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PubMed1976

Experimental galactosamine-induced hepatitis. Effect of anticoagulant and antifibrinolytic agents on microclot formation.

An experimental hepatitis was induced in rabbits by intravenous infusion of 1 g galactosamine per kilogram of body weight. Galactosamine administration caused microclot formation in kidneys, liver, lungs, and spleen in a low percentage. If, however, animals were infused with the fibrinolysis inhibitor epsilon-aminocaproic acid in addition to galactosamine, microclots were generated in a high percentage. The microclots exhibited typical staining characteristics like those observed in the generalized Shwartzman reaction. Some animals developed bilateral renal cortical necrosis. Heparin treatment prevented the occurrence of microclot fromation after galactosamine administration, but it neither prolonged the survival time of the animals nor prevented or reduced liver cell damage. Increases in serum GPT and bilirubin levels were similar in heparin-treated and untreated rabbits. The experiments indicate that disseminated intravascular coagulation is involved in galactosamine-induced hepatitis but does not contribute to the severity of the liver injury.

Alanine Transaminase↗
PubMed1986

The clearance of 125I-labelled fibrin from the subcutaneous tissue of limbs with lipodermatosclerosis.

The clearance of radioactive fibrin from the subcutaneous tissues has been measured in the rat and in the limbs of normal subjects, patients with varicose veins, and patients with lipodermatosclerosis. The animal experiments showed that the most effective way of producing a subcutaneous deposit of fibrin was by the simultaneous injection of labelled fibrinogen and thrombin. The clearance of these clots was delayed when fibrinolysis was depressed with epsilon-aminocaproic acid. Clearance of subcutaneous fibrin in man was significantly slower in the arms of patients with varicose veins and lipodermatosclerosis. Similarly clearance in the legs of patients with lipodermatosclerosis was significantly slower than that of the normal subjects and those with uncomplicated varicose veins. The clearance of fibrin from the legs of patients with lipodermatosclerosis was significantly slower than the clearance from their arms but there was no difference between arm and leg clearance in the normal subjects and those with uncomplicated varicose veins. The patients with lipodermatosclerosis had a significantly longer dilute blood clot lysis time. The inability to clear subcutaneous fibrin may be an aetological factor of lipodermatosclerosis.

Aminocaproates↗
PubMed2000

A study of the interaction between Helicobacter pylori and components of the human fibrinolytic system.

The interaction of plasminogen, tissue plasminogen activator (t-PA) and urokinase with a clinical strain of Helicobacter pylori was studied. Plasminogen bound to the surface of H. pylori cells in a concentration-dependent manner and could be activated to the enzymatic form, plasmin, by t-PA. Affinity chromatography assays revealed a plasminogen-binding protein of 58.9 kDa in water extracts of surface proteins. Surface-associated plasmin activity, detected with the chromogenic substrate CBS 00.65, was observed only when plasminogen and an exogenous activator were added to the cell suspension. The two physiologic plasminogen activators, t-PA and urokinase, were also shown to bind to and remain active on the surface of bacterial cells. epsilon-Aminocaproic acid caused partial inhibition of t-PA binding, suggesting that the kringle 2 structure of this activator is involved in the interaction with surface receptors. The activation of plasminogen by t-PA, but not urokinase, strongly depended on the presence of cells and a 25-fold enhancer effect on the initial velocity of activation by t-PA compared to urokinase was established. Furthermore, a relationship between cell concentration and the initial velocity of activation was demonstrated. These findings support the concept that plasminogen activation by t-PA on the bacterial surface is a surface-dependent reaction which offers catalytic advantages.

Aminocaproates↗
PubMed1995

Composite poly(methyl methacrylate-methacrylic acid-2-hydroxyethyl methacrylate) latex for immunoassay. The case of plasminogen.

