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)

Human alpha-thrombin-induced elevation of cytosolic free calcium ([Ca2+]i) and dense granule release was examined in platelets preincubated with either activators or an inhibitor of protein kinase C. 12-O-Tetradecanoylphorbol 13-acetate (TPA) or two 12-deoxy analogues of TPA, when added alone to platelets, did not elevate [Ca2+]i, as monitored by quin2 fluorescence, though small amounts of dense granule release were detected. Preincubation of the platelets with either TPA or 12-deoxyphorbol 13-phenylacetate, but not the parent, 4-beta-phorbol, produced a dose-dependent inhibition of the elevation of [Ca2+]i and 5-hydroxytryptamine release induced by human alpha-thrombin. Furthermore, this phorbol ester-mediated inhibition of human alpha-thrombin-induced activation could be prevented by H7 (1-[5-isoquinolinesulphonyl]-2-methylpiperazine), the recently described inhibitor of protein kinase C. These results suggest a role for protein kinase C as a modulator of receptor-operated calcium fluxes in human platelets.
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PMID:Phorbol esters modulate thrombin-operated calcium mobilisation and dense granule release in human platelets. 370 6

Addition of GTP markedly enhances the ability of thrombin to cause a leftward shift in the Ca2+ dose/response curve for 5-hydroxytryptamine secretion from permeabilised human platelets. Little effect is observed on addition of GTP in the absence of thrombin. Neither ADP nor adrenaline, in the presence or absence of GTP, causes such a shift, whereas 5-hydroxytryptamine does so to a small extent but only in the presence of GTP. The leftward shift in the Ca2+ dose/response curve induced by 12-O-tetradecanoyl-phorbol-13-acetate or 1-oleyl-2-acetylglycerol is not enhanced by addition of GTP. The thrombin concentration required for half-maximal enhancement of the response to Ca2+ is markedly reduced by addition of GTP. The results support the postulate that the effects of excitatory agonists in this system correlate with their ability to activate phospholipase C and provide further evidence for a role for GTP in signal transduction between the receptor and phospholipase C.
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PMID:Effect of various excitatory agonists on the secretion of 5-hydroxytryptamine from permeabilised human platelets induced by Ca2+ in the presence or absence of GTP. 387 12

Canatoxin is a toxic protein isolated from Canavalia ensiformis seeds. It induces death preceded by convulsions of spinal cord origin and also produces in vitro aggregation of platelets in rabbit, human and guinea-pig plasma. The aggregating effect is dose-dependent at nanomolar concentrations. Rabbit platelets pretreated with canatoxin became refractory to a second exposure to this protein or to collagen, but were still responsive to ADP, Paf-acether or arachidonic acid. [14C]-5-hydroxytryptamine was released from pre-labelled platelets on stimulation with canatoxin. Washed rabbit platelets, but not thrombin-degranulated ones, aggregated on stimulation with canatoxin provided that fibrinogen was added before the toxin. Canatoxin's pro-aggregating activity was inhibited by mepacrine, EDTA, caffeine, prostacyclin, adenosine monophosphate and also by the ADP scavenger system, creatine phosphokinase/creatine phosphate. Furthermore, 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW 755C), eicosatetraynoic acid (ETYA) and nordihydroguaiaretic acid (NDGA) were potent inhibitors of canatoxin-induced aggregation. In contrast, no inhibition was seen with indomethacin. The data indicate that canatoxin is mainly a release-reaction-promoting agent, being devoid of any direct aggregating activity. Thus the aggregation is totally dependent on the release of ADP. Furthermore, canatoxin-induced platelet activation is probably dependent on platelet phospholipase A2 and lipoxygenase activity but is not dependent on cyclo-oxygenase products or the release of Paf-acether.
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PMID:Platelet release reaction and aggregation induced by canatoxin, a convulsant protein: evidence for the involvement of the platelet lipoxygenase pathway. 391 94

Ethanol has been reported previously to inhibit chemically-induced platelet aggregation and the release of platelet contents. In platelet suspensions the mechanical stimulus of stirring can induce slow aggregation and the loss of endogenous arachidonic acid from phospholipids by activation of platelet phospholipases. These changes are prevented by the presence of ethanol 20-100 mM, whereas, in unstirred suspensions, ethanol alone has no effect on platelet phospholipids. Under similar conditions of reduced platelet: platelet contact, chemical stimuli, such as thrombi, although unable to produce visible aggregation, still cause the release of [3H]-5-hydroxytryptamine from platelets and also initiate the breakdown of platelet phospholipids. Ethanol does not now inhibit the thrombin-induced release of platelet contents and has little effect on phosphatidylinositol breakdown, though it inhibits phosphatidylcholine breakdown. Ethanol may therefore inhibit platelet aggregation by reducing the effect of mechanical and chemical stimuli on the activation of phospholipase A2. In contrast ethanol has rather little effect on the receptor-mediated breakdown of phosphatidylinositol which is apparently sufficient to trigger the release of platelet contents.
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PMID:Effect of ethanol on thrombin-induced platelet phospholipid breakdown and release of [3H]-5-hydroxytryptamine. 392 67

