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

Human protein C-inhibitor (PCI) was isolated from human citrated plasma by combining rivanol precipitation, ammonium sulfate precipitation, ion-exchange chromatography on DEAE-Sephacel and affinity chromatography on dextran sulfate Sepharose. The purified PCI migrated with the beta-globulins and was free from protein contaminations as judged by immunoelectrophoresis. In SDS-PAGE under reducing and unreducing conditions PCI showed a single band at Mr = 57,000. The specific activity of the inhibitor was 226 units/mg. Surprisingly, the isolated PCI inhibited the amidolytic activity of urokinase (u-PA) on Glu-Gly-Arg-pNA (S-2444) in a time-dependent manner. Heparin, dextran sulfate and pentosanpolysulfate accelerated the reaction catalytically. PCI revealed itself as a non-competitive inhibitor of u-PA. The Ki-value was determined to be 7.9 x 10(-8)M. Inhibition of amidolytic activity was found to be associated with the formation of an 1:1 equimolar complex with a Mr of 110,000 as demonstrated by means of polyacrylamide gel electrophoresis and following Western blotting technique using polyclonal antibodies against u-PA and PCI. The specific activity of the isolated PCI of 226 units/mg, which approximates the theoretical value of pure PCI, indicates a highly purified preparation of PCI. The heparin-dependent inhibition of urokinase by this highly purified protein as well as comparison of the kinetic data and amino-acid composition of both PCI and the recently described plasminogen activator inhibitor (PAI) 3 give high evidence of identity of PCI and PAI-3.
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PMID:Inhibition of urokinase by protein C-inhibitor (PCI). Evidence for identity of PCI and plasminogen activator inhibitor 3. 350 Dec 95

An 11 day-old neonate presented with bilateral renal venous thrombosis in the course of Salmonella Ibadan infection. 36 hours thrombolytic treatment with urokinase was associated with an immediate favorable outcome. Heparin and antibiotic treatment were pursued for 3 weeks. A 6 month follow-up and results of renal ultrasonography, urography and renal scanning allow to assess recovery, with restoration ad integrum for both kidneys.
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PMID:[Neonatal bilateral renal venous thrombosis and Salmonella ibadan infection. Cure with thrombolytic agents]. 359 18

Heparin is indicated in pulmonary embolism suspicion, in minor and a part of submassive embolism. The dose is 15,000-20,000 U (acute) and 40,000 U/day subsequently. Fibrinolytic therapy with streptokinase or urokinase is indicated in massive embolism. Submassive embolism is treated by fibrinolysis if no contraindications against fibrinolysis are to be registered.
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PMID:[Drug therapy of pulmonary embolism]. 380 72

Glial-derived neurite-promoting factor was found to be a slow-binding inhibitor of trypsin, urokinase, and thrombin. The kinetic mechanism of the inhibition differs among the three proteases. With trypsin and urokinase, an initial protease-factor complex formed which isomerized to a tighter complex. For thrombin, however, no initial complex was kinetically observed. The dissociation constants of the equilibrium complexes of the factor with trypsin, urokinase, and thrombin were 17, 280, and 18 pM, respectively, and the apparent second-order rate constants for the interaction of the factor with these enzymes were, respectively, 4.7 X 10(6), 1.2 X 10(5), and 2.1 X 10(6) M-1S-1. Heparin increased the rate at which the factor reacted with thrombin by over 40-fold to 8.9 X 10(7) M-1S-1 and decreased the dissociation constant of the complex by over 80-fold to 0.3 pM. The values obtained for the apparent second-order rate constants when compared with the kinetics of neurite induction by the factor indicate that the neurite-promoting activity of the factor is not due to the inhibition of urokinase but could be due to the inhibition of an enzyme with a specificity similar to that of thrombin or trypsin. Comparison of the values of the apparent second-order rate constants obtained for the factor with those obtained for protease nexin suggests that these two molecules are very similar in their inhibitory properties.
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PMID:Glial-derived neurite-promoting factor is a slow-binding inhibitor of trypsin, thrombin, and urokinase. 381 34

