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)

Abnormal platelet aggregation seen in experimentally induced diabetic, hypercholesterolemic and spontaneously hypertensive rats (SHR) has been linked with increased prostaglandin synthesis. The present study was conducted to examine the role of prostaglandins in rat platelet activation using normal Wistar Kyoto (WKY) and SHR rats. Up to 30 microM ADP did not induce secondary phase of platelet aggregation in rat PRP and up to 30 microM epinephrine did not produce any response in rat PRP. In other experiments ADP (1.0 microM) and epinephrine (2.0 microM) induced typical biphasic aggregation responses in human PRP. Up to 20 microM U46619, a stable analog of prostaglandin H2, did not induce platelet aggregation in rat PRP or washed rat platelets. In contrast 2.0 microM U46619 caused maximal aggregation in human PRP and washed human platelets. Arachidonic acid (1.5-2.0 mM) induced aggregation in washed rat platelets. However, this was associated with excessive (67% and 94%) loss of cytoplasmic LDH. The low concentrations of thrombin (0.04 and 0.05 U/ml), induced two to three-fold increase in aggregation response in SHR platelets as compared to WKY platelets. Higher concentrations of thrombin (0.1 and 0.3 U/ml) induced similar aggregation responses in SHR and WKY platelets. Thrombin (0.04-0.3 U/ml) induced serotonin secretion in a concentration dependent manner. The extent of secretion was the same in SHR and WKY platelets at all concentrations. Thrombin-induced synthesis of thromboxane A2 (TXA2) in WKY and SHR platelets was quantified using a radioimmunoassay for TXB2. Thrombin (0.04-0.3 U/ml) produced TXB2 in WKY and SHR platelets in a concentration dependent manner. The SHR platelets produced significantly larger amounts of TXB2 as compared to WKY platelets. In other experiments aspirin (500 microM) inhibited thrombin (0.05 U/ml) induced TXB2 synthesis by 75% in both WKY and SHR platelets but failed to inhibit aggregation or secretion in either WKY or SHR platelets. Based on these data it is suggested that: (a) rat platelets inspite of their ability to synthesize TXA2 do not require TXA2 for aggregation; and (b) the rat may not be an appropriate model to study the role of prostaglandins in normal or abnormal platelet aggregation.
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PMID:Evidence that the rat is not an appropriate model to study the role of prostaglandins in normal or abnormal platelet aggregation. 396 34

The effects of chelation of divalent cations in the interaction of platelets and tumor cells has been studied in a homologous human system using human platelet-rich plasma and two tumor cell lines of human origin: SKNMC (neuroblastoma) cells, which cause platelet aggregation by an adenosine diphosphate-dependent mechanism, and U87MG (glioblastoma) cells, which function by a thrombin-dependent mechanism. When added at zero time, citrate 14 mmol/L completely abolished aggregation in heparinized (5 U/ml) platelet-rich plasma by either cell line, but the degree of inhibition was reduced by later addition of the chelating agent. Calcium citrate 8 mmol/L reduced by only 10%, indicating that citrate anion was not responsible for the inhibition. Addition of Ca++ or Mg++ alone or in combination at concentrations up to 1.5 mmol/L did not reverse the inhibition. Addition of higher concentrations of Ca++ (2 mmol/L) caused immediate clotting, whereas concentrations of Mg++ up to 6 mmol/L were without effect. Inhibition could be reversed by washing the platelets free of citrate and resuspending in heparinized platelet-rich plasma. Aggregation by either cell line was inhibited by EDTA and EGTA. In the Baumgartner perfusion apparatus, platelet interaction with subendothelium was increased about 50-fold in the presence of SKNMC cells, but this effect was also abolished after addition of citrate. After addition of U87MG cells to heparinized PRP, there was a 400-fold increase in platelet interaction with subendothelium, and complex thrombi containing red cells, white cells, and fibrin were formed. This stimulation was reduced to control levels by addition of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of divalent cations on the interaction of platelets with tumor cells: aggregation and perfusion studies with two homologous human systems. 400 24

