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 effect of ditazole, a new antiaggregant oxazole derivative as well as its possible interaction with urokinase on the formation of electrically induced thrombus, was assayed in rabbits. The activity of ditazole in reducing thrombus weight was comparable to that of aspirin. In the ditazole- or aspirin-treated animals, the microscopical examination of the thrombus showed a reduction in the fibrin component, and well-isolated platelets not undergoing a viscous metamorphosis were present. Urokinase, administered in combination with these antiaggregant drugs, did not induce a further reduction in thrombus weight. However, this additional treatment did induce clearly visible lytic areas and histological modifications as observed with the antiaggregant drugs. These data suggest that the antiplatelet drug ditazole may be an effective antithrombotic agent in man and could facilitate the penetration of urokinase into the thrombus.
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PMID:Ditazole activity and its interaction with urokinase on experimental thrombosis. 2 45

Direct imaging of thrombi with isotopically labelled agents would provide a convenient atraumatic method of diagnosing deep venous thrombosis. Urokinase labelled with technectium-99m has many theoretical advantages and successful use of this agent has been reported. A method for tagging urokinase with Tc-99m has been developed which preserves the clot-lysing ability of the urokinase. The thrombus imaging previously reported has not been duplicated.
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PMID:Visualisation of thrombi with technetium-99m urokinase. A negative report. 6 May 71

The major plasmin inhibitors namely alpha2-plasmin inhibitor and alpha2-macroglobulin were compared for their effects on lysis of fibrin clot. Plasmin fibrinolytic activity was immediately inhibited by alpha2-plasmin inhibitor, whereas alpha2-macroglobulin inhibited plasmin progressively. Urokinase(plasminogen activator)-induced clot lysis was inhibited efficiently by alpha2-plasmin inhibitor present in the clot. Inhibition of urokinase-induced clot lysis by alpha2-macroglobulin was weak and the molar concentration necessary for alpha2-macroglobulin to achieve the same degree of inhibition as that achieved with alpha2-plasmin inhibitor was about 10 times higher than that of alpha2-plasmin inhibitor. Binding of Lys-plasminogen to fibrin was inhibited by alpha2-plasmin inhibitor but not by alpha2-macroglobulin. Molar concentrations of alpha2-plasmin inhibitor which were effective in inhibiting the binding were 30 times less than that of 6-aminohexanoicacid. alpha2-Plasmin inhibitor was found to interact with Lys-plasminogen to form a weakly-bound complex which is dissociable in the presence of 6-aminohexanoic acid, suggesting that inhibition of binding of Lys-plasminogen to fibrin by alpha2-plasmin inhibitor may be due to interaction of alpha2-plasmin inhibitor with a specific site of the plasminogen molecule and that the site may be 6-aminohexanoic acid-binding site. It is suggested that alpha2-plasmin inhibitor is more reactive and efficient inhibitor of fibrinolysis than alpha 2-macroglobulin.
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PMID:Effects of alpha2-plasmin inhibitor on fibrin clot lysis. Its comparison with alpha2-macroglobulin. 7 50

The binding of urokinase to human alpha2M (alpha2-macroglobulin) was investigated in comparison with the formation of the equimolar trypsin-alpha2M complex. Experiments were performed by molecular-sieving on Sephadex G-200, subunit conversion by sodium dodecyl sulphate-polyacrylamide-gel electrophoresis after reduction and isoelectric focusing in linear sucrose gradients with ampholytes pH 3.5-10.0. Urokinase activity was determined with alpha-N-acetyl-L-lysine methyl ester and by activation of plasminogen on unheated fibrin plates. alpha2M was determined by single radial immunodiffusion. alpha2M was capable of binding some urokinase by a non-specific type of attachment that could be disrupted by isoelectric focusing but not by gel filtration. The pI of the undissociated trypsin-alpha2M complex was 6.0, and differed from that of the pure alpha2M (5.2-5.4). Likewise the pI of the immunoreactive alpha2M was 5.2 after exposure to urokinase, whereas the dissociated urokinase focused at pI 10.2. This indicated lack of true inhibitor-complex formation, which was also sustained by total absence of subunit conversion. The results are in agreement with our previous findings with pancreatic and urinary kallikreins.
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PMID:Interaction of urokinase with alpha2-macroglobulin investigated by isoelectric focusing. Evidence for non-specific dissociable binding. 7 4

