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)

Aggregation and serotonin secretion were studied in washed rat platelets after oral administration of ticlopidine or its more potent analog PCR 4099. Besides a complete suppression of the ADP-induced aggregation, the two drugs significantly inhibited aggregation and secretion induced by three protein kinase C activators (1-oleoyl-2-acetyl-sn-glycerol, OAG; 12-0-tetradecanoyl phorbol-13-acetate, TPA; phospholipase C), by the calcium ionophore A 23187 and by thrombin. The highest inhibition was observed at low stimuli concentrations but could be partly or almost completely overcome by increasing their concentrations. The combination of aspirin (ASA) with the ADP scavenging system, creatine phosphate/creatine phosphokinase (CP/CPK) in vitro resulted in an inhibition similar to that observed ex vivo after ticlopidine or PCR 4099 treatment. Moreover, these in vitro and ex vivo treatments were not additive. As identical results were obtained with CP/CPK alone but not with ASA, it is concluded that ticlopidine and PCR 4099 do not interfere with protein kinase C or calcium movements but specifically inhibit the effects of released ADP, which might explain the broad spectrum anti-platelet activity of these drugs.
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PMID:Broad spectrum anti-platelet activity of ticlopidine and PCR 4099 involves the suppression of the effects of released ADP. 312 24

Induction of hypercholesterolemia in rats by diets containing milk fat, cholesterol and taurocholate caused increased sensitivity of platelets to thrombin-induced aggregation and release, but not to ADP- or collagen-induced aggregation or release. This hypersensitivity to thrombin persisted in the presence of CP/CPK to convert released ADP to ATP, and aspirin to block formation of thromboxane A2. The increased sensitivity of platelets to thrombin in hypercholesterolemic animals was associated with an increase in 18:1 omega 9, 18:2 omega 6 and 20:3 omega 6 and a decrease in 20:4 omega 6 and 22:4 omega 6 in their phospholipids. Hypercholesterolemic animals also had a shortened platelet survival that did not appear to be due to an alteration in the lipid composition of the platelets. The diet-induced changes in platelet function were not associated with enhanced thrombosis in animals with indwelling aortic catheters, but were associated with increased platelet accumulation on the exposed subendothelium.
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PMID:The effect of dietary saturated fat and cholesterol on platelet function, platelet survival and response to continuous aortic injury in rats. 360 33

A monoclonal anti-human platelet antibody, TP82, is described, which caused irreversible aggregation of platelets in association with the release of adenosine triphosphate or [14C] serotonin, and which inhibited ristocetin-induced agglutination. Immunofluorescence assay showed that the antibody binds to platelets, megakaryocytes, and common acute lymphoblastic leukemia cells. The antibody (IgG1) immunoprecipitated a polypeptide of 23,000 daltons with an isoelectric point of about 7.0. The aggregation induced by the purified antibody and/or F(ab')2 fragments occurred in platelet-rich plasma and with washed platelets, but not with formalin-fixed washed platelets. TP82-induced aggregation was completely inhibited by disodium ethylendiaminotetraacetate, diltiazem, W-7, PGE1, and several metabolic inhibitors. At a concentration of apyrase or CP/CPK, which inhibited adenosine 5-diphosphate-induced aggregation. TP82-induced aggregation was only partially affected. Thrombin was not required for the antibody-mediated effects, since two thrombin inhibitors failed to block the reaction. The antibody, at least at a high concentration, induced platelet aggregation by a mechanism almost independent of thromboxane A2 formation, since cyclooxygenase inhibitors had little inhibitory effect on aggregation. TP82 monoclonal antibody is a new platelet-aggregating substance that interacts with a low-molecular-weight binding site on the platelet membrane.
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PMID:A monoclonal anti-human platelet antibody: a new platelet aggregating substance. 396 86

