thromboxane-b2 and 2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid

Thromboxane has characteristics that signify potential importance in cardiovascular disease states. In models developed for studying thrombotic sudden death, thromboxane appears to be an important mediator. Thus, in arachidonic acid-induced sudden death, agents that either inhibit thromboxane generation or block thromboxane receptor activation prevent the occurrence of thrombotic death. Thromboxane mimetics are also useful in modeling sudden death; when injected i.v., these compounds elicit effects similar to those obtained with arachidonic acid. In this case, however, pretreatment with cyclooxygenase or thromboxane synthetase inhibitors confers no protection, whereas the thromboxane receptor antagonist retains its efficacy. Other factors that affect susceptibility to experimental sudden death include gender, species, and endocrine status. Thrombotic sudden death models have now been used to test, in vivo, the in vitro antiplatelet aggregatory effect of calcium-channel blockers. The data suggest that dihydropyridine agents such as nifedipine and nisoldipine are protective against thrombosis, whereas verapamil may have little such activity. Furthermore, sudden death induced by a variety of thrombotic challenges is prevented by pretreatment with nifedipine. The thrombotic sudden death models currently employed are useful for the in vivo study of the thrombotic process and for the evaluation of agents with potentially thrombotic or antithrombotic properties.

Topics: Angina Pectoris; Animals; Arachidonic Acid; Arachidonic Acids; Calcium Channel Blockers; Castration; Death; Estrogens; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Glucocorticoids; Humans; Male; Methacrylates; Prostaglandin Endoperoxides, Synthetic; Sex Factors; Testosterone; Thrombosis; Thromboxane A2; Thromboxane B2; Thromboxanes

In vitro pharmacological profiles of E3040, 6-hydroxy-5, 7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazole were investigated. Against the 5-lipoxygenase activity of rat basophilic leukemia cells, E3040 and zileuton (a 5-lipoxygenase inhibitor) had an IC(50) of 0.23 and 0.93 microM, respectively. Against the thromboxane A(2) synthetase activity of human platelets, E3040 had an IC(50) of 0.01 microM, which was comparable to that of OKY-1581 (sodium (E)-3-[4-(3-pyridylmethyl) phenyl]-2-methylacrylate, a thromboxane A(2) synthetase inhibitor). Against cyclooxygenase activity of sheep seminal vesicles, E3040 showed no inhibition (IC(50), >300 microM). Sulfasalazine and 5-aminosalicylic acid, therapeutic drugs for inflammatory bowel disease, inhibited 5-lipoxygenase activity with an IC(50) of 293 and 970 microM, respectively. Sulfasalazine inhibited thromboxane A(2) synthetase activity with an IC(50) of 20 microM. In rat peritoneal leukocytes, E3040 inhibited leukotriene B(4) and thromboxane B(2) production with an IC(50) of 0.17 and 0.24 microM, respectively. E3040 inhibited leukotriene B(4) production in human neutrophils and thromboxane B(2) production in human platelets (IC(50) of 0.21 and 0.09 microM, respectively). These results indicated that E3040 potently inhibited 5-lipoxygenase and thromboxane A(2) synthetase and blocked leukotriene B(4) and thromboxane B(2) production in rat peritoneal and human blood cells.

Topics: Animals; Arachidonate 5-Lipoxygenase; Benzothiazoles; Dinoprostone; Dose-Response Relationship, Drug; Eicosanoids; Humans; Hydroxyurea; Indomethacin; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mesalamine; Methacrylates; Neutrophils; Peritoneal Cavity; Prostaglandin-Endoperoxide Synthases; Pyridines; Rats; Rats, Inbred F344; Sheep; Sulfasalazine; Thiazoles; Thromboxane B2; Thromboxane-A Synthase

Eicosanoids, as modulators of inflammation, may be involved in the pathogenesis of inflammatory bowel disease. We investigated their potential role in a rat model of chronic granulomatous colonic inflammation induced by trinitrobenzene sulphonic acid. Luminal eicosanoid release was quantified in vivo using a dialysis bag placed into the distal colon. We tested the effect of drugs known to modify inflammatory activity or arachidonic acid metabolism. Three days after intracolonic injection of trinitrobenzene sulphonic acid at different dose levels, the dialysates showed a highly significant increase of prostaglandin E2, 6-keto-prostaglandin F1 alpha, thromboxane B2 (TXB2), and leukotriene B4, compared with levels in controls not subjected to the toxic agent. Remarkably, the release of TXB2 continued to increase during the stage of chronic inflammation (up to day 21), whereas the levels of the remainder eicosanoids declined. Treatment with prednisone or 5-aminosalicylic acid reduced TXB2 levels in the chronic stage of the inflammatory disease and improved the morphological damage as assessed macroscopically and histologically. Moreover, two selective thromboxane synthetase inhibitors, OKY 1581 and R70416, significantly reduced the development of chronic inflammatory lesions in the colon while inhibiting the release of TXB2. Our results indicate that (1) luminal release of thromboxane increases in the chronic stage of colonic inflammation, (2) anti-inflammatory treatment reduces tissue damage and thromboxane release, and (3) selective thromboxane synthetase inhibition improves the course of the disease in our experimental model.

