Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An acetylenic fatty acid: 9,12,15-octadecatrien-6-ynoic acid (dicranin), extracted from Dicranum Scoparium was preincubated with platelets stimulated by exogenous arachidonic acid (20:4 n-6). Dicranin (10(-4) M) weakly inhibited the cyclooxygenase activity as assessed by measurement of 12-hydroxy-heptadecatrienoic acid (HHT) In contrast, the 12-hydroxy-eicosatetraenoic acid (12-HETE) synthesized by the 12-lipoxygenase was strongly increased by about 650%. The same effects were observed with 10(-6) M of dicranin but to a lesser extent. The main platelet hydroxylated dicranin metabolite determined by GC-MS was a 13-hydroxy derivative Platelet aggregation induced either by thrombin or by arachidonic acid or by U46619, an structural PGH2 analogue was inhibited by 10(-4) M of dicranin.
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PMID:Effects of 9,12,15-octadecatrien-6-ynoic acid on the metabolism of arachidonic acid in platelets and on the platelet aggregation. 163 97

An acetylenic fatty acid: 9,12,15-octadecatrien-6-ynoic acid (dicranin) was extracted from Dicranum Scoparium and preincubated with platelets which were then stimulated by exogenous arachidonic acid (20:4 n-6). This molecule at 10(-4) M weakly inhibited the cyclooxygenase activity as assessed by measurement of 12-hydroxy-heptadecatrienoic acid (HHT) In contrast, the 12-hydroxy-eicosatetraenoic acid (12-HETE) synthesized by the 12-lipoxygenase was strongly increased by about 650%. The same effects were observed with 10(-5) M and with 10(-6) M of dicranin but to a lesser extent. Platelet hydroxylated dicranin metabolites were also found and the structure of the main compound determined by GC-MS was a 13-hydroxy derivative. Its origin has not yet been elucidated. Platelet aggregation induced by 1 microgram/ml of U46619, a structural PGH2 analogue was completely abolished in the presence of dicranin. Platelet aggregation induced either by thrombin or by arachidonic acid was inhibited by 10(-4) M of dicranin only after preincubation. This observation indicates that the formation of metabolites of dicranin are necessary to effect this inhibition. Dicranin is thus a new inhibitor of platelet aggregation and may prove to be useful for elucidating the effects of 12-HETE in biological systems.
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PMID:Effects of 9, 12, 15-octadecatrien-6-ynoic acid on the metabolism of arachidonic acid in platelets and on platelet aggregation. 163 61

Inhibitors of the endoplasmic reticulum Ca(2+)-ATPase like thapsigargin (TG) and 2,5-di (tert-butyl)-1,4-benzohydroquinone (tBuBHQ) cause increases in cytosolic calcium in intact human platelets resulting from prevention of reuptake. A maximal concentration of TG (0.2 microM) mobilized 100% of sequestered Ca2+ compared to the action of a receptor agonist like thrombin (0.1 U/ml). A maximal dose of tBuBHQ (50 microM) stimulated release of about 40% of intracellular calcium compared to thrombin and TG. The reduced ability of tBuBHQ to release calcium can be explained with an inhibitory effect on the cyclooxygenase pathway (Ki approximately 7 microM). Therefore tBuBHQ is not able to cause platelet aggregation compared to TG. In the presence of a cyclooxygenase inhibitor or a thromboxane A2 receptor antagonist the action of TG is identical to that observed with tBuBHQ. Generally, inhibition of calcium sequestration does not automatically result in platelet activation. In contrast to a receptor mediated activation Ca(2+)-ATPase inhibitors require the self-amplification mechanism of endogenously formed thromboxane A2 to cause a similar response. We conclude that the calcium store sensitive to Ca(2+)-ATPase inhibitors is a subset of the receptor sensitive calcium pool.
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PMID:Calcium mobilization in human platelets by receptor agonists and calcium-ATPase inhibitors. 164 69

