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)

The effects of water immersion restraint stress on collagen-induced platelet aggregation in whole blood, and on the fibrinolytic and serotonergic systems in rats have been studied. One hour long stress caused a release of tissue plasminogen activator (tPA) into the blood and a shortening of euglobulin clot lysis time (ECLT), whereas restraint of longer duration was responsible for a reduction in platelet aggregation, an elevation in the activity of plasminogen activator inhibitor with a concomitant fall in tPA and a prolongation of ECLT relative to controls. Whole-blood and plasma serotonin and its metabolite 5-hydroxyindoleacetic acid were also higher in the stressed rats and whole-blood serotonin level showed a negative correlation with tPA in the stressed rats. Either stress and/or its duration are responsible for changes in both fibrinolytic and serotonergic systems.
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PMID:Time-dependent changes in platelet aggregation, fibrinolytic activity, and peripheral serotonergic measures in rats subjected to water immersion restraint stress. 752 68

Twelve patients with Hunt and Hess neurological Grades III to V underwent thrombosis of aneurysms using cellulose acetate polymer within 23 hours of aneurysm rupture. On computerized tomography (CT), nine of these patients had difuse or localized thick subarachnoid blood clots, two had diffuse thin clots and one had intraventricular clots. Immediately after thrombosis, all patients were administered tissue plasminogen activator (TPA) through spinal or ventricular catheters. The pressure of the lumbar cerebrospinal fluid was maintained at 100 to 150 mm H2O. The TPA was given as multiple injections of 2 mg on Day 0 and 1 to 2 mg on the following 1 to 2 days. In two patients the second injection of TPA was not given because of severe brain damage resulting from the initial subarachnoid hemorrhage. Ten patients showed complete clearance of the cisternal clot on CT within 72 hours after thrombosis. Seven partially thrombosed aneurysms and five multiple aneurysms were clipped during delayed surgery. Only one patient experienced mild vasospasm as shown on the follow-up angiogram. Eight patients improved clinically and had a good recovery, two had severe disability, and two died. Urgent thrombosis of a ruptured aneurysm followed by immediate postthrombotic administration of TPA may be a safe and reasonable means of preventing vasospasm and improving patient outcome.
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PMID:Early treatment of subarachnoid hemorrhage after preventing rerupture of an aneurysm. 778 47

The present study was performed to investigate the acute effects of physiologically induced hyperinsulinemia on plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA) and triglycerides (TG). Forty-one male patients with chronic coronary heart disease (CHD) and moderate hypertriglyceridemia were studied for 3 h; 33 of them during an oral glucose tolerance test (OGTT), whereas eight patients served as controls, receiving water only. All subjects in the OGTT group were adequate responders to glucose administration, giving peak values of glucose (median 6.90 mmol l-1) and insulin (median 123 mU l-1) after 1 h. TG were unchanged throughout the test period in both groups. After 1 h PAI-1 activity and antigen decreased significantly more in the OGTT group than in the controls (median values: PAI-1 act 23-12 vs. 12-12 U ml-1; (p < 0.001). PAI-ag 45-35 vs. 18-16 ng ml-1 (p < 0.05)). t-PA increased more in the OGTT group (0.70-1.20 vs. 0.50-0.63 IU ml-1 (p = 0.08)). These differences tailored off after 3 h. We conclude that acute hyperinsulinemia, when generated during an OGTT, stimulates fibrinolysis with a consequent decrease in PAI-1 activity, but give no change in TG. The postulated regulating role of insulin for the steady state levels of PAI-1 could probably not be elucidated in the present dynamic model.
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PMID:Insulin and PAI-1 levels during oral glucose tolerance test in patients with coronary heart disease. 803 49

Safety and efficacy of the thrombolytic agent urokinase (URO) in the elimination of subarachnoid clot and prevention of chronic vasospasm was compared with tissue-type plasminogen activator (rt-PA) in a blind, randomized placebo-controlled trial. Twenty monkeys were randomly assigned to one of five groups of four. Each group underwent baseline cerebral angiography followed by bilateral craniectomy and experimental subarachnoid hemorrhage. An Ommaya reservoir was inserted on the right side with its catheter placed into the ipsilateral subarachnoid space. Twenty-four hours later, depending upon group assignment, the animals received 100,000 IU URO, 200,000 IU URO, 1 mg rt-PA, 2 mg rt-PA, or the equivalent volume of normal saline (control group). On Day 7, angiography was repeated and the animals were killed. One animal died as a result of complications during the baseline angiography, presumably due to blood loss and prolonged anesthesia, and a replacement animal was obtained. No animals demonstrated any delayed neurological deficits. The study demonstrated that a single intracisternal bolus injection of rt-PA, 2.0 mg in 2 ml sterile water, or URO, 200,000 IU in 2 ml sterile water, 24 hours after induction of experimental subarachnoid hemorrhage in primates, was equally effective in thrombolysing ipsilateral clot, but neither dosage prevented angiographic vasospasm. Vasospasm occurred bilaterally in all groups. Whereas gross subarachnoid clot was found bilaterally in all animals in the placebo group and both smaller-dose URO and rt-PA groups, right-sided subarachnoid clot was virtually absent and left-sided clot reduced in both higher-dose URO and rt-PA groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of intrathecal administration of urokinase and tissue plasminogen activator on subarachnoid clot and chronic vasospasm in a primate model. 823 10

We have characterized the effects of ultrasound on fibrinolysis in vitro to investigate the mechanism of ultrasonic potentiation of fibrinolysis and to identify potentially useful ultrasound parameters for therapeutic application. Radiolabeled clots in thin walled tubes were exposed to ultrasound fields in a water bath at 37 degrees C, and lysis was measured by solubilization of radiolabel. Ultrasound accelerated lysis of plasma, whole blood, and purified fibrin clots mediated by recombinant tissue-type plasminogen activator (rt-PA), urokinase, or streptokinase, but ultrasound by itself caused no clot solubilization. The degree of ultrasonic potentiation was dependent on plasminogen activator concentration, increasing from 2.2-fold at a streptokinase concentration of 75 U/mL to 5.5-fold at 250 U/mL in a 1 MHz ultrasound field at 4 W/cm2. Ultrasound exposure resulted in heating due to absorption by the plastic tube, but the temperature increase was insufficient to account for the increase in clot lysis rate, indicating that the primary effect was nonthermal. Ultrasound did not accelerate hydrolysis of a peptide substrate by rt-PA and did not alter the rate of plasmic degradation of fibrinogen, indicating that the augmentation of enzymatic fibrinolysis required the presence of a fibrin gel. The acceleration of fibrinolysis by ultrasound was greater at higher intensities and duty cycles and was maximum at frequencies between 1 and 2.2 MHz, but decreased at 3.4 MHz. These findings suggest that ultrasound accelerates enzymatic fibrinolysis by increasing transport of reactants through a cavitation-related mechanism.
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PMID:Characterization of ultrasound-potentiated fibrinolysis in vitro. 849 Jan 72

In order to obtain selective suicide substrates of trypsin-like proteases including plasminogen activators, plasmin, and thrombin, a series of cyclopeptides cyclo[Arg or Lys-aB(CH2X)-Gly4], in which a substituted o- or m-aminobenzoyl group constitutes a latent electrophile, have been prepared. Treatment of the corresponding phenyl ethers cyclo[P1-aB(CH2OC6H5)-Gly4] with HBr/HOAc or R1R2S/TFA gives the bromides (X = Br) or the sulfonium salts (X = +SR1R2 with R1 = R2 = Me or R1 = Me and R2 = C6H5), respectively. These water-soluble cyclopeptides behave as time-dependent inhibitors of bovine trypsin and human urokinase (u-PA) but have no effect on tissue plasminogen activator (t-PA) and no or poor effect on plasmin and thrombin. The compounds containing a m-aminobenzoic acid residue are more efficient inactivators than their anthranilic analogues. The kinetic criteria expected for a suicide inhibition are met. A mechanism of inhibition involving the formation of a quinonimmonium methide intermediate is proposed. The activity of the inhibitors is very sensitive to the nature of the X benzylic substituent. An increased efficiency for the inactivation of human urokinase is observed with the sulfonium salts. The selectivity of the inactivation of u-PA compared to t-PA could be of therapeutical significance in controlling cell proliferation and invasion.
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PMID:New mechanism-based inactivators of trypsin-like proteinases. Selective inactivation of urokinase by functionalized cyclopeptides incorporating a sulfoniomethyl-substituted m-aminobenzoic acid residue. 849 23

We have previously shown that humic acid (well-water humic acid, HA, and synthetic humic acid, SHA) enhances cell surface expression of tissue factor (TF). Here we report that incubation of human umbilical vein endothelial cells (HUVEC) for 2 hr with HA or SHA cause a rapid rise in TF mRNA levels, as shown by Northern blot analysis. To understand the cytotoxic and fibrinolytic effects of HA and SHA on cultured HUVEC, the cells treated with varying concentrations of HA and SHA for various periods of time. Both HA and SHA (10-200 micrograms/ml) inhibited the viability of subconfluent HUVEC, cultured in the presence or absence of 20% FBS (Fetal Bovine serum) in the culture medium, in a dose-dependent manner. Both HA and SHA induced surface changes in the HUVEC as revealed by scanning electron micrography (SEM). However, protocatechuic acid, the monomer of SHA, did not significantly inhibit cell growth, and showed a cytotoxic effect only at 200 micrograms/ml. Furthermore both HA and SHA stimulated HUVEC to produce plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) in a dose and time dependent fashion; the amount of PAI-1 produced was found to exceed that of t-PA. The monomer of SHA did not have this stimulatory effect. These results distinctly suggest that in addition to the inhibition of viability HA is involved in TF induction and PAI-1 synthesis in HUVEC and these may be some of the plausible mechanisms underlying the thrombotic disorders in Blackfoot disease.
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PMID:Effects of humic acid on the viability and coagulant properties of human umbilical vein endothelial cells. 861

The hypothesis that tea drinking may protect against coronary heart disease (CHD) through effects on clotting as measured by plasma fibrinogen, tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) was tested in 65 healthy volunteers (31 men and 34 women; aged 20-74 years) in a randomized, blind, placebo-controlled, crossover study lasting 10 weeks (run-in phase 2 weeks, tea and placebo phases 4 weeks). During the placebo phase, intakes of milk, sugar, water and caffeine were matched to those in the tea phase during which 6 mugs of tea were drunk daily. Compliance with tea intake was measured by marking tea bags with p-aminobenzoic acid and measuring recovery in 24-hour urine collections. The mean +/- SD fibrinogen level, PAI-1 activity and tPA antigen level at baseline of 2.91 +/- 0.81 g/l, 7.9 +/- 5.3 U/ml and 4.76 +/- 2.17 ng/ml, respectively, were in the normal range. No significant differences in these variables between the run-in, tea or placebo phases were observed. The putative protective effect of tea against development of CHD is not mediated through effects of black tea on fibrinogen, tPA or PAI-1.
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PMID:Tea drinking and haemostasis: a randomized, placebo-controlled, crossover study in free-living subjects. 869 79

Exogenous plasminogen activators (PAs), such as streptokinase (SK) and tissue plasminogen activator (tPA), have been shown to significantly improve the mortality of patients with acute myocardial infarction. However, reperfusion of the myocardium is associated with neutrophil activation and infiltration into the infarct region. Plasminogen activators influence neutrophil function in vitro, but no data exists regarding the effect of exogenous PAs on inflammation in vivo. Therefore, we evaluated the effect of PAs on inflammation using the carrageenan-induced rat footpad inflammation model. The magnitude of carrageenan-induced inflammation was determined by water-displacement and neutrophil infiltration, following administration of either tPA or SK to Sprague-Dawley rats. tPA (12 mg/kg) inhibited carrageenan-induced inflammation (p < .01). In contrast, administration of SK (40,000 U/kg) enhanced inflammation. These results suggest that exogenous PAs influence the inflammatory process but specific PAs differ in their actions. Ultimately, these differences may influence the efficacy of these agents in the management of acute myocardial infarction and lead to further evaluation of tPA in other inflammatory diseases such as acute respiratory distress syndrome (ARDS) and rheumatoid arthritis (RA), in which neutrophil-mediated injury is likely.
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PMID:Antiinflammatory activity of tissue plasminogen activator in the carrageenan rat footpad model. 903 37

Dry, excipient-free recombinant human tissue-type plasminogen activator (tPA) powder was prepared by lyophilization from ammonium bicarbonate solution. Ammonium bicarbonate sublimes into ammonia, water, and carbon dioxide upon lyophilization, without causing measurable harm to the protein. There were approximately 4 mol of residual ammonium ion per mole of lyophilized tPA. Under certain lyophilization conditions, a large pressure increase in the lyophilizer chamber occurred, presenting a pressure control problem. Microscopy and sublimation rate measurements on the frozen matrix revealed that ice sublimation occurred first, followed by the sublimation of ammonium bicarbonate. Analysis of the sectioned frozen matrix indicated that the bicarbonate salt was evenly distributed throughout the vial, suggesting that the delay of ammonium bicarbonate sublimation was not due to hindrance by ice. In the two-stage process, ice sublimation proceeded according to zero-order kinetics, whereas ammonium bicarbonate sublimation followed a grain-burning (2/ 3-order) model and was governed by a higher activation enthalpy. In most cases, the sublimation rate of ammonium bicarbonate in the presence of tPA was lower than that in the absence of the protein. Sublimation activation enthalpy for ammonium bicarbonate in the presence of tPA was 26.1 +/- 3.8 kcal/mol, which was approximately 10 kcal/mol greater than that for the tPA-free system. Consistent with a prediction from our kinetic modeling, a 6-h extension of primary drying enabled us to conduct lyophilization while maintaining pressure control.
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PMID:Preparation of excipient-free recombinant human tissue-type plasminogen activator by lyophilization from ammonium bicarbonate solution: an investigation of the two-stage sublimation phenomenon. 910 48


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