Topics: 6-Ketoprostaglandin F1 alpha; Aminosalicylic Acids; Animals; Colitis; Dinoprostone; Indomethacin; Leukotriene B4; Male; Mesalamine; Methacrylates; Pentanoic Acids; Prednisone; Pyridines; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Trinitrobenzenesulfonic Acid

Radiotracer studies and radioimmunoassay measurements demonstrate that minced tissues of human decidua produce chiefly thromboxane B2 (TxB2) (70% of total eicosanoids) and small amounts of prostaglandin F2 alpha (PGF2 alpha) (13%) PGD2 (8%), 6-keto-PGF1 alpha (5%) and PGE2 (4%). Inhibition of thromboxane synthesis with a specific inhibitor (OKY-1581: sodium (E)-3-[4(-3-pyridylmethyl)-phenyl]-2-methyl propenoate) increased prostaglandin formation in general, with the main product being PGF2 alpha (38%), a nonenzymic derivative of PGH2. Crude particulate fractions prepared from the same tissue synthesized two major products from [3H]arachidonate, TxB2 and 6-keto-PGF1 alpha (54 and 30%, respectively) and some PGF2 alpha and PGE2 (8-8%). However, in the presence of reduced glutathione (GSH), PGE2 became the main product (81%) (TxB2, 15%; PGF2 alpha, 2%; and 6-keto-PGF1 alpha, 2%). Half-maximal stimulation of PGE2 synthesis occurred at 46 microM GSH. The GSH concentration of tissue samples was found to be 110 +/- 30 microM. We conclude that human first trimester decidua cells possess the key enzymes of prostaglandin and thromboxane synthesis. Apparently, the production of these compounds is controlled by a specific mechanism in the tissue, which keeps PGE and prostacyclin synthesis in a reversibly suppressed state, whereas the formation of thromboxane is relatively stimulated.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Cell-Free System; Decidua; Dinoprost; Dinoprostone; Female; Glutathione; Humans; Methacrylates; Pregnancy; Prostaglandin D2; Prostaglandins; Thromboxane B2; Thromboxane-A Synthase

Leukotriene B4 contracts guinea pig lung parenchymal strips by an indirect mechanism dependent upon formation of myotropic cyclooxygenase metabolites. In contrast to the prevailing notion, our data indicate that thromboxane A2 is not necessarily the sole or essential mediator involved. Several points support this conclusion. First, the quantitative and temporal aspects of thromboxane B2 release and the myotropic response to leukotriene B4 were weakly correlated (r = 0.73). Second, the dose-response curve for thromboxane A2, based on the amount of thromboxane B2 generated by lung strips contracted with leukotriene B4, was inconsistent with dose-response curves for lung strips contracted with a stable thromboxane A2 mimetic, U-46619 or with synthetic thromboxane A2 itself. Third, thromboxane synthetase inhibitors, typified by OKY-1581 and UK-37248, did not inhibit the myotropic activity of leukotriene B4 under conditions in which thromboxane B2 formation was reduced by 80 to 90%. A thromboxane A2 receptor antagonist, BM 13.177, did not inhibit the myotropic activity of leukotriene B4 under conditions in which it antagonized the effects of U-46619. Cyclooxygenase metabolites other than thromboxane A2 must contribute to the mechanism of action of leukotriene B4 or leukotriene B4 effects may be mediated directly on certain cells or receptors.

Topics: Animals; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Leukotriene B4; Lung; Male; Methacrylates; Muscle Contraction; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

To clarify the role of thromboxane A2 (TXA2) in evoking coronary spasm, we compared coronary arterial spasticity induced by ergonovine maleate (EM) with coronary sinus thromboxane B2 (TXB2: a stable catabolite of TXA2) in 34 patients with documented variant angina and 11 patients with chest pain syndrome (CPS). We also examined the effect of OKY-1581 (8 mg/kg, i.v.), a TXA2 synthetase inhibitor, on the coronary arterial spasticity of these patients. When blood samples were taken from coronary sinus just before EM test, all patients with variant angina exhibiting markedly augmented TXB2 levels (424 +/- 138 pg/ml), had positive EM test results, while CPS exhibiting lower TXB2 levels (223 +/- 38 pg/ml), had negative EM test. We found that the amounts of EM needed to induce coronary spasm were inversely correlated with TXB2 levels in coronary sinus. In 7 out of these 8 patients, OKY-1581 was found to attenuate the increased spasticity with reduction of coronary sinus TXB2 levels. In 3 patients, an EM rechallenge at symptomatically quiescent stage resulted in negative test with augmented TXB2 levels being markedly decreased. These findings indicate that increased TXA2 in circulating plasma is closely correlated with the hypersensitivity of coronary arteries to EM in patients with variant angina, suggesting a possible role of augmented TXA2 production in the enhancement of coronary vascular spasticity.

Topics: Adult; Aged; Angina Pectoris, Variant; Coronary Circulation; Coronary Vasospasm; Ergonovine; Female; Humans; Male; Methacrylates; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