Poly(methyl methacrylate-methacrylic acid-2-hydroxyethyl methacrylate) latex (ACRYLAT) was synthesized by radical precipitation polymerization. The mass median diameter (MMD) and the geometrical standard deviation (GSD) of the ACRYLAT particles were 138 nm and 1.2, respectively. The concentration of the titrable carboxylic groups in the surface layer of latex particles was equal to 8.41 x 10(-6) mol m-2. Latex was able to bind up to 2.82 x 10(-7) mol of 1-aminopyrene per 1 m2 of the surface of the latex particles due to the ionic interactions between carboxylate anions and ammonium cations of protonated 1-aminopyrene. ACRYLAT was able to immobilize covalently human serum albumin in amounts up to 0.23 mg m-2. Aggregation of ACRYLAT with immobilized HSA, induced with specific antibodies (anti-HSA), was investigated turbidimetrically. The results indicated that in the model turbidimetric immunoassay, ACRYLAT coated with HSA can be used for the detection of anti-HSA in the goat anti-HSA serum diluted from 50 to 7000-fold. Immobilization of rabbit antibodies to plasminogen (anti-Plg) to ACRYLAT via the epsilon-aminocaproic acid linkers provided particles which were used for the development of the turbidimetric immunoassay for plasminogen. In this assay plasminogen could be detected in concentration ranging from 0.75 to 75 micrograms ml-1 in the blood plasma.

Acrylic Resins↗
PubMed1994

Evolution of the technique of congenital diaphragmatic hernia repair on ECMO.

With the increase in popularity of delayed repair of congenital diaphragmatic hernia (CDH), many institutions are using extracorporeal membrane oxygenation (ECMO) to stabilize patients preoperatively. This practice has led to controversy regarding whether the repair should be performed while the patient is on ECMO or after decannulation. This report details the authors' experience with repair of CDH on ECMO. Of the 154 high-risk CDH patients treated at Children's Hospital, Boston, MA, since ECMO became available (1984), 97 received ECMO, including 31 who had repair performed while on ECMO. In group I (nine patients), repair was carried out only if the patients were unweanable from ECMO after 7 days. Activated clotting times (ACT) were maintained at 200 to 220 seconds. In group II (22 patients), repair was performed on ECMO electively, before decannulation. ACT were maintained at 180 to 200 seconds. Additionally, all patients in group II received aminocaproic acid before surgery. This was administered continuously for 72 hours postoperatively or until decannulation. Patients in group II had significantly less overall blood loss (P = .02), and lower transfusion requirement (P = .0003) than those in group I. Additionally, four of the nine patients in group I required reexploration because of hemorrhage; this was not required for any patient in group II (P = .005). Although the survival rates differed, this may have been because of a bias in patient selection between the two groups. From these preliminary data, the authors conclude that repair of congenital diaphragmatic hernia on ECMO can be performed safely, with a minimum of hemorrhagic complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminocaproates↗
PubMed2006

Optimization of HPLC chromatographic conditions for determination of Transkarbam 12 and its degradation products.

This paper deals with searching of HPLC chromatographic conditions for determination and separation of Transkarbam 12 (T 12) and its two main degradation products (omega-aminocaproic acid and dodecylalcohol). T 12 is a new substance which belongs to the group of accelerators of transdermal penetration. Chromatographic separation was achieved using Separon SGX C18 analytical column (150 mm x 3 mm i.d.; 5 microm). Mobile phase contained acetonitrile and sodium acetate buffer pH 4.5 at the flow rate of 1 ml/min. Separation was carried out under the conditions of gradient elution. After the modification of the structure by derivatization reagent (3,5-dinitrobenzoyl chloride) detection at wavelength 230 nm was realized. The aim of this study was not only the optimization of the separation of derivatization reagent and derivatized T 12, Ak and D but also optimal derivatization processes for all three substances.

Aminocaproates↗
PubMed1980

T suppressor cells and suppressor factor which act at the efferent stage of the contact sensitivity skin reaction: their production by mice injected with water-soluble, chemically reactive derivatives of oxazolone and picryl chloride.

