidney Cortex; Muscle, Smooth, Vascular; Rats; Reference Values; Sodium, Dietary; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

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

The effect of the thromboxane synthesis inhibitor UK 38485 on glomerular filtration rate (GFR) and proteinuria was evaluated in a rat model of unilateral membranous nephropathy. Two and 24 hours following perfusion of kidneys with cationized human IgG and i.v. administration of anti-human IgG-antiserum (in situ ICGN), glomerular thromboxane B2 (TxB2) formation was significantly higher (2 hr: 448 +/- 116 pg/mg protein/min; 24 hr: 173 +/- 21 pg/mg protein/min) compared to control (C) kidneys (2 hr: 173 +/- 21 pg/mg protein/min, P less than 0.005; 24 hr: 154 +/- 17 pg/mg protein/min, P less than 0.025). Two and seven days after induction of ICGN these differences were no longer present. Pretreatment with the thromboxane synthesis inhibitor UK 38485 prevented the decrease in GFR, which occurred two hours after induction of the glomerular disease (without UK: 161 +/- 31; with UK 325 +/- 21 microliters/100 g body wt/min). This UK 38485 effect on GFR was no longer detectable at 24 hours, two days and seven days. Initiation of glomerular immune injury was followed by significant proteinuria which averaged 250 +/- 85 mg/24 hr at day two. UK 38485 treatment, which reduced TxB2 formation in isolated glomeruli by 90% did not influence proteinuria. These data demonstrate that induction of heterologous, in situ immune complex glomerulonephritis stimulates glomerular thromboxane B2 formation, an effect which partially modulates the decrease in GFR at two hours. Thromboxane, however, does not seem to play a role in the mediation of proteinuria in this animal model.

Topics: Animals; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Imidazoles; Proteinuria; Rats; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Time Factors

Some studies have indicated that PGs can modulate the single nephron tubuloglomerular feedback (TGF) response. The aim of this study was to define the specific role of the vasoconstrictor PG, TX, by administration to rats of either vehicle (group 1; n = 20) or drugs that inhibit either cyclooxygenase (indomethacin [indo], 5 mg.kg-1, group 2, n = 17), TX synthetase (UK-38,485 [UK], 100 mg.kg-1, group 3, n = 19), or TX receptors (SQ-29,548 [SQ], 8 mg.kg-1, group 4, n = 14, or L-641,953 [L], 50 mg.kg-1, group 5, n = 8). Indo reduced excretion of the prostacyclin derivative 6-keto-PGF1 alpha and TXB2 and lowered whole kidney GFR and renal plasma flow, whereas UK lowered excretion of TXB2 only and did not change basal renal hemodynamics. The TGF response (assessed from reduction in proximal tubule stop-flow pressure (Psf, mmHg) during increases in perfusion of the loop of Henle (LH) from 0 to 40 nl.min-1) was unchanged after vehicle (9.8 +/- 0.5-10.9 +/- 1.0, NS) but blunted (P less than 0.001) by 40-65% in rats of groups 2-5 (indo, 11.1 +/- 1.0-4.4 +/- 0.7; UK, 9.0 +/- 0.8-4.8 +/- 0.7; SQ, 10.3 +/- 0.6-4.8 +/- 0.6; L, 10.7 +/- 0.5-6.7 +/- 1.3). This blunting was due to lower values for Psf at zero LH flow after indo, SQ, and L, and higher values of Psf at 40 nl.min-1 LH flow after indo and UK. The fall in single nephron GFR (SNGFR, nl.min-1) with increasing LH perfusion was unchanged after vehicle (10.9 +/- 2.8-11.2 +/- 0.8) but was blunted (P less than 0.05) by 45-55% in rats given indo (13.9 +/- 1.2-6.2 +/- 2.2) or UK (12.8 +/- 2.1-7.0 +/- 1.5). UK produced dose-dependent reductions in TXB2 excretion (IC50, 15 mg.kg-1) and inhibition of the TGF response (IC50: 30 mg.kg-1). After blockade of TX receptors by SQ, UK had no further affect on the TGF response. The fall in Psf at high LH flow was blunted (P less than 0.05) by indo and UK, whereas the rise in Psf at zero LH flow was blunted by indo, SQ, and L. In conclusion, endogenous TX generation can modulate the reductions in Psf and SNGFR during increased delivery of NaCl to the LH.

Topics: Analysis of Variance; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Glomerular Filtration Rate; Hydrazines; Hydrostatic Pressure; Imidazoles; Indomethacin; Kidney Glomerulus; Kidney Tubules; Male; Prostaglandins F; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The aim of the present study was to explore the possible involvement of thromboxane A2(TxA2) in the development of cardiopulmonary dysfunction in experimental septic shock. Sepsis was induced in anesthetized cats by intravenous (i.v.) infusion of live Escherichia coli. One series (No. = 12) was pretreated with a specific TxA2 synthetase inhibitor, dazmegrel; another (No. = 8) served as a septic control series. In both series a systemic arterial hypotension developed after 2 hr; no differences in cardiac function were detected. After 2 hr bacteremia cardiac preload was increased by a rapid infusion of dextran. This showed that cardiac function was significantly more preserved in dazmegrel-pretreated cats compared with septic controls. Pretreatment with dazmegrel totally prevented the pulmonary vascular response to bacterial infusion. The pulmonary compliance decreased to 40% in controls but to only 75% in the dazmegrel series, and airway resistance increased to 300% and 140%, respectively. The ventilation-perfusion ratio was less impaired in the pretreated series. Pretreatment with dazmegrel abolished the increase in thromboxane B2 (TxB2), the stable metabolite of TxA2, seen in the untreated series. The rise in 6-keto-prostaglandin F1a (6-keto-PGF1a), the stable metabolite of prostaglandin I2PGI2, was evident in both series. We concluded that TxA2 is important for the impaired cardiac performance in septic shock. Furthermore, TxA2 is involved, but not as the only factor, in the development of pulmonary dysfunction.

