thromboxane-a2 and 2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid

Topics: Animals; Epoprostenol; Humans; Imidazoles; Methacrylates; Platelet Aggregation; Thromboxane A2; Thromboxane-A Synthase

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

The pathogenesis of intestinal damage caused by bolus intravenous injection of endotoxin (ETX; 3 mg/kg) was investigated. Administration of ETX to rats induced reddish discoloration suggestive of bleeding, increased hemoglobin amounts, and leakage of plasma protein in the intestine. However, light microscopic examination of the intestine demonstrated blood congestion of the microvessels. Plasma accumulation was partially inhibited by combined pretreatment with a histamine H1 antagonist and a serotonin (5-HT) antagonist. Neither a 5-lipoxygenase inhibitor, a soybean trypsin inhibitor, nor atropine was observed to inhibit plasma accumulation. Both the intestinal leakage of plasma and the accumulation of hemoglobin were completely inhibited by indomethacin, a selective thromboxane A synthetase inhibitor (OKY 1581), and a stable PGI2 analogue (beraprost). Intravital microscopic observation of the microvessels of the small intestinal villi demonstrated microthrombus formation within several minutes after the injection of ETX, and pretreatment with OKY 1581 attenuated the formation of microthrombus. Platelet counts decreased significantly 10 min after ETX administration, and the decrease was not inhibited by pretreatment with either OKY 1581 or beraprost. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were not prolonged. These observations thus suggest that microcirculatory disturbances by platelet thrombus, which are mediated by thromboxane A2 at least in part, play an important role in ETX-induced intestinal damage.

Topics: Animals; Capillary Leak Syndrome; Cyclooxygenase Inhibitors; Endotoxins; Enzyme Inhibitors; Epoprostenol; Escherichia coli; Gastrointestinal Hemorrhage; Indomethacin; Intestine, Small; Male; Methacrylates; Microcirculation; Platelet Activation; Rats; Rats, Sprague-Dawley; Shock, Septic; Specific Pathogen-Free Organisms; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

Differential effects on human platelet function of thromboxane A2 (TXA2) synthetase inhibition singly and of TXA2 synthetase inhibition combined with TXA2/prostaglandin endoperoxide receptor antagonism were revealed, using ridogrel as a probe. Ridogrel combines selective TXA2 synthetase inhibition with TXA2/prostaglandin receptor antagonism in one molecule: in washed human platelets, the compound reduces the production of TXB2 (IC50 = 1.3 X 10(-8) M) and increases that of PGF2 alpha, PGE2, PGD2 from [14C]arachidonic acid. Additionally, at higher concentrations (Ki = 0.52 X 10(-6) M), it selectively antagonizes the breakdown of inositol phospholipids, subsequent to stimulation of TXA2/prostaglandin endoperoxide receptors with U 46619. The latter happens in a competitive way with fast receptor association-dissociation characteristics. At low concentrations (1 X 10(-9)-1 X 10(-7) M) producing single TXA2 synthetase inhibition, ridogrel reduces the collagen-induced formation of TXB2 by washed platelets, but enhances [32P]phosphatidic acid (PA) accumulation and [3H]5-hydroxytryptamine (5-HT) release. At higher concentrations (1 X 10(-6)-1 X 10(-5) M) which additionally block U 46619-induced [32P]PA accumulation, ridogrel inhibits the [32P]PA accumulation and release of [3H]5-HT by human platelets stimulated with collagen. These observations, corroborated by results obtained with OKY 1581, sulotroban, indomethacin and human serum albumin, suggest a causal role for prostaglandin endoperoxides in the stimulation by TXA2 synthetase inhibition of platelet reactions to collagen. They reinforce the concept that TXA2 synthetase inhibition-induced reorientation of cyclic endoperoxide metabolism, away from TXA2 into inhibitory prostanoids, requires additional TXA2/prostaglandin endoperoxide receptor antagonism to achieve optimal anti-platelet effects.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Blood Platelets; Collagen; Humans; In Vitro Techniques; Indomethacin; Inositol Phosphates; Methacrylates; Platelet Activating Factor; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Serotonin; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