XC386 was a new antiplatelet compound, which inhibited the aggregation and release reaction of rat platelet-rich plasma induced by collagen. This inhibition was dose-dependent and the IC50 was calculated to be 1 mM on collagen-induced aggregation. In washed platelets, the aggregations induced by ADP and collagen were much more markedly inhibited by XC386 than those induced by thrombin, A23187 and arachidonate. High calcium (4 to 8 mM) could not antagonize the inhibition. XC386 did not alter the malondialdehyde (MDA) and thromboxane B2 (TXB2) levels of resting platelets. But MDA formation induced by collagen, thrombin and A23187, and TXB2 formation induced by collagen and thrombin were significantly inhibited, while both formations induced by arachidonate were not changed. Combination of indomethacin or CP/CPK and XC386 enhanced markedly the inhibitory effect of XC386 on collagen- or A23187-induced aggregation. It was concluded that XC386 might inhibit platelet aggregation before the step of arachidonic acid release by phospholipase A2.
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PMID:XC 386: a new antiplatelet agent. 643 27

AGEPC (PAF), at 1.9 x 10(-8) M or higher, induced concentration-dependent aggregation and release in human platelet-rich plasma. Comparative studies with arachidonate, collagen, ionophore, and ADP suggested that AGEPC was a strong stimulus for platelet aggregation and probably a moderate agonist for release, as well as a relatively weak inducer of TXA2 production. The initial phase of AGEPC-induced aggregation was independent of ADP release and TXA2 formation, since it was not inhibited by ASA, apyrase, or CP/CPK. Whereas irreversible aggregation always required ADP release, TXA2 formation was not essential in each instance. Thus, in several experiments, full aggregation responses took place in AGEPC-stimulated platelets that had been pretreated with ASA. AGEPC-induced release of 5-HT, beta -thromboglobulin and PF-4 occurred in parallel and were inhibited by both apyrase and ASA. Washed human platelets did not respond to exogenous AGEPC in the absence of ADP and did not appear to generate significant quantities of AGEPC upon stimulation with thrombin or ionophore.
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PMID:Effects of acetyl glyceryl ether phosphorylcholine on human platelet function in vitro. 645 58

Capsaicin was found to be a potent inhibitor of platelet aggregation and release reaction. It inhibited the aggregation of rat platelet induced by collagen and thrombin, but only slightly reduced those of AA and A23187. The IC50 on collagen-induced platelet aggregation was about 85 micrograms/ml. Less inhibition was observed in the aggregation of platelet-rich plasma. Increase of the calcium concentration could not overcome the inhibitory effect. Washing of the capsaicin-pretreated platelets only partially reversed the inhibition. Capsaicin also inhibited ATP release induced by thrombin and A23187 in the presence of EDTA. MDA and TXB2 formation were markedly inhibited by capsaicin in platelets challenged by collagen, thrombin and A23187. In AA-stimulated platelets, MDA formation was slightly decreased and TXB2 formation was not affected. Capsaicin showed more marked inhibition in the presence of CP/CPK, indomethacin or a combination of both. Capsaicin reduced the hemolysis of RBCs induced by hydrogen peroxide or hypotonicity. It was concluded that capsaicin had some membrane stabilizing property and this might lead to the interference of the activation of phospholipase A2.
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PMID:Antiplatelet effect of capsaicin. 652 10

