Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both augmentation of thrombin activity and activation of platelets have been reported to accompany administration of plasminogen activators in vivo. To determine whether the platelet activation is a consequence or a cause of the procoagulant effects, we assessed the effects of t-PA on spontaneous activation and aggregation of platelets and on clotting in recalcified human whole blood. Spontaneous activation of platelets occurred in the stirred samples 8.9 +/- 2 minutes (n = 5) after recalcification. Aggregation and clotting followed immediately afterward. Activation, aggregation and clotting were accelerated in a dose-dependent manner by 3 minutes of preincubation with t-PA (2-30 micrograms/ml) before recalcification. The procoagulant effect of t-PA (5 micrograms/ml) was abolished by concomitant incubation with hirudin (0.5 nM) or aprotinin (200 KIU/ml) consistent with the hypothesis of plasmin-mediated evolution of thrombin being responsible for the procoagulant effect. However, platelets could be activated independently by other agonists (collagen, 3 micrograms/ml; and ADP, 25 microM) in the presence of hirudin. Despite the procoagulant effect of t-PA, aggregation to collagen (2-5 micrograms/ml) and PAF (0.9 microM) was diminished in samples incubated with t-PA for 30 minutes (37 degrees C). Fibrinogen degradation products elaborated during this interval (25.6 micrograms/ml; n = 3) were responsible for this anti-aggregatory effect. The results indicate that platelet activation in recalcified whole blood depends on procoagulant effects of t-PA.
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PMID:The dependence of activation of platelets by a plasminogen activator on the evolution of thrombin activity. 172 1

PAF and structural analogues were investigated for their in vivo effects on fibrinolytic activity (FA) in the rat. The i.v. administration of 1 and 4 micrograms/kg PAF caused a dose-dependent increase in FA which was shown to be attributable to the release of tissue-type plasminogen activator (t-PA). 1-O-hexadecyl-2-O-ethyl-glycero-3-phosphoric acid-2'-N-propargyl-N,N'- dimethylammoniumethyl ester (I) and 1-O-hexadecyl-2-(n-propyl)-propanediol-3-phosphocholine (II) increased FA according to their proaggregatory activity. In contrast, 1-O-hexadecyl-2-O-ethyl-rac-glycero-3-phosphoric acid-5'-trimethylammoniumpentyl ester (III), a competitive antagonist of PAF, reduced the PAF induced increase of FA by 30%. Under identical conditions BN 52021 given at 1 and 10 micrograms/kg amounts diminished the effect of PAF by 47 and 77%, respectively. These results indicate that the PAF induced PA release in vivo is receptor mediated.
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PMID:Effects of synthetic analogues of platelet-activating factor (PAF) on fibrinolytic activity in the rat. 315 Feb 68

Platelet-activating factor (PAF-acether; 1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) induced the release of plasminogen activator in rat, both in vivo and in perfused hind legs. The released plasminogen activator was shown by immunologic and functional criteria to be tissue-type plasminogen activator (t-PA). Release of t-PA by PAF-acether could be inhibited by phospholipase inhibitors and by lipoxygenase inhibitors, but not by cyclooxygenase inhibitors. It is suggested that PAF-acether induces the release of t-PA from vascular endothelial cells by the (calcium-dependent) activation of a phospholipase-lipoxygenase pathway.
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PMID:PAF-acether-induced release of tissue-type plasminogen activator from vessel walls. 392 44

Blood fibrinolytic activity is mediated by plasma and cellular components. We have studied blood fibrinolytic activity in different species and investigated the distribution pattern in rats after modulation with PAF, dexamethasone, or retinoic acid. Whole blood and plasma activity were measured in an assay system using human or endogenous fibrin as substrate. When human fibrin was used as substrate marked species differences in distribution of fibrinolytic activity were observed. In rat and murine blood most fibrinolytic activity was associated with the plasma fraction (70% and 50% respectively) while in human and canine blood the plasma fraction contained only 30% of the blood fibrinolytic activity. When endogenous fibrin was used as substrate the distribution pattern of fibrinolytic activity in rat blood changed dramatically. Less than 25% of the blood fibrinolytic activity was now present in the plasma fraction. The fbrinolytic system was further investigated in rats using specific inhibitors of proteolytic activity. Blood fibrinolytic activity could be inhibited for 33% by antibodies raised against t-PA and 60% inhibition was obtained in the presence of amiloride. No significant effect of elastinal (an inhibitor of elastase) could be detected. Plasma fibrinolytic activity was not affected by these inhibitors. The fibrinolytic activity in plasma could be enhanced about 100-fold after i.v. PAF administration (10 micrograms/kg). This extra fibrinolytic activity could be fully blocked by antibodies raised against t-PA. Oral administration of dexamethasone or retinoic acid affected blood fibrinolytic activity by modulating selectively the activity mediated by the cellular fraction. Dexamethasone treatment (1 mg/kg) resulted in a 59% decrease of this fibrinolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibrinolytic activity in blood is distributed over a cellular and the plasma fraction which can be modulated separately. 774 Apr 59

The modulation of the induced acute release of tissue-type plasminogen activator (t-PA) and of von Willebrand factor (vWF) by compounds affecting cyclic nucleotide levels was studied, using an isolated rat hindleg perfusion system. Platelet-activating factor (PAF; 5 nM) or bradykinin (0.8 microM) were used to induce release of t-PA and vWF. The guanylate cyclase activators sodium nitroprusside and atrial natriuretic factor reduced the induced release of t-PA and vWF. Release was not affected by inhibiting nitric oxide production with NG-nitro-L-arginine. The effects of nitroprusside and atrial natriuretic factor could not be reproduced by infusion of 8-bromo-cGMP. The adenylate cyclase activator forskolin had no effect on bradykinin-induced release of t-PA and vWF, reduced PAF-induced t-PA release, but potentiated PAF-induced vWF release. These modulatory effects were only partially mimicked by infusion of 8-bromo-cAMP. None of the compounds tested was able to induce the release of t-PA or of vWF in the absence of stimulation by bradykinin or platelet-activating factor. Cyclic nucleotides can thus modulate, but not induce, the acute release of t-PA and vWF from perfused rat hindlegs.
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PMID:The role of cyclic nucleotides in the release of tissue-type plasminogen activator and von Willebrand factor. 809 63

In health, the vascular endothelium forms a multifunctional interface between the circulating blood and various tissues and organs of the body. It constitutes a selectively permeable barrier for macromolecules, as well as a nonthrombogenic and nonadhesive container that actively maintains the fluidity of blood. It is a metabolically active endocrine organ, serving as the source of multiple factors and mediators that are critical for normal homeostasis. These include vasodilators (nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor), vasoconstrictors (endothelin-1, thromboxane A2, prostaglandin H2 and components of the renin angiotensin system), various pro- and antithrombotic factors (e.g. tissue factor, platelet activating factor--PAF, von Willebrand factor), fibrinolytic activators and inhibitors (e.g. tissue plasminogen activator, plasminogen activator inhibitor-1), potent arachidonate metabolites (prostanoids), leukocyte adhesion molecules (e.g. E-selectin, P-selectin, intercellular adhesion molecule-1--ICAM-1, vascular cell adhesion molecule-1--VCAM-1), and multiple cytokines with activities of growth stimulators and inhibitors, transforming growth factors, proinflammatory and antiinflammatory mediators, tumour necrosis factors and chemotactic factors (chemokines). Besides these essential activities controlling the cardiovascular system, the endothelial cells represent an important part of the immune system as well. They have a pivotal role in the initiation and development of defensive and damaging inflammatory responses. Therefore endothelium can be considered as being the central equipment for the mutual exchange of life important information between the cardiovascular and immune systems. This in turn is leading to rapid advances in understanding the pathogenesis of some of the most serious and most common diseases, including inflammation, atherosclerosis and hypertension. (Tab. 7, Ref. 89.)
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PMID:[Vascular endothelium as a factor in information transfer between the cardiovascular and immune systems]. 958 73

In this study, Charlton's and Tomihisa's methods were modified to investigate the thrombolytic effect of corilagin from the Chinese herbal plant Phyllanthus urinaria L., as well as its effect on carotid artery patency status. The activity of type 1 plasminogen activator inhibitor (PAI-1) in rat plasma or platelet-released substances and tissue-type plasminogen activator (tPA) in rat plasma was assayed by use of a chromogenic substrate. The results showed that corilagin had a dose-dependent thrombolytic effect in rats. 5 mg/kg of corilagin produced a nearly similar reperfusion rate to that of 20000 U/kg of urokinase, whereas it produced a lower reocclusion rate than urokinase. Corilagin significantly inhibited PAI-1 activity in rat plasma or platelet-released substances while it elevated plasma tPA activity, in a concentration-dependent manner. Corilagin, however, had no influence on rabbit platelet aggregation. It is indicated that corilagin inhibited PAI-1 activity and increased tPA activity, and this property of corilagin is assumed to be responsible for the thrombolytic effect. Abbreviations. PO:persistent occlusion CR:cyclic reflow PP:persistent patency PAI-1:type 1 plasminogen activator inhibitor tPA:tissue-type plasminogen activator PBS:phosphate buffer solution IC (50):50 % of inhibitory concentration PRP:platelet-rich plasma ADP:adenosine diphosphate AA:arachidonic acid PAF:platelet-activating factor
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PMID:Modulation of PAI-1 and tPA activity and thrombolytic effects of corilagin. 1475 26