6-ketoprostaglandin-f1-alpha and dazoxiben

The immersion of a limb in a mixture of water and ice induces in normal humans an initial vasoconstriction mediated mainly by catecholamine release. In some studies the cold pressor test was associated with an increase in vasoconstrictor thromboxane A2 and in vasodilating prostacyclin. Dazoxiben hydrochloride, a thromboxane synthase inhibitor, has been reported to suppress cold-induced vasoconstriction. We compared in a double-blind, crossover, placebo-controlled study the effects of indomethacin (a cyclooxygenase inhibitor), dazoxiben hydrochloride, and BM13.177 (a novel thromboxane receptor antagonist) on the changes in cutaneous vascular resistance and arterial blood pressure induced by cold in 12 healthy volunteers. Cold challenge produced an increase in blood pressure and an initial decrease in finger blood flow, reflecting an increase in cutaneous vascular resistance. Neither effective suppression of thromboxane A2 generation or of the effects of thromboxane A2 on platelets by the three active treatments nor increase in prostacyclin generation after ingestion of dazoxiben hydrochloride modified the hemodynamic response to cold. In conclusion, thromboxane A2 and prostacyclin do not play a significant role in the modulation of the systemic hemodynamic response to cold. In addition, thromboxane receptor antagonism in normal humans does not influence basal blood pressure.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; beta-Thromboglobulin; Blood Pressure; Cold Temperature; Double-Blind Method; Epoprostenol; Fingers; Humans; Imidazoles; Indomethacin; Male; Platelet Aggregation; Regional Blood Flow; Sulfonamides; Thromboxane A2; Thromboxane B2; Vascular Resistance; Vasoconstriction

The effects of dazoxiben on finger-blood flow in response to cold challenge were studied in normal subjects and patients with Raynaud's phenomenon. In normal subjects concentrations of TXB2 and 6-oxo-PGF1 alpha were measured in blood taken from dorsal hand veins following cold challenge. In a parallel multicentre study we examined the effects of dazoxiben on finger temperature and capillary blood cell velocity in patients with Raynaud's phenomenon. Dazoxiben did not affect finger arterial inflow at rest or during cold challenge in patients or controls. However in both groups, recovery was quicker after cold challenge on dazoxiben treatment. In patients median flow was 5 ml (100(-1) ml) min-1 (range 1-10) v. 2 (0.5-15), P less than 0.05 dazoxiben v. placebo at 15 min after cold challenge. However, in normal subjects this did not prove to be statistically significant. In normal subjects there was a fall in TXB2 concentrations and relative rise in 6-oxo-PGF1 alpha following dazoxiben treatment indicating redirection of prostaglandin endoperoxides towards synthesis of PGI2. Comparison of the sum-total output of each eicosanoid following treatment with dazoxiben revealed a 65% reduction in TXB2 concentrations (P less than 0.025 compared with placebo) and a 40% increase in 6-oxo-PGF1 alpha concentrations (P less than 0.05 compared with placebo). However a simultaneous increase in concentrations of FPA indicated generation of thrombin, probably at the needle tip. Long-term treatment with dazoxiben resulted in no significant change in finger-skin temperature or capillary blood cell velocity, duration, or severity of attacks of Raynaud's phenomenon.

Topics: 6-Ketoprostaglandin F1 alpha; Cold Temperature; Drug Evaluation; Female; Fibrinopeptide A; Fingers; Humans; Imidazoles; Male; Random Allocation; Raynaud Disease; Regional Blood Flow; Skin; Thromboxane A2; Thromboxane-A Synthase

1 We have assessed the thromboxane synthetase inhibitor, dazoxiben (UK 37248), during dialysis in a double-blind, placebo-controlled crossover study. 2 Thromboxane generation was markedly inhibited, and there was an increase in serum 6-keto prostaglandin F1 alpha levels during active treatment studies. 3 We were unable to demonstrate any reduction of platelet activation, or dialyser fibrin deposition, nor were heparin requirements altered by the drug. 4 Dazoxiben had no adverse effects.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Coagulation; Clinical Trials as Topic; Double-Blind Method; Humans; Imidazoles; Oxidoreductases; Platelet Count; Renal Dialysis; Thromboxane B2; Thromboxane-A Synthase

Twenty-four men received either placebo, 0.1 g of the thromboxane synthetase inhibitor dazoxiben, 0.25 or 1.0 g of acetylsalicylic acid (ASA). Dazoxiben reduced the maximal rate of collagen-induced platelet aggregation, but less than did ASA. ASA abolished secondary, ADP-induced aggregation, dazoxiben not. Both drugs prolonged the bleeding-time. Plasma thromboxane B2 (TxB2) levels did not change significantly after dazoxiben, whereas the prostacyclin metabolite 6-keto-PGF1 alpha rose. The larger dose of ASA reduced both TxB2 and 6-keto-PGF1 alpha in plasma. Whole blood was allowed to clot in order to estimate prostaglandin metabolism. Both drugs prevented thromboxane production effectively. Formation of 6-keto-PGF1 alpha decreased by 95 per cent after ASA but was more than doubled after dazoxiben. Dazoxiben is a selective and effective thromboxane synthetase inhibitor, but has a weaker effect on platelet reactivity than ASA, possibly because endoperoxide formation is not prevented.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aspirin; Blood Platelets; Humans; Imidazoles; Male; Middle Aged; Oxidoreductases; Platelet Adhesiveness; Platelet Aggregation; Prostaglandins; Thromboxane B2; Thromboxane-A Synthase

The imidazole derivative UK-37 248, a thromboxane synthetase inhibitor, reduces the in-vitro formation of thromboxane B2 and hydroxyheptadecatrienoic acid by washed platelets, and this is compensated for by an increased production of prostaglandins E2 and F2 alpha; arachidonic acid challenged platelets pretreated with UK-37 248 also stimulate the production of prostacyclin by aspirin pretreated cultured endothelial cells. In a double-blind placebo controlled study to examine the in vivo properties of UK-37 248, human volunteers ingested 200 mg of the compound. Their serum thromboxane B2 levels dropped and their plasma 6-keto-prostaglandin F1 alpha values rose. Arachidonic acid induced platelet aggregation was completely inhibited whereas that elicited by adenosine-5'-diphosphate was unaffected. By reducing formation of pro-aggregatory tromboxane A2 and increasing production of anti-aggregatory prostacyclin, thromboxane synthetase inhibitors may be better than aspirin as antithrombotic agents.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Clinical Trials as Topic; Double-Blind Method; Fibrinolytic Agents; Humans; Imidazoles; Male; Oxidoreductases; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