Platelet scintigraphy with radioactive indium-111 may be used both to identify and to reflect the activity of thrombin in vivo in man. Forty-one patients with acute myocardial infarction were studied for active left ventricular thrombosis by platelet scintigraphy and followed until in-hospital death, discharge, or same-admission cardiac surgery for evidence of systemic embolization. A total of 4.7 +/- 2.4 X 10(9) platelets (mean +/- 1 SD) labelled with 381 mu Ci +/- 51 mu Ci of indium-111 was injected intravenously at 91 +/- 88 hours following the onset of chest pain. Patients were imaged in multiple views on the day of and three to four days after injection of the platelet suspension. Group 1 (n = 29) had transmural myocardial infarctions, of which 21 were anterior (peak total level of creatine phosphokinase [CPK], 2,272 +/- 2,026 IU; mean +/- 1 SD) and eight were inferior (CPK level, 1,673 +/- 589 IU). Group 2 (n = 12) had subendocardial myocardial infarctions (CPK level 799 +/- 751 IU). Those with subendocardial and transmural inferior myocardial infarctions had neither left ventricular thrombosis nor emboli. Ten (48 percent) of 21 with anterior transmural myocardial infarctions had left ventricular thrombosis by platelet scintigraphy. Three with and one without such thrombosis by scintigraphy had acute neurologic episodes. In the group with anterior myocardial infarctions, seven of ten patients with and four of 11 without left ventricular thrombosis received heparin subcutaneously (chi 2 = 1.22 [Yates correction]; p greater than 0.30). We conclude that platelet scintigraphy may be used to monitor antiplatelet and anticoagulant therapy in patients with anterior transmural myocardial infarctions who are at risk for left ventricular thrombosis and systemic embolization.
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PMID:Detection of active left ventricular thrombosis during acute myocardial infarction using indium-111 platelet scintigraphy. 673 89

The observation that platelet secretion occurs in parallel with the second wave of platelet aggregation necessitates reassessment of the generally accepted concept that secreted ADP is the cause of second-wave aggregation. The major evidence for an involvement of secreted ADP is inhibition of second-wave aggregation by enzyme-catalyzed removal of ADP, interpreted as removal of secreted ADP. An alternative hypotheses, that the observed inhibition is due to a decrease in potentiation by extracellular ADP present prior to addition of stimulus, has been tested with the enzyme system CP plus CPK (CP/CPK). Low levels of CP/CPK inhibited gamma-thrombin-induced second-wave aggregation only after preincubation. When the second wave of gamma-thrombin- or epinephrine-induced aggregation was inhibited by very high levels of CP/CPK, the inhibition was overcome by an increase in the level of stimulus. These results are inconsistent with the idea that CP/CPK blocks second-wave aggregation by removing secreted ADP, but they are consistent with a decreased potentiation of the platelets due to a lower level of extracellular ADP prior to stimulation. Freshly prepared platelet-rich plasma contained a mean (n = 16) of 12 nM extracellular ADP. These data demonstrate that inhibition by CP/CPK cannot be taken as evidence for the involvement of secreted ADP.
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PMID:Reassessment of the evidence for the role of secreted ADP in biphasic platelet aggregation. Mechanism of inhibition by creatine phosphate plus creatine phosphokinase. 735 Feb 41

Thrombin and adenosine diphosphate (ADP) supported the binding of 125I-fibrinogen to washed human platelets with similar kinetics and affinity. Platelet secretion, as measured by 14C-serotonin release, and fibrinogen binding exhibited an identical dependence on thrombin concentration. Enzymatic removal of ADP with apyrase or creatine phosphate/creatine phosphokinase (CP/CPK) from thrombin-stimulated platelets markedly inhibited 125I-fibrinogen binding, but pretreatment of platelets with CP/CPK prior to thrombin stimulation was without effect. Thus, ADP, released from the platelet, participates in the binding of fibrinogen to thrombin-stimulated platelets.
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PMID:Participation of ADP in the binding of fibrinogen to thrombin-stimulated platelets. 740 18

A platelet activating factor from earthworm, Eisenia foelide (EPAF, 25.9 mumol.L-1), induced human platelet aggregation and 5-HT (maximal release of 89% at EPAF 74.1 mumol.L-1) was detected during this process. Neither creatine phosphate/creatine phosphate kinase (CP/CPK) nor aspirin completely inhibited the EPAF-induced platelet aggregation. In the presence of fibrinogen, EPAF (55.6 mumol.L-1) induced the aggregation of human platelet which had been thrombin-treated and degranulated. Results indicated that EPAF was a potent platelet agonist and the EPAF-induced platelet aggregation was ADP- and TXA2-independent.
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PMID:Platelet activation by platelet aggregation factor from Eisenia foelide. 771 70


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