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

The appearance of the arachidonic acid metabolic pathway in human promyelocytic leukemia (HL-60) cells was investigated during 1 alpha,25-dihydroxyvitamin D-3-induced monocytic differentiation. 1 alpha,25-Dihydroxyvitamin D-3-treated HL-60 cells acquired the ability to convert [1-14C]arachidonic acid to thromboxane B2 and prostaglandin E2 during monocytic differentiation. The major cyclooxygenase product synthesized by the HL-60 cells after 3-4 days exposure to 1 alpha,25- dihydroxyvitamin D-3 (48 nM) was thromboxane B2 and its production was about 19-25-times higher than that of untreated HL-60 cells. The percent conversion of thromboxane B2 from [1-14C]arachidonic acid in the 1 alpha,25-dihydroxyvitamin D-3 (48 nM, 3 day exposure)-treated HL-60 cells was about 4.4% as compared to that (about 0.3%) of the untreated cells, whereas the percent conversion of thromboxane B2 from [1-14C]prostaglandin H2 in the 1 alpha,25-dihydroxyvitamin D-3-treated cell homogenate was about 22.4% as compared to that (about 13.6%) of the untreated cell homogenate. The stimulatory effect of 1 alpha,25-dihydroxyvitamin D-3 on thromboxane B2 production from [1-14C]arachidonic acid and from [1-14C]prostaglandin H2 in HL-60 cells was inhibited by the addition of cycloheximide (1 microgram/ml). However, 1 alpha,25-dihydroxyvitamin D-3 (48 nM) did not significantly stimulate the arachidonic acid release either in HL-60 cells or in 1 alpha,25-dihydroxyvitamin D-3-induced cells. These results suggest that the stimulatory effect of 1 alpha,25-dihydroxyvitamin D-3 on the thromboxane production in HL-60 cells was not due to the activation of phospholipase A2 but due to the induction of fatty acid cyclooxygenase and thromboxane synthetase activities. Thromboxane A2 actively produced during the monocytic differentiation of HL-60 cells could influence the cell adhesiveness of the monocyte-macrophage-differentiated cells.

Topics: Arachidonic Acid; Arachidonic Acids; Calcitriol; Carbon Radioisotopes; Cell Differentiation; Cell Line; Cycloheximide; Dimethyl Sulfoxide; Dose-Response Relationship, Drug; Humans; Leukemia, Myeloid, Acute; Methacrylates; Monocytes; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Thromboxane B2; Time Factors; Tretinoin

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

We investigated the effects of OKY-046 and OKY-1580, thromboxane A2 (TxA2) synthetase inhibitors, on plasma levels of 6-keto PGF1 alpha and TxB2 in anesthetized dogs with experimentally induced air embolism. The percentage increase of tracheal pressure induced by room air infusion was suppressed significantly by premedication with OKY-046. The percentage increase of pulmonary artery blood pressure was suppressed significantly by premedication with OKY-046 compared to that in control group. By room air infusion after the premedication with OKY-046 and OKY-1580, systemic artery blood pressure did not show any significant changes. Plasma 6-keto PGF1 alpha level showed a marked increase by an intravenous infusion of room air, and such an increase became more predominant by the premedication with OKY-046 and OKY-1580. On the other hand, plasma TxB2 level showed a marked increase by an intravenous infusion of room air, and such an increase became less predominant by the premedication with OKY-046 and OKY-1580. These results may suggest that OKY-046 and OKY-1580 are not only TxA2 synthetase inhibitors but also PGI2 synthetase accelerators and are useful drugs for treatment and prevention of thromboembolism.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Anesthesia; Animals; Blood Pressure; Dogs; Embolism, Air; Methacrylates; Pulmonary Artery; Pulmonary Embolism; Thromboxane B2; Thromboxane-A Synthase

Leukotrienes (LT) LTA4, LTB4, LTC4, LTD4 and LTE4 induced marked contractions of guinea pig lung parenchymal strips mounted in organ baths. These contractions were inhibited differentially (40-50% for LTA4, LTC4, LTD4 and LTE4, and 90% for LTB4) by indomethacin (20 micrograms.ml-1; 55.9 microM). Two novel inhibitors of thromboxane synthetase (OKY-1581 and OKY-046) reduced the myotropic activity of the lung strips and the release of prostaglandins and thromboxanes from the perfused guinea pig lungs stimulated by LTB4 and LTD4. The release of cyclooxygenase products prostaglandin F2 alpha, thromboxane B2 and 12-hydroxyheptadecatrienoic acid by guinea pig lungs following stimulation with LTB4 and LTD4 was also measured by gas chromatography-mass spectrometry. The role of prostaglandins and thromboxanes in the lung actions of leukotrienes was confirmed using a cascade superfusion system and classical organ baths. Although prostaglandins and thromboxanes contribute to the contractile effect of LTB4 on the guinea pig lung whereas they may play a lesser role in the action of the peptidoleukotrienes (approx. 40-50%), stimulation of their release by the peptidoleukotrienes is many times more effective than by LTB4.

Topics: Animals; Arachidonic Acids; Dinoprost; Female; Gas Chromatography-Mass Spectrometry; Guinea Pigs; Indomethacin; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lung; Male; Methacrylates; Prostaglandin-Endoperoxide Synthases; Prostaglandins F; SRS-A; Thromboxane B2

Previous studies have suggested an important role of thromboxane (Tx) in the pathogenesis of endotoxin shock in the rat. The present study evaluated the role of thromboxane in an LD70 primate model of endotoxin shock by administering 6 mg/kg of endotoxin to three groups of animals that were pretreated with either saline (5 ml), OKY 1581 (2 mg/kg, 10 min prior), or imidazole (25 mg/kg/hr starting 30 min prior), groups I, II, and III, respectively. There were significant differences between the groups with respect to changes in MAP, PAP, and CO. OKY 1581 effectively blocked endotoxin-induced increase in plasma Tx. However, as a result of shunting of the endoperoxides into the prostacyclin pathway, there was a greater increase in plasma 6-keto PGF1 alpha, the stable hydrolysis product of prostacyclin. Imidazole augmented the formation of both prostacyclin and Tx. Despite the differences in plasma prostanoids, there was no difference between the groups with respect to changes in platelet or WBC counts, nor in survival: I (4/10); II (4/10); III (2/6).. (i) endotoxin-induced neutropenia and decrease in the platelet count are not Tx mediated; (ii) Tx is not solely responsible for the decrease in CO during endotoxin shock; (iii) it is possible to prevent endotoxin-induced increase in the PAP by either blocking Tx formation or by increasing endogenous PGI2 production; and (iv) Tx may not be a major contributing factor in the mortality of endotoxin shock in baboons.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Hemodynamics; Imidazoles; Leukocyte Count; Male; Methacrylates; Papio; Random Allocation; Shock, Septic; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Time Factors

