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)

Mepacrine, papaverine, p-bromophenacyl bromide and 2,3-dibromo(4'-cyclohexyl-3'-chloro)-phenyl-4-oxo-butyric acid (CB 874) inhibit the hydrolysis of phospholipids induced by thrombin in dog platelets. They also exhibit anti-inflammatory and anti-aggregant properties. These biological activities may be explained by a direct or indirect inhibitory action on phospholipase A2. Phospholipase A2 inhibitors may block not only the release of arachidonic acid and its subsequent conversion into prostaglandins but also the formation of lysophospholipids involved in inflammation and/or platelet aggregation.
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PMID:Anti-inflammatory and platelet anti-aggregant activity of phospholipase-A2 inhibitors. 4 Oct 58

1 Gas chromatographic and radio-isotope labelling techniques have been used to establish the origin of the arachindonic acid used by the platelet cyclo-oxygenase for the synthesis of pro-aggregatory prostaglandin endoperoxide derivatives. 2 Measurements of total platelet arachidonate content indicated that more than 95% is esterified in the phosphatide fraction of the cells. 3 During aggregation by collagen or thrombin as much as 80% of the total platelet arachidonate may be liberated and transformed by the platelet enzymes into hydroxyacids and other more polar compounds. 4 The phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositol fractions are major sources of the arachidonate thus used. 5 Indomethacin, which prevents platelet aggregation by inhibiting the cyclo-oxygenase, did not affect this release of arachidonate from the phosphatides but did prevent the transformation of arachidonate to endoperoxide derivatives. 6 Mepacrine, a drug which possesses weak anti-phospholipase activity in platelets, also prevents aggregation by collagen or thrombin, but seems to do so by preventing substrate release from the phosphatide fraction. 7 It is suggested that phospholipase A2 plays a key role in the initial events during platelet aggregation induced by collagen.
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PMID:The distribution and metabolism of arachidonic acid in rabbit platelets during aggregation and its modification by drugs. 83 23

A potent platelet aggregation inducer was purified from Calloselasma rhodostoma snake venom by Sephadex G-75, CM-Sephadex C-50 and Sephacryl S-300 column chromatography. It was homogeneous as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, with a molecular weight estimated to be 28,160 +/- 1280. It was devoid of phospholipase A2, fibrino(geno)lytic and thrombin-like activities. The venom inducer elicited platelet aggregation and the serotonin release reaction in rabbit platelet-rich plasma and platelet suspension. Exogenous calcium was required for its platelet activation. Creatine phosphate/creatine phosphokinase and indomethacin did not inhibit the venom inducer-induced aggregation and release reaction. Mepacrine and verapamil preferentially inhibited aggregation, while PGE1 completely blocked both aggregation and release reaction. It is concluded that the venom inducer activates platelets through the activation of endogenous phospholipase A2 or C, leading to intracellular calcium mobilization, but independent of the ADP release reaction or thromboxane A2 formation.
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PMID:Purification and characterization of a platelet aggregation inducer from Calloselasma rhodostoma (Malayan pit viper) snake venom. 377 83

Addition of thrombin to human platelets results in production of lysophosphatidic acid. Such synthesis of lysophosphatidic acid can be inhibited by mepacrine, an inhibitor of the phospholipase A2 which attacks phosphatidic acid to give lysophosphatidic acid. In the present study, mepacrine was used at a concentration of 2.5-20 microM, sufficient to block aggregation and lysophosphatidic acid formation induced by 0.1 U/ml thrombin. Mepacrine, at this concentration, also blocked thrombin-induced phosphorylation of platelet myosin light chain and a 47 kDa protein, thrombin-induced secretion and thrombin-induced release of arachidonic acid from platelet phospholipids. However, mepacrine also partly inhibited the formation of phosphatidic acid in response to thrombin, consistent with some simultaneous inhibition of phospholipase C. Lysophosphatidic acid (2.5-22 microM) overcame the mepacrine block in thrombin-stimulated aggregation, protein phosphorylation and secretion without stimulating the release of arachidonic acid from platelet phospholipids or the formation of lysophosphatidic acid, and only slightly increasing phosphatidic acid formation. The results suggest that lysophosphatidic acid primarily acts distal to mepacrine inhibition of phospholipase A2 and phospholipase C and are consistent with the possibility that lysophosphatidic acid might be a mediator of part of the effects of low-dose thrombin on human platelets.
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PMID:Mepacrine (quinacrine) inhibition of thrombin-induced platelet responses can be overcome by lysophosphatidic acid. 393 92