The water soluble, chemically reactive thioglycollic acid thioether derivatives of oxazolone and picryl chloride were synthesized and tested for their ability to prevent the development of contact sensitivity. Mice given two injections of these agents showed partial or complete unresponsiveness when subsequently sensitized and challenged with oxazolone and picryl chloride, respectively. This unresponsiveness was associated with T suppressor cells, Ts-eff(cs), which blocked the efferent stage of the contact sensitivity reaction, i.e. the passive transfer of contact sensitivity. These Ts-eff(cs) were entirely specific when tested with the corresponding antigen. However, the suppression which they caused had a non-specific final common pathway. Cell from mice injected with the oxazolone and picryl thioethers and painted with the corresponding contact sensitizer produced a suppressor factor in vitro. This factor specifically blocked passive transfer by immune cells incubated in it. It also armed macrophages which then caused suppression. These macrophages were most effective when injected intraperitoneally. The suppressor factor had a molecular weight between 30,000 and 100,000 and the alpha-oxazolone factor was absorbed by oxazolone-albumin Sepharose and could be eluted with oxazolone-epsilon-aminocaproic acid. It was also absorbed by concanavalin-A-sepharose and could be eluted with alpha-methylmannoside. It is proposed that the ability of water soluble, chemically reactive haptenes to evoke a Ts-eff(cs) population may be relevent to the rarity of severe drug reactions following the injection of chemically reactive drugs.

Absorption↗
PubMed1988

ATP-dependent proteolysis of hemoglobin alpha chains in beta-thalassemic hemolysates is ubiquitin-dependent.

beta-Thalassemia is an inherited human disorder which is characterized by a deficient production of hemoglobin beta chains and an attendant accumulation of structurally normal alpha chains in the erythropoietic cells. The objective of this work is to understand the mechanism of intracellular proteolysis of these excess alpha chains. Dialyzed stroma-free hemolysates (32 mg/ml hemoglobin) of blood reticulocytes from four individuals with beta-thalassemia intermedia were incubated with human hemoglobin 3H-alpha chains (0.13 mg/ml) at 37 degrees C in a reaction mixture supporting protein degradation. In the presence of ATP and an ATP-generating system, the fraction of alpha chain 3H radioactivity made acid-soluble after 4 h ranged from 4 to 12% among the different hemolysates; in the absence of ATP or when hemolysates of normal human erythrocytes were used, only 1 to 2% of the 3H-alpha chains were degraded. It is likely that the ATP-dependent proteolysis of 3H-alpha chains in the beta-thalassemic hemolysates corresponds to the ATP-dependent turnover of newly synthesized soluble alpha chains in intact beta-thalassemic reticulocytes observed previously (Shaeffer, J. (1983) J. Biol. Chem. 258, 13172-13177) because of the following similarities between the two systems: (a) free 3H-alpha chains, but not 3H-labeled tetrameric hemoglobins, were readily degraded; (b) the rate of 3H-alpha chain proteolysis in the cell-free system was at least one-half of that observed for the turnover of newly synthesized alpha chains (t1/2 approximately 6 h) in intact cells; and (c) the ATP-dependent proteolytic activity of both systems was inhibited substantially by certain chemical agents (orthovanadate, N-ethylmaleimide, o-phenanthroline, and phenylmethylsulfonyl fluoride) but only slightly, if at all, by others (epsilon-aminocaproic acid and leupeptin). When excess human erythrocyte ubiquitin was added to the beta-thalassemic cell-free systems, a stimulation in ATP-dependent proteolysis of 3H-alpha chains ranging from 30 to 58% was observed. Conversely, addition of from 1.25 to 2.50 mg/ml affinity-purified rabbit antiubiquitin inhibited almost all (greater than 90%) of the ATP-dependent 3H-alpha chain proteolysis; in control experiments, antiubiquitin neutralized with excess ubiquitin inhibited only 13 to 30% of the total (including ubiquitin-stimulated) ATP-dependent proteolysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1994

Binding of recombinant apolipoprotein(a) to extracellular matrix proteins.

Elevated levels of lipoprotein(a), which consists of apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein-like moiety, is an independent risk factor for the development of atherosclerosis. We show that a recombinant form of apo(a) [r-apo(a)] binds strongly to fibronectin and fibrinogen, weakly to laminin, and not at all to von Willebrand factor, vitronectin, or collagen type IV. In contrast to the binding of plasminogen to fibronectin, r-apo(a) binding does not appear to be mediated by lysine-dependent interactions, based on the inability of epsilon-aminocaproic acid concentrations up to 0.2 mol/L to significantly decrease r-apo(a) binding to fibronectin. Plasminogen competed weakly for the binding of r-apo(a) to fibronectin, whereas r-apo(a) completely abolished plasminogen binding. The 29- and 38-kd heparin-binding thermolysin fragments of fibronectin, previously identified as the lipoprotein(a) binding domains, were digested with trypsin, and a peptide that retained the ability to bind r-apo(a) was isolated; the sequence of the peptide (AVTTIPAPTDLK) corresponds to the amino terminus of the 29- and 38-kd domains. A synthetic peptide with this sequence was able to compete effectively with fibronectin for r-apo(a) binding.