Ablation of greater than 70% of renal mass in the rat results in hypertension, proteinuria, and glomerular sclerosis of the remnant kidney. Rats with a remnant kidney have increased excretion of thromboxane in the urine when compared with normal rats. Chronic oral administration of OKY 1581, an inhibitor of thromboxane synthesis, in rats with a remnant kidney increases renal blood flow and glomerular filtration rate (GFR), decreases protein and thromboxane excretion in the urine, lowers blood pressure and cardiac index, and improves renal histology. The degree of hypertrophy of the remnant kidney was unaffected by administration of OKY 1581. Calculated values for single nephron plasma flow and GFR were significantly greater in rats with remnant kidneys given OKY 1581 than in rats given saline. Acute i.v. administration of OKY 1581 increased renal plasma flow and GFR in rats with a remnant kidney but not in normal rats or rats with a remnant kidney previously treated with acetylsalicyclic acid. OKY 1581 markedly inhibited platelet aggregation. We suggest that in this model of renal disease platelet aggregation and intraglomerular thrombosis play a key role in the development of glomerulosclerosis. Inhibition of platelet aggregation prevents development of glomerulosclerosis, hypertension, and cardiac hypertrophy. We suggest that hyperperfusion and hyperfiltration per se occurring in remnant glomeruli are not directly responsible for the development of glomerulosclerosis.

Topics: Acrylates; Animals; Blood Pressure; Disease Models, Animal; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Heart; Kidney; Kidney Diseases; Methacrylates; Nephrectomy; Oxidoreductases; Platelet Aggregation; Rats; Thromboxane B2; Thromboxane-A Synthase

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

Serial changes in thromboxane B2, a stable catabolite of thromboxane A2, were measured by radioimmunoassay in peripheral plasma of 55 patients with acute myocardial infarction. Twenty two of 31 patients who were admitted within 6 hr after the onset of acute myocardial infarction, exhibited high thromboxane B2 levels (greater than 300 pg/ml plasma) during the first 24 hr, whereas thromboxane B2 levels of 9 patients never exceeded 300 pg/ml during that period. The former cases were associated with a higher frequency of transmural myocardial infarction, accompanying higher cumulative creatine kinase release (1173 +/- 134 mIU/ml, mean +/- SEM), as compared with the latter cases (393 +/- 104 mIU/ml, P less than 0.001). To evaluate the efficacy of selective thromboxane A2 blockade on diminution of propagating acute myocardial infarction, another group of patients (24 cases) showing transmural myocardial infarction were subjected to therapeutic examination employing OKY-1581, a potent thromboxane A2 synthetase inhibitor. Eleven randomly selected patients were treated with an infusion of OKY-1581 (initiated within 6 hr after onset, 2-3 micrograms/kg per min) for 48 hr, while 13 patient served as controls. The treated patients exhibited a precipitous decrease in thromboxane B2 levels, as compared with the controls, returning to the normal range within 12 hr. The creatine kinase release in the treated patients was markedly reduced (978 +/- 97 mIU/ml) as compared with that in the control patients (1295 +/- 95 mIU/ml, P less than 0.05). These results indicate that a marked increase in thromboxane B2 levels is seen during the early phase of transmural myocardial infarction, and that OKY-1581-induced reduction of thromboxane B2 levels is effective in diminishing creatine kinase release. We suggest that an excessive generation of thromboxane A2 is associated with the evolution of transmural myocardial infarction.

Topics: Acrylates; Creatine Kinase; Electrocardiography; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Oxidoreductases; Prognosis; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

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

Topics: Adult; Angina, Unstable; Anticoagulants; Coronary Disease; Coronary Vessels; Electrocardiography; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Perfusion; Stroke Volume; Thiophenes; Thromboxane A2; Thromboxane B2; Ticlopidine; Tomography, Emission-Computed; Urokinase-Type Plasminogen Activator

This study demonstrates that the suppression of thromboxane biosynthesis by OKY-1581, a selective inhibitor of thromboxane biosynthesis, prevents dose-dependently taurocholate-induced gastric mucosal necrosis and enhances the cytoprotective effect of low dose of taurocholate against mucosal necrosis by large dose of this agent. In all animals treated with OKY-1581, a decrease in mucosal generation of thromboxane was accompanied by an increased production of PGs probably due to availability of greater amounts of a common substrate in a cyclooxygenase pathway. This study provides direct evidence that gastric mucosa generates thromboxanes which may be involved in the pathogenesis of taurocholate-induced gastric mucosal lesions.