1. Drugs that inhibit TxA(2) synthesis are used to reduce platelet aggregation. The aim of this study was to compare the effects of a cyclo-oxygenase (COX) inhibitor (acetylsalicylic acid, ASA), a thromboxane synthetase (TxS) inhibitor (dazoxiben) and a dual TxS inhibitor and TxA(2) receptor blocker (DT-TX 30) on platelet aggregation and the platelet-subendothelium interaction in flow conditions. 2. The techniques used in this in vitro study were platelet aggregometry in whole blood, and measurement of platelet thromboxane B(2) and prostaglandin E(2) production and leucocyte production of 6-keto-PGF(1alpha). The platelet-subendothelium interaction was evaluated in rabbit aorta subendothelium preparations exposed to flowing blood at a shear stress of 800 s(-1). Morphometric methods were used to calculate the percentage of subendothelium occupied by platelets. 3. The 50% inhibitory concentration (IC(50)) of DT-TX 30 in whole blood was in the range of 10(-7) micro M (induced with collagen or arachidonic acid) to 10(-5) micro M (induced with thrombin) or 10(-4) (induced with ADP). IC(50) values under all experimental conditions were lower with DT-TX 30 than with ASA. For thromboxane B(2) the IC(50) were: ASA 0.84+/-0.05 micro M, dazoxiben 765+/-54 micro M, DT-TX 30 8.54+/-0.60 micro M. Prostaglandin E(2) was inhibited only by ASA (IC(50) 1.21+/-0.08 micro M). Leucocyte 6-keto-PGF(1alpha) was inhibited by ASA (IC(50) 6.58+/-0.76 micro M) and increased by dazoxiben and DT-TX 30. The greatest reduction in percentage subendothelial surface occupied by platelets after blood perfusion was seen after treatment with DT-TX 30 in the range of concentrations that inhibited collagen-induced platelet aggregation (control group: 31.20+/-3.8%, DT-TX 30 at 0.1 micro M: 10.71+/-0.55%, at 1.0 micro M: 6.53+/-0.44%, at 5.0 micro M; 1.48+/-0.07%). All three drugs reduced thrombus formation, although ASA (unlike dazoxiben or DT-TX 30) increased the percentage surface occupied by adhesions. 4. In conclusion, the effect of specific blockage of TxS together with blockage of membrane receptors for TxA(2) can surpass the effect of ASA in inhibiting the platelet-subendothelium interaction in flow conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Aspirin; Blood Platelets; Chlorobenzenes; Cyclooxygenase Inhibitors; Dinoprost; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Imidazoles; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyridines; Rabbits; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Combined thromboxane synthase inhibitors and thromboxane receptors antagonists have been shown to have a beneficial effect on different models of thrombosis in vivo. We studied the action of one of these compounds (DT-TX 30) compared with dazoxiben (a thromboxane synthase inhibitor) on retinal vascularity in streptozotocin-diabetic rats. Ten nondiabetic animals were treated with isotonic saline, 30 (10 animals per group) were given 0.4, 4, and 8 mg kg(-1) per day of DT-TX 30 (p.o.) and 30 (10 animals per group) were given 10, 50, and 100 mg kg(-1) per day of dazoxiben (p.o.) over a 90-day study period. DT-TX 30 caused a dose-dependent decrease of platelet aggregation and thromboxane B2 synthesis. There was an increase of 9, 65, and 166% in the synthesis of prostacyclin after treatment with 0.4, 4, and 8 mg kg(-1) per day, respectively. Retinal vascularity increased in 51, 72, and 182% of animals in response to the three doses used. Synthesis of prostacyclin and the degree of retinal vascularity showed a linear correlation (r2=0.6528,p<0.00001). Dazoxiben, at doses that inhibited thromboxane synthesis as much as DT-TX 30, increased prostacyclin production and retinal vascularity with less potency than DT-TX 30. In conclusion, the antagonism of thromboxane receptors may be an important additional effect to the inhibition of thromboxane synthase in the prevention of ischemic retinal lesions in experimental diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Glucose; Chlorobenzenes; Collagen; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Enzyme Inhibitors; Imidazoles; Male; Platelet Aggregation; Pyridines; Rats; Rats, Wistar; Receptors, Thromboxane; Retinal Vessels; Thromboxane B2; Thromboxane-A Synthase

This study investigated, in isolated human internal mammary artery, the involvement of the cyclooxygenase and the lipoxygenase pathways of arachidonic acid metabolism in the contraction induced by angiotensin II.. Rings of human internal mammary arteries were suspended in organ baths for recording of isometric tension. In addition, the release of eicosanoids in response to angiotensin II (0.3 microM) was measured by enzyme immunoassay.. In human arterial rings without endothelial dependent relaxation in response to substance P or acetylcholine, the angiotensin II-induced contractions were significantly (P<0.05) reduced by 27% in the presence of GR32191 0.3 microM (thromboxane A(2) (TXA(2)) receptor antagonist) but remained unchanged in the presence of dazoxiben 100 microM (thromboxane synthase inhibitor). In addition, angiotensin II failed to modify TXB(2) and 6-keto-PGF(1alpha) production. These results suggest the contribution of a TXA(2)/PGH(2) agonist other than TXA(2) in angiotensin II-induced contractions. However, indomethacin increased (P<0.05) angiotensin II-mediated contractile response and cysteinyl leukotriene production, suggesting a redirection of arachidonic acid metabolism from the cyclooxygenase pathway to the lipoxygenase pathway. Indeed, the contractions induced by angiotensin II were inhibited (P<0.05) by phenidone 100 microM (cyclooxygenase and lipoxygenase inhibitor), baicalein 100 microM (5-, 12- and 15-lipoxygenases inhibitor), AA861 10 microM (5-lipoxygenase inhibitor) and MK571 1 microM (CysLT(1) receptor antagonist). Cysteinyl leukotrienes were released in response to angiotensin II (pg/mg dry weight tissue: 32+/-9 (basal, n=6) vs. 49+/-9 (angiotensin II 0.3 microM, n=6), P<0.05). LTD(4), and at a lesser degree LTC(4), induced contractions of internal mammary artery and MK571 1 microM abolished the contraction to LTD(4).. This study suggests that the in vitro vasoconstrictor effects of angiotensin II in human internal mammary artery are enhanced at least in part by eicosanoids produced by the cyclooxygenase pathway, probably PGH(2), acting on TXA(2)/PGH(2) receptors, and by lipoxygenase-derived products, particularly cysteinyl leukotrienes acting on CysLT(1) receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Angiotensin II; Benzoquinones; Biphenyl Compounds; Cyclooxygenase Inhibitors; Depression, Chemical; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavanones; Flavonoids; Heptanoic Acids; Humans; Imidazoles; In Vitro Techniques; Indomethacin; Leukotrienes; Lipoxygenase Inhibitors; Mammary Arteries; Propionates; Pyrazoles; Quinolines; Receptors, Thromboxane; Substance P; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

The role of vascular cyclooxygenase pathway on tissue-type plasminogen activator (t-PA) release after venous occlusion was studied in anesthetized rats. After the inferior vena cava was clamped for 30 min, fibrinolytic activity increased from 143.7 +/- 14.5 to 209.5 +/- 10.3 mm2 (mean +/- SE, P < 0.002). This increase was prevented by aspirin at high (100 mg/kg i.v.) but not at low doses (1 mg/kg i.v.). Dazoxiben (10 mg/kg i.v.), an inhibitor of thromboxane synthase, was ineffective on the fibrinolytic response. Both the basal levels of 6-ketoprostaglandin F1 alpha and its increase after venous occlusion were suppressed by 100 mg/kg aspirin administration (from 0.64 +/- 0.2 to 0.05 +/- 0.002 ng/ml before occlusion, P < 0.001; and from 1.08 +/- 0.2 to 0.06 +/- 0.002 ng/kg after occlusion, P < 0.001), whereas they were both unaffected by aspirin at low doses (from 0.53 +/- 0.06 before to 1.20 +/- 0.08 ng/ml after stasis). Moreover, iloprost, a stable analogue of prostacyclin, reversed the aspirin inhibitory effects on fibrinolytic activity by restoring t-PA vascular release after venous stasis. Our results provide experimental evidence that an intact cyclooxygenase pathway in vascular wall is required for the fibrinolytic activity increase after venous occlusion in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Pressure; Dose-Response Relationship, Drug; Fibrinolysis; Iloprost; Imidazoles; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred Strains; Thromboxane-A Synthase; Tissue Plasminogen Activator; Vena Cava, Inferior

We investigated the relation between the changes of TXA2-PG1 alpha balance and glomerular injury, and the effects of Dazoxiben, Chuan Xiong on in situ immune complex glomerulonephritis (ISICGN) produecd by C-BSA in rats. After two weeks of immunization, the level of renal cortical TXB2 and urine protein was increased, while that of 6-keto-PGF1 alpha was decreased. Four weeks later, the changes as mentioned above were more significant, and platelet aggregation revealed an increase of maximal aggregation. Positive correlation was seen between urine protein and renal cortical TXA2, and negative correlation between urine protein and 6-keto-PGF1 alpha. Histological examination showed morphological changes. Two treated-groups showed significant reduction of urine protein and renal cortical TXB2, but increase of 6-keto-PGF1 alpha. Besides the changes like worm-eaten in electron-dense deposits, foot process fusion disappeared. The thickened GBM and mesangial proliferation were lessened, especially in Dazoxiben group. These results suggests that there is a TXA2-PG1 alpha imbalance in ISICGN, and TXA2 plays an important pathogenetic role in the onset and progression of glomerulonephritis. Dazoxiben and Chuan Xiong might improve TXA2-PG1 alpha imbalance and attenuate glomerular injury to some extent in ISICGN.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antigen-Antibody Complex; Drugs, Chinese Herbal; Glomerulonephritis; Imidazoles; Kidney Cortex; Male; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine; Thromboxane B2; Thromboxane-A Synthase