To clarify the possible role of persistent thrombocytosis after splenectomy being a predisposing factor causing development of thromboembolism, blood coagulation profiles and platelet functions were studied in 34 cases being 1-18 years post-splenectomy from non-malignant diseases. Persistent thrombocytosis was observed in 16 with significant negative correlation between hemoglobin level and platelet count indicated the role of anemia on persistent post-splenectomy thrombocytosis. Blood coagulation profiles showed accelerated thrombin formation or hypercoagulability as measured by thrombin generation test especially in cases with thrombocytosis, together with decreased fibrinolytic activity and high fibrinogen, but in presence of high antithrombin III activity. Concerning the platelet, the aggregation to ristocetin was defective, the improved aggregation to ADP and adrenaline was achieved only in whom with intact spleen giving defective platelet aggregation. The finding indicated the role of spleen contributing to abnormal platelet aggregation. Another interesting observation was the decreased platelet 5-hydroxytryptamine content in splenectomized cases. The overall changes on blood coagulation and platelets post-splenectomy including those with persistent thrombocytosis did not thoroughly shift to hypercoagulable state, since a high antithrombin III activity and some platelet defect remained. These present findings, therefore, unlikely predisposed to the occurrence of thromboembolism even in those with persistent thrombocytosis.
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PMID:Blood coagulation and platelet profiles in persistent post-splenectomy thrombocytosis. The relationship to thromboembolism. 408 60

The relation of cyclic 3',5'-adenosine monophosphate to platelet function has been studied by investigating the influence of this compound and of its N(6)-2'-0-dibutyryl derivative on platelet aggregation and other aspects of platelet behavior after demonstration of adenyl cyclase activity in disrupted platelets. Dibutyryl cyclic AMP inhibited platelet aggregation induced by ADP, epinephrine, collagen, and thrombin. Cyclic AMP was also inhibitory but was less effective. The platelet "release reaction" was also inhibited; specifically, there was inhibition of the induction of platelet factor 3 activity and of the release of labeled 5-hydroxytryptamine. Platelet swelling produced by ADP was not inhibited. The action of dibutyryl cyclic AMP did not result from contamination with 5'-AMP, nor was it attributable to production of 5'-AMP by plasma enzymes. Dibutyryl cyclic AMP was degraded to 2'-O-monobutyryl cyclic AMP and to cyclic AMP in plasma, but plasma exhibited no cyclic nucleotide phosphodiesterase activity, and the production of 5'-AMP did not occur. The in vitro effects of dibutyryl cyclic AMP were associated with uptake of the compound by platelets. Adenyl cyclase activity of platelet homogenates was demonstrated with production of 9.27 x 10(-11) (+/-2.62 x 10(-11)) mole cyclic AMP per min per 10(10) platelets. The activity was increased by NaF and by prostaglandin PGE(1) and was decreased by epinephrine. The effect of epinephrine was blocked by phentolamine but not by propanolol. Adenyl cyclase activity was also inhibited by collagen, 5-hydroxytryptamine, and thrombin. ADP, dibutyryl cyclic AMP, and cyclic AMP did not alter adenyl cyclase activity. These observations are consistent with the hypothesis that platelet aggregation is favored by a decrease in platelet cyclic AMP and inhibited by an increase in cyclic AMP.
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PMID:Cyclic 3',5'-adenosine monophosphate in human blood platelets. II. Effect of N6-2'-o-dibutyryl cyclic 3',5'-adenosine monophosphate on platelet function. 432 65

1 The effect of perturbation of intact blood platelets with proteolytic enzymes was studied with respect to 5-hydroxytryptamine (5-HT) transport, adenine transport and intracellular Na(+) and K(+) levels.2 Leucine aminopeptidase and thrombin reduced 5-HT transport, released 5-HT from pre-labelled platelets and disturbed the gradient to monovalent cations. Leucine amino-peptidase, but not thrombin, inhibited adenine transport.3 alpha-Chymotrypsin and carboxypeptidases A and B were without effect on the parameters studied.4 Trypsin selectively reduced 5-HT transport. It did not release 5-HT from blood platelets or inhibit adenine transport.5 The action of proteolytic enzymes is discussed in terms of proteins localized in the external membrane that may function in part as membrane carriers.
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PMID:Effect of selective proteolysis on the accumulation of 5-hydroxytryptamine by intact rat blood platelets. 445 19