Ferriprotoporphyrin IX (FP) dissolved in 0.025N NaoH in concentrations of 0.01 - 0.04 microM/ul platelet suspension competitively inhibited platelet aggregation induced by a low concentration of collagen. 14C-serotonin release was also inhibited. Higher concentrations of collagen overcame the aggregation inhibition. A similar pattern of results was obtained with thrombin-, and arachidonic acid-induced aggregation and release. With ristocetin, there was little inhibition of aggregation although serotonin release was inhibited. ADP-induced aggregation was partially inhibited except at FP concentrations of 0.91 microM/mul. FP caused only platelet shape change and serotonin release of up to 8.1%. These changes were not associated with significant platelet lysis and could also not be attributed to pH or temperature changes. There was no inhibition of collagen-induced aggregation in PRP, but FP precipitates aggregated washed platelets and caused serotonin release. These results show that FP in solution inhibited platelet aggregation induced by the different agents studied. It did not interfere with platelet agglutination induced by ristocetin. The mechanism(s) of aggregation inhibition remains to be clarified.
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PMID:The inhibitory effects of ferriprotoporphyrin IX on platelet aggregation and release of serotonin. 408 31

BM 13.177 (0.1-100 microM) produced a concentration-dependent reduction of the platelet shape change, aggregation and (3H)serotonin release induced by the stable PGH2 analogues U 46619 and U 44069 or exogenous and endogenous arachidonic acid, the latter mobilized by hydrogen peroxide or collagen. BM 13.177 (100 microM) did not inhibit the primary platelet activation by ADP, serotonin, thrombin or collagen in washed platelets or citrated PRP that had been pre-treated with ASA (acetylsalicylic acid). The formation of TXB2 triggered by 100 microM hydrogen peroxide or 10 microM arachidonic acid was not influenced by BM 13.177 (10 microM). In spiral strips of rat and rabbit aorta, BM 13.117 markedly reduced the vasoconstriction triggered by U 46619 and PGF2 alpha. BM 13.177 did not inhibit the K+-or noradrenaline-induced constriction. The concentration/response curves of the U 46619-stimulated platelet shape change and of the vasoconstriction induced by U 46619 and PGF2 alpha were shifted in parallel to the right by BM 13.177, implicating a competitive antagonism. The pAx values were about the same in these models which indicates that BM 13.177 does not differentiate between the thromboxane receptors in human platelets and rabbit aorta. In mice, BM 13.177 prevented in a dose-dependent fashion the sudden death and the symptoms of respiratory depression and shock induced by i.v. injections of U 46619 or arachidonic acid. BM 13.177 did not exert partial agonist activity in the in vitro and in the animal models.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitory effects of the selective thromboxane receptor antagonist BM 13.177 on platelet aggregation, vasoconstriction and sudden death. 609 35

In their experimental researches the Authors showed that the well-known antihypertensive alpha-adrenergic stimulant drugs (clonidine, flutonidine and guanabenz) were able to antagonize at very high concentrations the platelet aggregation induced by ADP and by thrombin on rabbit PRP.
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PMID:[Platelet aggregation and antihypertensive alpha-adrenergic agonists]. 611 90

KF4939, 2,2'-dithiobis-(N-2-hydroxypropylbenzamide), is a potent inhibitor of platelet aggregation in vitro in rabbit and human PRP. This agent inhibited both cyclooxygenase product-dependent (collagen and arachidonate) and independent (ADP and thrombin)-platelet aggregations. This action carried over to ex vivo situation following intraduodenal dosing as demonstrated in rabbits. KF4939 inhibited experimentally induced thrombocytopenias in rats and pulmonary thrombosis in mice following oral doses in a range of 25-300mg/kg. These results indicate that KF4939 is a new orally active inhibitor of platelet aggregation possessing a different mode of action from cyclooxygenase inhibition.
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PMID:Inhibition of platelet aggregation by a new agent, 2,2'-dithiobis-(N-2-hydroxypropyl benzamide) (KF4939). 640 99

Mouse platelets were aggregated by arachidonate, thrombin, collagen and ADP. In general they were, like rat platelets, more aggregative in heparinized PRP than in citrated (3.8%) PRP. Mouse platelets underwent the release reaction when aggregated by arachidonate, collagen and thrombin, but not when stimulated by ADP. The aggregation of the platelets to arachidonate was inhibited by cyclooxygenase inhibitors and by prostacyclin. Studies with tritiated arachidonate showed that mouse platelets possess the lipoxygenase and cyclooxygenase pathways found in other mammalian platelets and produce thromboxane and 12-HETE. The mouse provides a convenient model for the study of many conditions known to affect platelet aggregation. The similarity of mouse platelets to the platelets of other mammals together with the ability to study large numbers of animals at low cost, should encourage further use of mouse platelets.
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PMID:Some properties of mouse platelets. 641 87