Advanced cirrhosis is known to be associated with extrahepatic organ dysfunction, but the mechanism for this cirrhosis complication is largely unknown. We measured tissue albumin leakage in rats with biliary cirrhosis or acute cholestasis and tested the hypothesis that arachidonic acid metabolites contribute to the vascular permeability change. Six weeks after bile duct ligation, rats with biliary cirrhosis exhibited increased extravascular leakage of 125I-albumin in lung (p < 0.001) and kidney (p < 0.01) but not in heart or brain. In contrast, in cholestatic rats 10 days after bile duct ligation, only the kidney albumin leak was significantly increased (p < 0.01). Tissue thromboxane B2 levels, measured with an enzyme immunoassay, were increased in lung, kidney and liver of cirrhotic and cholestatic rats. To determine whether thromboxane A2 contributes to the vascular permeability defects in cirrhosis, we pretreated cirrhotic rats with the thromboxane synthase inhibitor dazoxiben (10 mg/kg intraperitoneally every 8 hr) for 20 hr before assessment of vascular permeability. Dazoxiben blocked the increase in thromboxane B2 level in lung but not in kidney and lowered the lung but not the kidney albumin leak index. In cholestatic rats given a higher dose of dazoxiben (40 mg/kg intraperitoneally every 8 hr) for 20 hr, the kidney thromboxane B2 level but not albumin leak was significantly lowered. We conclude that chronic biliary obstruction in rats leads to increased vascular permeability in selected extrahepatic organs and that thromboxane A2 contributes to the vascular permeability increase in the lung. Whether thromboxane A2 plays a role in renal albumin leakage will require further study.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Bile Ducts; Capillary Permeability; Cholestasis; Eicosanoids; Imidazoles; Kidney; Ligation; Liver Cirrhosis, Biliary; Lung; Male; Rats; Rats, Sprague-Dawley; Serum Albumin, Radio-Iodinated; Thromboxane A2; Thromboxane B2

When injected i.v. to guinea pigs, the granulocyte secretagog N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) induces bronchoconstriction (BC), lung platelet sequestration and increased transendothelial albumin exchanges in lungs. We evaluated BC and the variations of the lung contents in radiolabeled platelets, erythrocytes and extravascular albumin, as measurements of platelet lung entrapment, reduction of lung blood volume and increase of transendothelial albumin exchanges, respectively. Trimetoquinol, a thromboxane A2 (TXA2)-endoperoxide receptor antagonist, inhibited BC and platelet entrapment by lungs induced by fMLP, but protection was nonspecific because it also suppressed BC by histamine. The specific TXA2 synthetase inhibitor/endoperoxide receptor antagonist ridogrel suppressed BC and reduced lung platelet entrapment, but failed to prevent the increase of extravascular albumin and the decrease of erythrocyte lung contents due to fMLP. Consequently, the fMLP-induced increase of vascular albumin exchanges and reduction of lung blood volume are TXA2-independent. Aspirin prevented BC, but failed to suppress lung platelet entrapment by fMLP, indicating that in vivo platelet activation is not TXA2-dependent, even though the levels of circulating TXB2, the stable metabolite of TXA2, were increased after fMLP concomitantly with that of 6-keto-prostaglandin (PG)F1 alpha, the stable metabolite of PGI2. The ridogrel-treated animals showed reduced blood level of TXB2 and increased levels of 6-keto-PGF1 alpha after fMLP challenge. Blocking the cyclooxygenase pathway with aspirin prevented ridogrel-induced protection against lung platelet sequestration after fMLP, supporting the concept that rechanneling of arachidonate metabolism toward protective prostaglandins accounts for protection by ridogrel.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Blood Platelets; Bronchoconstriction; Guinea Pigs; Imidazoles; Lung; N-Formylmethionine Leucyl-Phenylalanine; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Radioimmunoassay; Serum Albumin; Suprofen; Thrombocytopenia; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Tretoquinol

The in vitro properties of CS-518 (RS-5186; sodium 2-(1-imidazolylmethyl)- 4,5-dihydrobenzo[b]thiophene-6-carboxylate, CAS 113817-57-5), a new thromboxane (TX) synthetase inhibitor, as an antiplatelet agent were investigated. Incubation of clotting whole blood from man, rabbits, and dogs with CS-518 resulted in a concentration-dependent reduction of TXB2 production and an increase in 6-keto-PGF1 alpha. Similar properties were also observed for ozagrel and isbogrel, but both agents were less effective on TXB2 production. CS-518 inhibited arachidonic acid (AA)- or collagen-induced platelet aggregation in platelet rich plasma (PRP) from man, rabbits and dogs. In addition, antiaggregatory effects of CS-518 were confirmed in whole blood by two methods: impedance method and free platelet count method. TXA2 formation in washed canine platelets in response to AA (0.1 mmol/l) was dose-dependently inhibited by incubation with CS-518. This inhibition by CS-518 was gradually attenuated after platelets were subsequently washed with drug-free buffer, but a dose-dependent inhibition was still observed with platelets that had been washed three times. Ozagrel also inhibited TXB2 formation when incubated with platelets, whereas this inhibition disappeared with platelets only washed once. In contrast, platelets treated with acetylsalicylic acid, an irreversible inhibitor of cyclooxygenase showed a comparable inhibition before and after they were washed three times. These results indicate that CS-518 exerts antiplatelet effects in vitro via potent, selective, and long-lasting but reversible inhibition on TX synthetase.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Aspirin; Dogs; Humans; Imidazoles; In Vitro Techniques; Male; Methacrylates; Platelet Aggregation; Platelet Aggregation Inhibitors; Rabbits; Thiophenes; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

To clarify whether activated platelets play an important role in the occurrence and exacerbation of disseminated intravascular coagulation (DIC), we investigated the effects of 4 anti-platelet drugs, a PGI2 analog (CS-570), a thromboxane synthetase inhibitor (dazoxiben), a thromboxane receptor antagonist (BM-13177), and ticlopidine, in an experimental DIC model in rats. Experimental DIC was induced by a continuous infusion of lipopolysaccharide (LPS derived from E. coli, 055 B5, 25 mg/kg/hr) for 4 hrs. In the time-course determination of the coagulation parameters and prostanoids, an abrupt increase in TxB2 (a stable metabolite of TxA2) and 6-keto-PGF1 alpha (a stable metabolite of PGI2) was followed by a decrease in platelet count, a prolongation of blood coagulation time, and an increase in fibrinogen/fibrin degradation products (FDP). Four hours after the start of LPS infusion, the rats were considered to be in the state of DIC. The effects of the anti-platelet drugs were investigated 4 hrs after the start of LPS infusion. CS-570 and ticlopidine ameliorated DIC in a dose-dependent manner. CS-570 (10 micrograms/kg/min) improved DIC in the platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fbg), and FDP, without affecting TxB2 and 6-keto-PGF1 alpha formation. Ticlopidine (200 mg/kg, i.p.) prevented the exacerbation of DIC in such item parameters as platelet count, APTT, and FDP. Both dazoxiben and BM-13177 (30 mg/kg, i.p.) ameliorated DIC in following parameters as platelet count, APTT and FDP. Dazoxiben, but not BM-13177, significantly inhibited the increase in TxB2 concentration at 4 hr. These observations suggest that drugs which inhibit platelet activation by a TxA2-dependent route are effective in improving DIC induced by LPS, and that drugs which inhibit multiple platelet-activating routes improve DIC in more item parameters than drugs which inhibit only the TxA2-dependent activating route. Consequently, it is concluded that activated platelets might play an important role in the occurrence and exacerbation of DIC induced by LPS, and that one of the roles of TxA2 in DIC is to activate platelets.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Endotoxins; Epoprostenol; Fibrin; Humans; Imidazoles; Kidney Glomerulus; Male; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Count; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains; Sulfonamides; Thromboxane B2; Thromboxane-A Synthase; Ticlopidine

Dazoxiben, a selective TXA2 synthetase inhibitor, was studied in the incubating sections of porcine basilar arteries with arachidonic acid (AA) 50 mumols/L and calcimycin (calcium inophore A-23187) 50 mumol/L. TXB2 and 6-keto-PGF1 alpha were determined by radioimmunoassay. Leukotrienes (LT) were extracted and purified with SEP-PAK column, identified by HPLC and determined by bioassay with ileum of guinea pig. The results showed that the production of TXB2 was unaltered whether or not the incubation of arteries were induced by AA or calcimycin. Dazoxiben and indomethacin 0.05-50 mumols/L had no effects on the production of TXB2. However, dazoxiben 0.5, 5 and 50 mumols/L increased the production of 6-keto-PGF1 alpha by 16.3%, 19.0% and 30.7%, respectively. Indomethacin 0.5, 5 and 50 mumols/L decreased the production of 6-keto-PGF1 alpha by 22.3%, 24.9% and 24.0%, respectively. Meanwhile dazoxiben 1, 10 and 100 mumols/L decreased the production of LT by 33.4%, 45.6% and 66.4%, respectively. These results suggest that the protective effect of dazoxiben on the damages which resulted from brain ischemia may be related to the change of TAX2/PGI2 balance in the brain tissue as well as the inhibition of production of LT.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Basilar Artery; Biological Assay; Imidazoles; In Vitro Techniques; Indomethacin; Leukotrienes; Radioimmunoassay; Swine; Thromboxane B2; Thromboxane-A Synthase