Platelet activity is controlled, in part, by cytosolic free ionized calcium concentration ([Ca++]i). Regulation of platelet thromboxane (TXB2) synthesis may be by regulation of [Ca++]i. Dietary linoleate is a regulator of TXB2 synthesis, therefore, it may act by influencing [Ca++]i. Aspirin is a regulator of TXB2 synthesis by inhibition of cyclooxygenase; ouabain and nifedipine are regulators of [Ca++]i. This study was conducted to determine whether these affectors of TXB2 synthesis and [Ca++]i cause associated responses. Male nonobese Zucker rats were fed diets supplying 30% of energy (en%) as fat. Dietary fat was a mixture of corn oil and beef tallow to provide 3.0, 4.5, 6.0, or 7.5 en% linoleic acid, with cholesterol added to provide equal cholesterol in all diets. Rats were fed for 30 days with 6 rats/diet. Isolated rat platelets were assayed for FA composition; the percentage of linoleic acid in platelet FA rose linearly with increasing dietary linoleate (r = 0.76, P less than 0.0001). Resting and thrombin-stimulated platelet [Ca++]i and TXB2 synthesis were measured in the presence or absence of extracellular calcium and aspirin, ouabain, or nifedipine. Aspirin caused reductions in both parameters; nifedipine blocked [Ca++]i, but did not affect TXB2; ouabain increased both. Changes induced by those modifiers of TXB2 and platelet [Ca++]i caused changes that were in the same direction for both. CaCl2 caused an increase in both and the [Ca++]i was correlated with the square root of the TXB2; without CaCl2 the two were negatively correlated; aspirin, ouabain, and nifedipine treatments resulted in no significant correlations. The results suggest that there is a common modifier of [Ca++]i and TXB2 synthesis.
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PMID:The relationship between thromboxane and cytosolic calcium modifiers in rat platelets. 165 70

When platelets are activated by the recognition of exposed collagen fibers, they start synthesizing two major arachidonic acid metabolites, i.e. thromboxane A2 and 12S-hydroxyeicosatetraenoic acid (12-HETE) via cyclooxygenase and 12-lipoxygenase pathways, respectively. Although the physiological role of the former is well established, that of the latter has not been fully elucidated. Recently, we have revealed that 12-HETE interferes with collagen-induced platelet aggregation [Sekiya, F. et al. (1990) Biochim. Biophys. Acta 1044, 165-168]. In the present paper, we show that this substance enhances thrombin-induced aggregation of bovine platelets, in sharp contrast with the case of collagen. Additionally, 12-HETE is able to prevent the prostaglandin E1-induced elevation of platelet cAMP level and counteracts its inhibitory effect on platelet aggregations. With these observations, we propose a novel self-regulatory mechanism of platelets where 12-HETE plays a key role; it switches sensitivity of platelets from the primary agonist (collagen) to the secondary one (thrombin), and cancels the inhibitory effect of cAMP elevators.
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PMID:12S-hydroxyeicosatetraenoic acid plays a central role in the regulation of platelet activation. 165 54

12-Hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) as well as several other fatty acid hydroperoxides are potent inhibitors of platelet activation. 12-HPETE but not 12-hydroxy-5,8,10,14-eicosatetraenoic acid blocks the U46619- and the thrombin-triggered aggregation of aspirin-treated platelets, dose dependently. 12-HPETE suppresses thromboxane production by inhibiting platelet cyclooxygenase and stimulates its own production by increasing lipoxygenase activity, although this effect does not explain the inhibitory activity of 12-HPETE during the initial phase of cell activation. The inhibitory effect is related to altered calcium homeostasis during platelet activation. 12-HPETE inhibits calcium release from intracellular stores and modifies the influx of extracellular calcium. The inhibitory effect on calcium mobilization is explained by activation of soluble guanylate cyclase. These inhibitory properties are shared by sodium nitroprusside, a compound known to activate soluble guanylate cyclase. Fatty acid hydroperoxides, especially 12-HPETE, produce a rapid and dose-dependent activation of soluble guanylate cyclase, using intact human platelets as a detection system. Activation of the enzyme shows a position isomer specificity, with 12-HPETE being the most potent activator. The generation of the labile lipoxygenase product 12-HPETE during platelet activation may modulate platelet reactivity by increasing cyclic GMP. This pathway may contribute to a physiological feedback mechanism to limit the size of a growing platelet plug.
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PMID:12-hydroperoxyeicosatetraenoic acid inhibits main platelet functions by activation of soluble guanylate cyclase. 167 88

