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)

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.
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PMID:Investigation on a selective non-prostanoic thromboxane antagonist, BM 13.177, in human platelets. 642 61

The effects of parathyroid hormone (PTH), dihydroxycholecalciferol (1,25-(OH)2 D3), thrombin, epidermal growth factor (EGF) and 12-o-tetradecanoylphorbol-13-acetate (PMA) on the biosynthesis and release of arachidonic acid metabolites were studied in primary cultures of osteoblast-like cells isolated from 18-day-old chick embryo calvaria. Cells were labelled with (14C)-arachidonic acid for 30 h. The radioactive eicosanoids were extracted from the cell culture media after a further 30 h stimulation period and analysed on a PRP-1 column by HPLC. The radioactive products were characterized by co-elution of (3H) standard prostanoids. Osteoblasts showed a basal release of the prostanoids 6-keto-PGF1 alpha, TXB2, PGF2 alpha, PGE2, PGD2 and PGB2, the latter being the most abundant one. Indomethacin (10(-5) M) effectively inhibited the basal release, but not that of an as yet unidentified compound. The release of prostanoids was stimulated by PTH (2 U/ml), thrombin (0.4 NIH/ml), EGF (50 ng/ml) and PMA (25 ng/ml), the latter being by far the most potent one. 1,25-(OH)2D3 was found to slightly inhibit the prostanoid release. These results indicate: (1) primary cultures of osteoblasts synthesize several prostaglandins, thromboxane B2 and one unidentified product. (2) the action on bone of PTH and the various drugs tested may be, at least partly, mediated by an increased prostaglandin production by osteoblasts. Clearly this does not apply to 1,25-(OH)2D3.
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PMID:Stimulation of arachidonic acid metabolism in primary cultures of osteoblast-like cells by hormones and drugs. 644 Nov 89

The ultrastructure, cytochemistry, biochemistry, and functions of platelets from two patients with the familial gray platelet syndrome are described. Ultrastructural studies showed a lack of alpha-granules in the megakaryocytes in the vicinity of a marrow myelofibrosis and/or in platelets. A normal number of mitochondria and a slight increase of dense bodies was confirmed by labeling the whole patient with mepacrine. Platelet peroxidase (in the dense tubular system) and catalase-positive granules (revealed by the cytochemistry) were present. Platelets from both patients had severe deficiency of beta TG either after tritonization (less than 4% of normal) or thrombin treatment (less than 15% of normal), and the plasma beta TG levels were slightly increased. Functional studies of these platelets showed an uptake of [14C]5HT inhibited by reserpine similar to that in the control platelets. Thromboxane formation was within normal limits in the presence of arachidonic acid, ADP, collagen, or ionophore A23187, indicating that (1) the cyclooxygenase/thromboxane synthetase systems were not altered and (2) the phospholipase activities were not impaired. Although the platelet adhesion to prepolymerized fibrillar type III collagen and the ADP-, arachidonic acid-, and ionophore A23187-mediated aggregations were apparently normal, in every case the release of [14C]5HT was either at the low side of the normal range or decreased. This abnormality was increased when collagen or thrombin was added to either PRP or washed platelets from both patients, where at the same time, the aggregation and the release were markedly reduced. The results suggest that alpha-granules or their content has an influence on not only the platelet aggregation but also the dense bodies involved in the [14C]5HT release reaction.
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PMID:Gray platelet syndrome: alpha-granule deficiency. Its influence on platelet function. 645 43

The effect of heparin on platelet aggregation was systematically examined on platelets in plasma (PRP), as well as on gel-filtered, washed, and formaldehyde-fixed platelets. Results indicate that, although heparin causes a mild potentiation of platelet aggregation in the PRP systems, a significant inhibitory activity is observed when heparin is added to isolated platelets. This inhibitory activity appears to be specific and not related to the impurities in the heparin preparations, as heparinase, as well as protamine, effectively neutralizes the heparin-mediated inhibitory activity on platelet aggregation. Although heparin-mediated inhibitory activity can be demonstrated in the presence of a number of different agonists (ADP, arachidonic acid, thrombin, Ionophore A23187, epinephrine, and ristocetin), the most pronounced inhibition is seen in the presence of ristocetin. Further studies show that heparin enhances thromboxane generation in isolated platelets. Platelets pretreated with heparin, however, fail to respond to preformed thromboxane. These findings suggest that, in addition to the potentiation of thromboxane production in platelets, heparin may also attribute some change(s) to the platelet(s)/platelet membrane, which interferes with their ability to respond to the agonists of platelet aggregation. This antiaggregatory activity of heparin was found to be inhibited by a factor(s) present in plasma but not in serum.
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PMID:Effect of heparin on platelet aggregation. 647 40

Piribedil at high concentrations inhibits in vitro ADP and thrombin aggregation effect on the rabbit PRP.
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PMID:Piribedil and platelet aggregation. 659 6