Topics: Airway Resistance; Animals; Cats; Escherichia coli; Heart; Hemodynamics; Imidazoles; Lung; Lung Compliance; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Ventilation-Perfusion Ratio

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

A monoclonal antibody against thromboxane B2 which may be used in standard fluid phase radioimmunoassays with a detection limit of around 40 pg and a binding affinity of 1.98 X 10(9) M-1 is described. Limited crossreactivity could be observed only with structurally closely related compounds such as 2,3-dinor-thromboxane B2 (8.9%), thromboxane B1 (15.7%) and thromboxane B3 (39.7%). Detectable crossreactivity with 11-dehydro-thromboxane B2, omega-carboxy-thromboxane B2, omega-hydroxy-thromboxane B2, prostaglandins of the D-, E- and F-type as well as metabolites of prostacyclin was lacking. The monoclonal anti-thromboxane B2 antibody proved well suited for measuring the thromboxane B2 content in tissue culture supernatants as well as in human serum.

Topics: Animals; Antibodies, Monoclonal; Antibody Affinity; Antibody Specificity; Arachidonic Acid; Arachidonic Acids; Humans; Ibuprofen; Imidazoles; Immunoglobulin G; Indomethacin; Mice; Mice, Inbred BALB C; Platelet Aggregation; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Thromboxane-associated pulmonary hypertension occurs in animals during intravenous infusion of group B streptococcus (GBS), a gram-positive neonatal pathogen. We postulated that other gram-positive neonatal pathogens, such as Streptococcus fecalis (ENT) and Staphylococcus epidermidis (S. epi) would also induce increased thromboxane synthesis and pulmonary hypertension when infused into piglets. We observed similar hemodynamic and gas exchange abnormalities during stepwise increases in the dose of GBS, Ent, and S. epi (n = 3, 4, and 4 piglets receiving each bacteria, respectively). Pulmonary vascular resistance increased significantly in the absence of acidosis or reduced arterial or mixed venous pO2 at a dose of 2.5 x 10(8) cfu/kg/h for Ent and S. epi. In 14 additional piglets, pulmonary vascular resistance increased markedly after 60 min of intravenous infusion of 4 +/- 1 x 10(8) cfu/kg/h for each organism (p less than 0.05, GBS: 11.7 +/- 1.8 to 75.6 +/- 18.4 mm Hg/liter/min, Ent: 12.7 +/- 1.7 to 64.9 +/- 10.6 mm Hg/liter/min, S. epi: 10.5 +/- 0.8 to 56.9 +/- 6.0 mm Hg/liter/min), and blood thromboxane B2 levels increased (p less than 0.05, GBS: 30 +/- 10 to 1830 +/- 330 pg/ml, Ent: 20 +/- 7 to 1110 +/- 300 pg/ml, S. epi: 31 +/- 9 to 1260 +/- 350 pg/ml). This dose of each bacteria caused a similar degree of mild arterial hypoxemia (57-66 mm Hg). The thromboxane synthetase inhibitor, dazmegrel, completely reversed pulmonary hypertension, reduced TxB2 levels to near baseline values, and partially reversed arterial hypoxemia despite ongoing bacterial infusion. We conclude that thromboxane-associated pulmonary hypertension occurs in piglets during infusion of different gram-positive neonatal pathogens.

Topics: Animals; Animals, Newborn; Enterococcus faecalis; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Sepsis; Staphylococcal Infections; Staphylococcus epidermidis; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Thromboxane-A Synthase

This study was designed to assess the contribution of thromboxane A2 to high blood pressure in rats with angiotensin II (Ang II)-salt hypertension. Hypertension was induced in rats drinking 0.15 M NaCl by infusion of Ang II (125 ng/min i.p.) for 12 days. Relative to values in water-drinking rats without Ang II infusion, Ang II-salt hypertensive rats exhibited augmentation (p less than 0.05) of blood pressure (from 129 +/- 3 to 217 +/- 12 mm Hg), urinary thromboxane B2 excretion (from 5.4 +/- 0.9 to 25.4 +/- 2.1 ng/day), and thromboxane B2 release from renal cortex slices (from 71.3 +/- 6.7 to 121.1 +/- 14.4 pg/mg) and aortic rings (from 28.8 +/- 2.9 to 115.8 +/- 12.8 pg/mg). Treatment with an inhibitor of thromboxane A2 synthetase, UK 38485, had no effect on blood pressure in normotensive and Ang II-salt hypertensive rats. Treatment with a thromboxane A2 receptor blocker, SQ 29548, decreased blood pressure in Ang II-salt hypertensive rats from 191 +/- 9 to 152 +/- 9 mm Hg after 3 hours, but it had no effect on blood pressure in normotensive rats. Since SQ 29548 interfered with the pressor effects of the prostaglandin endoperoxide analogue U-46619, prostaglandin F2 alpha, and 9 alpha,11 beta-prostaglandin F2, we suggest that the SQ 29548-induced blood pressure reduction in Ang II-salt hypertensive rats is the manifestation of blockade of the vascular actions of one or more endogenous prostanoids including thromboxane A2 and prostaglandin endoperoxides. If so, pressor prostanoids may be contributory factors in the pathogenesis of severe Ang II-salt hypertension in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Arteries; Bridged Bicyclo Compounds, Heterocyclic; Dinoprost; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Kidney Cortex; Male; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Rats; Rats, Inbred Strains; Sodium Chloride; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