An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA2 synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl)-6-methyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA2 synthetase in rabbit and human platelets in vitro and reduced plasma TXB2 levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF1 alpha, reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Chemical Phenomena; Chemistry; Dihydropyridines; Drug Design; Fibrinolytic Agents; Humans; Hypertension; Imidazoles; Nitrendipine; Rats; Rats, Inbred SHR; Structure-Activity Relationship; Thromboxane B2; Thromboxane-A Synthase

The effects of dazoxiben, a TXA2 synthetase inhibitor, and indomethacin were compared on cerebrovascular resistance (CVR) and levels of serum TXB2, 6-keto-PGF1 alpha (the stable metabolites of TXA2 and PGI2, respectively) and on protection from acute brain ischaemia caused by ia arachidonic acid (AA) in rabbits. The flow represented the cerebral blood flow (CBF) in two internal jugular arteries were measured with electromagnetic flow meter after occlusion of bilateral vertebral arteries and external jugular arteries. CVR was represented as blood pressure/(CBF.100 g brain). Serum TXB2 and 6-keto-PGF1 alpha levels were determined by radioimmunoassay. The results showed that CVR and BP, EEG, ECG were not affected by treatment with iv dazoxiben 2 or 10 mg/kg. The CVR was enhanced by 35.5 and 49.8% at 30 and 40 min, respectively after iv indomethacin 10 mg/kg. The serum TXB2 level (872 +/- 85) was inhibited to 511 +/- 169 pg/ml (n = 5, P less than 0.05) and 6-keto-PGF1 alpha increased from 668 +/- 309 to 890 +/- 357 pg/ml (n = 5, P less than 0.05) at 30 min after iv 2 mg/kg dazoxiben. However, both TXB2 and 6-keto-PGF1 alpha decreased by 26.4 and 32.7%, respectively at 40 min after iv indomethacin 10 mg/kg. In a model of cerebral ischaemia caused by ia AA in rabbits, the EEG change and enhancement of CVR were antagonized by iv dazoxiben 10 mg/kg completely, but only partly antagonized by indomethacin 10 mg/kg. The results suggest that PGI2 and TXA2 may play a minor role in the regulation of CVR in the physiological condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cerebrovascular Circulation; Imidazoles; Male; Rabbits; Thromboxane B2; Thromboxane-A Synthase; Vascular Resistance

Goats were divided into three groups and given infusions of live Escherichia coli bacteria. Group I received no treatment, group II was treated with indomethacin (a cyclooxygenase inhibitor), and group III with dazoxiben (a thromboxane synthase inhibitor). Double indicator-dilution extravascular lung water (EVLW) in group I was significantly different from the treated groups. There was an early increase in EVLW in group I and group III but not in group II animals. At 6 h EVLW's in group I, group II, and group III were 100, 45, and 30% above base line, respectively. Lymph flow (QL) and lymph-to-plasma protein ratio (L/P) was not statistically different between groups. Estimated total fluid filtration [QL + d(EVLW)/dt] in group I and III was markedly elevated between 0 and 1.5-2 h after E. coli infusion. Cardiac output (QT) decreased to 40% of base line in group I, and it decreased slightly in group II because of the indomethacin but did not decrease after E. coli. QT decreased in group III but recovered more rapidly than group I. Mean pulmonary arterial pressure increased more rapidly in group I and reached a higher peak than either treated group. At 6 h these groups had similar pulmonary arterial and pulmonary arterial wedge pressures. We conclude that 1) indomethacin but not dazoxiben blocks the early increase in total fluid filtration after bacterial infusion, 2) dazoxiben does not prevent the increased endothelial permeability resulting from infusion of live bacteria, and 3) indomethacin may somewhat ameliorate the endothelial permeability change.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Body Water; Cardiac Output; Escherichia coli Infections; Imidazoles; Indomethacin; Lung; Lymph; Pulmonary Circulation; Reference Values; Thromboxane B2; Thromboxane-A Synthase

Dazoxiben, a thromboxane synthetase inhibitor, was infused i.v. in a first group of guinea pigs. Saline was given to a second group of animals as controls. Subsequently, the lateral cochlear walls of each animal were prepared and analyzed for thromboxane (TXA) and prostacyclin (PGI) using radioimmunoassay. These studies showed that dazoxiben crosses the blood-labyrinth barrier and shifts the TXA2/PGI2 balance in favor of the latter. The effects demonstrated are discussed with respect to the relevance of prostanoids in cochlear physiology.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cochlea; Epoprostenol; Female; Guinea Pigs; Imidazoles; Male; Thromboxane-A Synthase; Thromboxanes

CGS 15435A, a novel thromboxane (Tx) synthetase inhibitor (5-chloro-1-methyl-2-(3-pyridyl)-3-indolhexanoic acid HCl), had a selectivity for Tx synthetase 100,000-fold greater than that for cyclooxygenase, PGI2 synthetase and lipoxygenase enzymes. In conscious beagles, 1 h following a single 3 mg/kg p.o. dose, serum TxB2 was inhibited 95% by CGS 15435 and 82% by dazoxiben (DAZ). Unlike the short acting Tx synthetase inhibitor DAZ, CGS 15435A significantly inhibited TxB2 formation 4, 6, 12 and 24 h after dosing. Serum levels of 6-keto PGF1 alpha and PGE2 were significantly increased following the administration of either drug. CGS 15435A and DAZ were further examined in a model with known Tx involvement. Thrombotic sudden death, produced in anesthetized rabbits by injection of 0.75 mg/kg arachidonic acid (AA) i.v. resulted in a 45% fall in the platelet count and 0% survival. Pretreatment with DAZ (8.6 mumol/kg i.v.) at 0.25 or 2 h pre-AA resulted in 3 and 42% thrombocytopenia and 100 and 0% survival respectively. CGS 15435A (8.6 mumol/kg i.v.) prevented the increases in plasma TxB2 levels, thrombocytopenia and sudden death with pretreatment at 0.25 h (0% thrombocytopenia and 100% survival) or 24 h (11% thrombocytopenia and 83% survival) before AA. These data indicate that CGS 15435A is a potent and selective Tx synthetase inhibitor with a long duration of action, and suggest that the compound could be useful in chronic, non-symptomatic indications of Tx involvement.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase Inhibitors; Cytochrome P-450 Enzyme System; Death, Sudden; Dinoprostone; Dogs; Epoprostenol; Imidazoles; In Vitro Techniques; Indoles; Intramolecular Oxidoreductases; Lipoxygenase Inhibitors; Platelet Count; Prostaglandins E; Rabbits; Thromboxane B2; Thromboxane-A Synthase

We examined the direct effects of thrombin on pulmonary vasomotor tone in isolated guinea pig lungs perfused with Ringer albumin (0.5% g/100 ml). The injection of alpha-thrombin (the native enzyme) resulted in rapid dose-dependent increases in pulmonary arterial pressure (Ppa) and pulmonary capillary pressure (Ppc), which were associated with an increase in the lung effluent thromboxane B2 concentration. The Ppa and Ppc responses decreased with time but then increased again within 40 min after thrombin injection. The increases in Ppc were primarily the result of postcapillary vasoconstriction. Pulmonary edema as evidenced by marked increases (60% from base line) in lung weight occurred within 90 min after thrombin injection. Injection of modified thrombins (i.e., gamma-thrombin lacking the fibrinogen recognition site or i-Pr2P-alpha-thrombin lacking the serine proteolytic site) was not associated with pulmonary hemodynamic or weight changes nor did they block the effects of alpha-thrombin. Indomethacin (a cyclooxygenase inhibitor), dazoxiben (a thromboxane synthase inhibitor), or hirudin (a thrombin antagonist) inhibited the thrombin-induced pulmonary vasoconstriction, as well as the pulmonary edema. We conclude that thrombin-induced pulmonary vasoconstriction is primarily the result of constriction of postcapillary vessels, and the response is mediated by generation of cyclooxygenase-derived metabolites. The edema formation is also dependent on activation of the cyclooxygenase pathway. The proteolytic site of alpha-thrombin is required for the pulmonary vasoconstrictor and edemogenic responses.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Female; Guinea Pigs; Hirudins; Imidazoles; Indomethacin; Lung; Male; Organ Size; Pulmonary Artery; Pulmonary Wedge Pressure; Thrombin; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