Topics: Animals; Dinoprostone; Epoprostenol; Female; Gastric Mucosa; Indomethacin; Male; Methacrylates; Necrosis; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Taurocholic Acid; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Synthesis of vascular epoprostenol (PGI2) and platelet thromboxane (TX) A2 is influenced by the coagulation cascade in incompletely understood ways. To elucidate this, prostanoids were determined in human blood anticoagulated by different drugs and incubated with and without rat aortic rings. Control incubations were performed in Hanks balanced salt solution. PGI2 and TXA2 synthesis were assessed by radioimmunoassay of their stable hydrolysis products 6-oxo-prostaglandin (PG) F1 alpha and TXB2. Fresh aortic rings incubated in Hanks solution with a thrombin inhibitor (TCK) synthesized similar quantities of 6-oxo-PGF1 alpha in the presence or absence of sodium citrate. In contrast, the intracellular calcium antagonist TMB-8 inhibited 6-oxo-PGF1 alpha synthesis. In contrast to the finding in Hanks solution, sodium citrate inhibited 6-oxo-PGF1 alpha synthesis by fresh aortic rings incubated in blood anticoagulated with TCK. However, TXB2 synthesis was not affected by citrate. Blood incubated alone at 37 degrees C in plain glass tubes generated a small amount of immunoreactive 6-oxo-PGF1 alpha. A thromboxane synthase inhibitor, OKY1581, increased immunoreactive 6-oxo-PGF1 alpha. However, blood anticoagulated with TCK and incubated similarly, generated no detectable 6-oxo-PGF1 alpha either in the presence or absence of OKY1581, showing that 6-oxo-PGF1 alpha synthesis in the previous experiments was dependent on the vascular rings. OKY1581 had little or no effect on 6-oxo-PGF1 alpha synthesis in incubations of fresh aortic rings with blood anticoagulated with TCK, despite inhibition of TXB2 synthesis. However, OKY1581 increased 6-oxo-PGF1 alpha synthesis by rings pretreated with acetylsalicylic acid (ASA) when incubated in blood, presumably by diversion of platelet endoperoxide to vascular PGI2 synthase. Sodium citrate did not influence the increase in 6-oxo-PGF1 alpha synthesis by ASA pretreated aortic rings caused by OKY1581 in whole blood. This implies that the PGI2 stimulating activity of whole blood in the absence of citrate exerts its effect proximal to PGI2 synthase. It is concluded that a low molecular weight serum factor formed during activation of the intrinsic coagulation pathway in blood, modulates PGI2/TXA2 balance by an action on vascular cyclo-oxygenase, possibly by an effect on intracellular calcium.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Aspirin; Citrates; Epoprostenol; Humans; In Vitro Techniques; Male; Methacrylates; Muscle, Smooth, Vascular; Prostaglandins; Radioimmunoassay; Rats; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

When non-stimulated rat alveolar macrophages were incubated with exogenous 14C-arachidonic acid (7 microM) both cyclo-oxygenase and lipoxygenase metabolites were formed. The major cyclo-oxygenase metabolites were PGE2, PGF2 alpha and TXB2. The detected amounts of 5-lipoxygenase metabolites were small. Aspirin inhibited the formation of all cyclo-oxygenase metabolites, but had no effect on the formation of the lipoxygenase metabolites. In the presence of OKY-1581, an inhibitor of thromboxane synthetase, the formation of thromboxane B2 was decreased and that of the other cyclo-oxygenase metabolites was correspondingly increased. The present study indicates that OKY-1581 is a specific inhibitor of thromboxane synthetase also in rat alveolar macrophages and that the rate of formation of leukotrienes via the 5-lipoxygenase pathway is rather small in non-stimulated rat alveolar macrophages.

Topics: Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Dinoprost; Dinoprostone; Macrophages; Methacrylates; Oxidoreductases; Prostaglandins E; Prostaglandins F; Pulmonary Alveoli; Rats; Thromboxane B2; Thromboxane-A Synthase

The effect of the selective thromboxane A2 synthetase inhibitor OKY-1581, a pyridine derivative [sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methyl-2-propenoate], on thromboxane B2 and 6-keto-prostaglandin F1 alpha levels and platelet aggregation was studied in human volunteers. To clarify its effectiveness as an enzyme inhibitor, OKY-1581, at doses of 17, 83, 167, 417, 833, and 1667 micrograms/kg (n = 5 for each group), was injected intravenously, or was infused (10 micrograms/kg/min; n = 5) over 3 hr on 3 successive days. OKY-1580 (OKY-1581 free acid) was rapidly converted to its main beta-oxidized product, OKY-1565, and its reduced form, OKY-1558. During the study, plasma thromboxane B2 levels, inhibition of thromboxane B2 production in serum, and inhibition of rabbit platelet thromboxane A2 synthetase were monitored continuously. Twenty-five minutes after the injection of the above doses, plasma thromboxane B2 levels decreased by 4 +/- 7%, 40 +/- 14%, 57 +/- 7%, 68 +/- 6%, 93 +/- 5%, and 96 +/- 5% (mean +/- SD), respectively. Thromboxane B2 production in serum was decreased by 2 +/- 8%, 70 +/- 10%, 75 +/- 8%, 81 +/- 10%, and 96 +/- 8%, respectively, and rabbit platelet thromboxane A2 synthetase by 2 +/- 7%, 52 +/- 8%, 79 +/- 10%, 80 +/- 9%, 96 +/- 8%, and 95 +/- 7%. These parameters returned to the control levels 24 hr after the injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Adult; Arachidonic Acid; Arachidonic Acids; Biotransformation; Dose-Response Relationship, Drug; Humans; Male; Methacrylates; Oxidoreductases; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

