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)

Four chemically distinct PAF-acether antagonists were used to test the hypothesis that the cyclooxygenase and ADP-independent thrombin-induced aggregation of human platelets is due to PAF-acether. The compounds 48740 RP, CV-3988, BN 52021 and Ro 19-3704 inhibited aggregation by PAF-acether whereas 48740 RP also interfered with aggregation by arachidonic acid, U 46619, collagen and thrombin. Aspirin-treated platelets aggregated in response to PAF-acether and to 0.25 U/ml thrombin as much as control platelets in absence of detectable thromboxane A2, and were less responsive to 0.05-0.1 U/ml. Thrombin-induced aggregation of aspirin-treated platelets was unaffected by the PAF-acether antagonists BN 52021, CV-3988 and Ro 19-3704. In separate experiments, platelets were exposed for five min to convulxin, a glycoprotein extracted from a snake venom, which depletes granular ADP and ATP. A combination of PGI2, aspirin and anticrotalid serum used to disaggregate allowed the recovery of approximately 80% free platelets, which failed to respond to PAF-acether, but still aggregated in presence of thrombin. This residual ADP and cyclooxygenase-independent aggregation is not accountable for by the platelet formation of PAF-acether, since it was not modified by the latters' antagonists nor by platelet exposure to convulxin. Our results do not support the proposal that PAF-acether mediates a third pathway of human platelet aggregation.
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PMID:Antagonists of PAF-acether do not suppress thrombin-induced aggregation of ADP-deprived and aspirin-treated human platelets. 311 70

Ethanol, at physiologically tolerable concentrations, did not affect the primary phase of ADP-induced aggregation of human or rabbit platelets, which is not associated with the secretion of granule contents. Potentiation by epinephrine of the primary phase of ADP-induced aggregation of rabbit platelets was also not inhibited by ethanol. However, ethanol did inhibit the secondary phase of ADP-induced aggregation which occurs with human platelets in citrated platelet-rich plasma and is dependent on the formation of thromboxane A2. Inhibition by ethanol of thromboxane production by stimulated platelets is likely due to inhibition of the mobilization of arachidonic acid from membrane phospholipids, as ethanol had little or no effect on aggregation and secretion induced by arachidonic acid or the thromboxane mimetic U46619. Rabbit platelet aggregation and secretion in response to low concentrations of collagen, thrombin, or PAF were inhibited by ethanol. Inhibition of the effects of thrombin and PAF was also observed with aspirin-treated platelets. Thus, in addition to inhibiting the mobilization of arachidonate for thromboxane formation that occurs with most agonists, ethanol can also inhibit aggregation and secretion through other effects on platelet responses.
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PMID:Effects of ethanol on pathways of platelet aggregation in vitro. 314 75

Changes in intracellular Ca2+ concentrations [( Ca2+]i) in platelets stimulated with aggregating agents were measured with the fluorescent indicator dye quin 2. Ca2+ influx, but not intracellular mobilization, in response to adenosine diphosphate (ADP), platelet aggregating factor (PAF-acether), and sodium arachidonate was significantly inhibited by monoclonal antibodies against the glycoprotein (GP) IIb-IIIa complex; inhibition of thrombin-stimulated influx was inhibited to a lesser extent and reached statistical significance only at thrombin concentrations of 0.1 U/mL and below. Anti-GP Ib and HLA-ABC monoclonal antibodies had no effect on Ca2+ influx in response to any agonist. Thrombasthenic platelets gave normal [Ca2+]i responses to ADP and thrombin, which were not inhibited by an anti-GP IIb-IIIa antibody. It is suggested that Ca2+ influx in response to weak agonists occurs predominantly via a channel closely adjacent to the GP IIb-IIIa complex, but that higher concentrations of thrombin and A23187 also stimulate influx via another pathway.
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PMID:Glycoprotein IIb-IIIa complex and Ca2+ influx into stimulated platelets. 316 63