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

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

Intravascular complement activation results in thromboxane (TxA2) production, pulmonary hypertension, hypoxemia, and increased lung vascular permeability. The purpose of this study was to determine the role of TxA2 as a mediator of these responses. Experiments were made in anesthetized sheep subjected to intravenous injections of zymosan-activated plasma (ZAP) every 30 min for 4 h. Sheep were pretreated with dazoxiben, a TxA2 synthetase inhibitor, or SK and F 88046, a TxA2 end-organ antagonist, and the results were compared with those from untreated sheep. Dazoxiben, but not SK and F 88046, inhibited TxA2 release. The hypertensive response averaged 74 +/- 3 cm H2O after each injection of ZAP in untreated sheep. Neither drug altered this response. Pao2 decreased an average of 20 +/- 1 mmHg in untreated sheep, 3 +/- 1 mmHg in dazoxiben-treated sheep, and 11 +/- 1 mmHg in SK and F 88046-treated sheep. Increases in lung lymph flow and lymph protein clearance were unaffected by treatment. TxA2 appears to be an important mediator of hypoxemia during intravascular complement activation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Capillary Permeability; Complement Activation; Hypertension, Pulmonary; Hypoxia; Imidazoles; Leukocytes; Lung Diseases; Plasma; Pulmonary Circulation; Sheep; Sulfonamides; Thromboxane A2; Zymosan

Administration of dazoxiben (5 mg/kg, i.v.), which effectively suppressed plasma thromboxane concentrations, decreased the number of dogs that deteriorated into shock following a temporary (3-hr) splanchnic artery occlusion (SAO). Dazoxiben pretreatment also moderated the rise of plasma prostacyclin, but it augmented circulating prostaglandin E2 following the release of SAO. These alterations in arachidonic acid metabolism were accompanied by a moderation in the rise of plasma beta-glucuronidase activity, suggesting a moderation of tissue damage in the ischemic splanchnic region, and mitigation of the progressive hemodynamic deterioration caused by the SAO. The possible existence of causal relationships between the plasma eicosanoid concentrations, extent of damage in the ischemic splanchnic region, hemodynamic deterioration, and ultimate production of circulatory failure in dogs subjected to SAO are discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cardiac Output; Dogs; Female; Glucuronidase; Heart Rate; Imidazoles; Indomethacin; Ischemia; Kinetics; Male; Shock; Splanchnic Circulation; Thromboxane B2; Thromboxane-A Synthase; Vascular Resistance

During infusion of thrombin in rats pulmonary arterial pressure rose from 15 +/- 2 to 35 +/- 3 mmHg and mean arterial pressure fell from 120 +/- 6 to 49 +/- 27 mmHg. Plasma thromboxane B2 (TxB2) increased from 0.3 +/- 0.04 to 3.6 +/- 0.5 ng/ml. Ninety minutes later the lung weight and albumin concentration in the lung were increased (2.21 +/- 0.13 g and 22.7 +/- 4.7 mg/g) compared with controls (1.12 +/- 0.14 g and 8.5 +/- 0.9 mg/g). An inhibitor of thromboxane synthetase, Dazoxiben R, reduced the elevated pulmonary arterial pressure and the elevated plasma TxB2 concentration following infusion of thrombin. Ninety minutes after infusion of thrombin, the in vitro synthesis of TxB2 in lung tissue was increased. Dazoxiben and antineutrophil serum reduced this synthesis of TxB2 in vitro. The lung weight (2.18 +/- 0.20 g) and lung albumin concentration (21.4 +/- 3.4 mg/g) was not affected by Dazoxiben. The results indicate that TxA2 is an important mediator of the pressure changes in the early phase after infusion of thrombin and that neutrophils are associated with thromboxane formation in the lung tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cattle; Fibrinogen; Fibrinolysis; Imidazoles; Indomethacin; Lung; Lung Diseases; Male; Organ Size; Platelet Count; Rats; Rats, Inbred Strains; Serum Albumin; Thrombin; Thromboxane B2; Thromboxane-A Synthase

The effects of indomethacin, dazoxiben and EPO45 on collagen-induced platelet aggregation in vivo were studied in guinea-pigs and rats to determine the involvement of the prostaglandin endoperoxide/thromboxane A2 pathway in the aggregatory response. Indomethacin and EPO45 (a thromboxane receptor antagonist) partially inhibited platelet aggregation in rats. It was concluded that only one third of the aggregatory response to collagen was mediated by the products of cyclo-oxygenase conversion of arachidonic acid. In rats, dazoxiben was inactive although the conversion of the prostaglandin endoperoxides to thromboxane A2 was inhibited (measured as thromboxane B2). 6-keto PGF1 alpha was detected in plasma after collagen was injected into dazoxiben-treated rats. In this species therefore, the endoperoxides have significant aggregatory activity whilst the apparent increase in the level of prostacyclin was not sufficient to have any anti-aggregatory effect. All three drugs were active in the guinea-pig. About 60% of the aggregatory response to collagen was due to the products of the cyclo-oxygenase pathway, the main mediator being thromboxane A2. In guinea-pigs, dazoxiben also elevated 6-keto PGF1 alpha in the plasma after an injection of collagen. However, this apparent increase in prostacyclin production did not contribute to the anti-aggregatory effect.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Collagen; Female; Guinea Pigs; Imidazoles; In Vitro Techniques; Indomethacin; Male; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Species Specificity; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dipyridamole; Drug Synergism; Humans; Imidazoles; Male; Oxidoreductases; Platelet Aggregation; Thromboxane-A Synthase

The effect of a selective inhibitor of thromboxane synthesis (dazoxiben) was evaluated in different acute models for thrombosis and hemostasis. Dazoxiben significantly reduced the thrombogenicity of the modified human umbilical vein (Dardik Biograft) inserted in the carotid artery position in sheep. The effect was evident concerning patency, thrombus weight and platelet accumulation at the distal anastomosis. This paralleled a decreased production of thromboxane in both anastomoses and the midgraft region. Dazoxiben did not reduce either the frequency of jugular vein thrombosis (induced by a combination of endothelial damage and flow restriction) or arteriolar microembolism after laser injury in rabbits. Neither did it influence initial hemostasis as evaluated by measuring the hemostatic plug formation in the rabbit mesenteric microcirculation. It is concluded that thromboxane synthesis inhibition may be of value when attempting to improve the performance of small diameter vascular prostheses, the data obtained indicating a low risk for hemorrhagic complications.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Carotid Arteries; Female; Hemostasis; Humans; Imidazoles; Jugular Veins; Male; Oxidoreductases; Rabbits; Sheep; Thrombosis; Thromboxane B2; Thromboxane-A Synthase; Umbilical Veins

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Female; Humans; Imidazoles; Male; Middle Aged; Migraine Disorders; Oxidoreductases; Thromboxane-A Synthase

The effect of various factors upon prostaglandin (PG) production by the osteoblast was examined using osteoblast-rich populations of cells prepared from newborn rat calvaria. Bradykinin and serum, and to a lesser extent, thrombin, were all shown to stimulate PGE2 and 6-keto-PGF1 alpha (the hydration product of PGI2) secretion by the osteoblastic cells. Several inhibitors of prostanoid synthesis, dexamethasone, indomethacin, dazoxiben and nafazatrom, were tested for their effects on the calvarial cells. All inhibited PGE2 and PGI2 (the major arachidonic acid metabolites of these cells) production with half-maximal inhibition by all four substances occurring at approximately 10(-7) M. For dazoxiben and nafazatrom, this was in contrast to published results from experiments in vivo which have indicated that the compounds stimulated PGI2 production. Finally, since the osteoblast is responsive to bone-resorbing hormones, these were tested. Only epidermal growth factor (EGF) was shown to modify PG production. At early times EGF stimulated PGE2 release, however, the predominant effect of the growth factor was an inhibition of both PGE2 and PGI2 production by the osteoblastic cells. The present results suggest that the bone-resorbing hormones do not act to cause an increase in PG by the osteoblast and that any increase in PG production by these cells may be in response to vascular agents.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Bradykinin; Cells, Cultured; Dexamethasone; Dinoprostone; Epidermal Growth Factor; Imidazoles; Indomethacin; Osteoblasts; Prostaglandins; Prostaglandins E; Pyrazoles; Pyrazolones; Rats; Thrombin