We describe here an experimental model of peripheral arterial thrombosis and the effect of several drugs which are known to affect vessel and platelet biological functions. A similar method has been previously applied by us and others on dog coronary arteries. Male Beagle dogs, under pentobarbital anesthesia, were instrumented to measure arterial pressure, heart rate, ECG, femoral blood flow and expired CO2. A segment of the femoral artery was squeezed with forceps to damage the endothelium, and a plastic cylinder was placed around the vessel in the area of the damage. The cylinders had a length of 2 mm and an internal diameter of 1.6-1.8 mm. Under these circumstances blood flow in the stenosed artery was reduced by about 60-70% from control value and showed cyclic blood flow variations (CBFV). CBFV eventually led either to a total occlusion of the vessel (documented by blood flow measurement and by angiographic analysis), or to a spontaneous partial restoration of flow, followed by another decrease, in a repetitive fashion. Drug effect was monitored by observing the changes in frequency and amplitude of CBFV. Ketanserin (0.25 mg/kg), dazmegrel (0.5 mg/kg), and chlorpromazine (0.5 mg/kg), abolished or greatly reduced CBFV in all the experiments, while acetylsalycilic acid (ASA, 10 mg/kg) reduced or abolished CBFV in 60% of the treated dogs. Heparin (50 I.U./kg), dipyridamole (1.0 mg/kg) and prazosin (0.1 mg/kg) did not change CBFV. These results emphasize the importance of serotonin and thromboxane as mediators of vascular occlusion in this particular experimental model. This approach provides a reproducible in vivo preparation to study the pharmacological control of peripheral arterial thrombosis.

Topics: Angiography; Animals; Blood Pressure; Blood Vessels; Dogs; Femoral Artery; Heart Rate; Imidazoles; In Vitro Techniques; Ketanserin; Male; Regional Blood Flow; Thrombosis; Thromboxane B2; Thromboxane-A Synthase

The circulating prostaglandins have been implicated as mediators of microcirculatory derangements in skin and skin-muscle flaps. The study described here investigated the roles of thromboxane A2 and prostacyclin, measured as thromboxane B2 (TxB2) and prostaglandin 6-keto-F1a (PGF1a), in ischemic skin flaps, and the effects of thromboxane synthetase inhibition on flap blood flow and survival. A canine ventral island flap model was used to measure the appearance of TxB2 and PGF1a in the central arterial and venous plasma, and in the tissue and venous effluent of acutely raised flaps; with and without pretreatment with the specific thromboxane A2 synthetase inhibitor UK38485. Prostaglandin levels change significantly during flap elevation, and can be modified beneficially by thromboxane A2 synthetase inhibition, causing dramatic increases in flap blood flow and survival, as predicted by intravital dye penetration. The results presented in this article suggest that the manipulation of these compounds may provide a method of producing a pharmacological delay phenomenon and perhaps even allow effective intervention in the failing flap.

Topics: Animals; Dogs; Epoprostenol; Female; Imidazoles; Ischemia; Platelet Aggregation; Prostaglandins F; Skin; Surgical Flaps; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Neonatal group B streptococcal (GBS) sepsis produces pulmonary arterial hypertension and hypoxemia that are preventable by pretreatment with the selective thromboxane A2 synthase inhibitor, dazmegrel. In the present experiment we administered dazmegrel (8 mg/kg) 2 h after the initiation of a 2 1/2 h infusion of 5 X 10(8) GBS/kg/h in ten 2- to 3-wk-old piglets. The multiple inert gas elimination technique was used to measure intrapulmonary shunt and alveolar ventilation to pulmonary perfusion mismatching. Thromboxane B2, the stable metabolite of thromboxane A2, and 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin, were assayed in arterial blood. Pulmonary arterial pressure increased immediately after initiation of the GBS infusion, rising from 12 +/- 2 to 34 +/- 4 torr (p less than 0.02); pulmonary vascular resistance increased by 400% (p less than 0.01). Arterial hypoxemia developed (p less than 0.02) in association with an increase in the low ventilation-perfusion ratio index but without a significant increase in intrapulmonary shunt. Thromboxane B2 levels increased 10-fold. Infusion of the carrier substance for dazmegrel after 2 h of GBS infusion produced no change in any variables. In contrast, infusion of the drug resulted in the return to pre-GBS infusion baseline values for both pulmonary arterial pressure and pulmonary vascular resistance. However, no improvement in arterial pO2 or in the low ventilation-perfusion ratio index occurred. Both pulmonary vascular resistance and pulmonary arterial pressure remained normal for 0.5 h after dazmegrel administration despite continued GBS infusion. Thromboxane B2 levels were decreased 30 min after dazmegrel (p less than 0.02), but remained greater than pre-GBS levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Blood Pressure; Imidazoles; Infusions, Intravenous; Pulmonary Wedge Pressure; Sepsis; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Thromboxane-A Synthase; Time Factors

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

Thromboxane A2 is a prostanoid having potent platelet aggregatory and vasoconstrictor properties. To determine a possible role for thromboxane A2 in the development of severe hypertension and stroke, we chronically administered the selective thromboxane A2 synthase inhibitor UK-38,485 (Dazmegrel) to stroke-prone spontaneously hypertensive rats (SHRSP). Serum thromboxane B2 (the stable hydrolysis product of thromboxane A2) generation was significantly greater in incubates of whole blood from SHRSP than in those from normotensive control Wistar-Kyoto rats and was inhibited greater than 89% by UK-38,485 administered in vivo. In 10 male SHRSP fed a Japanese-style rat chow and given 1% NaCl in drinking water to accelerate the occurrence of stroke, treatment with 100 mg/kg/day UK-38,485 by gavage starting at 8.6 weeks of age diminished systolic blood pressure elevation at 10 (205 +/- 2 vs. 220 +/- 4 mm Hg, p less than 0.01) and 11 weeks of age (210 +/- 4 vs. 239 +/- 7 mm Hg, p less than 0.01) compared with 10 untreated SHRSP. The ultimate establishment of severe hypertension was not prevented by UK-38,485. Stroke-related mortality was 70% in both UK-38,485-treated and control SHRSP at 14 weeks of age. Histologic examination revealed cerebrovascular lesions consistent with the occurrence of stroke in both control and UK-38,485-treated SHRSP. Our results support a possible role for thromboxane A2 in the elevation of blood pressure in SHRSP but do not support a possible role for the prevention of stroke by thromboxane A2 synthase inhibition in these rats.

