Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The requirement of heparin in experimental coronary thrombolysis induced by tissue-type plasminogen activator (t-PA) was studied in closed-chest dogs with one hour old coronary thrombi and compared with that in urokinase (UK)-induced coronary thrombolysis. Animals were divided into 5 treatment groups as follows: group 1 received intracoronary t-PA alone (1,000 IU/kg/min; n = 5), and if thrombolysis was not induced within 40 to 50 min, dogs then received an intravenous injection of heparin (300 U/kg) plus intracoronary t-PA; group 2 received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received intracoronary t-PA (n = 5); group 3 also received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received t-PA but intravenously, as compared with the groups administered by the intracoronary route (n = 6); group 4 received intracoronary UK alone (1,000 IU/kg/min; n = 6); group 5 received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received intracoronary UK (n = 5). Thrombolysis was confirmed angiographically. In group I, coronary thrombolysis could not be induced within 44 +/- 4 min by intracoronary t-PA alone, but it occurred in 8 +/- 4 min when administered in combination with heparin in all dogs. Heparin alone failed to elicit reperfusion within 10 min in group 2, 3 and 5. t-PA, however, induced successful reperfusion in 16 +/- 5 min (group 2) and in 23 +/- 6 min (group 3), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heparin requirement in tissue-type plasminogen activator-induced experimental coronary thrombolysis: comparison with urokinase-induced coronary thrombolysis. 244 Oct 82

The activity of tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) is stimulated by heparin. Heparin binds tightly to t-PA, u-PA, and plasminogen and decreases the usual stimulatory effect of fibrin on t-PA activity. In the present study we have found that low molecular weight heparin (LMW-heparin) preparations obtained by nitrous acid depolymerization or heparinase treatment of standard heparin have different properties with respect to their interaction with the fibrinolytic system. LMW-heparin prepared by either method does not stimulate plasmin formation by t-PA. However, these preparations of heparin still efficiently accelerate the inhibition of thrombin by antithrombin III. Binding data show that LMW-heparin does not bind t-PA and Glu-plasminogen and only binds very weakly to Lys-plasminogen. These results illustrate that it is possible to selectively destroy the fibrinolytic stimulating properties of heparin while leaving the classical anticoagulant characteristics intact.
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PMID:Anticoagulant low molecular weight heparin does not enhance the activation of plasminogen by tissue plasminogen activator. 250 19

Protein C inhibitor was purified from human plasma by a modification of a published procedure (Suzuki, K., Nishioka, J., and Hashimoto, S. J. Biol. Chem. 258, 163-168, 1983). Approximately 1 mg of pure protein was obtained from 1 L plasma, a yield of about 17%. The protein C inhibitor preparation did not lose activity over 4 weeks at 4 degrees C. Second order rate constants were measured for the inhibition of activated protein C, thrombin, and urokinase, and bimolecular complexes of protein C inhibitor with activated protein C and thrombin were visualized by denaturing polyacrylamide gel electrophoresis. Heparin accelerated the inhibition of the three proteinases in a manner consistent with a template mechanism. Plasma or pure protein C inhibitor (at the same concentration) showed the same effect of heparin on activated protein C inhibition, indicating that protein C inhibitor accounts for all the heparin-dependent inhibition of activated protein C in vivo.
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PMID:Protein C inhibitor: purification and proteinase reactivity. 254 38

An assay system for protein C (PC) activity and PC-inhibitor in plasma was developed. The assay was based on: (1) binding of PC to wells of a microtiter plate coated with a murine monoclonal anti-PC antibody (C3) that did not interfere with the activity or activation of PC; (2) activation of immobilized PC with Protac C; (3) incubation with or without a source of activated PC inhibitor; and (4) measurement of amidolytic activity using the substrate S-2366. The activity assay was specific for PC and sensitive to less than 1 microliter of plasma or 4 ng PC. Inhibition of activated PC by plasma followed pseudo first order kinetics. Heparin caused a dose dependent increase in the inhibition rate with half maximal stimulation at approximately 3 U/ml and maximal stimulation at heparin concentrations greater than or equal to 10 U/ml. This assay is suitable not only for determination of functional plasma levels of PC and PC inhibitor activities but also for kinetic studies of inhibition of activated PC in complex systems, such as plasma. Studies showed that urokinase interfered with the inhibition of APC by plasma inhibitor(s).
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PMID:Functional assays for protein C activity and protein C inhibitor activity in plasma. 254 80

To assess the role of inhibitors of proteolytic enzymes, such as plasminogen activator (PA) and collagenase in the ovulatory process, inhibitor activity and mRNA levels were examined in periovulatory rat and human ovaries. In the rat, immature animals received 20 IU of pregnant mare serum gonadotropin (PMSG) followed 52 h later by 10 IU of hCG. Ovaries were removed at intervals from 0 to 20 h after human chorionic gonadotropin (hCG) administration. Inhibitor activity for metalloproteinases, such as collagenase, increased from 60.5 +/- 4.1 inhibitor units/ovary at 0 h (i.e., time of hCG treatment) to a maximum of 218.2 +/- 11.4 units/ovary at 8 h after hCG before decreasing at 12 h (time of ovulation) and 20 h (122.2 +/- 7.9 and 71.6 +/- 8.1 units/ovary, respectively). Human follicular fluid and granulosa cells were obtained from preovulatory follicles of patients in our in vitro fertilization program. Metalloproteinase inhibitor activity was evaluated in follicular fluid as well as the levels of PA and PA inhibitor (PAI) mRNA by Northern analysis. Increasing metalloproteinase inhibitor activity was positively correlated with follicular levels of estradiol (p less than 0.001) and progesterone (p less than 0.02, N = 26). Chromatographic separation of follicular fluid resulted in two peaks of metalloproteinase inhibitor activity. The large molecular weight (MW) inhibitor had an approximate size of 700 kilodaltons (kDa) and may represent alpha 2-macroglobulin, a serum-derived inhibitor. The small MW inhibitor shared many of the characteristics of tissue-derived inhibitors of metalloproteinases. Partial purification of the small MW inhibitor by Concanavalin A-Sepharose and Heparin-Sepharose chromatography demonstrated the inhibitor to be a glycoprotein with an approximate MW = 28-29 K. Northern analysis of human granulosa cell total RNA from preovulatory follicles showed little or no detectable tissue-type PA or urokinase-type PA mRNA. In contrast, two species of PA inhibitor type-1 mRNA were detected in relative abundance. The present findings demonstrate the presence of proteolytic inhibitors in periovulatory ovaries of the rat and human. These ovarian inhibitors may play a role in regulating connective tissue remodeling during follicular rupture.
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PMID:The role of ovarian proteases and their inhibitors in ovulation. 255 99

The effect of a selective thrombin inhibitor, (2R, 4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]- L-arginyl]-2-piperidinecarboxylic acid (MCI-9038), on the fibrinolysis induced by t-PA and u-PA was studied in vitro and in vivo. MCI-9038 remarkably reduced the lysis time of the plasma clot generated by the addition of calcium chloride to the plasma at the concentration ranging from 0.01 to 0.3 microM. Heparin also reduced the plasma clot lysis time with a lower effect than MCI-9038. The fibrin crosslinkage in the plasma clot was inhibited by MCI-9038 or heparin. MCI-9038 potently inhibited the factor XIIIa generation from factor XIII by thrombin. The effect on the in vivo thrombolysis was studied on the arterial thrombosis generated by the endothelial cell injury of the rabbit carotid artery by acetic acid. t-PA dissolved the thrombi with the infusion at 0.96 mg/kg over 2 h without a significant activation of a systemic fibrinolysis. u-PA dissolved the thrombi with the infusion at 180,000 and 360,000 IU/kg over 2 h. At a dose of 0.48 mg/kg t-PA or 90,000 IU/kg u-PA, the thrombi were not dissolved, but the combined use of MCI-9038 at 1.2 mg/kg over 2 h effectively dissolved the thrombi. Thus, combination of MCI-9038 with plasminogen activators accelerated thrombolysis of an experimental thrombosis in rabbits.
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PMID:Effect of a selective thrombin inhibitor MCI-9038 on fibrinolysis in vitro and in vivo. 287 8

The amidolytic plasmin activity of a mixture of tissue plasminogen activator (tPA) and plasminogen is enhanced by heparin at therapeutic concentrations. Heparin also increases the activity in mixtures of urokinase-type plasminogen activator (uPA) and plasminogen but has no effect on streptokinase or plasmin. Direct analyses of plasminogen activation by polyacrylamide gel electrophoresis demonstrate that heparin increases the activation of plasminogen by both tPA and uPA. Binding studies show that heparin binds to various components of the fibrinolytic system, with tight binding demonstrable with tPA, uPA, and Lys-plasminogen. The stimulation of tPA activity by fibrin, however, is diminished by heparin. The ability of heparin to promote plasmin generation is destroyed by incubation of the heparin with heparinase, whereas incubation with chondroitinase ABC or AC has no effect. Also, stimulation of plasmin formation is not observed with dextran sulfate or chondroitin sulfate A, B, or C. Analyses of heparin fractions after separation on columns of antithrombin III-Sepharose suggest that both the high-affinity and the low-affinity fractions, which have dramatically different anticoagulant activity, have similar activity toward the fibrinolytic components.
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PMID:Interaction of heparin with plasminogen activators and plasminogen: effects on the activation of plasminogen. 294 15

The formation and composition of the insoluble heparin-fibronectin-collagen complex and its degradation by proteolysis was investigated. At fixed concentrations of the other molecular components of the complex, the maximal rate of complex formation, measured turbidimetrically, was reached at a concentration of 4 microM heparin and 0.9 microM collagen, while the rate of complex formation was linearly related to concentrations of fibronectin as high as 3 microM. Heparin was incorporated into the complex in a saturable manner, and was released in active anticoagulant form by plasmin but not by urokinase. The complex formation was inhibited by 5 mM calcium or 250 mM NaCl as well as by polybrene or spermin. It is suggested that fibronectin binds both heparin and collagen cooperatively to form an insoluble ternary complex of the extracellular matrix.
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PMID:Conditions of formation of the heparin-fibronectin-collagen complex and the effect of plasmin. 295 94

It is now generally well accepted that heparin and related substances increase the fibrinolytic activity in vivo. The stimulation of the amidolytic, plasminogenolytic and fibrinogenolytic activity of tissue plasminogen activator and urinary plasminogen activator through heparin was investigated in vitro. A concentration-dependent stimulation of the plasminogenolytic and fibrinogenolytic activity of both urinary and tissue-type plasminogen activators was observed in the presence of heparin. No heparin dependence was observed in the amidolytic assay. Heparin stimulates the plasminogenolytic activity of tissue plasminogen activators in the same manner as fibrin. Both activators form complexes with heparin; the heparin-binding-site seems to be identical or related with the fibrin-binding-site of tissue plasminogen activator. The physiological role of these interactions is discussed.
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PMID:Study on the mechanism of action of heparin and related substances on the fibrinolytic system: relationship between plasminogen activators and heparin. 308 55

Use of urokinase to treat heparin-associated thrombocytopenia and thrombosis in one patient is described, and various treatments proposed for this syndrome are discussed. A 56-year-old man received an intravenous bolus dose of heparin sodium at his local hospital and was transferred to another institution for treatment of suspected pulmonary embolism; he had received heparin two weeks earlier during coronary angiography. The patient's platelet count was reported to be normal before heparin administration. When embolism was confirmed, heparin was discontinued and streptokinase was given for 24 hours. Heparin infusion was then restarted at 1000 units/hr and continued for four days. Platelet count on admission to the second hospital was 47,000/cu mm; 12 hours later it was 19,000/cu mm, and it remained low despite platelet transfusions. Five days after admission, deep-vein thrombosis developed in the left leg. Heparin was discontinued and urokinase and warfarin were started. Urokinase was infused at 320,000 IU/hr for 12 hours and continued at dosages of 160,000-320,000 IU/hr for a total of 40 hours. The initial warfarin sodium dose was 15 mg, followed by a dosage of 10 mg/day. Symptoms of deep-vein thrombosis improved within 12 hours and platelet count increased after heparin was discontinued. If it is recognized early enough, heparin-associated thrombocytopenia can be reversed by discontinuation of heparin. Transfusions of platelets are of little benefit. Dipyridamole, cyclo-oxygenase inhibitors such as aspirin, and protamine sulfate may be useful. Long term anticoagulation with warfarin is recommended to prevent recurrent thrombosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombolytic therapy in heparin-associated thrombocytopenia with thrombosis. 348 69


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