Aminocaproates↗
PubMed1973

Factor VIII recombination after dissociation by CaCl12.

Factor VIII is a large protein molecule of molecular weight 2,000,000 or larger that elutes in the void volume on agarose gel chromatography. It has been shown previously that high concentrations of alkali halides and, more specifically, 0.25 M Ca(2+) dissociate the molecule into a large carrier protein and a small fragment that retains the factor VIII activity. Factor VIII was prepared from normal canine plasma collected in sodium oxalate and heparin and adsorbed with BaSO(4). Results with Ca(2+) dissociation were the same as those obtained with fraction prepared from canine plasma collected in sodium citrate. The addition of 0.1 M epsilon-aminocaproic acid in the dissociation step had no effect. Fractionation of canine hemophilic plasma produced preparations without activity, and no activity was found when these inert preparations were dissociated with Ca(2+). These results indicate that the Ca(2+) dissociation is a true dissociation and not caused by enzymatic degradation by plasmin, thrombin, or activated factors VII, IX, or X. The apparent molecular weight of the small active fragment of factor VIII determined by gel chromatography was about 100,000. Finally, when the large carrier protein and the small active fragment of factor VIII were separated by gel chromatography, mixed, and dialyzed free of Ca(2+), they recombined to form a large active molecule that appeared in the void volume on agarose gel chromatography.

Aminocaproates↗
PubMed1996

Analogs of human plasminogen that are labeled with fluorescence probes at the catalytic site of the zymogen. Preparation, characterization, and interaction with streptokinase.

Fluorescent analogs of the proteinase zymogen, plasminogen (Pg), which are specifically inactivated and labeled at the catalytic site have been prepared and characterized as probes of the mechanisms of Pg activation. The active site induced non-proteolytically in Pg by streptokinase (SK) was inactivated stoichiometrically with the thioester peptide chloromethyl ketone. N alpha-[(acetylthio)acetyl]-(D-Phe)-Phe-Arg-CH2Cl; the thiol group generated subsequently on the incorporated inhibitor with NH2OH was quantitatively labeled with the fluorescence probe, 2-((4'-iodoacetamido)anilino)naphthalene-6-sulfonic acid; and the labeled Pg was separated from SK. Cleavage of labeled [Glu]Pg1 by urokinase-type plasminogen activator (uPA) was accompanied by a fluorescence enhancement (delta Fmax/Fo) of 2.0, and formation of 1% plasmin (Pm) activity. Comparison of labeled and native [Glu]Pg1 as uPA substrates showed that activation of labeled [Glu]Pg1 generated [Glu]Pm1 as the major product, while native [Glu]Pg1 was activated at a faster rate and produced [Lys]Pm1 because of concurrent proteolysis by plasmin. When a mixture of labeled and native Pg was activated, to include plasmin-feedback reactions, the zymogens were activated at equivalent rates. The lack of potential proteolytic activity of the Pg derivatives allowed their interactions with SK to be studied under equilibrium binding conditions. SK bound to labeled [Glu]Pg1, and [Lys]Pg1 with dissociation constants of 590 +/- 110 and 110 and 11 +/- 7 nM, and fluorescence enhancements of 3.1 +/- 0.1 and 1.6 +/- 0.1, respectively. Characterization of the interaction of SK with native [Glu]Pg1 by the use of labeled [Glu]Pg1 as a probe indicated a approximately 6-fold higher affinity of SK for the native Pg zymogen compared to the labeled Pg analog. Saturating levels of epsilon-aminocaproic acid reduced the affinity of SK for labeled [Glu]Pg1 by approximately 2-fold and lowered the fluorescence enhancement to 1.8 +/- 0.1, whereas the affinity of SK for labeled [Lys]Pg1 was reduced by approximately 98-fold with little effect on the enhancement. These results demonstrate that occupation of lysine binding sites modulates the affinity of SK for Pg and the changes in the environment of the catalytic site associated with SK-induced conformational activation. Together, these studies show that the labeled Pg derivatives behave as analogs of native Pg which report functionally significant changes in the environment of the catalytic site of the zymogen.