Topics: Animals; Blood Pressure; Brain; Cerebrovascular Disorders; Disease Susceptibility; Hypertension; Imidazoles; Male; Osmolar Concentration; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane B2

In 8 female pigs complete unilateral ureteral obstruction was investigated over a 4 weeks period. The pigs were monitored with intrapelvic pressure measurements and by 131-I-hippuran scintigraphy twice a week; one group without and one with TxA2 blocking, UK-38,485 [3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indol-1-propanoic acid], which is a well-known selective thromboxane synthetase inhibitor. During the course of obstruction there was an ipsilateral linear reduction of split function to background level and a net reduction in total hippuran clearance in both groups. On the obstructed side there was a linear reduction of hippuran clearance from 116 +/- 26 ml/min to 11 +/- 3 ml/min during the first 2 weeks of obstruction. The TxA2 synthetase inhibitor, 5 mg/kg reduced se-TxB2 to almost zero for at least one hour after i.v. administration. One week after obstruction the pelvic pressure was 45 +/- 5 cm H2O) administration of the TxA2 synthetase inhibitor. The pelvic pressure remained elevated throughout the period of observation. The study confirmed earlier work which showed that total ureteral obstruction caused complete cessation of kidney function within a few weeks, but contradicts previous studies because there was no increase in renal blood flow after thromboxane blockade. These differences may be explained by several mechanisms. The continuing increase in pelvic pressure suggested that it was not only a preglomerular vasoconstriction which was responsible for the renal flow reduction, but that there was also a postglomerular vasoconstriction.

Topics: Animals; Imidazoles; Iodohippuric Acid; Kidney; Pelvis; Pressure; Regional Blood Flow; Swine; Thromboxane B2; Thromboxane-A Synthase; Ureteral Obstruction; Vasoconstriction

We examined the effect of glomerular immune complex (IC) deposition on glomerular eicosanoid synthesis and the role of the eicosanoids in glomerular pathophysiology. Rats received daily 10 mg i.v. injections of native bovine gamma-globulin (NBGG) or cationic bovine gamma-globulin (CBGG) for 21 days; age-matched controls were maintained. Immunofluorescence and electron microscopy showed mesangial deposits of IC in the NBGG group and capillary wall deposits in the CBGG group, without light or electron microscopic evidence of leukocyte infiltration. One week after the last antigen dose, GFR was similar in all three groups, but RPF increased in the rats given CBGG; (8.37 +/- 0.90 vs. control 5.54 +/- 0.56 ml/min, P less than 0.05). Glomerular synthesis of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) was normal in animals that received NBGG. Rats given CBGG had increased glomerular production of PGE2, (2.23 +/- 0.37 vs. control 1.03 +/- 0.16 ng/mg glomerular dry wt, P less than 0.05) and TxB2 (3.12 +/- 0.50 vs. control 0.48 +/- 0.07 ng/mg glomerular dry wt, P less than 0.001). Proteinuria only developed in the rats given CBGG, 86.6 +/- 18 mg/24 hr, which correlated with glomerular TxA2 synthesis, r = 0.82, P = 0.01. Acute administration of the TxA2 synthesis inhibitor, UK-38,485, and a TxA2 receptor antagonist, EP-092, to rats given CBGG did not affect GFR or RPF. The cyclo-oxygenase inhibitor, indomethacin, reduced both GFR and RPF by up to 40% in CBGG-immunized rats. Oral administration of UK-38,485 for six days to nephrotic rats did not result in a statistically significant reduction of proteinuria despite 85% inhibition of glomerular TxB2. We conclude that cationic antigen induces a glomerular disease pathologically similar to membranous nephropathy. The increment of RPF is most probably due to increased glomerular PGE2. The increased TxA2 has no effect on glomerular hemodynamics and probably is not a component in the pathogenesis of proteinuria.

Topics: Animals; Antigen-Antibody Complex; Cations; Dinoprostone; gamma-Globulins; Glomerular Filtration Rate; Glomerulonephritis; Imidazoles; Immunization; Immunoglobulin G; In Vitro Techniques; Indomethacin; Kidney Glomerulus; Microscopy, Electron; Prostaglandins E; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane B2

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

Indomethacin has been used to lower proteinuria in human glomerular diseases with controversial results. The mechanism of indomethacin beneficial effects has not been established. A possible explanation is that indomethacin reduces proteinuria by inhibiting the synthesis of renal prostaglandins (PGs); however, appropriate studies to address this issue have never been done. The objectives of the present study were: to investigate whether indomethacin influences protein excretion in an experimental model of immunologically-mediated glomerular disease; to establish if the possible favorable effect of indomethacin on proteinuria is related to a reduction in glomerular filtration rate (GFR); to establish the possible association between the antiproteinuric effect of indomethacin and its inhibitory effect on arachidonic acid (AA) metabolites of renal or extrarenal origin; and to further investigate the relationship between proteinuria and renal thromboxane (Tx) synthesis previously demonstrated in experimental models of nephrotoxic nephritis and adriamycin (ADR) nephrosis. To this purpose we used an experimental immune-complex disease, passive Heymann nephritis (PHN) which was induced in the rat by a single intravenous (i.v.) injection of heterologous serum directed against a brush border component (gp 330 antigen). Indomethacin at a dose of 6 mg/kg intraperitoneally (i.p.) administered for four consecutive days to PHN animals during the period of heavy proteinuria, effectively reduced urinary protein excretion. The reduction in proteinuria does not appear to be a consequence of a reduction in GFR as documented by inulin clearance. Glomerular synthesis and urinary excretion of vasodilatory prostacyclin (PGI2) and PGE2 were decreased or unchanged in PHN animals in respect to control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dinoprostone; Glomerulonephritis; Imidazoles; Immune Complex Diseases; In Vitro Techniques; Indomethacin; Kidney Function Tests; Kidney Glomerulus; Male; Microvilli; Prostaglandins E; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane B2; Time Factors