Radioimmunoassay and bioassay techniques have been used to investigate the ability of leukotriene (LT)F4 to release products of arachidonic acid metabolism from guinea pig isolated lungs perfused via the pulmonary artery. Also, the abilities of LTC4, LTD4, LTE4 and LTF4 to contract guinea pig ileal smooth muscle (GPISM) was studied. Each of the LT's contracted GPISM. The rank order of potency was LTD4 greater than LTC4 greater than LTE4 much greater than LTF4 in a ratio of 1:7:170:280 respectively. Bioassay of pulmonary effluents indicated the passage of LTF4 through the lungs caused a contraction of rabbit aorta as well as an FPL-55712 sensitive contraction of GPISM. The contractions of rabbit aorta were inhibited by pretreatment of the lungs with Indomethacin but not with the thromboxane synthetase inhibitor Dazoxiben. Radioimmunoassay of the lung effluents indicated LTF4 to cause a 70-fold increase in thromboxane B2 (TXB2), 4-fold increase in prostaglandin (PG)E2 and a 16-fold increase in 6-keto PGF1 alpha levels. The LTF4-induced increments of these immunoreactive metabolites was inhibited by pretreatment of the lungs with Indomethacin. Pretreatment of lungs with Dazoxiben inhibited the LTF4-induced increment in TXB2 and enhanced the effluent levels of PGE2 24-fold (compared with untreated lungs). There were no detectable differences in either immunoreactive LTC4 or immunoreactive LTB4 levels. It is concluded LTF4 is a relatively weak agonist on GPISM and can induce the release of cyclooxygenase products of arachidonic acid metabolism from guinea pig perfused lung.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Biological Assay; Dinoprostone; Female; Guinea Pigs; Imidazoles; In Vitro Techniques; Indomethacin; Lung; Male; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; SRS-A; Thromboxane B2

The TxA2 synthetase inhibitor, dazoxiben, and the TxA2 antagonist, +/- SQ 29,548, were examined for effects on release and vasoactivity of TxA2 and prostacyclin. Isolated perfused guinea pig lungs were used as the enzyme source from which TxA2 and prostacyclin were released in response to injections of arachidonic acid or bradykinin. Both dazoxiben and +/- SQ 29, 548 inhibited contraction of the superfused rat aorta and bovine coronary artery after arachidonic acid injection through the lung. +/- SQ 29,548 abolished contractions of the rat aorta, but significant aorta contracting activity persisted during dazoxiben treatment. Dazoxiben significantly inhibited arachidonate-induced release of TxA2 (immunoreactive TxB2) into the superfusate, but TxA2 release was significantly potentiated by +/- SQ 29,548. Thus, in the presence of enhanced TxA2 concentrations, +/- SQ 29,548 effectively antagonized the vasospastic effect of TxA2. Dazoxiben diverted a significantly greater amount of arachidonic acid into prostacyclin synthesis (immunoreactive 6-keto-PGF1 alpha), changing original coronary vasoconstriction into relaxation. +/- SQ 29,548 did not significantly modify lung prostacyclin synthesis. Moreover, with +/- SQ 29,548, the absence of TxA2-mediated coronary contraction unmasked active relaxation of the superfused bovine coronary artery, coincident with thromboxane and prostacyclin release. Dazoxiben consistently inhibited TxA2 synthesis and enhanced prostacyclin synthesis. +/- SQ 29,548 augmented TxB2 release in response to arachidonate, but not bradykinin, and did not significantly alter 6-keto-PGF1 alpha release in response to either arachidonate or bradykinin. In terms of vasoactivity measured in vitro, +/- SQ 29,548 and dazoxiben produced similar anti-vasospastic effects, although this was accomplished by completely different mechanisms.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Bradykinin; Bridged Bicyclo Compounds, Heterocyclic; Cattle; Epoprostenol; Fatty Acids, Unsaturated; Guinea Pigs; Hydrazines; Imidazoles; Male; Muscle Contraction; Muscle, Smooth, Vascular; Oxidoreductases; Rats; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Humans; Imidazoles; Oxidoreductases; Radioimmunoassay; Thromboxane-A Synthase

The amounts of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) produced by the endothelial surfaces of paired samples of human pulmonary arteries and veins, obtained from patients undergoing thoracic surgery, were measured. The amounts of 6-keto-PGF1 alpha and TxB2 produced by arteries compared with veins were not different. However, both arteries and veins produced more 6-keto-PGF1 alpha than TxB2, the ratio being approximately 7.5:1 for both. 6-keto-PGF1 alpha synthesis by arteries was significantly correlated with that produced by veins but the relative amounts of TxB2 were not correlated. 6-keto-PGF1 alpha synthesis was correlated with TxB2 synthesis for veins but not for arteries. 8 of the 12 arterial samples exhibited some degree of intimal fibrosis. Incubation with the thromboxane synthase inhibitor, dazoxiben , caused a significant inhibition of vascular TxB2 synthesis and a significant increase in 6-keto-PGF1 alpha synthesis. In 3 of the 5 cases the increase in 6-keto-PGF1 alpha was too large to be explained by the fall in TxB2.

Topics: 6-Ketoprostaglandin F1 alpha; Endothelium; Epoprostenol; Humans; Imidazoles; Oxidoreductases; Pulmonary Artery; Pulmonary Veins; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Dazoxiben, a specific thromboxane synthetase inhibitor, was evaluated in 21 patients with Raynaud's phenomenon in a double-blind, placebo-controlled crossover experiment. Total fingertip blood flows were measured by plethysmography and capillary blood flows were measured by 133Xe disappearance rate. Subjects were studied in both a warm (28 degrees) and a cold (20 degrees) room. Arteriovenous (AV) shunt flow was estimated by subtraction of capillary flow from total flow. Ex vivo production of thromboxane B2 (TXB2) and 6-keto PGF1 alpha was determined by specific radioimmunoassay in serum from venous blood incubated for 1 hr (37 degrees). Plasma concentrations of TXB2 and 6-keto PGF1 alpha were also monitored. Dazoxiben (100 mg 4 times a day for 14 days) inhibited ex vivo TXB2 production (from 463.1 +/- 69.9 to 101.8 +/- 13.4 ng/ml/hr; (means +/- SE], enhanced ex vivo 6-keto PGF1 alpha production (from 1.38 +/- 0.05 to 3.76 +/- 0.18 ng/ml/hr), reduced plasma TXB2 concentration (from 88.1 +/- 13.9 to 38.8 +/- 5.9 pg/ml). There were no changes in plasma concentration of 6-keto PGF1 alpha. Dazoxiben did not improve total digital blood flow, capillary flow, AV shunt flow, or forearm blood flow at 28 degrees or 20 degrees. There was no subjective improvement in frequency or severity of Raynaud's attacks (assessed by patient diaries). It is concluded that dazoxiben is a potent and specific thromboxane synthetase inhibitor capable of altering arachidonic acid metabolism, but is of little or no benefit in the treatment of Raynaud's phenomenon.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Double-Blind Method; Drug Evaluation; Female; Forearm; Humans; Imidazoles; Male; Middle Aged; Plethysmography; Radioimmunoassay; Raynaud Disease; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Imidazoles; Male; Oxidoreductases; Pyridines; Thromboxane-A Synthase; Time Factors

Radioimmunoassay (RIA) and high-resolution gas chromatography-mass spectrometry (HRGC-MS) were compared for the determination of serum 6-keto-PGF-1 alpha and TXB2 in a situation of drug-altered arachidonate metabolism. Results were comparable for TXB2 in both conditions. 6-keto-PGF1 alpha RIA determinations (with two different antisera) revealed increased levels in dazoxiben-treated samples, which were not confirmed by HRGC-MS. The assay were repeatedly checked in controlled conditions to investigate these discrepancies. Interference was found with both antisera, due to the drug-induced change in metabolism.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Gas Chromatography-Mass Spectrometry; Humans; Imidazoles; In Vitro Techniques; Oxidoreductases; Radioimmunoassay; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Adaptation, Physiological; Animals; Blood Coagulation Factors; Epoprostenol; Female; Fetal Death; Hemodynamics; Humans; Hypertension; Imidazoles; Lupus Coagulation Inhibitor; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Thrombosis; Thromboxane-A Synthase; Vitamin E Deficiency