PAF-receptor antagonists are known to inhibit gastrointestinal damage induced by endotoxin. In the present study, the interaction between the biosynthesis of PAF and thromboxane (TX) A2, as putative mediators of the acute intestinal damage induced by endotoxin, has been investigated in the anaesthetised rat. Bolus intravenous administration of lipopolysaccharide from E. coli (5-50 mg/kg) induced dose-related jejunal damage, assessed using both macroscopic and histological techniques. This damage was accompanied by significant increases in the jejunal formation of PAF determined by bioassay, and of TXB2, determined by radioimmunoassay. Pretreatment with the structurally-unrelated thromboxane synthase inhibitors, 1-benzyl imidazole (10-50 mg/kg) or OKY 1581 (25 mg/kg) substantially reduced both jejunal damage and TXB2 formation, but did not inhibit PAF formation. Likewise, pretreatment with indomethacin (5 mg/kg) or BW 755C (50 mg/kg) reduced jejunal damage and TXB2 formation but did not affect PAF formation. Pretreatment (2h) with dexamethasone (4 mg/kg) reduced jejunal damage and the formation of both TXB2 and PAF. Intravenous infusion of PAF (100 ng/kg/min for 10 min) induced jejunal damage and significantly increased the formation of TXB2, whereas non-specific jejunal damage induced by oral administration of ethanol did not augment PAF formation. The present findings that inhibition of jejunal thromboxane formation is associated with a substantial reduction in jejunal damage, with no corresponding inhibition in PAF formation, therefore suggests a complex interaction or sequential release of these tissue destructive mediators underlying the intestinal damage induced by endotoxin.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Escherichia coli; Ethanol; Imidazoles; Indomethacin; Jejunum; Lipopolysaccharides; Male; Methacrylates; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Bridged Bicyclo Compounds, Heterocyclic; Cats; Dinoprost; Fatty Acids, Unsaturated; Hydrazines; Lung; Methacrylates; Prostaglandin Endoperoxides, Synthetic; Respiratory Function Tests; Thromboxane A2; 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

Topics: Animals; Epoprostenol; Ibuprofen; Methacrylates; Rabbits; Thromboxane A2; Wound Healing

This paper demonstrates that in the presence of indomethacin, a cyclooxygenase inhibitor, 100% of the mice died when infected with live Listeria, whereas none of the animals died in the absence of the drug. The death of the animals correlated with the numbers of bacteria found extraperitoneally in the spleen and not with the Ia expression of the peritoneal macrophages. Increases in the spleen bacterial numbers between mice treated with either indomethacin or a specific thromboxane synthase inhibitor, OKY1581, and those not receiving either drug, were found as early as 2-4 h after infection. The differences in the initial increased bacterial spleen counts in the presence of indomethacin were reversed by administration of a stable thromboxane A2 analog or another potent vasoconstrictor, phenylephrine. Because thromboxane A2 does not regulate macrophage or T cell functions directly (Tripp, C.S., A. Wyche, E.R. Unanue, and P. Needleman, 1986, J. Immunol., In press; and Ceuppens, J.S., S. Vertessen, H. Deckmyn, and J. Vermylen, 1985, Cell Immunol., 90:458-463), but is probably generated at the site of an infection (Tripp, C.S., K.M. Leahy, and P. Needleman, 1985, J. Clin. Invest., 76:898-901), these data suggest an important role for the vasoconstrictive properties of thromboxane A2 in the regulation of immunity to Listeria infection.

Topics: Animals; Histocompatibility Antigens Class II; Indomethacin; Listeriosis; Macrophages; Methacrylates; Mice; Mice, Inbred Strains; Phenylephrine; Thromboxane A2; 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

