thromboxane-b2 and sulotroban

In a randomized pilot study we compared the antiplatelet effects of aspirin and BM 13.177 in two groups of 7 patients each undergoing PTCA. As compared with the pretreatment values template bleeding time was prolonged and collagen induced aggregation was inhibited in PRP and WB in all patients. In the course of angiography and PTCA a rise in platelet factor 4 and beta thromboglobulin was observed in both groups, followed by a decrease below the baseline levels. Thromboxane B2 in plasma and serum decreased in the aspirin group but remained unchanged during BM 13.177 treatment. In PRP and WB aggregation induced by U 46 619 was inhibited after ingestion of BM 13.177 but not following ASA. After three months a control coronary angiography was done. There was no difference in regard to the degree of restenosis between both groups. Medication was well tolerated, compliance was good and no side effects were noted.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angioplasty, Balloon; Arteriosclerosis; Aspirin; Bleeding Time; Blood Platelets; Clinical Trials as Topic; Collagen; Cyclooxygenase Inhibitors; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane B2; Thromboxanes

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

Thromboxane may play an important role in the pathogenesis of smoked mediated injury. We studied this possibility in 13 chronically instrumented sheep, which had the left lung exposed to smoke. BM 13,177, a thromboxane receptor antagonist, was given intravenously to six animals prior to smoke inhalation and during the experimental period. Seven animals received the vehicle. All animals were studied for 24 h under ventilatory support, then killed prior to harvesting lung tissue. Airway peak and plateau pressures in the vehicle-treated animals were elevated by 27% and 25% from baseline at 24 h post smoke inhalation. Concomitantly, the left pulmonary vascular resistance index rose continuously throughout the study period (baseline = 822 +/- 58; 24 h = 1819 +/- 84 dyn.s.cm-5.m2).BM 13,177 treatment completely prevented the rise in airway pressure, while the left pulmonary vascular resistance index was significantly attenuated (baseline = 726 +/- 79; 24 h = 1470 +/- 158 dyn.s.cm-5.m2) resulting in a significantly higher percentage of cardiac output being delivered to the smoked lung, compared to vehicle-treated animals. Thromboxane receptor blockade did not prevent smoke induced pulmonary edema formation. There was likewise no effect of BM 13,177 on the systemic hemodynamic changes seen following smoke inhalation. There was a decrease in cardiac index and an increase in systemic vascular resistance index in both groups. We conclude that smoke induced changes in airway and pulmonary vascular resistances may be mediated by thromboxanes. However, thromboxanes appear to play no role in the development of pulmonary edema and elevation of systemic vascular resistance following smoke inhalation injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Carboxyhemoglobin; Cardiac Output; Female; Hemodynamics; Leukocyte Count; Neutrophils; Organ Size; Oxygen; Pulmonary Circulation; Receptors, Thromboxane; Sheep; Smoke Inhalation Injury; Sulfonamides; Thromboxane B2; Vascular Resistance

To investigate the potential pathogenetic and therapeutic roles of thromboxane A2 (TXA2) and its receptor blockade, respectively, in the early phase of ischemic acute renal failure (ARF), renal function, TXB2 excretion, and the effects of the specific TXA2 receptor antagonist sulotroban (SU) in a model of unilateral renal artery occlusion in conscious female Sprague-Dawley rats were studied. Occlusion of the left renal artery for 1 h in untreated (i.e., vehicle-treated) rats (N = 8) resulted in oliguric ARF. In SU-treated rats (N = 8), the drug was given as an i.v. bolus of 5 mg/kg body wt, followed by a continuous infusion of 0.5 mg/min.kg body wt from 1 h before and during ischemia and for 6 h after reflow. After 1 h of ischemia, urine volume of left ischemic kidneys from untreated rats had decreased from 13.2 +/- 2.8 to 1.0 +/- 0.3 and 0.5 +/- 0.2 microL/min.100 g at 2 and 6 h of reflow, respectively, and GFR had decreased from 0.32 +/- 0.04 mL/min.100 g body wt to undetectable values. At 6 h of reflow, medullary Na-K-ATPase was slightly (P < 0.05) reduced in left ischemic kidneys, whereas medullary and papillary enzyme activities were compensatorily increased (P < 0.01) in right intact kidneys. The ADP/O ratio of cortical mitochondria was 41% (P < 0.05) and ATP synthesis was 77% (P < 0.01) lower than in right intact kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Calcium; Female; Ischemia; Kidney; Mitochondria; Oliguria; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Sodium-Potassium-Exchanging ATPase; Sulfonamides; Thromboxane B2