The five stable metabolites [prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha)] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in M5076 ovarian reticulosarcoma (M5) homogenates at various times after tumor implantation (Days 15, 18, 21, and 24). Vegetating tumor showed an active AA overall metabolism, which significantly increased during tumor growth. Synthesis of selected products (TXB2, PGD2, and PGE2) increased markedly over time (up to 10.6, 3.5, and 0.9 micrograms/g, respectively). The overall metabolic profile was TXB2 much greater than PGD2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 on Day 15 and TXB2 much greater than PGD2 much greater than PGF2 alpha greater than 6-keto-PGF1 alpha on Day 24. TXB2 was also by far the most abundant product of in vitro-cultured M5 cells. Chronic treatment of M5-bearing mice with dazmegrel (UK-38,485), a selective thromboxane synthetase inhibitor (100 mg/kg p.o. daily, from Day 7 to killing), resulted in incomplete TXB2 synthesis inhibition, AA metabolism diversion toward the other prostaglandins, and no effects of tumor growth and metastasis. More frequent dazmegrel treatment (100 mg/kg p.o. every 8 h from Day 1 to killing) resulted in complete TXB2 synthetase inhibition, AA metabolism diversion, and increased tumor growth and metastasis. These data do not support the hypothesis of thromboxane synthetase inhibitors reducing tumor growth. However, since TXB2 suppression was accompanied by the production of other products possibly interfering in tumor growth, no conclusions on the effective role of TXA2 in malignancy can be drawn.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Dinoprostone; Female; Gas Chromatography-Mass Spectrometry; Imidazoles; Lymphoma, Non-Hodgkin; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Ovarian Neoplasms; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

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

Because thromboxane synthesis enhances gastric mucosal damage we have investigated whether the thromboxane synthesis inhibitor dazmegrel might be protective to the mucosa. Dazmegrel at a dose of 1 and 5 mg per rat (4.8 and 23.8 mg/kg) significantly reduced the damage caused by acidified taurocholate. In parallel experiments dazmegrel exerted a selective and dose dependent inhibition of ex vivo thromboxane synthesis by gastric fragments over the dose range in which protection was observed. As dazmegrel can be given to man, these experiments suggest that investigation of mucosal protection would be justified.

Topics: Animals; Dinoprostone; Dose-Response Relationship, Drug; Gastric Mucosa; Imidazoles; Male; Prostaglandin Antagonists; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase

To determine whether the induction of immune-mediated glomerular injury influences the formation of cyclooxygenase products by glomerular cells, we determined prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) (as the stable metabolite of TXA2) formation in isolated glomeruli of rats with passive Heymann nephritis (PHN). PHN is a model of membranous nephropathy mediated by antibody and complement independent of inflammatory cells. Five days following induction of PHN by injection of heterologous antibody to rat proximal tubular brush border antigen (Fx1A) rats developed proteinuria 36.5 +/- 34 (controls 3.8 +/- 1 mg/day). Treatment with cobra venom factor, which depleted complement C3 levels to less than 10% of baseline, prevented the development of proteinuria (6.9 +/- 2 mg/day). The development of subepithelial, glomerular immune-complex deposits and proteinuria was associated with a significant stimulation of glomerular PGE2 (87%) and TXB2 (183%) formation. This increment in glomerular prostanoid biosynthesis was significantly inhibited (PGE2 increased 22%, TXB2 increased 75%) in animals that were complement depleted with cobra venom factor. Cobra venom factor had no effect on glomerular prostanoid formation in normal rats. In additional experiments we tested the hypothesis that TXA2 may contribute to mediation of proteinuria in PHN. We utilized a thromboxane synthetase inhibitor UK38485. UK38485 reduced glomerular TXB2 formation by 80% without influencing glomerular deposition of 125I-labeled antibody, and did not alter levels of urine protein excretion in rats with PHN (control 42 +/- 21, UK 38485, 39 +/- 24 mg/day, P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Complement C3; Dinoprostone; Glomerulonephritis; Imidazoles; Kidney Glomerulus; Male; 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

The capacity of platelets to generate thromboxane A2, reflected by measurement of serum thromboxane B2 (TxB2), greatly exceeds the systemic production of thromboxane in vivo. Thus, it is possible that substantial but incomplete inhibition of thromboxane formation ex vivo would still allow marked augmentation of thromboxane production in vivo. To address this hypothesis, we administered aspirin 120 mg, a selective inhibitor of thromboxane synthase (TxSl), 3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid (UK-38, 485) 200 mg, and a combination of both drugs to 12 healthy volunteers and measured the effects on serum TxB2 and urinary 2,3-dinor-thromboxane B2 (Tx-M), an index of endogenous thromboxane biosynthesis. Although serum TxB2 was maximally inhibited by 94 +/- 1% after aspirin and 96 +/- 2% after the TxSl, maximal depression of Tx-M was only 28 +/- 8% and 37 +/- 9%, respectively. Combination of aspirin with the TxSl resulted in a small but significant increase in inhibition of thromboxane generation ex vivo (98 +/- 1% v 94 +/- 1%; P less than 0.05), but a disproportionately greater fall in thromboxane synthesis in vivo (58 +/- 7%; P less than 0.01). Consistent with further inhibition of platelet thromboxane synthesis, addition of the TxSl abolished the transient decline in prostacyclin formation after aspirin alone. Administration of a lower dose of aspirin (20 mg) to 6 healthy subjects caused a small reduction in Tx-M (12 +/- 4%; P less than 0.05) and inhibited serum TxB2 by 48 +/- 2%. The relationship between inhibition of platelet capacity to form thromboxane ex vivo (serum TxB2) and synthesis in vivo (Tx-M) departed markedly from the line of identity. When total blockade of the capacity of platelets to generate thromboxane is approached, minor decrements in capacity result in a disproportionate depression of actual thromboxane biosynthesis. These results imply that pharmacologic inhibition of serum TxB2 must be virtually complete before thromboxane-dependent platelet activation is influenced in vivo.