Thromboxane (Tx) inhibition prevents pulmonary leukostasis after acid aspiration. This observation prompted study of polymorphonuclear leukocyte (PMN) accumulations and products of cyclooxygenase. Experiments were conducted with a skin abrasion preparation. Five groups of six rabbits were pretreated intravenously with: (1) placebo, (2) ibuprofen, (3) imidazole and two other Tx syntase inhibitors, (4) OKY 1555, or (5) OKY 046. Zymosan-activated serum (ZAS) and leukotriene B4 were used as chemotaxins and balanced salt solution as control. After pretreatment with placebo, PMN accumulation in leukotriene B4 sites was 2130 +/- 874 PMN/mm3 (mean +/- SD). Pretreatment with ibuprofen, imidazole, or OKY 046 decreased (p less than 0.05) accumulations to 205 +/- 139 PMN/mm3, 485 +/- 387 PMN/mm3, and 504 +/- 260 PMN/mm3, respectively. In ZAS sites, placebo pretreatment led to 2006 +/- 866 PMN/mm3, while the ibuprofen, imidazole, and OKY 046 groups had decreased (p less than 0.05) responses of 295 +/- 218 PMN/mm3, 444 +/- 477 PMN/mm3, and 386 +/- 151 PMN/mm3, respectively. Pretreatment with OKY 1555 did not produce significant reductions in response. Six animals in each group received intradermal injections of the two chemotaxins or Hank's balanced salt solution. Reduction in PMN accumulations after cyclooxygenase and Tx inhibition were similar to those observed in the skin abrasion preparation. Pretreatment with either ibuprofen, imidazole, or OKY 046 resulted in a decreased concentration of Tx in abrasion fluid exudate in response to leukotriene B4, 275 +/- 164 pg/ml, 460 +/- 144 pg/ml, and 440 +/- 260 pg/ml, respectively, as compared with 1168 +/- 380 pg/ml in the placebo group. The reduced responses were not the result of a decrease in regional perfusion as measured by 133Xe washout. The in vitro chemotactic response of PMN to leukotriene B4 and ZAS was unchanged after incubation in either ibuprofen, imidazole, OKY 1555, or OKY 046. These data show that cyclooxygenase and Tx syntase are integrally associated with PMN accumulations.

Topics: Animals; Chemotaxis, Leukocyte; Cyclooxygenase Inhibitors; Ibuprofen; Imidazoles; Male; Methacrylates; Neutrophils; Premedication; Prostaglandin-Endoperoxide Synthases; Rabbits; Skin; Skin Tests; Thromboxane A2; Thromboxane-A Synthase

Human peritoneal eosinophils were obtained from the waste dialysis bags of patients undergoing continuous ambulatory peritoneal dialysis. The number of eosinophils obtained from each bag varied from 3 X 10(7) to 288 X 10(7). The cells were incubated for 1 h in tissue culture medium and prostaglandin E2 (PGE2), 6-keto-prostaglandin F1 (6-keto-PGF1), and thromboxane B2 (TXB2) were determined by radioimmunoassay of the supernatant. The basal release as well as the stimulated release from the purified eosinophils of TXB2 were five times greater than the release of PGE2 and thirty times greater than the release of 6-keto-PGF1. A dose-response curve was achieved for all three cyclooxygenase products with the calcium ionophore A23187. The release of TXB2 was inhibited in a dose-dependent manner by the specific thromboxane A2 (TXA2) synthase inhibitor OKY-1581 and a corresponding increase in PGE2 and 6-keto-PGF1 was obtained. Indomethacin (5.6 X 10(-6) M) inhibited the cyclooxygenase products to almost undetectable levels.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Calcimycin; Dinoprostone; Eosinophils; Epoprostenol; Humans; Indomethacin; Methacrylates; Peritoneal Cavity; Peritoneal Dialysis, Continuous Ambulatory; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Thromboxane A2

Administration of the thromboxane A2 (TXA2) synthase inhibitor OKY 1581 to rats significantly increased the urine output elicited by the loop diuretic frusemide. The administration of the TXA2 receptor antagonist SQ 29548 significantly increased the diuretic effect of frusemide. Another TXA2 receptor antagonist L-640,035 increased significantly the diuretic effect of frusemide. Both the sodium excretion rate and urine osmolar excretion rate were significantly increased in rats treated with the TXA2 synthase inhibitor OKY 1581 and frusemide. The data suggest that TXA2 is released during frusemide-induced diuresis in rats, and the released TXA2 has an opposing antidiuretic effect. Key words: antidiuretic hormone, frusemide diuresis, thromboxane inhibitor and antagonists.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Dibenzothiepins; Diuresis; Drug Synergism; Fatty Acids, Unsaturated; Furosemide; Hydrazines; Male; Methacrylates; Osmolar Concentration; Rats; Rats, Inbred Strains; Sodium; Thromboxane A2; Thromboxane-A Synthase

The development of hydronephrotic atrophy as measured by dry and wet weight in relation to wholebody weight, in rats after complete unilateral ureteral obstruction could be influenced by oral administration of OKY 1581, an inhibitor of thromboxane A2 synthesis. The data are consistent with the thesis that preglomerular thromboxane A2-mediated active vasoconstriction is involved, most likely by ischemia, in the development of hydronephrotic atrophy, at least in the renal cortex.