Manoalide (MND), a sesterterpenoid first isolated from the marine sponge Luffariela variabilis and later synthesized by Japanese chemists, exhibits anti-inflammatory activity and directly inactivates bee and snake venom phospholipase A2. We investigated the effects of MND on platelet aggregation induced by PAF-acether, arachidonic acid (AA), ADP and thrombin. Rabbit platelet aggregation was inhibited by MND in a dose-dependent manner. MND also inhibited the aggregation induced by AA and ADP but not that induced by thrombin. Since this marine natural product is also a potent inhibitor of lipoxygenase in human polymorphonuclear neutrophils, MND appears to be a useful tool for determining the role of phospholipase A2 in biological processes.
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PMID:Inhibition of platelet aggregation by manoalide: preliminary results. 320 66

The anti-aggregatory effect of endothelium-derived relaxing factor (EDRF) on aggregation of washed, aspirin-treated platelets was compared with that of nitric oxide. Nitric oxide produced a dose-dependent inhibitory effect on PAF-induced aggregation: the antiaggregatory activity was unstable and was completely preventable by pretreating the platelets with haemoglobin (10 mumol/l). Bovine aortic endothelial cells (EC) were grown to confluence on microcarrier beads, pretreated with aspirin (1 mmol/l), and their addition to the platelet cuvette also caused a dose-dependent inhibition of aggregation induced by PAF, thrombin and A23187. The inhibitory effect of the EC on platelet aggregation was partly prevented in the presence of haemoglobin (10 mumol/l). Both nitric oxide and EC showed synergy with prostacyclin, in that the latter potentiated the anti-aggregatory action of both these factors against PAF-induced platelet aggregation. Thus cultured endothelial cells release a non-prostanoid anti-aggregatory factor, which, like nitric oxide, shows a synergistic interaction with prostacyclin and is blocked by haemoglobin. This anti-aggregatory factor has the characteristics of EDRF.
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PMID:Synergistic inhibition of platelet aggregation by endothelium-derived relaxing factor and prostacyclin. 328 74

Platelet aggregation induced by three thrombin-like enzymes of snake venoms was compared with that by thrombin. Acutin was isolated from Agkistrodon acutus venom and thrombocytin and batroxobin were from Bothrops atrox venom. The fibrinogen-clotting activities were 700, 170 and 7 U/mg for batroxobin, acutin and thrombocytin, respectively. They induced aggregation and ATP release of washed rabbit platelets. The aggregating activity of thrombin was 10(2), 10(4) and 10(5) times more potent than those of thrombocytin, acutin and batroxobin, respectively. Platelet-activating potency of the thrombin-like enzymes was correlated with their effectiveness on the retractility and elasticity of the clots. Platelet aggregation induced by thrombin or thrombocytin could be inhibited by heparin with antithrombin III while that by acutin or batroxobin could not. Indomethacin showed weak inhibition on the aggregation while the ADP-scavenging system, creatine phosphate/creatine phosphokinase, inhibited the aggregation induced by the three thrombin-like enzymes but not that by thrombin. Platelet aggregation induced by the thrombin-like enzymes could not be inhibited by PAF antagonists-BN 52021, kadsurenone or L-652,731. In the presence of EGTA, only thrombin could induce ATP release from platelets. Thrombin-like enzymes and low concentration of thrombin did not form thromboxane B2. Nitroprusside and prostaglandin E1 completely inhibited the aggregation, mepacrine and imipramine showed marked inhibition while verapamil had only weak inhibition. It is concluded that the aggregation induced by the thrombin-like enzymes is different from that of thrombin and mainly due to ADP released from platelets.
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PMID:Comparison of the platelet aggregation induced by three thrombin-like enzymes of snake venoms and thrombin. 329 Nov 84