Palmitaldehyde acetal phosphatidic acid ( PGAP ) caused dose-dependent aggregation of human platelets resuspended in modified Tyrode medium, with a threshold concentration of 0.5-1 microM and an EC50 of 4 microM. Concentrations of PGAP which elicited biphasic irreversible aggregation concomitantly induced formation of 1.02 +/- 0.029 nmol (mean +/- s.e. mean) of malondialdehyde (MDA) per 10(9) platelets and caused release of 58 +/- 2.8% of platelet [14C]-5-hydroxytryptamine ([14C]-5-HT) from prelabelled platelets; no MDA formation or [14C]-5-HT release occurred at lower doses of PGAP which elicited only monophasic reversible aggregation. Adenosine 5'-pyrophosphate (ADP)-induced platelet activation resulted in formation of 0.344 +/- 0.004 nmol of MDA per 10(9) platelets in association with irreversible aggregation and 49.1 +/- 1% release of [14C]-5-HT. Mepacrine, a phospholipase A2 inhibitor, at 2.5 microM reduced PGAP -induced MDA formation and [14C]-5-HT release by the resuspended platelets without affecting irreversible aggregation; higher concentrations of mepacrine abolished all three responses. Chlorpromazine, a calmodulin antagonist, similarly inhibited PGAP -induced MDA formation and irreversible aggregation, and at 100 microM abolished monophasic aggregation. The cyclo-oxygenase inhibitor indomethacin caused a concentration-dependent reduction of PGAP -induced MDA formation by resuspended human platelets without significantly inhibiting [14C]-5-HT release or irreversible aggregation; concentrations (greater than or equal to 1.75 microM) which inhibited MDA formation by more than 94% abolished [14C]-5-HT release, and converted second phase irreversible aggregation to an extensive reversible response. 2-Methylthioadenosine 5'-phosphate (2 methylthio-AMP), an ADP antagonist, inhibited PGAP -induced MDA formation, [14C]-5-HT release and second phase aggregation in the human platelet suspensions in a parallel, concentration-dependent manner; at 9.4 microM 2-methylthio-AMP, both MDA formation and [14C]-5-HT release were abolished and monophasic, reversible aggregation remained. Albumin was required for aggregation of washed human platelets to PGAP . Irreversible PGAP -induced aggregation of washed [14C]-arachidonate-labelled platelets was accompanied by a low net loss of 14C from platelet phospholipids, an equivalent increase in 14C in free fatty acids, and the appearance of 14C in thromboxane (Tx)B2; mepacrine reduced the loss in 14C from phospholipids and inhibited aggregation and formation of [14C]-TxA2. Thrombin-induced aggregation was accompanied by substantial loss of 14C from phospholipids and equivalent gains of 14C in free fatty acids and TxB2; mepacrine pretreatment caused partial inhibition of thrombin-induced aggregation, halved the net 14C loss from phospholipids, but had little effect on the appearance of 14C in TxB2. 6 It is concluded that in human platelets PGAP-induced dense granule release and irreversible aggregation are dependent on the liberation of arachidonate and its metabolism via prostaglandin endoperoxides to thromboxane, that PGAP and thrombin elicit mobilization of arachidonate from different pools of membrane phospholipids, and that the mechanism of PGAP-activation of human platelets differs from those of thrombin- and ADP-activation.
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PMID:Arachidonate metabolism, 5-hydroxytryptamine release and aggregation in human platelets activated by palmitaldehyde acetal phosphatidic acid. 642

Lipolytic factors associated with myocardial ischemia and factors which activate phospholipase A2 in cells other than heart cells were tested for their actions on the rhythmicity of cultured heart cells. Exogenous triglyceride lipase was without a significant effect on beating while phospholipase A2 produced concentration-related arrhythmias in concentrations as low as 0.0375 U/ml. Quinacrine, a phospholipase inhibitor, demonstrated concentration-dependent inhibition of reoxygenation-induced arrhythmias. Of the compounds known to activate phospholipase only kallikrein and thrombin produced arrhythmias; only bradykinin, thrombin and trypsin depressed beating. Lysophosphatidylcholine, a reaction product of phospholipase A2 on phospholipids, inhibited reoxygenation arrhythmias in a concentration-dependent manner.
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PMID:Arrhythmogenic and antiarrhythmic effects of lipolytic factors on cultured heart cells. 663 27

The mechanism of vasoactive agents on plasminogen activator (PA) release was studied in isolated perfused pig ears. In the perfusion with atropine (3 microM)-containing Tyrode's solution, the enhancement of PA release caused by acetylcholine (1.0 micrograms) was completely inhibited; however, increases caused by other potentiators, namely, bradykinin (1.0 micrograms), histamine (1.0 micrograms), dilazep (30 micrograms), and thrombin (6 U) were not affected. In the case of mepyramine (10 microM), the increase of PA release caused by histamine (1.0 micrograms) was completely inhibited; and that caused by dilazep (30 micrograms) was partially inhibited, however, increases caused by acetylcholine, bradykinin, and thrombin were not influenced. Papaverine (30 microM) which could completely abolish the hypertensive effect of norepinephrine (1.0 micrograms) exerted a partial inhibition of the enhancement of PA release caused by dilazep; however, it did not affect those caused by other agents. Quinacrine (50 microM) and indomethacin (100 microM) did not have any effects on the enhancements of PA release caused by the five potentiators.
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PMID:A possible mechanism of vasoactive agents on plasminogen activator release in isolated perfused pig ears. 668 79