Topics: Animals; Atrophy; Female; Hydronephrosis; Kidney Cortex; Kidney Medulla; Methacrylates; Rats; Thromboxane A2; Ureteral Obstruction

Eicosanoid metabolites may play a role in the pathophysiology of nephrotoxic serum nephritis (NSN), a model of immune renal disease. Our purpose was to determine the relative importance of vasoconstrictor [thromboxane A2 (TX)A2] and vasodilator [prostaglandin E2 (PG)E2] eicosanoids as mediators of hemodynamic and renal functional changes. Glomerular filtration rate (GFR; inulin clearance), and renal plasma flow (RPF; para-aminohippurate clearance/extraction) were measured in rats on day 1 and day 14 of NSN. Specific inhibitors of TXA2 synthesis and receptor binding, and cyclooxygenase inhibitors were used to determine the relative roles of TXA2 and PGE2. In vitro glomerular production of radioimmunoassayable PGE2 and TXB2 were measured after clearances. At 1 day GFR is decreased compared to control, 1.9 +/- 0.2 vs. 2.6 +/- 0.2 ml/min. RPF is numerically increased, 10.0 +/- 1.0 vs. 7.0 +/- 0.6 ml/min. By 14 days GFR is normal, 2.2 +/- 0.2 ml/min, as a consequence of significantly increased RPF, 11.7 +/- 1.0 ml/min. Glomerular production of PGE2 and TXB2 was increased 11- and 15-fold respectively at both 1 and 14 days. Pretreatment with OKY-1581, or acute treatment with UK-38,485, both inhibitors of TXA2 synthesis, had no effect on GFR or RPF in NSN rats. Addition of EP 092, a TXA2 receptor antagonist was similarly without effect. In contrast, acute treatment with the cyclooxygenase inhibitors meclofenamate or indomethacin resulted in a 50% decrease in both RPF and GFR; these inhibitors had no effect in control rats. We conclude that PGE2 (vasodilator) is of greater relative significance than TXA2 (vasoconstrictor) with respect to renal function in the NSN rat at 1 and 14 days.

Topics: Animals; Dinoprostone; Glomerular Filtration Rate; Glomerulonephritis; Hemodynamics; Imidazoles; Kidney; Male; Methacrylates; Prostaglandins E; Rabbits; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane A2; Thromboxanes

Arachidonic acid causes dose-dependent increases in pulmonary vascular resistance in perinatal lambs. The specific metabolites that produce this effect are not known; however, a role for thromboxanes (TX's), potent constrictors of vascular smooth muscle, has been proposed. The effects of a specific inhibitor of TX synthase, OKY-1581, were tested in newborn and ventilated fetal lambs using an in situ pump-perfused lower left lobe preparation. Pulmonary and systemic responses of newborns and ventilated fetuses to infusions of arachidonic acid were evaluated in the presence and absence of OKY-1581. Increases in pulmonary vascular resistance caused by arachidonic acid were diminished by TX synthase inhibition. The degree of systemic hypotension observed with arachidonic acid infusions was significantly greater in animals receiving OKY-1581 than in animals without the inhibitor. The effect of OKY-1581 on periods of hypoxia was also evaluated in newborn lambs. There were no significant differences in the hypoxic pressor response in lambs with and without TX synthase inhibition. These results suggest that OKY-1581 can reduce most of the pulmonary vasoconstriction produced by arachidonic acid in perinatal lambs.