Topics: Adult; Aspirin; Blood Platelets; Humans; Imidazoles; Male; Metabolic Clearance Rate; Middle Aged; Platelet Count; Salicylates; Thromboxane A2; Thromboxane B2

We examined the possibility that glomerular prostaglandin E2 (PGE2) regulates the action of angiotensin II (ANG II) on mesangial contraction and filtration surface area. Using isolated rat glomeruli we indirectly assessed mesangial contraction and filtration surface area through measurements of glomerular planar surface area (GPSA) by image-analysis microscopy. ANG II reduced GPSA by approximately 20% in human and rat glomeruli, with threshold concentrations of 1 X 10(-13) M and maximum effect at 5 X 10(-11) M ANG II. Inhibition of glomerular PG synthesis with indomethacin or meclofenamate potentiated the threshold response of ANG II to reduce GPSA. Arachidonic acid (5 micrograms/ml) blunted both the threshold and the maximum responses of GPSA to ANG II. PGE2, 10(-8) and 10(-9) M, also decreased glomerular contraction to ANG II. Endoperoxide (EP) analogues decreased GPSA and EP 045, a thromboxane A2 (TXA2) receptor blocker, eliminated the contractile responses of glomeruli to the EP analogues. Authentic TXA2, synthesized from sheep platelet microsomes, also reduced GPSA. We conclude that glomerular products of arachidonate cyclooxygenation may either relax or contract the mesangium, thereby preserving or reducing filtration surface area. PGE2 exerts protective actions to reduce the mesangial contraction of ANG II, primarily through postreceptor effects. TXA2 may decrease glomerular filtration rate in certain diseases through direct actions on the mesangium.

Topics: Angiotensin II; Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cyclooxygenase Inhibitors; Dinoprostone; Eicosanoic Acids; Humans; Imidazoles; Kidney Glomerulus; Methacrylates; Microsomes; Prostaglandins E; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

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

In vitro formation of prostaglandins (PG) E2, F2 alpha, 6-keto-F1 alpha, and thromboxane B2 (TxB2) by glomeruli from rats with reduced renal mass (RRM) were evaluated by radioimmunoassay. Four weeks following ablation of renal mass, PGE2, PGF2 alpha, and TxB2 production by glomeruli from RRM rats was significantly greater, when compared with glomerular PG and TxB2 production of sham-operated control (C) rats. The effect of cyclooxygenase inhibition with indomethacin and the selective inhibition of thromboxane formation with UK 38485 on glomerular filtration rate (GFR) was investigated in experiments in vivo. In RRM rats indomethacin reduced GFR from 212 +/- 17 to 138 +/- 14 microliter/100 g/body weight (p less than 0.05) without effect on C rats. Thromboxane synthesis inhibition with UK 38485, however, increased GFR significantly in RRM rats (221 +/- 26 to 303 +/- 21; p less than 0.05). The data suggest that vasodilatory PGs and TxB2 modulate GFR in rats with ablation of renal mass.

Topics: Animals; Dinoprost; Dinoprostone; Glomerular Filtration Rate; Imidazoles; In Vitro Techniques; Indomethacin; Kidney; Kidney Glomerulus; Male; Prostaglandins; Prostaglandins E; Prostaglandins F; Rabbits; Rats; Rats, Inbred Strains; Thromboxane B2

Twenty-four hours of complete unilateral ureteral obstruction (UUO) produces intense renal vasconstriction in the rat even after release of obstruction. In the ex vivo perfused hydronephrotic rabbit kidney, bradykinin stimulates increased production of the vasoconstrictor autocoid thromboxane. In the present study, we measured basal and bradykinin-stimulated thromboxane and prostaglandin E2 production by UUO and contralateral rat kidneys perfused ex vivo. Furthermore, we evaluated thromboxane synthetase inhibition by imidazole and by two of its substituted derivatives, UK 37248 and UK 38485, in vitro. We compared these in vitro findings with in vivo measurements of renal hemodynamics and excretory function before and after the intrarenal artery administration of thromboxane synthetase inhibitors. Both basal and bradykinin-stimulated thromboxane and prostaglandin E2 production were significantly increased in hydronephrotic kidneys. Imidazole and its substituted congeners were effective inhibitors of bradykinin-stimulated thromboxane B2 production in vitro. However, the substituted imidazoles were more potent, more efficacious, and more selective for thromboxane synthetase inhibition than the parent compound. In vivo, administration of imidazole into the renal artery of the UUO kidney improved function slightly, whereas administration of UK 37248 or UK 38485 doubled renal blood flow and excretory function but did not restore them to normal. We conclude that the hydronephrotic rat kidney produces increased amounts of the vasoconstrictor eicosanoid thromboxane and that thromboxane is an important mediator of vasoconstriction in this model of disease.