The in vivo effectiveness of the thromboxane synthetase inhibitor OKY-1581 was tested in normal and infarcted canine myocardium. A rapid in vitro assay was developed which permits an accurate assessment of the status of the tissue thromboxane synthetase at the time of sacrifice. Reperfused infarcts were created by two hours of coronary artery occlusion followed by release of occlusion and three days of recovery. OKY-1581 was infused at 100 micrograms/kg/min for 15 minutes, a dose previously found to cause an 85% inhibition of canine platelet thromboxane synthetase in vivo. The heart was rapidly excised and transmural tissue plugs of infarcted and normal areas were obtained. These were incubated for 5 minutes with prostaglandin endoperoxide (PGH2) in phosphate buffer. Thromboxane production was inhibited from 16 +/- 1 ng TxB2 per tissue plug to 5 +/- 1 in normal myocardium and from 27 +/- 5 to 6 +/- 1 in infarcted areas of myocardium. Control incubations showed no further inhibition with the in vitro addition of 20 micrograms/ml OKY-1581, confirming the completeness of in vivo inhibition. Thus significant inhibition of thromboxane synthetase by intravenous OKY-1581 occurs even in a reperfused zone of infarction.

Topics: Acrylates; Animals; Dogs; Male; Methacrylates; Myocardial Infarction; Oxidoreductases; Prostaglandins H; Thromboxane B2; Thromboxane-A Synthase

Topics: Acrylates; Adult; Angina Pectoris; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Oxidoreductases; Physical Exertion; Platelet Aggregation; Reference Values; Thromboxane B2; Thromboxane-A Synthase

Topics: Blood Coagulation; Blood Platelets; Humans; Indomethacin; Methacrylates; Sulfinpyrazone; Thromboxane B2; Thromboxanes; Verapamil

Thromboxane B2 (TXB2), along with other primary prostaglandins, was synthesized when rat liver microsomes were incubated with radioactive arachidonic acid. TXB2 was identified directly by chemical ionization mass spectrometry and indirectly by using specific inhibitors of TX synthetase, viz., imidazole and OKY-1555 ((E)-3(4-(3-pyridyl-methyl) phenyl)-2 methyl acrylic acid HCl). The supernatant fraction obtained after centrifugation at 105,000 X g for 60 min contained a possible regulatory component that suppressed thromboxane synthesis. The regulatory influence is lost after partial hepatectomy.

Topics: Animals; Chromatography, Thin Layer; Cytosol; Female; Imidazoles; Liver; Mass Spectrometry; Methacrylates; Microsomes, Liver; Rats; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Adult; Animals; Blood Platelets; Humans; Kinetics; Male; Methacrylates; Oxidoreductases; Rabbits; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Calcimycin; Humans; Kidney Failure, Chronic; Macrophages; Methacrylates; Peritoneal Dialysis, Continuous Ambulatory; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Human umbilical veins have been shown to produce small amounts of TXA2 in addition to PGI2. We measured relative TXA2 and PGI2 production by umbilical veins in the presence of selective TXA2 synthetase inhibitor OKY 1581. OKY 1581 treatment resulted in inhibition of TXA2 but a marked increase in PGI2 release, which may relate to diversion of cyclic endoperoxides to PGI2 pathway or to removal of a feedback control at the level of AA mobilization.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Blood Vessels; Epoprostenol; Humans; Indomethacin; Methacrylates; Oxidoreductases; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction

Addition of arachidonic acid (AA) to human platelet rich plasma caused a reversible platelet aggregation and a concomitant formation of thromboxane B2 (TXB2). Both AA-induced platelet aggregation and TXB2 formation were inhibited by OKY-1581 and the amounts of PGE2 and PGF2 alpha formed were correspondingly increased. The formation of 6-keto-PGF1 alpha was smaller and was increased only slightly by OKY-1581. ADP-induced platelet aggregation did not result in the formation of TXB2 and it was inhibited only slightly by OKY-1581. When ADP was added to platelet rich plasma six minutes after the addition of AA, the ADP-induced aggregation was greatly decreased in the presence and absence of OKY-1581. The present study indicates that the AA-induced platelet aggregation is inhibited by OKY-1581 and that OKY-1581 is a specific inhibitor of thromboxane synthesis in platelet rich human plasma.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Adenosine Diphosphate; Adult; Arachidonic Acid; Arachidonic Acids; Dinoprost; Dinoprostone; Humans; In Vitro Techniques; Male; Methacrylates; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Thromboxane B2; Thromboxanes

To elucidate the role of thromboxane A2 in the development of endotoxin shock following administration of endotoxin, the effects of three thromboxane A2 synthetase inhibitors, (E)-3-(4-(1-imidazolyl)phenyl)-2-propenoic acid hydrochloride monohydrate (OKY-046), sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methylacrylate (OKY-1581) and imidazole were examined. Intravenous administration of E. Coli endotoxin (3 mg/kg) produced shock and all rats died within ten hours. Pretreatment with thromboxane A2 synthetase inhibitors markedly improved the survival rates. The untreated endotoxin shock group showed marked increase in thromboxane B2 levels in the venous blood, while no such changes were seen in the pretreated groups. There were no statistically significant differences in 6-keto prostaglandin F1 alpha levels in the venous blood. In the untreated shock group, microthrombi were observed in 64% of the glomeruli in the kidneys two hours after endotoxin injection. In the groups pretreated with OKY-046, OKY-1581 and imidazole, microthrombi were seen only in 22, 19 and 24%, respectively. Thus, thromboxane A2 plays an important role in the development of endotoxin shock and thromboxane A2 synthetase inhibitors, in particular OKY-046 and -1581, are prophylactic.