Topics: Acrylates; Animals; Animals, Newborn; Arachidonic Acid; Arachidonic Acids; Fetus; Hypoxia; Lung; Methacrylates; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Circulation; Respiration, Artificial; Sheep; Thromboxane A2; Thromboxane-A Synthase; Time Factors; Vascular Resistance; Vasoconstriction

The effects of 1-iodo-3-aminomethyl-5,6,7,8-tetrahydro-2-naphthol (ONO-3122) which increases endogenous PGH2, and sodium (E)-2-methyl-3-[4-3-pyridylmethyl)phenyl]-2-methylpropenoate (OKY-1581) which inhibits thromboxane A2 synthesis, on vasopressin-induced osmotic water flow in the bladder of the toad, Bufo bufo japonicus, were examined. ONO-3122 significantly inhibited the vasopressin-induced water flow at a concentration of 1 X 10(-4) M. OKY-1581 inhibited the vasopressin-induced water flow at 1 X 10(-6) M, but enhanced it at 1 X 10(-4) M. These results suggest that ONO-3122 indirectly inhibits the vasopressin-induced osmotic water flow in the toad bladder; that is, ONO-3122 causes an increase in the conversion of arachidonic acid into PGH2. These results also suggest that OKY-1581 at a low concentration suppresses the vasopressin-induced water flow due to inhibition of cyclooxygenase activity. Both ONO-3122 and OKY-1581 provide a useful means for studying the action of prostaglandins.

Topics: Acrylates; Animals; Body Water; Bufo bufo; In Vitro Techniques; Methacrylates; Naphthols; Osmolar Concentration; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Thromboxane A2; Thromboxane-A Synthase; Urinary Bladder; Vasopressins

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

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

OKY-1581, a thromboxane A2 (TXA2) synthetase inhibitor, was administered to cats with normal and constricted basilar arteries. At a dose of 60mg/kg (i.v.), both normal and constricted vessels dilated, and the mean arterial blood pressure (MABP) fell from 55 to 75 mmHg. If MABP remained constant, vessel diameter did not change. Subarachnoid hemorrhage (SAH) was simulated by intracisternal injection of autologous arterial blood. Regional cerebral blood flow (rCBF) was assessed by the heat clearance and H2 clearance methods. The two methods presented similar response profiles. rCBF responses to intravenous OKY-1581 fell into 3 categories: A) no change in rCBF, B) decrease in rCBF related to MABP and C) increase in rCBF in the presence of hypotension. Types A and B were observed in 3 out of 10 control cats and 4 out of 14 SAH-induced cats, with Type C responses in the remainder. There was no significant difference between the groups. While the results do not support a major role for TXA2 in cerebral vasospasm pathogenesis, OKY-1581 may still be useful in the treatment of cerebral vasospasm, as it improves distal and deep circulation and inhibits platelet aggregation.

Topics: Acrylates; Animals; Blood Pressure; Cats; Cerebrovascular Circulation; Epoprostenol; Ischemic Attack, Transient; Mathematics; Methacrylates; Oxidoreductases; Thromboxane A2; Thromboxane-A Synthase; Vasodilation

Subarachnoid hemorrhage (SAH) was induced in 50 rabbits by injecting 1.25 cc/kg of autologous, well heparinized, fresh arterial blood into the cisterna magna, followed by suspending the animals in a head-down position at 30 degrees for 15 minutes. The animals were evenly divided into five groups: a control group, or groups receiving post-SAH prostacyclin (PGI2), carbacyclin, thromboxane A2 (TXA2) synthetase inhibitor (OKY-1581), or nutralipid. Radiographic vertebrobasilar arterial spasm was demonstrated on the 3rd day post-SAH in the control animals. This was decreased in the prostacyclin and the carbacyclin groups and was absent in the OKY-1581 and the nutralipid groups. Cerebral blood flow (CBF) measurements on the 4th day post-SAH using the xenon-133 technique failed to reveal any significant difference between the prostacyclin, the carbacyclin, and the control groups, but flows in the nutralipid and the OKY-1581 groups were significantly higher. There was a good correlation between the clinical status and the CBF. Intracytoplasmic vacuolation and detachment of the vascular endothelium, seen ultrastructurally, may account for the impaired synthesis of prostacyclin. Exogenous prostacyclin and carbacyclin decreased vasospasm but failed to improve cerebral perfusion. OKY-1581 blocked the synthesis of the potent vasoconstrictor, TXA2, which is not only formed during platelet aggregation but also induces platelet aggregation. Nutralipid contains linolenic acid, a precursor of eicosapentaenoic acid (EPA), which is more potent in inhibiting platelet aggregation and in blocking TXA2 production. The various fatty acid constituents of nutralipid bind to albumin and thereby shorten the half-life of TXA2.