The i.v. bolus application of 1 nmol/kg endothelin-1 (ET-1) in anaesthetized and ventilated guinea-pigs caused an increase in mean arterial blood pressure (BP) and a bronchoconstriction. Both have been reduced or abolished by COX inhibition (ASA) or substances specifically reducing the thromboxane A2 (TXA2) generation (HOE 944) or receptor binding (BM 13177). The significant increase in TXB2 concentrations in plasma and bronchoalveolar lavage (BAL) after ET-1 challenge (15-fold and 4-fold, respectively) have been reduced or abolished by ASA as well as HOE 944 and not altered by BM 13177.

Topics: Animals; Aspirin; Blood Pressure; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Endothelins; Guinea Pigs; Imidazoles; Male; Naphthalenes; Prostaglandin-Endoperoxide Synthases; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Vasopressins

The platelet-activating factor (PAF) induced a marked increase of the thromboxane (TX) B2-formation in the incubation medium of isolated myocardium and tissue from other organs. The content of the 6-oxo-prostaglandin (PG)F1 alpha, the inactive metabolite of PGI2, remained uninfluenced or showed a small decrease. PAF, given in a concentration of 2.10(-9) mol/l or a single dose of 100 ng, significantly reduced the contraction force and the coronary flow of isolated guinea-pig hearts. This effect was connected with a high efflux of TXA2. The PAF-antagonist, WEB 2086, nearly abolished the cardiac effects of PAF, and iloprost or a pretreatment with indomethacin markedly reduced the PAF-influence on the heart. The TXA2-antagonist BM 13177 was ineffective. The results indicate a close interaction between the myocardial PAF-effect and the TXA2-formation of the heart tissue, but gave no suggestion for a mediation of the PAF-effect by TXA2. The PAF-antagonistic action of WEB 2086, iloprost and indomethacin could be of some interest in the therapy of cardiovasculatory diseases.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Azepines; Guinea Pigs; Heart; Iloprost; In Vitro Techniques; Indomethacin; Myocardial Contraction; Perfusion; Platelet Activating Factor; Prostaglandins; Sulfonamides; Thromboxane A2; Thromboxane B2; Triazoles

The effects of thromboxane B2 (TxB2) and of two thromboxane mimetics, dl-(9,11), (11,12)-dimethano-TxA2 (ONO 11006) and 9,11-dideoxy-11,9-epoxymethano prostaglandin F2 alpha (U46619) on the cardiac response to adrenergic nerve stimulation in isolated guinea-pig atria were evaluated. All the agonists dose dependently reduced the positive inotropic effect induced by field stimulation, U46619 being the most active. The inhibitory effect of U46619 was reduced by the thromboxane receptor antagonists, sulotroban and AH 23848B. U46619 did not significantly reduce the positive inotropic effect induced by exogenous noradrenaline. However U46619 was unable to modify the tritium overflow induced by field stimulation in preparations preloaded with [3H]noradrenaline. In addition to this influence on adrenergic neurotransmission, U46619 also had a direct positive inotropic effect on cardiac contractility, which was antagonized by AH 23848B. These results indicate that U46619 reduces the cardiac response to sympathetic nerve stimulation and that is also has a direct stimulatory effect on cardiac muscle.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biphenyl Compounds; Dose-Response Relationship, Drug; Electric Stimulation; Guinea Pigs; Heart Atria; In Vitro Techniques; Male; Norepinephrine; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Sympathetic Nervous System; Synaptic Transmission; Thromboxane A2; Thromboxane B2