Topics: Animals; Fibrinogen; Glucuronidase; Kidney; Male; Methacrylates; Oxidoreductases; Platelet Count; Rats; Rats, Inbred Strains; Shock, Septic; Thrombosis; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Glomerular arachidonate cyclooxygenation by isolated rat glomeruli was assessed in vitro in antiglomerular basement membrane (anti-GBM) antibody-induced glomerulonephritis by radioimmunoassay for prostaglandins (PG) and thromboxane. After a single intravenous injection of rabbit anti-rat GBM serum, we observed enhancement of glomerular thromboxane B2 (TxB2) synthesis as early as 2 to 3 h with smaller increments in PGF2 alpha, PGE2 and 6-keto-PGF1 alpha synthetic rates. On day 2 of the disease, the glomerular synthesis of TxB2 and, to a lesser extent, PGF2 alpha and PGE2 remained enhanced, whereas on days 8, 11, and 14, TxB2 was the only prostanoid synthesized at increased rates. Glomerular TxB2 synthesis correlated with the presacrifice 24-h protein excretion. 60 min after intravenous infusion of anti-GMB serum, glomerular filtration rate (GFR) decreased (0.66 +/- 0.04 to 0.44 +/- 0.03 ml/min per 100 g, P less than 0.05), without a significant change in renal plasma flow (RPF): 1.97 +/- 0.23 to 1.80 +/- 0.23 ml/min per 100 g) and without a change in glomerular PG synthetic rates. At 2 h, GFR and RPF reached a nadir (0.25 +/- 0.04 and 1.3 +/- 0.1 ml/min per 100 g, respectively) coinciding with a fivefold increment in glomerular TxB2. By 3 h GFR and RPF partially recovered to 0.43 +/- 0.07 and 1.77 +/- 0.20 ml/min per 100 g, respectively, P less than 0.05, despite further increments in TxB2 synthesis. This recovery of GFR and RPF coincided with increments in vasodilatory PG, (PGE2 and PGI2). The thromboxane synthetase inhibitor OKY-1581 markedly inhibited platelet and glomerular TxB2 synthesis and preserved GFR at 1, 2, and 3 h. Another thromboxane synthetase inhibitor, UK-38485, also completely inhibited platelet and glomerular TxB2 synthesis and prevented decrements of GFR at 2 and 3 h. A cyclooxygenase inhibitor, ibuprofen, inhibited platelet TxB2 and PGE2 synthesis and significantly reduced glomerular PGE2 but not TxB2 synthesis. In the ibuprofen-treated rats, the partial recoveries of GFR and RPF at 3 h were attenuated. The in vitro glomerular TxB2 synthesis correlated inversely with the presacrifice GFR and filtration fraction. These observations indicate that in anti-GBM nephritis there is enhanced synthesis of TxA2 and PG in the glomerulus that mediate changes in renal hemodynamics.

Topics: Animals; Blood Physiological Phenomena; Glomerular Filtration Rate; Glomerulonephritis; Ibuprofen; Kidney Glomerulus; Male; Methacrylates; Nephrotic Syndrome; Prostaglandin Antagonists; Prostaglandins; Rabbits; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

In a series of 18 experiments on long-term myocardial preservation we evaluated whether vasoactive substances like thromboxane and prostacyclin are associated with the secondary increase in coronary resistance during preservation perfusion of the canine heart. In a control group (n = 12) and in a group treated with a specific thromboxane synthetase inhibitor (OKY 1581) coronary resistance was measured at 10 and 30 min, and at 1, 4, and 24 hr. At the same time intervals thromboxane A2 and prostacyclin (PGI2) production were determined as TXB2 and 6-keto PGF1 alpha, respectively. After OKY 1581 treatment no increase in TXB2 occurred and no secondary increase in coronary resistance was observed, while in the control group both TXB2 levels and resistance increased (P less than 0.01); 6-keto PGF1 alpha levels showed the same increase in control and in treated hearts. From this study it is concluded that during 24-hr myocardial preservation the characteristic secondary increase in coronary resistance is related to thromboxane production in the heart and is prevented by inhibition of thromboxane synthetase.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Dogs; Heart; Methacrylates; Myocardium; Organ Preservation; Perfusion; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Time Factors; Vascular Resistance

The biosynthetic mechanism of prostaglandin D2 in human platelet-rich plasma has been investigated. Platelet-rich plasma was separated into washed platelets and platelet-poor plasma, and [1-14C]prostaglandin H2 was incubated with each fraction. The enzymatic conversion of the endoperoxide to prostaglandin D2 was found only in platelet-poor plasma and not in washed platelets or platelet lysate. This prostaglandin D synthetase activity was purified to homogeneity and identified as serum albumin by sodium dodecyl sulfate polyacrylamide gel electrophoresis, isoelectric focusing, and immunoelectrophoresis. The optimal pH and Km value for prostaglandin H2 were 9.0 and 6 microM, respectively. Glutathione was not required for the activity. Although prostaglandin H2 ws converted to prostaglandin D2 and E2 in the reaction, only the prostaglandin D2 formation was dependent on the protein amount and abolished by prior boiling. The action of this activity under physiological conditions was examined in a model system constituted of serum albumin and washed platelets. Prostaglandin D2 formation was observed in association with thrombin-evoked platelet aggregation in this system and was proportional to the number of platelets and the concentration of serum albumin, suggesting that thrombin-stimulated platelets released prostaglandin H2, and the latter compound was then converted to prostaglandin D2 by the action of serum albumin. Consistent with this interpretation, prostaglandin H2 added to platelet-rich plasma was converted in part to prostaglandin D2, and the aggregation caused by this endoperoxide was greatly enhanced by neutralizing the action of prostaglandin D2 with anti-prostaglandin D2 antiserum.