This study investigates the effect of platelet/neutrophil interactions on eicosanoid production. Human platelets and polymorphonuclear leukocytes (PMNs) were stimulated alone and in combination, with calcium ionophore A23187 and the resulting eicosanoids 12S-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoic acid (12-HETE), 12S-heptadecatrienoic acid (HHT), 5S,12R-dihydroxy-(6Z,8E,10E,14Z)-eicosatetraenoi c acid (LTB4) and 5S-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoic acid (5-HETE) were measured by HPLC. The addition of PMNs to platelet suspensions caused a 104% increase in 12-HETE, a product of 12-lipoxygenase activity, but had only a modest effect on the cyclooxygenase product HHT (increase of 18%). By using PMNs labelled with [14C]arachidonic acid it was shown that the increases in these platelet eicosanoids could be accounted for by translocation of released arachidonic acid from PMNs to platelets and its subsequent metabolism. The observation that 12-lipoxygenase was about five times more efficient than cyclooxygenase at utilising exogenous arachidonic acid during the platelet/PMN interactions was confirmed in experiments in which platelets were stimulated with A23187 in the presence of [14C]arachidonic acid. Stimulations of platelets with thrombin in the presence of PMNs resulted in a decrease in 12-HETE and HHT levels of 40% and 26%, respectively. The presence of platelets caused a small increase in neutrophil LTB4 output but resulted in a decrease in 5-HETE production of 43% during stimulation with A23187. This study demonstrates complex biochemical interactions between platelets and PMNs during eicosanoid production and provides evidence of a mechanism to explain the large enhancement in 12-HETE production.
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PMID:Enhancement of platelet 12-HETE production in the presence of polymorphonuclear leukocytes during calcium ionophore stimulation. 173 56

Several workers have described desensitization of endothelial prostacyclin production but conflicting evidence has been published regarding the mechanism of desensitization, whether it is homologous (agonist specific) or heterologous, and whether inactivation of cyclooxygenase is involved. The purpose of the present study was to determine the relation between the intensity of a first thrombin stimulus and the subsequent response to a repeat thrombin, histamine, ionophore A23187 or aluminium fluoride (AlF4) stimulation and to determine possible targets of desensitization. Following thrombin stimulation of confluent cultured human umbilical vein endothelial cells (HUVEC) only homologous desensitization of inositol phosphate production was observed. Both homologous and heterologous desensitization of arachidonic acid release and prostacyclin production occurred, the latter towards both histamine and the ionophore A23187. For any given dose of the first stimulant there was a much greater effect on the homologous response than on the heterologous response. These differences suggest different mechanisms. The homologous desensitization probably involves the receptor whereas the present results suggest that the target of heterologous desensitization is distal to calcium mobilization in the signal transduction pathway. The possibilities include decreased activity of phospholipase A2 or a decreased pool of accessible arachidonic acid.
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PMID:Different mechanisms of homologous and heterologous desensitization of thrombin-induced endothelial prostacyclin production. 176 77

A better knowledge of platelet activation mechanisms has made it possible to develop antiplatelet agents that are capable of inhibiting primary haemostasis at very precise levels. Many of these agents block the synthesis or receptor of an hemostasis I agonist. Thus, the thromboxane A2 receptor can be blocked, or its synthesis can be interrupted, by thromboxane synthetase inhibitors, by cyclooxygenase inhibitors, or by omega 3 fatty acids which are competitive inhibitors. Inhibitors of thrombin (hirudin), PAF acether and serotonin (ketanserin) also are available. Other antiplatelet agents secreted by endothelial cells act as haemostasis I antagonists by elevating platelet cAMP or cGMP levels (prostacyclins and analogues, nitrate derivatives). Monoclonal antibodies and RGD peptides directly inhibit the glycoproteins that are responsible for platelet adhesion or aggregation, but their users are faced with problems of cost and route of administration. Of all these new antiplatelet agents, only ticlopidine, which has an imperfectly known mode of action, has proved effective in multiple situations, but its use is limited by its side-effects.
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PMID:[New developments of antiplatelet drugs]. 177 22

A 64-year-old woman with a 15-years-history of rheumatoid arthritis developed generalized hemorrhagic diathesis. Routine coagulation tests revealed a slightly diminished platelet count only. Platelet aggregation in vitro induced by ADP, collagen, thrombin, arachidonic acid and ristocetin were reduced. The patient's plasma aggregating activity was significantly diminished which was due to a decrease of the intraplatelet nucleotide pool. The number of mepacrine labelled bodies as well as dense bodies in electron microscopy was below the normal values as well. Moreover, the intraplatelet concentration of cyclooxygenase--malonylodialdehyde (MDA) and lipoxygenase pathway products were lowered. Total platelet immunoglobulin G and M contents were significantly increased. The platelet survival time (in vitro aspirin method) was slightly shortened. Finally the diagnosis of delta-acquired platelet storage pool deficiency (delta-SPD) was established and possibilities of treatment were discussed.
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PMID:[Acquired platelet storage pool deficiency in rheumatoid arthritis]. 178 43


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