Acetylhydrolase, the enzyme which inactivates platelet-activating factor (PAF, 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine), was selectively released from bovine platelets by aggregation with physiological concentrations (0.1-10 nM) of PAF with no cell lysis. The release of the acetylhydrolase paralleled that of serotonin. The acetylhydrolase released was active over a broad pH range (pH 5.4-8.6) and was not affected by Ca2+ (1-4 mM) or EDTA (1-8 mM). The Km value of the enzyme was 4.6 microM. Net specific acetylhydrolase activity recovered in the 130,000 x g supernatant after stimulation with PAF could be determined in the presence of EDTA without the activity of Ca2+-dependent phospholipase A2 which was also released from the cells at the same concentration of PAF. The acetylhydrolase was inhibited competitively by specific PAF antagonists, rac-3-(N-n-octadecylcarbamoyloxy)-2-methyoxypropyl-2-thiazolioe thyl phosphate (CV-3988) and (2RS)-1-O-hexadecyl-2-O-ethyl-3-O-(7-thiazolinoheptyl)-glycerol methanesulfonate (ONO-6040). Their Ki values for the enzyme were 1.17 microM and 0.84 microM, respectively. The release of the enzyme could also be detected when the platelets were aggregated with ADP (2.3 microM) or thrombin (0.5 unit). These results suggest that the enzyme released from the aggregated platelets to the blood plasma may also have a physiological function cooperating with the plasma acetylhydrolase.
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PMID:Release of acetylhydrolase from platelets on aggregation with platelet-activating factor. 334 57

Activated platelets adopt a characteristic spiculate morphology. A wide variety of anionic and zwitterionic amphipathic compounds were found to effect a similar shape change and to cause the open canalicular system to become less prominent. Several cationic amphipaths reversed thrombin-, PAF-, and amphipath-induced spiculation and restored the discoid shape. Higher concentrations of cationic amphipaths caused the cells to assume spheroid and indented forms, and caused the canalicular system to appear more prominent. Three amphipaths were studied further to address possible mechanisms underlying their morphological effects. Dilauroylphosphatidylcholine was found to induce spiculation without causing the changes in protein phosphorylation and inositide metabolism generally associated with platelet activation. Two other amphipaths, chlorpromazine (which induced sphering) and dilauroylphosphatidylserine (which caused spiculation followed by sphering) caused specific changes in protein and/or lipid phosphorylation, which may be responsible for some, but not all, of the morphological effects of these compounds. To account for these findings, we propose that platelet shape can be influenced by changes in the plasma membrane bilayer balance. Agents that bind to the membrane outer monolayer are accommodated by spiculation; those that bind to the inner monolayer are accommodated by sphering.
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PMID:Membrane bilayer balance and platelet shape: morphological and biochemical responses to amphipathic compounds. 335 15

In a medium containing 1 mM extracellular Ca2+ (Ca2+o), the prior addition of 0.5 microM adrenaline to quin 2-loaded human platelets increased both the rate and amplitude of the rise in cytosolic free Ca2+ (Ca2+i) in response to sub-threshold concentrations of thrombin and PAF and these effects were not prevented by blocking either fibrinogen binding and aggregation or cyclo-oxygenase. In the presence of 2 mM EGTA [( Ca2+o] less than 100 nM), the rate, but not the extent of rise of [Ca2+i] was enhanced by adrenaline, and this was also unaffected by blockade of cyclo-oxygenase. Addition of adrenaline 1 min after the other agonist in the presence of 1 mM Ca2+o resulted in aggregation without further elevation of [Ca2+i]. Adrenaline thus enhances both influx and intracellular mobilization of Ca2+ by a mechanism independent of both fibrinogen binding and thromboxane production, but these effects do not fully explain its potentiation of aggregation by other agonists.
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PMID:Potentiation by adrenaline of Ca2+ influx and mobilization in stimulated human platelets: dissociation from thromboxane generation and aggregation. 338 94

The effect of platelet-activating factor (PAF-acether) on cytosolic free calcium, [Ca2+]i, in adherent human vascular endothelial cells in culture was directly determined using a new fluorescent calcium indicator, fura-2. It was found that PAF-acether but not lyso PAF-acether induced a rapid and transient increase in [Ca2+]i in endothelial cells. Restimulation with PAF-acether after the first challenge did not cause further response, while the cells were able to respond to thrombin. In the absence of extracellular calcium, PAF-acether evoked a similar transient increase, suggesting that PAF-acether raises [Ca2+]i mainly by discharging calcium from intracellular pools. PAF-acether-induced rise in [Ca2+]i was completely blocked by a specific antagonist, BN 52021. These results suggest the receptor-mediated increase in [Ca2+]i as an early event in PAF-acether activation of human vascular endothelial cells.
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PMID:Transient increase of cytosolic free calcium in cultured human vascular endothelial cells by platelet-activating factor. 340 4


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