The pathophysiology of deep-vein thrombosis (DVT) and pulmonary embolism (PE) is briefly discussed, and the efficacy, dosage and administration, laboratory monitoring, and adverse effects of thrombolytic agents, heparin, and warfarin are reviewed. Acute therapy of DVT and PE is usually initiated with intravenous heparin; however, thrombolytic agents such as streptokinase and urokinase may be preferred in patients with massive PE or severe DVT when clot lysis rather than clot stabilization is deemed necessary. For DVT or PE, an intravenous loading dose of streptokinase or urokinase is given, followed by a continuous infusion of the drug. Therapy with streptokinase is continued for 24 hours in patients with PE and for 72 hours in those with DVT; urokinase is continued for 12 hours in patients with PE. Monitoring of blood coagulation tests during thrombolytic therapy is recommended primarily for ensuring that a lytic state is achieved. Intravenous heparin is preferred for acute treatment of DVT or PE; controversy exists regarding whether administration by continuous infusion or intermittent bolus injection is superior. Heparin dosage is usually adjusted to maintain the activated partial-thromboplastin time (APTT) ratio between 1.5 and 2.5; however, the ideal therapeutic range has never been firmly established. After acute treatment with heparin, most patients should continue to receive either warfarin or subcutaneous heparin for several months to prevent recurrent thromboembolism. Bleeding is the major adverse effect of thrombolytic agents and anticoagulants. The risk of bleeding with heparin and warfarin therapy increases with excessive prolongation of the APTT and prothrombin time (PT), respectively. Future clinical trials should further define the role of thrombolytic agents in the treatment of DVT and PE and the efficacy of less-intense warfarin therapy for pulmonary embolism or arterial thromboembolic events.
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PMID:Pathophysiology and treatment of deep-vein thrombosis and pulmonary embolism. 389 Dec

The isotopic method described previously for quantification of plasmin- (125)I by disc gel electrophoresis was modified by inclusion of euglobulin precipitation to expand its applicability to plasmas containing low radioactivity of plasmin- (125)I and plasminogen- (125)I. It was found that the euglobulin precipitation method precipitates 72.4+/-2.1 (sd)% of both plasmin- (125)I and plasminogen- (125)I. Using this method and plasminogen- (125)I as a tracer, studies were first made of the effects of heparin and epsilon-aminocaproic acid in dogs on plasmin- (125)I generation in responese to a single injection of urokinase and to venous injury; second, of the effects of venous occlusion and thrombosis on plasmin- (125)I generation; and third, in vitro studies of plasminogen- (125)I affinity to fibrin and its activation in blood clots. The venous injury was produced by the damage of venous endothelium by an injection of 90% phenol and the thrombosis by a thrombin injection into an occluded vein. Heparin and epsilon-aminocaproic acid under the present experimental conditions inhibited about 78 and 100%, respectively of plasmin- (125)I generation by the urokinase injection. Similar inhibitory effects of heparin and epsilon-aminocaproic acid were observed on plasmin- (125)I generation in response to venous injury. The venous occlusion caused a small degree of plasmin- (125)I generation, but thrombin thrombosis did not seem to stimulate the generation of plasmin- (125)I. The in vitro studies showed that plasminogen- (125)I does not have a specific affinity to fibrin and is incorporated into blood clots in approximately equal concentrations as those in serum during clotting processes, and that blood clots per se do not stimulate plasmin- (125)I generation. These results suggest that injured veins release considerable amounts of vascular plasminogen activators into circulation and that these play an important role in thrombus dissolution in vivo.
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PMID:Effects of heparin and epsilon-aminocaproic acid in dogs on plasmin-125-I generation in response to urokinase injections and venous injury. 426 19

Interventional angiographic techniques are of increasing importance in the management of arteriosclerosis and its complications. Two areas of particular interest are the treatment of focal arterial stenoses by percutaneous transluminal angioplasty and the treatment of arterial thromboemboli with selective infusion of thrombolytic agents. The administration of multiple drugs, in various combinations, is a critical factor in the success of these interventions. To effectively use this new pharmacoangiography, it is important to understand both the pathophysiology of the atherosclerotic or thrombotic process being treated and the actions of the drugs used. Preserving the effect of angioplasty relies on preventing thrombus formation and preventing recurrence of the atherosclerotic obstruction. Heparin during the procedure is clearly useful for the former, and aspirin in small doses and other antiplatelet medications are indicated for the latter. The precise utility of long-term anticoagulation, of low molecular weight dextran, and of various antiplatelet regimens remains to be proven. The theoretical importance of these medications in improving long-term patency rests on the effects they have on platelet and vessel wall prostaglandins, on intimal smooth muscle cell proliferation, and on the thrombogenicity of injured arterial intima. Fibrinolytic therapy, with streptokinase and urokinase, has been used for many years. Selective intraarterial use, however, is a new and promising application. Intracoronary streptokinase infusion during acute myocardial ischemia appears to prevent or limit infarction in certain patients. Peripheral use for acute arterial occlusion, either in native vessels or in grafts, is an area of great promise. Key considerations are thrombus age, size, and location, and the status of the arterial flow proximal and distal to the obstruction.
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PMID:Pharmacology of angioplasty and intravascular thrombolysis. 618 69

It was found that the effect of heparin on the amidase activity of urokinase (E C 3.4.21.31), plasmin (E C 3.4.21.7) and trypsin (E C 3.4.21.4) depended on the substrate used. No effect of heparin on the amidase activity of urokinase and trypsin was observed when Pyro Glu-Gly-Arg-p-nitroanilide (S-2444) and alpha-N-acetyl-L-lysine-p-nitroanilide (ALNA) were used as substrates. Heparin acted as a uncompetitive inhibitor of trypsin (Ki = 1.2 X 10(-6) M), plasmin (Ki = 4.9 X 10(-6) M) and urokinase (Ki = 1.0 X 10(-7) M) when Bz-Phe-Val-Arg-p-nitroanilide (S-2160), H-D-Val-Leu-Lys-p-nitroanilide (S-2251) and plasminogen, respectively, were used as substrates. These results, as well as the data obtained by studying the effect of the simultaneous presence of heparin and competitive inhibitors suggest that although heparin is not bound at the active center of these enzymes, it may influence the effectivity of catalysis.
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PMID:Kinetic study of the effect of heparin on the amidase activity of trypsin, plasmin and urokinase. 622 10

The state of thrombin-plasmin system was studied in 34 rabbits with Masuga nephritis untreated or treated with the use of heparin, urokinase, and uroplasmin. The untreated animals developed long-term activation of thrombinogenesis (hypercoagulation) with simultaneous inhibition of fibrinolysis accompanied by deposition of fibrin-postive substances in the lumens of capillaries and glomerular capsules, along basal membranes, and inside epithelial and endothelial cells. Heparin inoculated prophylactically prevented the development of nephritis and typical changes in the thrombin-plasmin system. Treatment with heparin, urokinase or uroplasmin produced regression of nephritis, elimination of fibrin-positive substances from the kidneys and gradual complete normalization of the functional status of the thrombin-plasmin system. It is suggested that not only heparin but also urokinase and uroplasmin can inhibit the immune process. The experimental results favours the immunocoagulation theory of nephritis pathogenesis.
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PMID:[State of the thrombin-plasmin system in nephrotoxic nephritis treated with heparin, urokinase, and uroplasmin]. 644 26

Blood shed into a closed peritoneal cavity is incoagulable. We have investigated this poorly understood phenomenon in animal experiments. Nonthrombogenic femoral vein-peritoneal cavity shunts were established in five dogs and 10 ml/kg blood admixed with 125I-dog fibrinogen was rapidly drained into the peritoneal cavity. After 1 hr the peritoneal cavity was entered and incoagulable blood aspirated; 125I-fibrinogen Mr distribution was assessed by AGPC, demonstrating complete degradation of fibrinogen into core fragments D and E with no evidence of soluble fibrin complexes or crosslinked fibrin fragments. Peritoneal cavity clotting factors II, V, and VIII and platelets were sharply reduced compared to venous control samples. Plasminogen and antiplasmin levels in peritoneal cavity blood showed mean declines of 17% and 15%, respectively. By comparison, incubation of dog blood with 1 to 2 X 10(3) U/ml urokinase for 1 hr in vitro was insufficient to degrade 125I-dog fibrinogen to core fragments D and E, although plasminogen and antiplasmin were reduced by 66% and 100%, respectively. Pretreatment of dogs with epsilon ACA (0.13 gm/kg, N = 4) resulted in massive intraperitoneal cavity clotting, and aspirated fluid blood contained only small quantities of radiolabel. Heparin treatment (300 U/kg bolus, 150 U/kg/hr infusion; N = 4) eliminated the peritoneal cavity lytic response; analytical gel permeation chromatography consistently demonstrated intact fibrinogen only. Therefore it is apparent that blood in a closed peritoneal cavity undergoes limited clotting followed by brisk plasmin-mediated fibrinolysis as opposed to fibrinogenolysis. The closed peritoneal cavity fibrinolytic response to clotting blood represents a striking example of the efficiency of the "tissue-type" plasminogen activator.
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PMID:Peritoneal fibrinolysis: evidence for the efficiency of the tissue-type plasminogen activator. 668 80


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