Vasopressor response and release of eicosanoids following intravenous injection of arachidonic acid (AA) were examined in normotensive rats. AA administration caused a rapid initial fall of arterial pressure followed by a brief rise and a subsequent prolonged fall in anesthetized rats. Immediately after AA injection the blood levels of TXB2 and 6-keto-PGF1 alpha, the stable metabolites of TXA2 and prostacyclin, rose, from 1.52 +/- 0.23 ng/ml to 176.4 +/- 42.6 ng/ml and from 4.05 +/- 0.67 ng/ml to 171.4 +/- 31.2 ng/ml, respectively. Blood pressure behaviour and eicosanoid blood level were influenced by different inhibitors and antagonists of vasoactive mediators. The cyclooxygenase inhibitor acetylsalicylic acid completely eliminated the second blood pressure depression after AA injection and simultaneously diminished TXB2 and 6-keto-PGF1 alpha formation in murine blood, whereas the TXA2 receptor antagonist BM 13.177 prevented the return of the blood pressure to preinjection level after the initial brief fall in arterial pressure. Although the TXA2 synthase inhibitor HOE 944 markedly inhibited TXB2 formation, no influence on AA-induced blood pressure changes could be registered. The receptor antagonist of platelet activating factor BN 52021 and the serotonin and histamine receptor antagonist cyproheptadine also reduced TXB2 amounts, in murine blood without any effects on blood pressure behaviour.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Aspirin; Blood Pressure; Cyproheptadine; Diterpenes; Ginkgolides; Imidazoles; Injections, Intravenous; Lactones; Male; Naphthalenes; Rats; Rats, Inbred Strains; Sulfonamides; Thromboxane B2

Escherichia coli hemolysin, a transmembrane pore-forming exotoxin, is considered an important virulence factor. In the present study, the possible significance of hemolysin production was investigated in a model of septic lung failure through infusion of viable bacteria in isolated rabbit lungs; 10(4) to 10(7) E. coli/ml perfusate caused a dose- and time-dependent appearance of hemolysin, accompanied by release of potassium, thromboxane A2, and PGI2 into the perfusate. Concomitantly, marked pulmonary hypertension developed. Inhibitor studies suggested that the pressor response was predominantly mediated by pulmonary thromboxane generation. Administration of hemolysin-forming E. coli additionally caused a protracted, dose-dependent increase in the lung capillary filtration coefficient, followed by severe edema formation. The permeability increase was independent of lung prostanoid generation. An E. coli strain that releases an inactive form of hemolysin completely failed to provoke the described biophysical and biochemical responses. Preapplication of 2 x 10(8) human granulocytes was without effect in the present experimental model. We conclude that the hemolysin produced by low numbers of E. coli organisms can provoke thromboxane-mediated pulmonary hypertension and severe vascular leakage. E. coli hemolysin and, possibly, other related cytolysins may thus contribute directly to the pathogenesis of acute respiratory failure under conditions of sepsis or pneumonia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Pressure; Capillary Permeability; Epoprostenol; Escherichia coli; Female; Hemolysin Proteins; Hypertension, Pulmonary; In Vitro Techniques; L-Lactate Dehydrogenase; Lung; Male; Neutrophils; Perfusion; Potassium; Pulmonary Artery; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Respiratory Insufficiency; Sulfonamides; Thromboxane B2; Thromboxanes