Topics: Acrylates; Animals; Cerebrovascular Circulation; Epoprostenol; Fatty Acids; Female; Ischemic Attack, Transient; Male; Methacrylates; Rabbits; Subarachnoid Hemorrhage; Thromboxane A2; 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

Topics: Acrylates; Animals; Arachidonic Acids; Dose-Response Relationship, Drug; Guinea Pigs; In Vitro Techniques; Lung; Male; Methacrylates; Muscle Contraction; Muscle, Smooth; Oxidoreductases; Thromboxane A2; Thromboxane-A Synthase; Trachea

Topics: Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Biological Assay; Blood Platelets; Cerebral Infarction; Haplorhini; Kinetics; Methacrylates; Muscle Contraction; Oxidoreductases; Platelet Aggregation; Rabbits; Rats; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

Effects of intravenous injections of prostaglandin I2 (PG I2) and thromboxane A2 (TXA2) synthetase inhibitor (OKY-1581) on mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), renal blood flow (RBF), and uterine blood flow (UBF) were investigated in the anesthetized pregnant dog. A dose-dependent fall in MAP was observed with these two agents. HR was almost unchanged by both PG I2 and TXA2 synthetase inhibitor. PG I2 and TXA2 synthetase inhibitor produced increases in CO and RBF in a dose-dependent manner. PG I2 caused a dose-dependent decrease in UBF, while TXA2 synthetase inhibitor was followed by an insignificant decrease in UBF. PG I2 and TXA2 synthetase inhibitor did not induce any increase in intrauterine pressure (IUP). The possibility of treatment of pregnancy-induced hypertension with PG I2 or TXA2 synthetase inhibitor is discussed.

Topics: Acrylates; Animals; Blood Pressure; Cardiac Output; Dogs; Electrocardiography; Epoprostenol; Female; Hemodynamics; Methacrylates; Oxidoreductases; Prostaglandins; Renal Circulation; Thromboxane A2; Thromboxane-A Synthase

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

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Cats; Chromatography, Thin Layer; Female; Indomethacin; Male; Methacrylates; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Artery; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction; Vasodilation

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

The effects of the stable thromboxane agonist, U46619, and sodium arachidonate were tested by i.v. injection into male and female mice. U46619 produced dose-dependent mortality in both sexes equally, in contrast to the gender-differentiated effects of arachidonic acid. The thromboxane receptor antagonist, SQ 26,536, protected in a dose-dependent manner against both arachidonate and U46619. The thromboxane antagonist was more effective against arachidonate toxicity in male than in female mice, but was equiactive against U46619 in both sexes. Neither the thromboxane synthetase inhibitor, OKY-1581, nor the cyclooxygenase inhibitor, indomethacin, protected against U46619-induced sudden death. However, cortisone acetate increased survival of mice challenged with U46619. The results support the hypothesis that thromboxane A2 mediates arachidonate-induced sudden death. The effects of arachidonate can be mimicked by the thromboxane agonist and are attenuated by the thromboxane antagonist. The gender difference in arachidonate toxicity is apparently not due to differences in sensitivity to thromboxane A2, as the thromboxane agonist was equally toxic in males and females. The greater protective effect of the thromboxane antagonist against arachidonate toxicity in males suggests that thromboxane A2 is a more important mediator of arachidonate-induced sudden death in males compared to female mice.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acids; Cortisone; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Indomethacin; Male; Methacrylates; Mice; Prostaglandin Endoperoxides, Synthetic; Sex Factors; Thromboxane A2; Thromboxanes

Platelet aggregation was measured in rat and human platelet-rich plasma (PRP) after the addition of various amounts of arachidonic acid (AA), prostaglandin H2 (PGH2), adenosine diphosphate (ADP), or collagen. AA but not PGH2 caused rat platelets to aggregate in citrated or heparinized PRP. Both AA and PGH2 produced significant amounts of thromboxane A2 (TxA2) measured as thromboxane B2 (TxB2). The lack of aggregation of rat platelets with PGH2 was not due to the formation of an inhibitor of aggregation such as a prostaglandin. Thus, the formation of TxA2 may not be necessary for aggregation of rat platelets. Human platelets were aggregated by PGH2 with the concomitant formation of TxB2.