The ;swirling' seen when platelet-rich plasma is stirred is caused by the average asymmetry of the platelets and a technique for recording the swirling is reported. After the addition of adenosine diphosphate, 5-hydroxytryptamine, thrombin, and collagen, platelets become rounded and more symmetrical immediately before they become sticky. Monoiodo-acetate and adenosine prevent both the change in shape and sticking whereas E.D.T.A. and p-tosyl arginine methylester prevent sticking but the shape still changes. Adrenaline produces sticking but no change in shape. The effects of temperature and E.D.T.A. are also reported. All these findings are discussed and diagrammatic representations of some reactions are tentatively proposed.
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PMID:Effect of aggregating agents and their inhibitors on the mean platelet shape. 495 38

1. Measurements were made of the uptake, metabolism and release of [(3)H]-adrenaline by human platelets in citrated plasma or in an artificial medium.2. Radioactive adrenaline was not taken up at 0-2 degrees C. At 37 degrees C there was a slow uptake which continued for at least 5 hours.3. About half of the radioactivity in the platelets was intact adrenaline. The other half was an acidic metabolite from which adrenaline was released by acid hydrolysis.4. The immediate uptake of adrenaline was proportional to its concentration in the plasma up to at least 1 x 10(-5)M. Uptake measured after 1 h also increased linearly with concentration up to about 1 x 10(-4)M but less with higher concentrations. The highest concentration ratio was about 12.5. The concentration of metabolite in the platelets increased with the concentration of added adrenaline only up to about 2 x 10(-4)M.6. The immediate uptake of adrenaline was partially inhibited by phentolamine and dihydroergotamine. Measurement of uptake both immediately and after 1 h showed that the inhibition produced was not increased beyond about 50% by these drugs or by (+/-)-propranolol, chlorpromazine or amitriptyline up to 1 x 10(-4)M.7. Formation of the metabolite was inhibited by pyrogallol, 8-hydroxyquinoline, or tropolone. This inhibition was associated with a corresponding increase in the adrenaline accumulated intact. Formation of the metabolite was not inhibited by monoamine oxidase inhibitors.8. Reserpine caused a small decrease in the uptake of adrenaline radioactivity in 1 h and a great increase in the proportion recovered as metabolite.9. Thrombin caused the release from platelets of intact adrenaline but not of the metabolite.10. Platelets of albino patients with spontaneous haemorrhages accumulated adrenaline radioactivity at the normal rate but this radioactivity was wholly accounted for by metabolite and not released by thrombin.11. After taking up adrenaline, platelets resuspended in artificial medium at 37 degrees C slowly released both adrenaline and its metabolite. At the same time, the intracellular adrenaline was slowly metabolized.12. The Result suggest that human platelets take up adrenaline by two processes, one of which is inhibited by both alpha- and beta-adrenoceptor blocking agents ad well as by phenothiazines; and that in the platelets adrenaline is partly stored in organelles from which, like 5-hydroxytryptamine, it can be specifically released.
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PMID:Uptake, metabolism and release of (3H)-adrenaline by human platelets. 548 50

1. Adenosine diphosphate (ADP) and adrenaline caused the aggregation of human platelets suspended in plasma containing citrate anticoagulant and stirred at 37 degrees C. The aggregation occurred in two phases and the second phase was associated with the appearance in the plasma of up to 30% of the ATP and 55% of the ADP present in the platelets. The concentration of ADP appearing in the plasma was up to 7 times the concentration added.2. Radioactivity was released by ADP and by adrenaline from platelets labelled with radioactive 5-hydroxytryptamine; this release was closely correlated with the second phase of aggregation and with the release of nucleotides.3. Acid phosphatase, beta-glucuronidase and adenylate kinase were released to a small extent during second phase aggregation by ADP or adrenaline; thrombin and collagen particles caused significantly greater release of beta-glucuronidase than of either acid phosphatase or of adenylate kinase.4. Morphological changes indicating degranulation of the platelets were observed during the second phase of aggregation produced by adrenaline and by ADP.5. The second phase of aggregation, degranulation of platelets, and the release of nucleotides, of labelled 5-hydroxytryptamine and of enzymes, were all inhibited by concentrations of amitriptyline which did not inhibit aggregation.
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PMID:The release of nucleotides, 5-hydroxytryptamine and enzymes from human blood platelets during aggregation. 564 42


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