Activation of human platelets by diverse receptor-transduced signals is followed by an intracellular calcium increase. Calcium liberation from an inositol 1,4,5-trisphosphate-sensitive compartment is recognized to be one of the prime events, followed by further mechanisms to amplify the signal. Among these, the formation of prostaglandin endoperoxides and thromboxane A2 are part of the self-amplificating activation system. Two inhibitors of intracellular Ca(2+)-ATPases, thapsigargin and 2,5-di-(tert-butyl)-1,4-benzohydroquinone have been reported to deplete the intracellular inositol 1,4,5-trisphosphate-responsive stores. In human platelets with EGTA present, we found that these inhibitors of the microsomal Ca2+ sequestration generate quite different Ca2+ transients due to an inherent cyclooxygenase inhibition by the benzohydroquinone derivative compared to thapsigargin, and, therefore, only one-half of the fura-2 signal is generated. For a maximal calcium release, Ca(2+)-ATPase inhibitors depend on the self-amplification system involving thromboxane formation. Following the thapsigargin-induced [Ca2+]i transient, thrombin was unable to raise [Ca2+]i, indicating that thapsigargin mobilizes calcium from the thrombin-responsive store, as long as the self-amplifying system of platelets is intact. With the thromboxane receptor blocked, thapsigargin releases only one-half of the calcium, and, hence, thrombin was able to release additional calcium. Interestingly, in the converse experiment, thrombin did not prevent a raise of [Ca2+]i by thapsigargin at all, although applying thrombin a second time was without any effect. Therefore, we propose two calcium pools in human platelets: receptor activation transiently releases calcium from an inositol-sensitive pool including the thapsigargin-sensitive compartment, followed by reuptake within minutes. Sequestration occurs into the thapsigargin-sensitive compartment from where it can be released even when the endoperoxide/thromboxane receptor is blocked. Calcium release from both compartments allows the formation of thromboxane B2, but not if only the Ca(2+)-ATPase inhibitor-sensitive pool is emptied. In the presence of a protonophor, a calcium accumulation in the Ca(2+)-ATPase-sensitive pool could be observed.

Topics: Antioxidants; Blood Platelets; Calcium; Calcium-Transporting ATPases; Fibrinolytic Agents; Humans; Hydroquinones; Nigericin; Platelet Activation; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Terpenes; Thapsigargin; Thrombin; Thromboxane A2; Thromboxane B2

Isolated hepatocytes incubated in the presence of either Ca2+ ionophore A23187 or thromboxane B2 develop many plasma membrane blebs which are a characteristic feature of toxic or ischaemic cell injury. When hepatocytes are incubated in the presence of both Ca2+ ionophore A23187 and any one of three thromboxane receptor antagonists (SK and F 88046, B.M. 13505, B.M. 13177), bleb formation is strongly inhibited. Hepatocytes incubated in the presence of both thromboxane B2 and any one of the three thromboxane receptor antagonists are also well protected from the formation of blebs. Treatment of isolated hepatocytes with Ca2+ ionophore A23187 is known to stimulate the production of thromboxanes. The data presented are consistent with thromboxane B2 acting as an intermediary in a proposed mechanism of cell injury and death in which elevated cytosolic free Ca2+ levels activate phospholipase A2 and the arachidonate cascade.

Topics: Animals; Calcimycin; Calcium; Cell Death; Cell Membrane; Liver; Male; Phenylacetates; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Signal Transduction; SRS-A; Sulfonamides; Thromboxane B2

We studied the in vitro effects of picotamide (N,N' bis 3 picolyl-4-methoxy-isophthalamide) on human platelet aggregation, the release reaction and the production of thromboxane B2 (TxB2) induced by several platelet agonists. The effects of picotamide were compared to those of acetylsalicylic acid (ASA). Picotamide (0.5 mmol/l) inhibited platelet aggregation, the release of ATP and TxB2 production induced by ADP, arachidonic acid (AA), collagen or the prostaglandin endoperoxide (PE) analogue U46619. ASA (0.5 mmol/l) did not affect platelet aggregation and the release of ATP induced by U46619. Picotamide and ASA inhibited the AA-induced platelet TxB2 production both under stirring and non-stirring conditions, whereas the pure thromboxane A2 receptor antagonist BM13177 (0.5 mmol/l) was inhibitory only under stirring conditions. Since under non-stirring conditions platelet aggregation does not occur, picotamide directly inhibits TxB2 production, whereas BM13177 inhibits the potentiation of TxB2 production due to TxA2/PE-dependent platelet aggregation. Malondialdehyde (MDA) production by unstirred platelets stimulated with AA was not significantly inhibited by picotamide. In conclusion, picotamide inhibits the TxA2/PE-dependent platelet responses to agonists by a double mechanism: (i), TxA2/PE antagonism; (ii) inhibition of thromboxane synthase.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Arachidonic Acid; Aspirin; Blood Platelets; Collagen; Drug Interactions; Female; Humans; Male; Malondialdehyde; Phthalic Acids; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Sulfonamides; Thromboxane B2