Human Factor VIII associated von Willebrand factor (VIII:vWF) binds to human platelets in vitro only in the presence of a mediator such as ristocetin, thrombin or ADP. Studies reported here were designed to determine if human platelets will adhere to solid-phase VIII:vWF. Human VIII:vWF was purified from a phosphate precipitate of A1(OH)3 absorbed plasma using 4% agarose and DEAE cellulose. Purified VIII:vWF (90 units of VIII:vWF activity/mg) was coated on dialysis membranes using ultrafiltration (final concentration of 0.4 units/cm2). Membranes (0.5 cm2) were held stationary in human citrated PRP suspension or washed platelet suspensions and stirred continuously for 5 minutes at 37 degrees C. The membranes were then rinsed in phosphate buffered saline, fixed, stained, and examined by light and scanning electron microscopy. Abundant normal platelets adhered to VIII:vWF-coated membranes, while minimal adhesion was seen on uncoated membranes and membranes coated with albumin. Adhesion occurred without ristocetin, thrombin, ADP or other agonist and in the presence of Ca+2/Mg+2 ions. Preincubation of the VIII:vWF coated membranes with monospecific rabbit anti-VIII:vWF inhibited the adhesion reaction. However, preincubation of VIII:vWF coated membranes with naturally occurring human anti-FVIIIc antibodies failed to interfere with platelet adhesion. Platelets from a patient with Bernard-Soulier Syndrome (BSS) which did not bind human VIII:vWF in the presence of ristocetin or aggregate with bovine cryoprecipitate also did not adhere to VIII:vWF-coated membranes.
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PMID:Adhesion of human platelets to purified solid-phase von Willebrand factor: studies of normal and Bernard-Soulier platelets. 641 73

We studied the effect of the methanol extract of garlic bulbs (EOG) and of three pure components isolated from it (F1, F2, F3), on human platelet aggregation induced by ADP, epinephrine, collagen, thrombin, arachidonate, PAF, and the ionophore A-23187. Incubation of PRP with EOG, either in methanol or in homologous PPP, inhibits platelet aggregation induced by all of the above mentioned agonists. F1, F2, and F3 also inhibit platelet aggregation, however, F3 was about four times more potent. Addition of EOG or F3 to platelets that have already been irreversibly aggregated by 10 microM ADP, induces rapid deaggregation. Inhibition of aggregation was still present after three hours. The inhibitory effect persisted even after the treated platelets were Gel-Filtered (GFP) or separated from plasma through a metrizamide gradient and resuspended in new homologous PPP. Thrombin-induced release of ATP from GFP was inhibited by 75-80% after EOG or F3 treatment. Incorporation of [3-H]-arachidonate by intact platelets was decreased by 50-60% in treated platelets. However, platelets incubated with the inhibitors after incorporation of radiolabeled arachidonate, although did not aggregate, produced, after thrombin activation similar amounts of radiolabeled TXB2 and lipoxygenase products as the controls. Electron microscopy of inhibited platelets, in the presence of thrombin, showed no degranulation but an increase of spherical forms. Our results suggest that the effects described might be mediate by a perturbation of the physicochemical properties of the plasma membrane rather than by affecting arachidonate or calcium metabolism in the cells. Chemical structures of F1, F2 and F3 have been provisionally assigned: F1 is diallytrisulfide, F2 is 2-vinyl-1,3-dithiene, and F3 is most probably allyl 1,5-hexadienyltrisulfide.
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PMID:Effects of garlic extract and of three pure components isolated from it on human platelet aggregation, arachidonate metabolism, release reaction and platelet ultrastructure. 641 74

TXB2 formation in PRP after thrombin or arachidonic acid stimulation was determined in 23 young compensated insulin-dependent diabetic patients, and in 10 control subjects of equivalent age. No significant difference in TXB2 synthesis during the times sampled was observed. Six out of 23 diabetics had circulating immune complexes (CIC) in their sera as detected by the C1q-SP; after the addition of arachidonic acid and thrombin the amount of TXB2 in PRP from CIC-positive patients was significantly higher than in PRP from CIC-negative patients. The increased synthesis of PG endoperoxides in CIC-positive patients could be a direct effect of antigen-antibody complexes on platelets.
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PMID:Platelet thromboxane synthesis in treated childhood diabetes mellitus. 641 83


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