The effects of a cyclooxygenase inhibitor (indomethacin), a thromboxane synthetase inhibitor (dazoxiben), and a thromboxane antagonist (EPO45) on rabbit platelet aggregation induced by collagen were studied and compared with effects on platelet uptake both by damaged rabbit aorta and by collagen-coated glass. Platelet aggregation and associated release of serotonin were inhibited to a similar extent both by indomethacin and EPO45. Dazoxiben had a minimal inhibitory effect on aggregation but reduced the release of serotonin by about 40% compared with control. Platelet uptake onto collagen-coated glass was markedly reduced both by indomethacin and EPO45 but not by dazoxiben. In contrast, EPO45 and dazoxiben were equally effective in reducing platelet adhesion to damaged rabbit aorta. At the concentrations used for adhesion studies the formation of thromboxane B2 was reduced both by dazoxiben and by indomethacin (both greater than 95% inhibition compared with control) and to a lesser extent by EPO45 (less than 40% inhibition). The results indicate that thromboxane A2 (and cyclic endoperoxide) released by adherent platelets may enhance thromboxane synthesis and promote platelet uptake both onto collagen-coated glass and onto damaged rabbit aorta. In the presence of vascular tissue, cyclic endoperoxides are readily metabolized and thereby removed. The potential antithrombotic activity of TXA2 synthetase inhibitors could be impaired in situations in which endoperoxide clearance is limited (e.g., accompanying platelet uptake onto artificial surfaces) but not at the damaged vessel wall. Thus, both inhibitors and antagonists are likely to have similar potency as antithrombotic agents in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Collagen; Imidazoles; In Vitro Techniques; Indomethacin; Male; Muscle, Smooth, Vascular; Platelet Adhesiveness; Platelet Aggregation; Prostaglandins, Synthetic; Rabbits; Serotonin; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Chemical Phenomena; Chemistry, Physical; Gas Chromatography-Mass Spectrometry; Humans; Imidazoles; Immunoassay; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Recent studies suggest that platelet activation and subsequent thromboxane (TX) A2 release play important roles in certain coronary syndromes. To further test this possibility, we examined the ability of a selective TXA2-synthetase inhibitor, dazoxiben (UK-37-248), to abolish cyclic flow reductions (CFRs) that occur in experimentally stenosed canine coronary arteries. CFRs, which are characterized by progressive declines in coronary blood flow and interrupted by sudden and usually spontaneous restorations of flow, were produced by placing hard plastic cylindrical constrictors (5 mm long X 4.5 mm outer diameter) on the proximal left anterior descending or circumflex coronary artery in open-chest, anesthetized dogs. Coronary blood flow was measured with pulsed Doppler flow probes placed proximal to the constrictors and regional myocardial blood flow with 15 micron radiolabeled microspheres. CFRs were observed for 1 hr, during which coronary blood flow was monitored continuously. Regional myocardial blood flow was measured before constriction, when coronary blood flow appeared to be at its nadir, and after spontaneous restorations of flow. After 1 hr dazoxiben (2.5 mg/kg iv) or an equal volume of saline was given and coronary blood flow was monitored for another hour. Dazoxiben abolished CFRs completely in 18 of 28 dogs and significantly reduced their frequency in the dogs receiving the drug (10.1 +/- 0.8 vs 3.2 +/- 1.0 per hour [+/- SE]; p less than .001, n = 28). The frequency and magnitude of variations in cyclic blood flow were unchanged after saline (8.8 +/- 0.8 vs 9.0 +/- 1.0 per hour; p = NS, n = 13). The lowest levels of coronary blood flow before and after dazoxiben were 8.6 +/- 2.2% and 48.8 +/- 5.4% of control, respectively (p less than .001, n = 28), whereas this parameter remained unchanged after saline (18.7 +/- 5.7% vs 13.4 +/- 4.1%, respectively; n = 13). The levels of TXB2 and 6-keto-prostaglandin (PG) F1 alpha (stable breakdown products of TXA2 and prostacyclin, respectively) were measured in blood collected from aortic and distal coronary arterial catheters before coronary constriction (control), during CFRs, and after administration of dazoxiben. TXB2 levels measured distal to the stenosis were increased fivefold during CFRs (352 +/- 126 vs 71 +/- 18 pg/ml plasma; p less than .03) and were reduced to preconstriction (control) levels by dazoxiben (57 +/- 12 pg/ml). Aortic TXB2 levels almost doubled with CFRs and also returned to control le

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Female; Hemodynamics; Imidazoles; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Thromboxane B2

Urinary excretion of the vasoconstrictor metabolite thromboxane B2 is increased in some patients with the hepatorenal syndrome. To define the role of thromboxanes in this syndrome and to evaluate a potential treatment for the renal impairment, we administered the thromboxane synthetase inhibitor dazoxiben to 5 patients with alcoholic hepatitis and rapidly progressive renal failure. Dazoxiben 200 mg/day followed by 400 mg/day reduced urinary thromboxane B2 by approximately 50% without altering prostaglandin E2 or 6-keto prostaglandin F1 alpha and without improving creatinine clearance (6 +/- 2 to 6 +/- 3 ml/min). In 3 additional patients, a higher dose of dazoxiben of 600 mg/day reduced thromboxane B2 by approximately 75% without consistent improvement in renal function. Thus, as judged by selective thromboxane inhibition with dazoxiben, thromboxanes are unlikely to be the key renal vasoconstrictor factor in the hepatorenal syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Creatinine; Dinoprostone; Drug Evaluation; Hepatitis, Alcoholic; Humans; Imidazoles; Middle Aged; Oxidoreductases; Prostaglandins E; Syndrome; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Epoprostenol; Fibrin; Imidazoles; Indomethacin; Jaundice; Kidney; Male; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

1 The effects of pretreatment with the thromboxane synthetase inhibitor UK 37248 (dazoxiben) administered 30 min before intravenous endotoxin (S. enteriditis) in the rat was investigated 2 Plasma prostaglandins and thromboxanes were determined via radioimmunoassay. Endotoxaemia was associated with significant elevations above control values (less than 200 pg/ml) in plasma thromboxane B2 (TXB2), prostaglandin E (PGE) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Within 30 min after endotoxin administration plasma immunoreactive (i) iTXB2 was 875 +/- 90 pg/ml (n = 9), iPGE was 1670 +/- 271 (n = 9) and i6-keto-PGF1 alpha was 1191 +/- 209 pg/ml (n = 10). By 4 h plasma iTXB2 was 1743 +/- 328 pg/ml (n = 5), iPGE was 2589 +/- 494 pg/ml (n = 9) and i6-keto-PGF1 alpha was 4251 +/- 984 pg/ml (n = 10). UK 37248 pretreatment resulted in a significant (P less than 0.001) decrease in plasma iTXB2 at 30 min and 4 h to 193 +/- 28 pg/ml (n = 5) and 421 +/- 57 pg/ml (n = 5), respectively. Unexpectedly UK 37248 also significantly decreased plasma i6-keto PGF1 alpha at 30 min and 4 h to 360 +/- 75 pg/ml (n = 10) (P less than 0.005) and 1920 +/- 513 pg/ml (n = 10) (P less than 0.05), respectively, iPGE plasma levels were not significantly changed in the UK 37248-pretreated rats 30 min (2210 +/- 370 pg/ml (n = 9) or 4 h 3529 +/- 1093 pg/ml (n = 13) after endotoxin compared to the vehicle-treated rats. 3 UK 37248 significantly (P less than 0.05) reduced the endotoxin mortality rate at 24 h from 69% (n = 13) to 30% (n = 13), UK 37248 also reduced splanchnic infarction from 90% (n = 20) to 6% (n = 16). 4 UK 37248 significantly improved the endotoxin-induced thrombocytopaenia, disseminated intravascular coagulation, hypoglycaemia and lysosomal labilization. 5 We conclude that UK 37248 provides significant beneficial effects in experimental endotoxic shock in the rat.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Glucose; Endotoxins; Imidazoles; Macrophages; Male; Oxidoreductases; Platelet Count; Prostaglandins E; Radioimmunoassay; Rats; Salmonella enteritidis; Shock, Septic; Splanchnic Circulation; Thromboxane-A Synthase