Topics: Animals; Dinoprostone; Dose-Response Relationship, Drug; Hydronephrosis; Imidazoles; Methacrylates; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Ureteral Obstruction

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

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

Whereas numerous studies have investigated the role of prostacyclin and thromboxane A2 in the maintenance of coronary blood flow, most of these have focused on normal vessels. In the present investigation, we examined the prostaglandin- and thromboxane-synthesizing capacity of isolated coronary artery segments obtained from the site of a critical coronary artery stenosis. Cyclic flow variations were produced by placing a hard cylindrical constrictor on the proximal left anterior descending coronary artery in open-chest, anesthetized dogs. Cyclic flow variations are characterized by progressive declines in coronary blood flow, interrupted by sudden spontaneous restorations of flow. After cyclic flow variations had been induced, the hearts were removed, and the left anterior descending and circumflex coronary arteries were dissected. The vessels were cut into segments and incubated in the presence of increasing concentrations of arachidonic acid (10(-4)-10(-6) M). The synthesis of prostaglandin E2, thromboxane B2, and 6-keto prostaglandin F1 alpha by the coronary segments was measured by radioimmunoassay. When incubated in the presence of 10(-5) M arachidonic acid, coronary artery segments obtained from the left anterior descending coronary artery undergoing cyclic flow variations produced substantially more thromboxane B2 (142 +/- 27 vs. 29 +/- 3 pg/mg P less than 0.01) and less 6-keto prostaglandin F1alpha (125 +/- 12 vs. 350 +/- 30 pg/mg, P less than 0.01) than control circumflex coronary artery segments. Circumflex coronary vessels in which the endothelium was removed ex vivo produced 6-keto prostaglandin F1alpha levels comparable to those found in the left anterior descending coronary artery (147 +/- 17 pg/mg), but did not synthesize thromboxane B2 (23 +/- 2.6 pg/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aortic Valve Stenosis; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Coronary Circulation; Coronary Vessels; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Imidazoles; Male; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Regional Blood Flow; Thromboxane A2; Thromboxane B2; Thromboxanes

The effect of inhibiting endogenous brain thromboxane (TXB2) on pentylenetetrazole-induced seizures was studied using the thromboxane synthetase inhibitors OKY-1581 (20 mg/kg) and UK 38,485 (50 mg/kg). Both compounds selectively decreased (greater than 90%) TXB2 production in brain measured after 2 min of convulsive activity but had no effect on brain PGE2, PGF2 alpha, or 6-keto-PGF1 alpha. No effect of these agents on the tonic seizure threshold was observed, whereas 10 mg/kg ip indomethacin, an agent which inhibits both TXB2 and prostaglandin production, reduced the tonic seizure threshold from 78 +/- 2.6 mg/kg in controls to 62 +/- 3.7 mg/kg. Thus, this study concludes that the availability of TXB2 with convulsant activity is unlikely to be a factor in altering tonic seizure activity observed with indomethacin.

Topics: Animals; Brain; Brain Chemistry; Female; Imidazoles; Indomethacin; Methacrylates; Mice; Pentylenetetrazole; Prostaglandins; Seizures; Thromboxane B2; Thromboxanes

Altered glomerular metabolism of arachidonic acid (AA) has already been demonstrated in experimental nephrotoxic nephritis. The enhanced synthesis of thromboxane A2 (TxA2) in isolated glomeruli that has been found may mediate changes in renal hemodynamics. The objectives of this investigation were: to check whether glomerular AA metabolism is also altered in a model of glomerulopathy in which no leukocyte infiltration or platelet deposition could be demonstrated; to establish a correlation between the altered AA metabolism and proteinuria; and to explore whether the alteration of the prostaglandin (PG) pathway found in isolated glomeruli is an in vitro artifact or reflects a modification in vivo. We used a model of glomerular damage characterized by heavy and persistent proteinuria, which was induced in the rat by a single intravenous injection of adriamycin. At light microscopy, minimal glomerular abnormalities were found in this model. Electron microscopy showed profound alterations of glomerular epithelial cells with extensive fusion of foot processes and signs of epithelial cell activation. Electron microscopy of numerous glomeruli showed no platelet deposition or macrophage and leukocyte infiltration in this model. Isolated glomeruli from nephrotic rats studied 14 or 30 d after a single intravenous injection of adriamycin (7.5 mg/kg) when animals were heavily proteinuric generated significantly more TxB2, the stable breakdown product of TxA2, than normal glomeruli. No significant changes were found in the other major AA metabolites formed through cyclooxygenase. Urinary excretion of immunoreactive TxB2 was also significantly higher in nephrotic than in normal animals. Administration of a selective Tx synthetase inhibitor, UK-38,485, from day 14 to day 18 after adriamycin resulted in a significant reduction of proteinuria compared with pretreatment values. Glomerular synthesis and urinary excretion of TxB2 were normal during the UK-38,485 treatment. Additional experiments showed that elevated glomerular synthesis and urinary excretion of TxB2 were not a consequence of increased substrate availability. Maximal stimulation of the renin-angiotensin axis with furosemide increased glomerular TxB2 synthesis in normal rats, which was significantly lower than in nephrotic animals. Finally, experiments using a unilateral model of adriamycin nephrosis indicated that the enhancement of glomerular TxB2 synthesis is not simply a consequence of the nephrotic syndro

Topics: Animals; Blood Platelets; Doxorubicin; Imidazoles; Kidney; Kidney Glomerulus; Male; Nephrosis; Prostaglandins; Proteinuria; Rats; Rats, Inbred Strains; Sulindac; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Time Factors