Topics: Arachidonic Acid; Arachidonic Acids; Blood Platelets; Humans; Kinetics; Methacrylates; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins D; Serum Albumin; Thrombin; Thromboxane B2; Thromboxane-A Synthase

There is growing evidence that blood vessels generate TXA2 in addition to PGI2. We examined effluents from continuously perfused human umbilical vein and supernatants from umbilical vein rings for TXB2 and 6-keto-PGF1 alpha measurements (stable metabolites of TXA2 and PGI2, respectively). TXB2 and 6-keto-PGF1 alpha were identified in all samples. 6-keto-PGF1 alpha to TXB2 ratio was higher in intact vein effluents than in the venous ring supernatants (112:1 and 28:1, respectively, P less than 0.01). Arachidonate stimulation increased 6-keto-PGF1 alpha and TXB2 levels similarly in the intact vein effluent. In contrast, stimulation of the venous rings resulted in a relatively larger increase in TXB2 than in 6-keto-PGF1 alpha. This caused 6-keto-PGF1 alpha to TXB2 ratio to decline (p less than 0.01). The identity of TXB2 was confirmed in several different ways. These data suggest that 1) human umbilical veins produce TXA2 in addition to PGI2, 2) TXA2 release is more by venous rings than by the intact vein probably reflecting contribution from non-endothelial layers, and 3) arachidonate stimulation causes relatively greater release of TXA2 than of PGI2 from the venous rings, whereas release of PGI2 and TXA2 is similar from the intact vein.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Aspirin; Epoprostenol; Humans; Methacrylates; Models, Biological; Prostaglandins; Specimen Handling; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Umbilical Veins

Endotoxin-induced pulmonary hypertension can be attenuated by nonsteroidal anti-inflammatory drugs and is associated with increased plasma levels of thromboxane (Tx) B2, prostaglandin (PG) F2, PGE and PGI2. Because nonsteroidal anti-inflammatory drugs block prostacyclin production and may also shift arachidonic acid into the lipoxygenase pathway, we have evaluated a selective Tx synthetase inhibitor (OKY 1581) as a means for preventing endotoxin-induced pulmonary hypertension. An LD70 dose of Escherichia coli endotoxin (6 mg/kg) was given i.v. to two groups of unanesthetized baboons. Group I received endotoxin alone and Group II was pretreated with i.v. OKY 1581 (2 mg/kg) 10 min before the endotoxin. OKY 1581 produced a significant decrease in the basal plasma TxB2 from 0.432 +/- 0.82 to 0.147 +/- 0.032 ng/ml (P less than .01), but no significant change in plasma 6-keto PGF1 alpha. After the administration of the endotoxin, Group I developed pulmonary hypertension (from 11 +/- 1 to 19 +/- 2 mm Hg. P less than .005) and an 8-fold increase in plasma TxB2 (P less than .02), whereas Group II did not develop pulmonary hypertension or an increase in plasma TxB2. However, Group II had a 26-fold increase in plasma 6-keto PGF1 alpha (P less than .05). From these studies, we conclude that: 1) OKY 1581 is an effective Tx synthetase inhibitor in vivo; 2) endotoxin-induced pulmonary hypertension is mediated largely by increased Tx; and 3) the inhibition of Tx synthetase results in shunting of endoperoxides into the prostacyclin pathway.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Hypertension, Pulmonary; Male; Methacrylates; Oxidoreductases; Papio; Shock, Septic; Thromboxane B2; Thromboxane-A Synthase

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Blood Pressure; Epoprostenol; Female; Heart Rate; Infusions, Parenteral; Male; Methacrylates; Papio; Prostaglandins; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Acrylates; Animals; Lipopolysaccharides; Macrophages; Methacrylates; Oxidoreductases; Prostaglandins F; Rats; Thromboxane B2; Thromboxane-A Synthase

OKY-1581 is an effective inhibitor of thromboxane synthesis in vivo and in vitro. The generation of thromboxane B2 (TxB2), prostaglandin E (PGE) and prostaglandin F (PGF) was measured following clotting and during platelet aggregation induced by collagen. The presence of OKY 1581 either in vivo or in vitro caused a reduction in TxB2 generation during clotting and platelet aggregation with a concomitant increase in PGE and PGF. The effect could be observed two hours after oral or subcutaneous administration of 5 to 100 mg per rabbit and lasted for 24 to 48 hours. The reduction in TxB2 was not accompanied by an inhibition of clotting or platelet aggregation. OKY-1581 appears to be a suitable agent for studying the role of TxB2 in atherosclerosis.

Topics: Acrylates; Animals; Arteriosclerosis; Blood Platelets; In Vitro Techniques; Male; Methacrylates; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Rabbits; Thromboxane B2; Thromboxanes