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

The possible role of thromboxane (TX) A2 in mediating the bronchopulmonary effect of endothelin (ET) was studied in isolated guinea pig airways (trachea, upper bronchi and parenchyma). ET (1-100 nM) evoked a concentration-dependent contraction of all three tissues. The contractile response was significantly attenuated by pretreatment of the tissues with the specific thromboxane receptor blockers, BM 13177 (10-50 microM) and BM 13505 (1-5 microM). Furthermore, ET caused a dose-dependent TXB2 release from trachea and parenchyma. These findings suggest that the bronchopulmonary action of ET is mediated, in part, by the release of TXA2.

Topics: Animals; Anti-Arrhythmia Agents; Bronchi; Dose-Response Relationship, Drug; Endothelins; Epoprostenol; Guinea Pigs; Lung; Male; Muscle Contraction; Muscle, Smooth; Phenylacetates; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane B2; Thromboxanes; Trachea

In isolated perfused rat liver, adenosine infusion (50 microM) led to increases in glucose output and portal pressure and a net K+ release of 3.7 +/- 0.21 mumol/g, which was followed by an equivalent net K+ uptake after cessation of the nucleoside infusion. These effects were accompanied by a transient stimulation of hepatic prostaglandin D2 and thromboxane B2 release. The Ca2+ release observed upon adenosine infusion (50 microM) was 23.5 +/- 5.2 nmol/g, i.e. 10-20% of the Ca2+ release observed with extracellular ATP (50 microM). Indomethacin (10 microM) prevented the adenosine-induced stimulation of glucose output and the increase in portal pressure by 79 and 63% respectively, and completely abolished the stimulation of prostaglandin D2 release. The thromboxane A2 receptor antagonist BM 13.177 (20 microM), the phospholipase A2 inhibitor 4-bromophenacyl bromide (20 microM) and the cyclo-oxygenase inhibitor ibuprofen (50 microM) also decreased the glycogenolytic and vasoconstrictive responses of the perfused rat liver upon adenosine infusion by 50-80%. When the indomethacin inhibition of adenosine-induced prostaglandin D2 release was titrated, a close correlation between prostaglandin D2 release and the metabolic and vascular responses to adenosine was observed. These findings suggest an important role for eicosanoids in mediating the nucleoside responses in the perfused rat liver. Since eicosanoids are known to be formed by non-parenchymal cells in rat liver [Decker (1985) Semin. Liver Dis. 5, 175-190], the present study gives further evidence for an important role of eicosanoids as signal molecules between the different liver cell populations.

Topics: Acetophenones; Adenosine; Animals; Blood Pressure; Glucose; Ibuprofen; Indomethacin; Liver; Male; Portal System; Prostaglandin D2; Rats; Rats, Inbred Strains; Secretory Rate; Sulfonamides; Thromboxane B2

We examined the ability of the prostaglandin endoperoxide/thromboxane A2 antagonist, sulotroban (BM 13.177; SK&F 95587) to enhance the thrombolytic efficacy of a minimally effective thrombolytic dose of streptokinase. A critical stenosis sufficient to just abolish the hyperemic response to a 20-sec total occlusion was placed on the left circumflex coronary artery of anesthetized open chest dogs using an adjustable screw occluder clamp. Thrombi were formed by applying a 150 microA anodal current to a wire placed within the lumen of the left circumflex just proximal to the screw occluder clamp. After thrombus formation, animals were given either streptokinase (20,000 I.U. bolus + 2,000 I.U./min x 180 min, N = 10), streptokinase + sulotroban (5 mg/kg bolus + 5 mg/kg/hr, N = 10), streptokinase + heparin (300 I.U./kg bolus + 100 I.U./kg/hr, N = 9) or streptokinase + heparin + sulotroban (N = 9). Plasma thromboxane A2 level (as measured by the metabolite, thromboxane B2) was not significantly reduced by any treatment, whereas the dose of sulotroban used completely abolished U46619-induced ex vivo platelet aggregation. Of 10 animals receiving streptokinase alone, only 1 reperfused at 55 min after the start of the streptokinase infusion. Conversely, 9 of 10 animals receiving streptokinase + sulotroban reperfused at 79.4 +/- 10.5 min poststreptokinase (P less than .05). When animals were treated with heparin before streptokinase administration, 8 of 9 animals receiving the streptokinase + heparin combination reperfused in an average of 66.8 +/- 8.6 min after the start of streptokinase infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dogs; Drug Synergism; Fibrinolytic Agents; Hemodynamics; Heparin; In Vitro Techniques; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Receptors, Prostaglandin; Receptors, Thromboxane; Regional Blood Flow; Streptokinase; Sulfonamides; Thromboxane A2; Thromboxane B2