Platelet adhesion to rabbit aortic subendothelium or collagen-coated glass was quantitated in a rotating probe device by uptake of radio-labelled platelets. Under conditions in which aspirin had no effect, dazoxiben, a selective inhibitor of thromboxane synthetase, reduced platelet adhesion to aortic subendothelium by about 40% but did not affect adhesion to collagen-coated glass. Pre-treatment of aortic segments with 15-HPETE, a selective inhibitor of PGI2-synthetase, abolished the inhibitory effect of dazoxiben on adhesion. Concentrations of 6-oxo-PGF1 alpha in the perfusate were raised in the presence of dazoxiben alone, and following addition of thrombin (10 units/ml) there was a 2--3 fold increase in concentration. Perfusion of damaged aorta with platelets labelled with (14C)-arachidonic acid in the presence of thrombin and dazoxiben resulted in the appearance of (14C)-labelled-6-oxo-PGF1 alpha. Inhibition of thromboxane synthetase limits platelet adhesion probably by promoting vascular synthesis of PGI2 from endoperoxides liberated from adherent platelets, which subsequently promotes detachment of cells from the surface.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Epoprostenol; Imidazoles; Male; Oxidoreductases; Platelet Adhesiveness; Rabbits; Thrombin; Thromboxane B2; Thromboxane-A Synthase

Five rabbits treated with the thromboxane synthetase inhibitor Dazoxiben and five control rabbits received pig renal xenografts. Plasma albumin, complement factor C3, TXB2, 6-keto-PGF1 alpha, and serum TXB2 and 6-keto-PGF1 alpha were determined before and 1/2 hour after transplantation. The xenograft survival was significantly decreased in the Dazoxiben treated animals compared to the placebo treated animals determined as time to total cyanosis of the graft, total urine production, and time to stop of urine production. Lack of TXB2 production during blood coagulation confirmed inhibition of platelet thromboxane synthesis. The other determined variables showed no significant differences between the treated and the placebo animals.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Drug Evaluation, Preclinical; Graft Survival; Imidazoles; Kidney Transplantation; Rabbits; Swine; Thromboxane B2; Thromboxane-A Synthase; Transplantation, Heterologous

1 Acute thrombosis was induced in the carotid arteries of anaesthetized rabbits by local electrical stimulation (1 mA for 2 min) of the vessel wall. Histological findings confirmed the platelet-rich composition of the thrombus. Platelet accumulation at the stimulus site was quantitated with 111Indium-labelling of autologous platelets. 2 In rabbits injected intravenously with either the thromboxane synthetase inhibitor dazoxiben 2 mg/kg or aspirin 10 mg/kg, accumulation of labelled platelets was considerably reduced. Animals which received vehicle injection only, showed no such reduced thrombus formation. 3 In separate experiments in anaesthetized rabbits, the levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha in clotting blood were measured in blood samples taken from animals which had received the above drug treatments. Aspirin markedly reduced the production of both arachidonate metabolites. In contrast, dazoxiben almost totally inhibited TXB2 production but caused a 3.5-fold increase in the levels of 6-keto PGF1 alpha. 4 These findings demonstrate an antithrombotic effect and confirm the mechanistic selectivity of a thromboxane synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Platelets; Electric Stimulation; Imidazoles; Indium; Male; Oxidoreductases; Rabbits; Radioisotopes; Thrombosis; Thromboxane B2; Thromboxane-A Synthase

Leukotriene D4 (LTD4) administered intravenously to anesthetized, spontaneously breathing guinea pigs elicited decreases in dynamic lung compliance (Cdyn) and airway conductance (GAW) with a maximal response achieved at 0.5 min. Simultaneously, plasma levels of the thromboxane metabolite, TxB2, and the prostacyclin metabolite, 6-keto-PGF1 alpha, increased 10-fold over pre-LTD4 levels. Pretreatment of the guinea pigs with meclofenamic acid delayed the onset of the LTD4-induced bronchoconstriction, antagonized the magnitude of the decreases in Cdyn and GAW, and blocked the increase in plasma TxB2 and 6-keto-PGF1 alpha levels. The thromboxane synthetase inhibitor, UK 37,248, suppressed the LTD4-induced bronchoconstriction, while it completely blocked TxB2 production without significantly affecting 6-keto-PGF1 alpha. The SRS-A end organ antagonist, FPL 55712, blocked both the LTD4-induced bronchoconstriction and the production of the arachidonic acid metabolites. These results suggest that thromboxane A2 plays an important role in mediating part of the bronchoconstriction elicited by intravenously administered LTD4 in the guinea pig.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchi; Chromones; Guinea Pigs; Imidazoles; Meclofenamic Acid; SRS-A; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

N(7-Carboxyheptyl) imidazole, 4-[2-(1H-imidazol-1-yl) ethoxy] benzoic acid (dazoxiben) and imidazo [1,5-alpha] pyridine-5-hexanoic acid (CGS 13080) are potent selective inhibitors of platelet thromboxane synthetase that have little or no effect on the cyclooxygenase activity. Oral doses of the substances given to rats inhibited platelet thromboxane B2 production induced by intra-venous administration of collagen (100 micrograms/kg). Plasma concentrations of immunoreactive 6-keto PGF1 alpha in treated animals were increased above corresponding concentrations in untreated animals. There were small effects on the thrombocytopenia with CGS 13080 and carboxyheptylimidazole but not with dazoxiben. However these results did not always achieve statistical significance. Confirmation that the immunoreactive prostaglandin measured was actually 6-keto PGF1 alpha was obtained by the facts that indomethacin abolished its appearance in plasma and that the other prostaglandins were not present in sufficient quantities to cross-react with the antiserum to 6-keto PGF1 alpha. Two different antisera to 6-keto PGF1 alpha detected the same changes. Administration of thromboxane synthetase inhibitors to rats causes redirection of prostaglandin production from thromboxane to prostacyclin when platelets are stimulated with collagen in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Collagen; Imidazoles; Indoles; Indomethacin; Male; Oxidoreductases; Pyridines; Radioimmunoassay; Rats; Rats, Inbred Strains; Thrombocytopenia; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

The delayed clearance of endotoxins in obstructive jaundice may cause renal impairment by inducing renal vasoconstriction and glomerular fibrin deposition as a consequence of intravascular coagulation. As endotoxins activate arachidonic acid metabolism we have examined the effects of selective inhibitors on mortality, plasma TXB2 and 6-oxo-PGF1 alpha production and renal fibrin deposition in rats with obstructive jaundice following endotoxin administration. Jaundiced rats had a high mortality following endotoxin--58 per cent at 4 h and 83 per cent at 24 h. Pretreatment with indomethacin 3 mg/kg i.p., dazoxiben 3 mg i.p. or prostacyclin 300 ng/kg i.v. produced significant improvements in survival. Endotoxaemia was associated with significant elevations of plasma TXB2 and early inhibition of plasma 6-oxo-PGF1 alpha generation. Renal fibrin deposition, assessed using indirect immunofluorescence and a 125I-labelled fibrinogen uptake ratio, occurred in jaundiced kidneys following endotoxin and could be prevented using indomethacin, dazoxiben and prostacylin. These results suggest that endotoxin-induced TXA2 production can cause renal fibrin deposition in obstructive jaundice, thus contributing in the pathogenesis of the renal impairment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cholestasis; Endotoxins; Epoprostenol; Escherichia coli; Fibrin; Imidazoles; Indomethacin; Kidney; Male; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

Acute thrombosis was induced in the carotid arteries of anaesthetised rabbits by local electrical stimulation (1mA for 2 min) of the vessel wall. Histological findings confirmed the platelet-rich composition of the thrombus. Platelet accumulation at the stimulus site was quantitated with "'Indium-labelling of autologous platelets. In rabbits injected intravenously with either 2 mg/kg dazoxiben or 10 mg/kg aspirin, accumulation of labelled platelets was considerably reduced. Animals which received vehicle injection only, showed no such reduced thrombus formation. In separate experiments in anaesthetised rabbits, the levels of TxB2 and 6KPGF1 alpha in clotting blood were measured in blood samples taken from animals which had received the above drug treatments. Aspirin markedly reduced the production of both arachidonate metabolites. In contrast, dazoxiben almost totally inhibited TxB2 production but caused a 3.5 fold increase in the levels of 6KPGF1 alpha. These findings demonstrate an anti-thrombotic effect and confirm the mechanistic selectivity of a thromboxane synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Aspirin; Carotid Artery Thrombosis; Cells, Cultured; Enzyme Inhibitors; Fibrinolytic Agents; Imidazoles; In Vitro Techniques; Oxidoreductases; Platelet Aggregation; Rabbits; Thromboxane B2; Thromboxane-A Synthase