Human platelets appear to accumulate quinacrine both in a thrombin-releasable compartment (dense bodies or amine storage vesicles) and in another compartment from which it is released by agents known to collapse pH gradients (possibly lysosomes with an acidic interior). Approximately 61% of the total amount of quinacrine present in human platelets resides in dense bodies and 14+ in lysosomes, with the remainder probably present in the cytoplasm. Other basic amines are accumulated in the three compartments to widely varying extents, suggesting that several factors besides the existence of pH gradients act to determine the distribution of these substances within the cell. The fluorescence emission of quinacrine excited with 420 nm light is completely quenched for quinacrine inside both dense bodies and lysosomes, and the absorption of 440 nm light is decreased by approximately 25%. Quinacrine added to dense bodies at 37 degrees C induces the efflux of 5-hydroxytryptamine (5HT) from the bodies. There is, however, no 5HT loss following quinacrine entry at 0 degree C, and the relationship between the two types of amine movement varies according to incubation time at 0 degree C and 37 degrees C. This action of quinacrine therefore does not appear to be associated with stoichiometric exchange of 5HT and quinacrine, but rather to modulation of the passive permeability of the dense body membrane for 5HT.
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PMID:Quinacrine and basic amines in human platelets: subcellular compartmentation and effects on serotonin. 670 2

In stimulated platelets phosphatidylinositol is degraded by a phosphatidylinositol-specific phospholipase C to 1,2-diacylglycerol which is then phosphorylated to phosphatidic acid. Thrombin stimulation of horse and human platelets prelabeled with [32P]orthophosphate induces the formation of [32P]lysophosphatidylinositol, suggesting that phosphatidylinositol is also degraded by a phospholipase of A type activity. Stimulation of platelets prelabeled with 32P or with 32P plus [3H]inositol produces a lysophosphatidylinositol which has a 32P-specific activity and a 3H/32P ratio which has a 32P-specific activity and a 3H/32P ratio identical with those of phosphatidylinositol. These results suggest that the lysophosphatidylinositol derives from phosphatidylinositol. Thrombin stimulation of platelets double label with 32P and [3H]arachidonate induces loss of [3H]arachidonate from phosphatidylinositol and formation of [32P]lysophosphatidylinositol, suggesting the involvement of a phospholipase A2 activity. Ionophore A23187 also induces the formation of lysophosphatidylinositol in horse and human platelets. With either stimulus, [32P]lysophosphatidylinositol appears within seconds after stimulation and parallels the loss of [3H]arachidonic acid from phosphatidylinositol. The lysophosphatidylinositol produced by thrombin or by ionophore A23187 represents 40% of the degraded phosphatidylinositol as assessed by lipid phosphorus. Quinacrine, which inhibits the liberation of arachidonic acid from phospholipids, also blocks the formation of lysophosphatidylinositol. The results presented here indicate that phosphatidylinositol is degraded by both phospholipases, C and A2, in stimulated platelets.
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PMID:Formation of lysophosphatidylinositol in platelets stimulated with thrombin or ionophore A23187. 680 48

We have examined whether inhibition by mepacrine or freeing of arachidonic acid from platelet phospholipids inhibits platelet aggregation to collagen, thrombin or ADP, and the release reaction induced by thrombin or collagen. Loss of arachidonic acid was monitored by measuring the amount of 14C feed from platelets prelabelled with 14C-arachidonic acid. Mepacrine inhibited 14C loss by more than 80% but did not inhibit thrombin-induced platelet aggregation and had a small effect on release. ADP-induced platelet aggregation did not cause 14C loss. Mepacrine inhibited ADP-induced platelet aggregation by inhibiting the association of fibrinogen with platelets during aggregation. The effect of mepacrine on fibrinogen binding could be considerably decreased by washing the platelets but the inhibition of 14C loss persisted. Platelets pretreated with mepacrine and then washed show restoration of aggregation to collagen. Thus, mepacrine has two effects; 1. it inhibits phospholipases, 2. it inhibits fibrinogen binding. Freeing of arachidonic acid is not necessary for platelet aggregation or the release reaction.
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PMID:The effect of phospholipase inhibitor mepacrine on platelet aggregation, the platelet release reaction and fibrinogen binding to the platelet surface. 728 Nov 5


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