We studied the effect of pretreatment with two doses of the thromboxane antagonist BM 13.177 and its solvent on the development of electrically induced coronary artery thrombosis in pigs. Results were compared with those obtained in animals pretreated with intravenously administered acetylsalicylate and its solvent. The effects of both compounds on the overall cardiovascular performance (heart rate, mean arterial blood pressure, cardiac output, systemic vascular resistance) were minimal. In the animals receiving solvent or acetylsalicylate the time to occlusive coronary thrombosis was 33 +/- 4 and 32 +/- 6 min, respectively. BM 13.177, in a dose of 5 mg.kg-1, did not modify the time to thrombotic occlusion (35 +/- 7 min), but in six of the eight animals that had received 10 mg.kg-1 BM 13.177, there was no occlusion within 120 min. In the acetylsalicylate-treated animals, collagen-induced platelet aggregation and plasma thromboxane B2 declined by 72 and 82%, respectively. The decreases were 46 and 20%, respectively, with the higher dose of BM 13.177. It is concluded that, in this porcine model of coronary artery thrombosis, the thromboxane antagonist BM 13.177 effectively suppressed formation of occlusive thrombi whereas acetylsalicylate was ineffective at a dose that lowered arterial thromboxane levels.

Topics: Animals; Anti-Arrhythmia Agents; Aspirin; Coronary Disease; Coronary Thrombosis; Electric Stimulation; Hemodynamics; In Vitro Techniques; Platelet Aggregation; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Swine; Thromboxane B2

The capacity of the perfused rat liver to produce thromboxane after stimulation by phorbol myristate acetate was examined. A total of 109 +/- 20 and 155 +/- 28 pmol/g liver were found in the perfusate and in the bile, respectively, after 40 min. The amount of thromboxane recovered in the perfusate and in the bile accounted for 12.6% of the production calculated from the same number of Kupffer cells in primary cultures, indicating that a major part of thromboxane was taken up and inactivated by hepatocytes. The effect of endogenously synthesized thromboxane on the liver was assessed by using CGS 13080, a thromboxane synthase inhibitor, or BM 13.177, a thromboxane receptor antagonist. 20 nM CGS 13080 in the perfusate inhibited the synthesis of thromboxane and at the same time the elevation of portal pressure and glycogenolysis following administration of phorbol 12-myristate 13-acetate (PMA). The thromboxane receptor antagonist BM 13.177 did not inhibit the synthesis of thromboxane, but reduced the PMA-related elevation of portal pressure and glycogenolysis to the same extent (greater than 60%) as CGS 13080. Sodium nitroprusside, a vasodilator, inhibited the rise in portal pressure caused by PMA to the same extent as CGS 13080 or BM 13.177 but reduced the increase in glycogenolysis only by 25%. These results indicate that thromboxane released by stimulated Kupffer cells of the liver elevates portal pressure and glycogenolysis in the perfused rat liver, although by different mechanisms.