Urokinase, the plasminogen activator from human urine, produces a dose-dependent increase in blood flow in the canine superior mesenteric artery when injected intraarterially at doses from 10(-1) to 10(3) units kg-1. This vasodilation persists despite blockade of beta-adrenergic and histamine H1 and H2 receptors as well as inhibition of plasminogen activation, suggesting that these mechanisms are not involved. Infusion of urokinase at 10(2) CTA (Committee on Thrombolytic Agents) units kg-1 min-1 does not produce a sustained vasodilation, but is effective in achieving complete lysis of thrombi within 100 min in the superior mesenteric arterial circulation. Increasing the dose slightly to 125 CTA units kg-1 min-1 results in unwanted clotting abnormalities without attaining a vasodilator level. Decreasing the dose to 75 CTA units kg-1 min-1 still results in complete thrombolysis. In contrast to the results in the femoral circulation, the dose required for fibrinolysis-thrombolysis does not overlap with that for vasodilation in the superior mesenteric artery. Nevertheless, these experiments provide some basis for the use of intraarterial urokinase infusion in the treatment of nonocclusive mesenteric ischemia and, perhaps, thrombotic occlusion of the superior mesenteric artery.
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PMID:Vasodilation, fibrinolysis, and thrombolysis with intraarterial infusion of urokinase in the canine superior mesenteric artery. 9 90

Physico-chemical characteristics of urokinase in urine were studied by immunological and chemical methods. By agar zone electrophoresis, commercial urokinase preparations could be separated into an anodic and cathodic fraction. The latter reacted with urokinase antibodies with two precipitation bands. Band I displayed the major part of urokinase activity and migrated as a beta-globulin with a molecular weight of 32,000 daltons. Band II showed immunological identity with human serum, human albumin, alpha-2-macroglobulin and alpha-2-HS-glycoprotein. The specific activity of the cathodic fractions was up to 80,000 ploug units/mg protein. The ratio esterase/fibrinolytic activity did not change during the purification procedure. Further purification of the fractions with higher specific activity by affinity chromatography was unable to eliminate material cross reacting with human antisera (Band II). These findings permit the conclusion, that urokinase activity in urine is not confined to a homogeneous protein fraction. Activity is found both in a low molecular weight fraction and in a high molecular weight complex which contains serum proteins. These cannot be removed by exhaustive purification procedures and may play an important role in stabilizing and/or protecting urinary urokinase against proteolytic degradation. With Todd's technique diffuse fibrinolytic activity could be demonstrated in the kidney in the iuxtamedullary border region, (venae arcuatae, venae interlobulares, vasa recta) and in the epithelium of the calyces. Urokinase activity was specifically blocked by highly purified urokinase antibodies and could thus be distinguished from nonspecific proteolytic activity. The topographic relationship to medulla and uroepithelium may point to a role of urokinase in maintaining patency in slow flow systems.
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PMID:Isolation and renal localisation of urokinase. 10 50

Three types of plasminogen activator could be distinguished in extracts from human uterine tissue. The activators differed in thermostability or in mode of inhibition by EACA. All the extracts contained stable as well as labile activators. The saline extracts were uniformly inhibited by increasing concentrations of EACA. Extracts made with 2 M ammonium thiocyanate were either uniformly inhibited by EACA or showed deflections indicating contamination with an activator, which was inhibited in a biphasic manner. It was possible to distinguish between: (1) An activator, abundantly present in the tissue, which was uniformly inhibited and stable. (2) Another uniformly inhibited activator, which was labile. (3) An activator, inhibited in a biphasic manner, similar to urokinase, which was present in varying amounts in uteri with the endometrium in the proliferative phase. Gel filtration of the uterine extracts showed two major activity peaks corresponding to particle sizes of 60,000 dalton and about 10,000 dalton. Antiserum to purified plasminogen activator, prepared from porcine ovaries, inhibited the activity of the human uterine extracts, but not the activities of human urokinase or urine. Urokinase antiserum in a concentration completely inhibiting human urine or urokinase, inhibited only 10% or less of the activities of human uterine extracts.
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PMID:Separation of plasminogen activators from human uterine tissue and a comparison with activators from human urine and porcine tissue. 11 1