Topics: Animals; Arachidonic Acids; Male; Methacrylates; Platelet Aggregation; Prostaglandin Endoperoxides; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxanes

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

Thromboxane A2 is not produced in normal rabbit kidneys, but its synthesis is induced in numerous renal pathological states. The presence of this potent vasoconstrictor could readily compromise renal hemodynamics. We found that the thromboxane synthetase inhibitor, OKY-1581 (sodium-3-[4,3-pyridylmethyl)phenyl]-2-methylacrylate) is effective in the perfused hydronephrotic kidney in selectively inhibiting thromboxane production without altering prostaglandin E2 or prostacyclin release. The vasoactive peptides bradykinin and angiotensin cause the hydronephrotic kidney to produce thromboxane A2, which results in a profound renal vasoconstriction which is reversed by pretreatment with OKY-1581. Thus, OKY-1581 provides a powerful tool which can be used to assess the participation of thromboxane in pathophysiological states and to ascertain the therapeutic potential of thromboxane synthetase inhibitors in numerous disease states.

Topics: Animals; Bradykinin; Dinoprostone; Epoprostenol; Hydronephrosis; Methacrylates; Perfusion; Prostaglandins E; Rabbits; Renal Circulation; Thromboxane A2; Thromboxanes; Vascular Resistance

The actions of leukotriene (LT) C4 and D4 on the systemic arterial pressure and the insufflation pressure in guinea pigs and rabbits were examined. In guinea pigs, 0.3 - 3 nmole/kg of LTC4 and 0.1 - 1.0 nmole/kg of LTD4 administrated from left jugular vein caused dose-dependent increase of the airway resistance measured by the Konzett-Rössler method and a triphasic blood pressure response; an initial hypotension, a secondary hypertension and a third long-lasting hypotension. All of the hypertensive phase and 100 - 150% of the increase of the airway resistance by LTC4 and LTD4 were inhibited by a selective thromboxane synthetase inhibitor, OKY-1581 (10 mg/kg, i.v.) and only the hypotension was observed. Indomethacin (10 mg/kg, i.p.) also inhibited not only the airway resistance increase, but also the prolonged hypotension by LTC4 and shortened the duration of the hypotension by LTD4. It is suggested that thromboxane might be involved in bronchoconstriction and hypertensive effects by LTC4 and LTD4 and that hypotensive prostaglandin might be involved in the hypotensive phase after LTC4 and LTD4. In rabbits, the increase of the airway resistance by LTC4 and LTD4 (upto 100 nmole/kg, i.v.) was negligible and only the hypotension was observed.

Topics: Airway Resistance; Animals; Blood Pressure; Bronchi; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Indomethacin; Male; Methacrylates; Rabbits; SRS-A; Thromboxane A2; Thromboxanes

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

Effects of new inhibitors of thromboxane synthetase, (E)-3-([1-imidazolmethyl) phenyl]-2-propenoic acid and (E)-3-[4-(pyridylmethyl) phenyl]-2-methyl-2-propenoic acid on cyclical reduction of flow in the partially constricted coronary artery were examined in anesthetized beagle dogs. Intravenous injections of both agents with a dose of 20 mg/Kg eliminated the cyclical reduction induced by constriction in the majority of experiments. However, they failed to eliminate the cyclical reduction induced by indomethacin. Indomethacin-induced reduction was eliminated by prostaglandin I2 in all experiments. It is suggested that thromboxane A2 acted as an accelerator in the cyclical reduction of coronary flow induced by coronary constriction, but did not in the reduction induced by indomethacin.

Topics: Acrylates; Animals; Constriction; Coronary Circulation; Coronary Vessels; Dogs; Epoprostenol; Indomethacin; Methacrylates; Oxidoreductases; Thromboxane A2; Thromboxane-A Synthase