Topics: Animals; Bile; Female; Imidazoles; Kinetics; Liver; Perfusion; Prostaglandins; Pyridines; Rats; Rats, Inbred Strains; Reference Values; Sulfonamides; Tetradecanoylphorbol Acetate; Thromboxane B2; Thromboxane-A Synthase

We investigated the effect of a thromboxane antagonist, BM 13.177, during endotoxin-induced pulmonary vasoconstriction in sheep. In control animals intravenous E-coli endotoxin (1 microgram/kg) caused a transient increase of pulmonary artery and airway pressure paralleled by large concentration increases of TXB2: in comparison peak plasma concentrations of 6-keto-PGF1 alpha (a prostacyclin metabolite) were small and delayed in time. Pre-treatment with BM 13.177 (bolus 5 mg/kg), followed by 0.75 mg/kg/min intravenously) abolished the rise of pulmonary artery and airway pressure. Plasma concentrations of TXB2 and 6-keto-PGF1 alpha were similar to controls. These and previous investigations imply that BM 13.177 specifically antagonizes TXA2 on the putative receptor in pulmonary vascular and airway smooth muscle.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Female; Hypertension, Pulmonary; Lung; Sheep; Sulfonamides; Thromboxane A2; Thromboxane B2; Vasoconstriction

The effect of the thromboxane (TX) synthase inhibitors dazoxiben and imidazole on platelet activation by endogenous and exogenous arachidonic acid (AA) was tested with human washed platelets. Dazoxiben (1-20 microM) inhibited the formation of TXB2 and markedly enhanced the shape change, aggregation, and (3H)serotonin release induced by added AA or when prostaglandin synthesis from endogenous AA was triggered by collagen, hydrogen peroxide or methyl mercury chloride (methyl-Hg). Platelet activation by hydrogen peroxide (20-1200 microM) or methyl-Hg (1-5 microM) was entirely dependent on endogenous prostaglandin (PG) synthesis since acetylsalicylic acid (ASA), indomethacin or the cyclic endoperoxide/TXA2-antagonist BM 13.177 counteracted these stimulants with and without dazoxiben. Apparently, the potentiation is due to accumulating cyclic endoperoxides which during TX synthase inhibition reach greater platelet-activating potency than TXA2. Albumin or human platelet-poor plasma inhibited the platelet activation by hydrogen peroxide and methyl-Hg and suppressed the potentiation by dazoxiben. The latter effect of albumin may result from its PGD isomerase activity which redirects the cyclic endoperoxide metabolism to the platelet-inhibitory PGD2. The results show that non-platelet factors such as albumin are necessary to prevent a potentiating effect of TX synthase inhibitors on platelet activation.

Topics: Arachidonic Acid; Arachidonic Acids; Blood Platelets; Collagen; Drug Interactions; Humans; Hydrogen Peroxide; Imidazoles; In Vitro Techniques; Indomethacin; Methylmercury Compounds; Oxidoreductases; Platelet Aggregation; Serotonin; Serum Albumin; Sulfonamides; Thromboxane B2; Thromboxane-A Synthase

Seven males with atherosclerotic disease received daily 1.6 g of the thromboxane antagonist BM 13.177 in two separate oral dosages over a period of four days. The drug significantly reduced elevated plasma levels of thromboxane B2, beta-thromboglobulin and platelet factor 4, whereas thromboxane B2 generation was only slightly depressed. BM 13.177 inhibited platelet aggregation by collagen, and to a minor degree the second wave of ADP induced aggregation. Platelet sensitivity to prostacyclin and aggregation by ristocetin were not altered. Bleeding time was prolonged. All effects disappeared within 24 hours after the last application of the drug. No side effects were noted. Thus BM 13.177 appears to be a safe and effective new antiplatelet drug.

Topics: Arteriosclerosis; beta-Thromboglobulin; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; Male; Metabolic Clearance Rate; Middle Aged; Platelet Aggregation; Platelet Factor 4; Sulfonamides; Thromboxane B2

BM 13.177 (4-[2-(benzenesulfonamido)-ethyl]-phenoxyacetic acid) is a representative of a new class of sulfonamidophenylcarboxylic acids which possess platelet-inhibitory and anti-thrombotic activity and inhibits the contraction of rabbit aorta stimulated by PG endoperoxides and TXA2. BM 13.177 5 mg/kg body weight p.o. protected rabbits from arachidonate-induced sudden death and greater than or equal to 10 mg/kg dose-dependently reduced the experimental thrombus formation induced in the rabbit aorta by perivascular administration of silver nitrate. In guinea-pigs, the collagen-induced bronchoconstriction was inhibited in a dose- and time-dependent fashion. The formation of TXA2 and the TXA2-induced platelet aggregation and smooth muscle contraction are probably crucial events in these experimental models. The protective effect of BM 13.177 may, therefore, be due to the TXA2-antagonizing effect of BM 13.177, which has been conclusively demonstrated in human platelets (PATSCHEKE and STEGMEIER, Thrombosis Res., 33, 277-288 (1984). The antagonism of TXA2 is supported by the observation that BM 13.177 also specifically inhibits the contraction of isolated arterial strips from rabbits which were stimulated with the thromboxane A2 mimetic U 46619. Schild-plot with a slope close to unity suggests a competitive type of antagonism. BM 13.177 exhibited neither anti-inflammatory nor ulcer-inducing activity of cyclooxygenase inhibitors. Furthermore it did not block the TXB2 formation in spontaneously clotting blood from rabbits and did not inhibit the release of prostacyclin-like activity from rabbit aortas. The lack of toxicological effects in long-term toxicity studies in rat and dog, together with the absence of objective and subjective side effects in the first human studies have encouraged us to initiate clinical trials in order to evaluate the therapeutic benefit of this new approach in humans.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Epoprostenol; Female; Fibrinolytic Agents; Guinea Pigs; Male; Muscle Contraction; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Rabbits; Sulfonamides; Thrombosis; Thromboxane A2; Thromboxane B2; Thromboxanes

The mode of action of BM 13.177 (4-[2-(benzenesulfonamido)-ethyl] phenoxyacetic acid), a new anti-aggregating and anti-thrombotic agent, was studied in human washed platelets and citrated PRP. With ASA-treated platelets, BM 13.177 (0.1 - 100 microM) did not inhibit the shape change and the aggregation induced by ADP, serotonin, adrenaline, thrombin, or collagen. Therefore, BM 13.177 is neither an antagonist of ADP, serotonin, adrenaline, thrombin, or collagen nor a common pathway inhibitor like PGE1, or an inhibitor of the platelet interactions during aggregation. However, BM 13.177 (greater than or equal to 0.1 microM) produced a dose-dependent reduction of shape change, aggregation and release of [3H]serotonin induced by the stable PGH2 analogues U 46619 and U 44069 in ASA-treated platelets or ASA-treated citrated PRP. In untreated platelets, BM 13.177 inhibited platelet activation by U 46619 or U 44069 and by exogenous arachidonic acid or by endogenous arachidonic acid mobilized by hydrogen peroxide. Consequently, the ADP- and adrenaline-induced secondary aggregation and [3H]serotonin release in citrated PRP and the major effects of collagen were also inhibited. In washed platelets treated with 10 microM arachidonic acid or 100 microM hydrogen peroxide, the formation of TXB2 was not inhibited by 10 microM BM 13.177. However, the TXB2 formation after stimulation with 1,200 microM hydrogen peroxide was partially reduced by BM 13.177 to the same extent as by PGE1. This reduction may be due to the absence of a secondary release of arachidonic acid from phospholipids if the platelets were prevented from activation by BM 13.177 or PGE1. Arachidonic acid and hydrogen peroxide also induced the shape change, aggregation and release of washed platelets when thromboxane formation was inhibited by dazoxiben. Under these conditions, BM 13.177 was able to abolish the platelet response which was due to accumulating prostaglandin endoperoxides. These results show that BM 13.177 acts as a selective antagonist of TXA2 and prostaglandin endoperoxides. Its inhibitory effect on platelet function does not depend on an inhibition of either the primary release of arachidonic acid or the activities of cyclooxygenase or thromboxane synthetase.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Collagen; Dose-Response Relationship, Drug; Epinephrine; Humans; Hydrogen Peroxide; Imidazoles; Indomethacin; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Prostaglandins E; Serotonin; Sulfonamides; Thromboxane A2; Thromboxane B2; Thromboxanes