The data presented in this paper show that when rabbit plasminogen is activated to plasmin by urokinase at least two peptide bonds are cleaved in the process. Urokinase first cleaves an internal peptide bond in plasminogen, leading to two-chain disulfide-linked plasmin molecule. The plasmin heavy chain of molecular weight 66,000 to 69,000 possesses an NH2-terminal amino acid sequence identical with the original plasminogen (molecular weight 88,000 to 92,000). The plasmin light chain of molecular weight 24,000 to 26,000 is known to be derived from the COOH-terminal portion of plasminogen. The plasmin generated during the activation of plasminogen is capable, by a feedback process, of cleaving a peptide of molecular weight 6,000 to 8,000 from the NH2 terminus of the heavy chain, producing a proteolytically modified heavy chain of molecular weight 58,000 to 62,000. Plasmin also can cleave this same peptide from the original plasminogen, yielding an altered plasminogen of molecular weight 82,000 to 86,000. This plasmin-altered plasminogen and the plasmin heavy chain derived from it by urokinase activation process NH2-terminal amino acid sequences which are identical with each other and with the plasminolytic product of the original plasmin heavy chain. These studies support a mechanism of activation of plasminogen by urokinase which involves loss of a peptide located on the NH2 terminus of plasminogen. However, these same results show that this NH2-terminal peptide need not be released from rabbit plasminogen prior to the cleavage of the internal peptide bond which leads to the two-chain plasmin molecule. Furthermore, these studies show that urokinase cannot remove this peptide from either the original rabbit plasminogen molecule or from the heavy chain of the initial plasmin formed.
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PMID:The mechanism of activation of rabbit plasminogen by urokinase. 12 29

Compared with streptokinase, thrombolytic treatment with urokinase has the advantages of being better tolerated and of practically unlimited applicability. Its disadvantage is the high cost. A good lytic action can be obtained with a dosage of 150,000 Ploug Units/12 hours for a duration of lysis of 8-14 days combined with heparin, the therapy being monitored by determination of the products of fibrinolysis. This dosage is not possible if the time factor plays a decisive role in the success of the treatment, e.g. in myocardial infarction. Urokinase is indicated when streptokinase cannot be used, or if continuation of the streptokinase therapy is necessary because of extensive thromboses.
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PMID:[Thrombolytic treatment with urokinase (author's transl)]. 12

Using human urokinase in vivo thrombolysis was studied in autologous artificial thrombi in the pulmonary circulation of rabbits by immunofluorescence and Todd's fibrinolysis autography techniques. As compared to the control thrombi of the untreated rabbits, a small increase of thrombolysis was found in the rabbits treated with urokinase. Urokinase fluorescence was observed in the leukocytes, but not along the fibrin fibrils in the thrombi of the rabbits treated with urokinase. By Todd's fibrinolysis autography, lytic areas were observed around aggregated leukocytes in the thrombi of the rabbits treated with urokinase. The small lysis of autologous artificial thrombi of rabbits by human urokinase may be caused by (1) low affinity of human urokinase for rabbit plasminogen, (2) weak adsorption of human urokinase to rabbit fibrin, (3) phagocytosis of human urokinase by leukocytes and (4) high level of antifibrinolytic activity of rabbit plasma.
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PMID:Immunohistochemical and histochemical investigations on in vivo thrombolysis with urokinase in rabbits. 48 51


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