The purpose of this investigation was to determine the effects of thromboxane synthase inhibition on vascular responsiveness. To achieve this goal, the effects of thromboxane synthase inhibitors on mesenteric vascular responses to sympathetic nerve stimulation, norepinephrine, and angiotensin II were determined in vivo. In normotensive rats, chronic treatment with the thromboxane synthase inhibitor, UK38,485 (100 mg/kg X d X 7 d), attenuated vascular responses to nerve stimulation and angiotensin II, but not to norepinephrine. Indomethacin treatment (5 mg/kg X three doses) did not attenuate vascular responses, but did prevent chronic UK38,485 administration from attenuating vascular reactivity. A single dose of UK38,485 (100 mg/kg) did not modify vascular responses to nerve stimulation or angiotensin II, even though platelet thromboxane synthase was inhibited completely. In spontaneously hypertensive rats, chronic administration (100 mg/kg X d X 7 d) of either UK38,485, OKY1581, or U-63557A (three structurally distinct thromboxane synthase inhibitors) attenuated vascular responses to nerve stimulation and angiotensin II. Only U-63557A suppressed responses to norepinephrine. Chronic treatment with UK38,485 or U-63557A did not influence vascular reactivity in hypertensive rats treated with indomethacin. Also, chronic administration of lower doses of UK38,485 or U-63557A (30 mg/kg X d X 7 d) did not affect vascular responsiveness in hypertensive rats, despite complete blockade of platelet thromboxane synthase. These data indicate that chronic administration of high doses of thromboxane synthase inhibitors attenuates vascular responses to sympathetic nerve stimulation and angiotensin II, but not usually to norepinephrine. This action may be mediated by endoperoxide shunting within the blood vessel wall.

Topics: Acrylates; Angiotensin II; Animals; Aorta, Abdominal; Benzofurans; Blood Platelets; Blood Pressure; Electric Stimulation; Imidazoles; Methacrylates; Norepinephrine; Rats; Thromboxane B2; Thromboxane-A Synthase; Vascular Resistance

The purpose of this study was to determine the effects of chronic administration of the thromboxane synthetase inhibitor, UK 38,485, on noradrenergic neurotransmission. Male Sprague Dawley rats (n = 14) were treated once daily with either UK 38,485 (100 mg/kg; n = 7) or the vehicle of UK 38,485 (olive oil; n = 7) by gavage. The dose of UK 38,485 chosen was sufficient to inhibit ex vivo platelet TXB2 production by greater than 90% for 24 hours. One week into the treatment animals were prepared for in situ perfusion of their mesenteric vascular beds. Vasoconstrictor responses to both exogenous norepinephrine and periarterial nerve stimulation were determined both before and during an infusion of angiotensin II (9 ng/min) into the superior mesenteric artery. UK 38,485 significantly (P less than 0.02) attenuated the vascular response to periarterial nerve stimulation without altering the vascular response to either norepinephrine or angiotensin II. UK 38,485 did not influence the baseline perfusion pressure, the mean arterial blood pressure or the potentiation of neurotransmission by angiotensin II. These data indicate that in the in situ rat mesentery UK 38,485 attenuates the release of neurotransmitter from sympathetic nerve terminals.

Topics: Angiotensin II; Animals; Blood Pressure; Drug Synergism; Electric Stimulation; Imidazoles; Male; Norepinephrine; Oxidoreductases; Perfusion; Rats; Rats, Inbred Strains; Synaptic Transmission; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

The effects of two thromboxane synthetase inhibitors ( dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat. Infusion of E. coli endotoxin (41.7 ng kg-1 min-1) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia. The above changes were accompanied by a marked elevation in plasma thromboxane B2 concentrations (e.g. endotoxin-treated 935 +/- 150 pg ml-1 at 1 h compared with pre-endotoxin values of 125 +/- 30 pg ml-1). The administration of either dazoxiben (30 mg kg-1 i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg-1 given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B2 concentrations. Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality. These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.

Topics: Animals; Blood Glucose; Blood Pressure; Escherichia coli; Heart Rate; Imidazoles; Lactates; Lactic Acid; Male; Platelet Count; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2; Thromboxanes

The purpose of this investigation was to study the effects of a selective thromboxane A2 (TXA2) synthetase inhibitor (TSI) upon the evolution of cerebral infarction in the cat. Adult cats, lightly anesthetized with nitrous oxide, underwent right middle cerebral artery (MCA) occlusion for 4 hours followed by a 2-hour period of reperfusion before sacrifice. Ten cats received 3 mg/kg TSI intravenously immediately before, and 10 cats received 3 mg/kg TSI intravenously immediately after MCA occlusion. Ten cats were used as controls receiving no treatment. The bleeding time was determined at baseline and at the end of each experiment. Electroencephalographic (EEG) recordings were obtained before and after MCA clipping and MCA release, and at hourly intervals thereafter. Regional cerebral blood flow (rCBF) was measured using the xenon-133 (133Xe) clearance technique before and after MCA occlusion, after MCA reopening, and before terminating each experiment. Thirty minutes before each cat was sacrificed, Evans blue dye and sodium fluorescein were given intravenously. The animals were then perfused with colloidal carbon and the brains removed and evaluated for midline shift. Evans blue dye and sodium fluorescein extravasation, carbon staining, and infarct size. The bleeding time, arterial blood pressure, rCBF changes, brain swelling, and vital dye extravasation were not statistically different between the three treatment groups. The EEG changes, carbon staining, and infarct size differences between the three groups also failed to reach statistical significance, but there was a suggestion that these parameters were adversely affected in the cats pretreated with TSI. Ten additional cats undergoing MCA occlusion and reperfusion were used for pharmacological studies. Five of them received 3 mg/kg TSI intravenously immediately after MCA occlusion, and serial drug and thromboxane B2 (TXB2) levels (a stable metabolite of TXA2) were determined. Another five cats were not treated and serial TXB2 levels were obtained. Production of TXA2 was inhibited by 95% in cats receiving TSI. In conclusion, thromboxane synthetase inhibition failed to modify favorably the evolution of cerebral infarction. When TSI was given before MCA occlusion, cerebral infarction tended to be more extensive.

Topics: Animals; Brain Ischemia; Cats; Cerebral Infarction; Imidazoles; Oxidoreductases; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes