Specific Thromboxane Synthetase Inhibitor Research Articles

Effect of cyclooxygenase and thromboxane synthetase inhibition on furosemide-stimulated plasma renin activity.

We studied the effects of a specific thromboxane (TX) synthetase inhibitor (U-63,557A) and a cyclooxygenase inhibitor on furosemide-induced renin release. Furosemide (2.0 mg X kg-1) was injected into Sprague-Dawley rats pretreated with indomethacin (10 mg X kg-1, i.v.), U-63,557A (1.0-32.0 mg X kg-1, i.v.), or vehicle (Na2CO3 0.03 M). Plasma renin activity was measured in blood samples collected 0, 10, 20, and 40 min after the injection of furosemide. Blood was also collected after the administration of vehicle, indomethacin, or U-63,557A for serum TXB2, a measure of platelet TXA2 synthesis. The results demonstrated that plasma renin activity rose with time following furosemide in the various groups of rats; indomethacin suppressed the furosemide-induced increments in plasma renin activity, while U-63,557A at doses of 4-8 mg X kg-1 augmented it. At doses below 4 mg X kg-1 or above 8 mg X kg-1, U-63,557A did not augment renin secretion. Indomethacin and U-63,557A reduced serum thromboxane by 81 and 90%, respectively. Thus, these experiments suggest that thromboxane synthetase inhibition, within a narrow dosage range, potentiates furosemide-induced renin release while cyclooxygenase inhibition suppresses it.

Rabbit nephrotoxic nephritis: effect of a thromboxane synthetase inhibitor on evolution and prostaglandin excretion.

Accelerated anti-glomerular basement membrane nephritis was induced in rabbits, and the immunological, clinical and histological evolution studied in relation to urinary immunoreactive thromboxane B2 (i-TXB2) and immunoreactive prostaglandin E2 (i-PGE2) excretion. In control nephritic animals, urinary i-TXB2 increased 5-fold on day +1, but was normal again by day +5. The urinary i-TXB2 showed a positive correlation with creatinine clearance (CCr), proteinuria and anti-sheep immunoglobulin antibody. Urinary i-PGE2 excretion increased by 50% on day +1, but was indistinguishable later from controls. The effects of the specific thromboxane synthetase inhibitor OKY-046 on this model was studied. In non-nephritic control animals, OKY-046 did not affect the CCr, the urinary protein excretion or the number of monocytes in glomeruli but reduced the excretion of i-TXB2. Although OKY-046 markedly inhibited the i-TXB2 excretion throughout the experiment in nephritic animals, the creatinine clearances were significantly worse, the proteinuria greater, and the number of infiltrating monocytes greater at day +5; by day +10 there was no difference from controls. There was no evidence that TXB2 is involved in the induction of proteinuria, and increased PGE2 synthesis did not protect against later proteinuria and fall in creatinine clearance. Inhibition of thromboxane synthetase appears to make this model of nephritis worse, rather than better.

Attenuation of permeability lung injury after phorbol myristate acetate by verapamil and OKY-046.

Phorbol myristate acetate (PMA), which produces an experimental model of acute lung injury similar to the adult respiratory distress syndrome, was studied in isolated dog lung lobes perfused at constant pressure in Zone 3 conditions. The effect of 25 to 50 micrograms PMA on pulmonary vascular permeability and resistance was observed in 4 groups of lungs: Group 1, perfused with a plasma/dextran solution; Group 2, perfused with blood; Group 3, blood-perfused and pretreated with verapamil (a calcium channel blocker); and Group 4, blood-perfused and pretreated with OKY-046 (a thromboxane synthetase inhibitor). Permeability changes were assessed by determining capillary filtration coefficient (Kf), isogravimetric capillary pressure (Pci), and in blood-perfused lungs, the protein reflection coefficient (sigma d). An increase in Kf, a decrease in Pci, and a decrease in sigma d, all indicative of an increase in vascular permeability, occurred 1 h after PMA in blood-perfused but not in plasma/dextran-perfused lungs. An increase in pulmonary vascular resistance occurred in both blood- and plasma/dextran-perfused lungs. Verapamil (2 X 10(-5) M) and OKY-046 (7 X 10(-4) M) pretreatment in blood-perfused lungs essentially blocked the PMA-induced change in permeability and significantly attenuated the increased vascular resistance. Total leukocyte and platelet counts fell in all blood-perfused lungs, whether pretreated or not. We conclude that cellular components of blood (platelets and/or leukocytes) are required to produce the permeability injury but not the pulmonary vasoconstriction and that the injury can be attenuated by either a calcium channel blocker or a specific thromboxane synthetase inhibitor. The left ventricular volume change caused by increasing right ventricular volume was measured at normal and elevated pericardial pressures.

Platelet prostaglandin D 2 dehydrogenase in patients with myeloproliferative disorders

NADP-linked 15-hydroxyprostaglandin dehydrogenase for prostaglandin D 2 (PGD2DH) transforms prostaglandin D 2 (PGD 2) to inactive 15-keto-PGD 2. This enzyme activity was spectrophotometrically determined in the cytosol of platelets and platelet sensitivities to PGD 2 were studied in patients with myeloproliferative disorders (MPD) as well as in normal subjects. Platelet sensitivities to exogenous and endogenous PGD 2 were estimated by IC 50 of added PGD 2 for platelet aggregation and by the inhibitory effect of a specific thromboxane synthetase inhibitor (OKY-046) on collagen-induced aggregation, respectively. PGD 2DH activities of MPD patients were significantly higher than those of normal subjects (p < 0.01). Although decreased sensitivity to exogenous PGD 2 was detected in some MPD patients, they were not always associated with the increased enzyme activities. Furthermore, no specific correlation was found between PGD 2DH activities and the inhibitory effects of OKY-046. Thus, PGD 2DH seems to have little effect on the action of PGD2 against platelet aggregation in MPD patients and normal subjects.

糖尿病患者に対するＴｈｒｏｍｂｏｘａｎｅ Ｓｙｎｔｈｅｔａｓｅ Ｉｎｈｉｂｉｔｏｒ（ＯＫＹ‐０４６）の臨床的効果

It is known that in diabetic patients with microangiopathy, the potency of blood coagulation and thromboxane production are activated. A specific thromboxane synthetase inhibitor, OKY-046 was given to 15 diabetic patients to study its effects on platelets, blood coagulation-fibrinolysis and renal function.Plasma thromboxane B2 tended to decrease after administration of OKY-046. Plasma 6-keto PGF1α indicated a significant increase after 1 month. Plasma thromboxane B2/6-keto PGF1α ratio showed a significant decrease after 2 weeks, with a gradual increase thereafter. Urinary thromboxane B2 also showed a significant decrease after 2 months. As the renal function, urinary β2-microglobulin (β2MG) showed a significant decrease after 2 months. In view of urinary β2MG and NAG levels which are said to be the early indices of nephropathy, OKY-046 was markedly effective in 3 cases, effective in 10 cases, ineffective in 2 cases and no aggravation. In view of blood β2MG which is said to reflect glomerular filtration rate, the drug was markedly effective in 2 cases, effective in 1 case and ineffective in 12 cases with no aggravation.We conclude that OKY-046 suppresses thromboxane production, activates PGI2 production and reduces thromboxane B2/6-keto PGF1α ratio in diabetic patients, suggesting to have an effect to improve diabetic nephropathy.

The Effect of a Specific Thromboxane Synthetase Inhibitor on Coagulation Parameters in Insulin Dependant Diabetics

Conference Abstract| December 01 1985 The Effect of a Specific Thromboxane Synthetase Inhibitor on Coagulation Parameters in Insulin Dependant Diabetics K.J.C Dallinger; K.J.C Dallinger 1Departments of Medicine and Haematology, University of Birmngham and East Birmingham Hospital Search for other works by this author on: This Site PubMed Google Scholar O.H.B Gyde; O.H.B Gyde 1Departments of Medicine and Haematology, University of Birmngham and East Birmingham Hospital Search for other works by this author on: This Site PubMed Google Scholar A.H. Barnett A.H. Barnett 1Departments of Medicine and Haematology, University of Birmngham and East Birmingham Hospital Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1985) 69 (s12): 81P. https://doi.org/10.1042/cs069081P Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation K.J.C Dallinger, O.H.B Gyde, A.H. Barnett; The Effect of a Specific Thromboxane Synthetase Inhibitor on Coagulation Parameters in Insulin Dependant Diabetics. Clin Sci (Lond) 1 December 1985; 69 (s12): 81P. doi: https://doi.org/10.1042/cs069081P Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1985 The Biochemical Society and the Medical Research Society1985 Article PDF first page preview Close Modal You do not currently have access to this content.

Thromboxane synthetase inhibition: potential therapy in migraine.

SYNOPSISSixteen patients with migraine were treated prophylactically for 3 months with dazoxiben, a specific thromboxane synthetase inhibitor, in an open study, Frequency of all attacks was reduced by more than 50% in 7 patients, and of severe attacks in 8 of 10 patients who initially suffered severe attacks. Reductions in thromboxane B2 levels measured at intervals during treatment by radioimmunoassay may have reflected standards of compliance with the 6‐hourly treatment regimen. However, a relationship emerged between thromboxane reduction and clinical response, with significantly greater reductions observed in patients who reported good symptomatic relief. This appears to support the hypothesis that platelet activation features in migraine causation.

Nifedipine in the treatment of Raynaud's phenomenon. Evidence for inhibition of platelet activation

Platelet activation has been reported to occur in patients with Raynaud's phenomenon; however, the effect of calcium channel blockers and thromboxane synthetase inhibitors has not been prevlously studied. The effect of two drugs that potentially inhibit platelet activation were studied: nlfedipine, a calcium channel blocker, and dazoxiben, a specific thromboxane synthetase Inhibitor. Two platelet-specific proteins released during platelet activation, betathromboglobulin and platelet factor 4, were measured during a double-blind clinical trial of these two drugs In patients with Raynaud's phenomenon. The plasma beta-thromboglobulin level was significantly elevated In the patient population (53.8 ± 7.6 ng/ml) during the, placebo period compared with that in a normal control population (27.0 ± 3.1 ng/ml) (p <0.01). The plasma platelet factor 4 level was 8.7 ± 2.2 ng/ml in the patients compared with 6.5 ± 1.0 ng/ml in the normal subjects (p = NS). These findings indicate the presence of In vivo platelet activation in patients with Raynaud's phenomenon. Nifedipine lowered the levels of beta-thromboglobulin to near the normal range (33.4 ± 4.6 ng/ml). The inhibition of platelet activation by nifedipine was associated with clinical improvement in Raynaud's phenomenon with fewer and less intense episodes. Beta-thromboglobulin was not lowered by dazoxiben (58.1 ± 9.0 ng/ml) compared with the placebo. The reduction of beta-thromboglobulin levels by nifedipine Indicates that In vivo platelet activation was inhibited by this agent. Since this was associated with a reduced frequency of attacks, It is not clear whether this was a direct effect of the drug on platelet activation, leading to decreased frequency of vasospasm, or an effect on vascular smooth muscle leading to decreased vasospasm and a secondary decrease in platelet activation.

エンドトキシン・ショックにおけるＯＫＹ‐０４６（ＯＫＹ）の効果

It is known that endotoxin activates the complement system via the alternative pathway and induces many pathophysiological changes. We compared the effect of OKY, a specific thromboxane synthetase inhibitor, with that of FUT-175 (FUT), a protease inhibitor, on endoxin-induced decrease in platelet count and complement activation. OKY 10mg/kg and FUT 0.3mg/kg but not aspirin 1mg/kg, inhibited the decrease in platelet count induced by injection of endotoxin in rabbits. PGI2 10μg/kg also inhibited the endotoxin-induced platelet decrease. OKY markedly inhibited the endotoxin-induced increase in plasma TXB2 level and enhanced 6-keto-PGF1α level, but FUT did not. Endotoxin released lactate dehydrogenase (LDH) which is a marker enzyme of platelt lysis from rabbit plateets in vitro. FUT 10-5M and PGI2 3×10-7M, but not OKY 10-4M, inhibited the LDH release from platelets. FUT 10-6-10-5M dose-dependently inhibited the decrease in total hemolytic activity of complement system (CH 50). On the other hand PGI2 inhibited the binding of complement (C3 and C5) to guinea-pig platelets induced by endotoxin. These results suggest that OKY inhibited the decrease in platelet count induced by endotoxin may be due to formation of PGI2 which inhibits the binding of complement to platelet, while FUT inhibited this via inhibition of complement activation.

Thromboxane production by perturbed bovine aortic endothelial cells in culture.

Bovine aortic endothelial cells in culture were incubated with endotoxin. The amount of thromboxane A2 synthesized was then determined by a specific radioimmunoassay for thromboxane B2. After a lag of several hours the cells changed their shape and parallel to the change in cell shape release of thromboxane B2 occurred. At 24 h the amount of thromboxane B2 generated in response to endotoxin was 200-fold above baseline. Thromboxane B2 generation could be blocked by aspirin and the specific thromboxane synthetase inhibitor UK 37248. The endotoxin effect was dependent on protein and RNA synthesis as evidenced by the inhibitory action of cycloheximide (1.5 microM) and actinomycin D (2 micron).

Dihomogammalinolenic acid, but not eicosapentaenoic acid, activates washed human platelets

Dihomogammalinolenic acid (2.5–20 μM) added to suspensions of washed human platelets induces platelet shape change and the formation of 1,2-diacylglycerol and phosphatidic acid, indicating the activation of phospholopase C. It also stimulates the phosphorylation of a 40 kDa protein, indicating the activation of protein kinase C. Dihomogammalinolenic acid is converted mainly to 12-hydroxyheptadecadienoic acid and to a smaller extent to prostaglandin E 1 and thromboxane B 1. Small quantities of the lipoxygenase product 12-hydroxyeicosatrienoic acid are also observed. Indomethacin, by blocking platelet cyclooxygenase, prevents the activation of phospholipase C, protein kinase C, and platelet shape change induced by dihomogammalinolenic acid. Compound UK 38485, a specific thromboxane synthetase inhibitor, does not block platelet activation induced by dihomogammalinolenic acid. The results indicate that endoperoxides derived from dihomogammalinolenic acid, such as prostaglandin G 1 or prostaglandin H 1, may be responsible for the stimulation of phospholipase C and protein kinase C, and for the induction of platelet shape change. Eicosapentaenoic acid does not activate platelets and is poorly metabolized by platelet cyclooxygenase and lipoxygenase. Eicosapentaenoic acid is a better inhibitor of platelet activation induced by various agonist in washed platelets than dihomogammalinolenic acid. Eicosapentaenoic acid and dihomogammalinolenic acid are, however, equally effective in inhibiting aggregation induced by collagen in platelet-rich plasma. We suggest that eicosapentaenoic acid might be a better antithrombotic agent than dihomogammalinolenic acid.

Dazoxiben, a thromboxane synthetase inhibitor, in Raynaud's phenomenon.

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.

SPECIFIC THROMBOXANE SYNTHETASE INHIBITION AND ALBUMIN EXCRETION RATE IN INSULIN-DEPENDENT DIABETES

Albumin excretion rates (AER) were measured in 30 insulin-dependent diabetics during a 16-week double-blind, randomised, placebo-controlled study of the specific thromboxane synthetase inhibitor UK-38,485. 6 of 15 subjects in the active group had microalbuminuria (defined as mean pretreatment AER 20-150 μg/min); in these patients AER fell from 32±3 μg/min to 11±1 μg/min at 8 weeks and 9±1 μg/min at 16 weeks. The AER rose again (to 29±8 μg/min) within 12 weeks of stopping the drug. There was no significant change in the 10 patients with microalbuminuria who received placebo. There was a strong correlation between change from baseline values and the baseline values themselves in the active, but not in the placebo group, and the change from baseline differed significantly between the two groups. There was no change in glycosylated haemoglobin or mean blood glucose levels during the study. In a separate study UK-38,485 caused significant suppression of thromboxane B2 synthesis in diabetic and non-diabetic subjects.

1-benzylimidazole, a thromboxane synthetase inhibitor acutely lowers blood pressure mainly by alpha-adrenoceptor blockade in spontaneously hypertensive rats (SHR)

Selective inhibitors of thromboxane (TX) formation have potential utility in the treatment of hypertension, atherosclerosis, thrombosis, myocardial ischemia, cancer metastasis, etc. This class of compounds not only removes TX, a potent vasoconstrictor and inducer of platelet aggregation, but may also enhance the production of a potent vasodilator and inhibitor of platelet aggregation, viz. , prostacyclin (epoprostenol, PGI 2). The specific thromboxane synthetase (TXS) inhibitor 1-benzylimidazole (1-BI) demonstrated a weak and OKY-1581 (OKY) a potent inhibition of TX formation in SHR-derived platelets in vitro . The acute antihypertensive effects produced by 1-BI were marked while those of OKY were less significant in SHR. 1-BI and OKY did not demonstrate an inhibition of PGI 2). formation in SHR-derived aortic rings in vitro . Indomethacin (I), which inhibits the formation of both TX and PGI 2). was not antihypertensive and did not antagonize the blood pressure lowering effects of 1-BI in the present studies. Oral and intravenous dosing with 1-BI, unlike OKY, produced epinephrine reversal in SHR, indicating the blockade of alpha-adrenoceptors. In conclusion, the acute antihypertensiv6 effects of 1-BI in SHR result mainly from alpha-adrenoceptor blockade, not inhibition of TXS activity.

Long-term myocardial preservation: Thromboxane production and coronary resistance

In a series of 18 experiments on long-term myocardial preservation we evaluated whether vasoactive substances like thromboxane and prostacyclin are associated with the secondary increase in coronary resistance during preservation perfusion of the canine heart. In a control group ( n = 12) and in a group treated with a specific thromboxane synthetase inhibitor (OKY 1581) coronary resistance was measured at 10 and 30 min, and at 1, 4, and 24 hr. At the same time intervals thromboxane A 2 and prostacyclin (PGI 2) production were determined as TXB 2 and 6-keto PGF 1α, respectively. After OKY 1581 treatment no increase in TXB 2 occurred and no secondary increase in coronary resistance was observed, while in the control group both TXB 2 levels and resistance increased ( P < 0.01); 6-keto PGF 1α levels showed the same increase in control and in treated hearts. From this study it is concluded that during 24-hr myocardial preservation the characteristic secondary increase in coronary resistance is related to thromboxane production in the heart and is prevented by inhibition of thromboxane synthetase.

Mechanism of action of dipyridamole

Dipyridamole appears to act in vivo by synergistically modifying several biochemical pathways, including: a) inhibition of platelet cAMP-phosphodiesterase; b) potentiation of adenosine inhibition of platelet function by blocking reuptake by vascular and blood cells, and subsequent degradation of adenosine; and possibly, c) potentiation of PGI 2 antiaggregatory activity and enhancement of PGI 2 biosynthesis. These independent processes inhibit platelet function by increasing platelet cAMP through both a reduction in enzymatic cAMP-degradation, and stimulation of cAMP formation via activation of adenylcyclase by adenosine and possibly PGI 2. Only the inhibition of cAMP phosphodiesterase appears to be involved in the dipyridamole inhibition of isolated platelets in vitro, since adenosine and PGI 2 originate in vivo from tissues other than platelets and any blood concentrations existing in vivo will disappear before platelet-rich plasma has been prepared for in vitro platelet studies. The antithrombotic effects of dipyridamole in a baboon model of arterial thromboembolism are unaffected by simultaneous administration of dazoxiben, a specific thromboxane synthetase inhibitor, but are optimally potentiated by the simultaneous addition of aspirin in doses of 20 mg/kg/day. Since this dose of aspirin has no detectable antithrombotic effects when used alone, but blocks vascular PGI 2 synthesis, the antithrombotic effects of dipyridamole, at least in this model, appear to be independent of prostacyclin.

Cerebrovascular effects of prostaglandin inhibitors in the gerbil.

Autoregulation of cerebral blood flow (CBF) to mean arterial blood pressure (MABP) of 40-50 mm Hg has been demonstrated in the spontaneously breathing gerbil anaesthetised with barbiturate (60 mg/kg). CO2 reactivity has also been assessed at 2.8% change CBF/mm Hg change in arterial PCO2. In six animals pretreated with indomethacin (3 mg/kg), autoregulation was preserved although the resting CBF was significantly reduced, but CO2 reactivity was completely abolished. 1-n-Butyl imidazole, a specific thromboxane synthetase inhibitor, was used in six other animals (3 mg/kg), and this abolished CO2 reactivity while preserving autoregulation; the effect of this agent has not been described previously. Both drugs inhibit different pathways of prostaglandin metabolism and may interfere with normal CO2 reactivity in several ways. Two explanations are that prostaglandins constitute the final common pathway in effecting cerebrovascular response to CO2 or, alternatively, that the free radicals and ionic fluxes generated during prostaglandin metabolism are a coincidental source of the hydrogen ion changes required.

Thromboxane and pulmonary hypertension following E. coli endotoxin infusion in sheep: Effect of an imidazole derivative

We assessed the effect of a specific thromboxane synthetase inhibitor (an imidazole derivative) on pulmonary hemodynamics and the concentrations of TxB 2 (TxA 2), 6-keto-PGF 1α (PGI 2), and PGF 2α in pulmonary lymph and transpulmonary blood samples following intravenous administration of E. coli endotoxin (1 μg/kg) in sheep. In control animals the rise in pulmonary artery pressure correlated with increases in plasma and lymph TxB 2 concentrations and large transpulmonary concentration gradients of this metabolite were measured. In imidazle treated animals both pulmonary hypertension as well as increases in plasma and lymph TxB 2 concentrations were substantially reduced. In contrast, peak concentrations of 6-keto-PGF 1α (PGI 2) and PGF 2α were severalfold higher than those measured in control animals. This suggests a shunting of endoperoxide metabolism towards prostacyclin and primary prostaglandins and documents the specificity of the thromboxane synthetase inhibitor. Out study provides evidence that endotoxin-induced pulmonary hypertension is mediated by pulmonary synthesis of TxA 2.