In 13 type II hyperlipidemics (10 males and 3 females; mean age 50.2 +/- 10.6 years), in 10 type IV hyperlipidemics (7 males and 3 females; mean age 51 +/- 13.3 years) and in 23 healthy age- and sex-matched controls, the following parameters were measured: plasma cholesterol; plasma TG; plasma C-HDL; VLDL, separated in a preparative ultracentrifuge; C-LDL; Apo B, with immunoelectrophoretic method; platelet sensitivity to prostacyclin; TXB2 formation in PRP; TXB2 in serum. This study provides evidence for: 1. Reduced platelet sensitivity to prostacyclin, more evident in type II hyperlipidemia that provides an additional mechanism involved in increased platelet aggregation found in type II hyperlipidemia. 2. Enhanced TXB2 formation in PRP after thrombin stimulation (664.65 +/- 142.18 pmol/10(8) platelets) only in type II hyperlipidemics and such enhanced formation was positively correlated to C-LDL (r = 0.53; p less than 0.05) and to Apo B (r = 0.62; p less than 0.05); serum TXB2 formation rate was also increased in type II hyperlipidemia.
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PMID:Platelet sensitivity to prostacyclin and thromboxane production in hyperlipidemic patients. 675 32

TxB2 formation in PRP after thrombin stimulus, serum TxB2 and platelet sensitivity to prostacyclin and the correlation with ambient fasting plasma glucose and lipoproteins were determined in 20 insulin-independent diabetics (IID) with macroangiopathy, 10 insulin-dependent diabetics (IDD) with microangiopathy and 30 matched controls. Platelets obtained from insulin-independent diabetics synthetize significantly higher amounts of TxB2 than those of insulin-dependent diabetics and matched controls. IDD and IID patients required significantly higher concentrations of prostacyclin (p less than 0.001) for a similar degree of platelet aggregation inhibition. The amount of prostacyclin required for 50% platelet aggregation inhibition was correlated with fasting plasma glucose (r = 0.64, p less than 0.001) and HbA1% (r = 0.48, p less than 0.01) in all diabetic subjects. We conclude that: 1) only PRP, obtained from some insulin-independent diabetics with a concomitant macroangiopathy, shows an increased synthesis of TxB2; 2) platelet sensitivity to prostacyclin is highly dependent on the fasting ambient plasma glucose.
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PMID:Thromboxane B2 formation and platelet sensitivity to prostacyclin in insulin-dependent and insulin-independent diabetics. 676 93

A new method for the separation from plasma and washing of human platelets is described. The use of prostacyclin (PGI2) throughout the procedure prevents the activation of platelets. The method allows a 60-70% yield of platelets from PRP. The platelet sensitivity to ADP, collagen, adrenaline, arachidonic acid and thrombin is the same as in PRP. The platelet suspension is stable for long periods and the reactivity to aggregating agents remains unchanged for periods greater than 48 h when platelets are stored at 4 degrees C.
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PMID:The use of prostacyclin in the separation from plasma and washing of human platelets. 681 68

Pyridoxal 5'-phosphate (PALP) inhibited ADP, thrombin, adrenaline, PAF and AA induced aggregation and 14C-5HT release. Thromboxane B2 (TxB2) generation induced by all the above agents except AA was also inhibited indicating that PALP may be inhibiting AA release via phospholipase A2 activation rather than AA metabolism. PALP inhibited ristocetin induced aggregation in PRP and agglutination in formaldehyde-treated washed platelets (FWP). Inhibition of ADP, adrenaline, PAF and AA-induced aggregation and 14C-5HT release by PALP was found in resuspended platelets pretreated with PALP and sodium borohydride suggesting that inhibition was mediated by Schiff base formation with platelet surface amino groups. Irreversible fixation of PALP to the platelet membrane by borohydride reduction also inhibited thrombin induced 14C-5HT release and TxB2 generation but no thrombin induced primary aggregation or ristocetin induced agglutination in FWP. This suggests that PALP may interact with specific glycoproteins on the platelet membrane involved in ADP, adrenaline and PAF induced primary aggregation and that PALP could be inhibiting ristocetin induced agglutination by direct interaction with ristocetin or F VIII RCoF.
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PMID:Effect of pyridoxal 5'-phosphate (PALP) on human platelet aggregation, dense granule release and thromboxane B2 generation--role of Schiff base formation. 689 Nov 7

2-Propargyloxy-5-amino-N-butyl-benzamide (parsalmide), an antiinflammatory drug, inhibits human platelet function in vitro and ex vivo. The degree of inhibition of ADP- and collagen-induced platelet aggregation "in vitro" is dose-dependent and parsalmide shows a more marked effect than equal concentrations of acetylsalicylic acid (ASA) and indometacin. Moreover, malondialdehyde levels in human PRP after addition of thrombin were inhibited at the same degree by parsalmide, ASA and indometacin. In ex vivo experiments, the administration of 400 mg p.o. of parsalmide in arthropathic patients shows a significant inhibitory effect on ADP-induced platelet aggregation at 3 and 24 h after treatment, while a drop of malondialdehyde levels was observed only at 3 h after treatment. No significant inhibitory effect was observed in collagen-induced platelet aggregation.
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PMID:Inhibition of human platelet function by parsalmide. 689 11


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