Enzyme Precursors↗
PubMed1986

Proteolysis of platelet glycoprotein Ib by plasmin is facilitated by plasmin lysine-binding regions.

We have characterized the effects of plasmin on glycoprotein Ib (GpIb), a platelet membrane receptor for von Willebrand factor (vWF), and on glycocalicin, a fragment of the alpha chain of GpIb that contains the vWF-binding region. The addition of 4.5 X 10(-7) mol/L plasmin to washed platelets caused a time-dependent decrease in ristocetin-induced, vWF-dependent platelet agglutination. epsilon-Aminocaproic acid (EACA) inhibited plasmin release of glycocalicin-related antigen from washed platelets and preserved vWF-dependent platelet agglutination, thus indicating that the lysine-binding sites on plasmin facilitated its degradation of GpIb. To demonstrate a direct interaction between plasmin and the vWF-binding region of GpIb we incubated purified glycocalicin with plasmin. Plasmin degraded the glycocalicin into two small carbohydrate-poor peptides and into a larger carbohydrate-rich fragment. EACA was able to inhibit plasmin-mediated degradation of glycocalicin in a concentration-dependent fashion. These studies indicated that plasmin degradation of GpIb was due to a direct interaction between plasmin and GpIb and that this effect was mediated by the lysine-binding region of the plasmin molecule.

Aminocaproates↗
PubMed1978

Autolysis induction of malignant lymphoblasts.

BALB/C mice were treated with epsilon aminocaproic acid (EACA), 0.1 to 3.2 mg/g body weight, subcutaneously every 24 hours for six days, starting on the second day after intraperitoneal transplantation of L5178Y lymphoma. Complete involution was observed in 20 to 90 per cent of the ascitic tumor and in 50 per cent of the solid tumor 72 hours after EACA was discontinued, tumoral involution and dosage were directly proportional. One hundred per cent of the non treated controls died 10 +/- 0.6 days after intraperitoneal lymphoma transplantation. During tumor involution malignant cells underwent autolysis and were attacked or phagocytized by activated macrophages. Since EACA is a proteolytic enzyme inhibitor, inhibition during treatment and activation of these enzymes after EACA was discontinued could have been the cause of autolysis of the L5178Y lymphoma cells.

Aminocaproates↗
PubMed1977

Altered morphology and increased cell adhesiveness of chinese hamster ovary cells cultured on fibrin.

Chinese hamster ovary cells cultivated on fibrin exhibited different characteristic from cells growing on plastic. While sparsely plated cells on plastic dishes had an epithelioid morphology, cells on fibrin assumed a round shape and then converted to a stretched form with protruded processes that increased with cell density. Within a few days, cells fibrinolysed adjacent fibrin and returned to the morphology seen in plastic dishes. When fibrinolysis was inhibited by epsilon-aminocaproic acid (EACA), cells continued to grow on the fibrin for a longer period and showed dense, criss-crossed fibroblast-type congestion. Whereas, cells on plastic maintained pavement-like epitheloid appearance when they grew to a confluent monolayer. The other altered characteristics on fibrin was increased accumulation of cells in multilayers. Normally as Chinese hamster cells on plastic proliferate, many cells float into the medium instead of piling up after they form a monolayer. On the other hand, cells on fibrin, being maintained by the addition of EACA, remained adherent, piling up multilayers instead of floating into the medium. A possible explanation of these findings is that the surface properties of the stretched cells on fibrin are altered to make them more adhesive. A possible link of these characteristics of the cells on fibrin to tumor cell behavior in vivo is dicussed.

Aminocaproates↗
PubMed1973

Formation of C3a and C5a anaphylatoxins in whole human serum after inhibition of the anaphylatoxin inactivator.

Two biologically and chemically distinct anaphylatoxins (ATs) could be generated in whole human serum after removal of the AT inactivator (AI) by immune-absorption or after inhibition of AI with 1 M epsilon-aminocaproic acid (EACA). Both human ATs could be generated by treatment of serum with antigen-antibody complexes, which activate the classical complement pathway, and with inulin or yeast, both of which trigger the alternate pathway. The ATs were isolated from serum in active form and characterized as C3a and C5a. Although human C3a had been characterized previously, C5a had not. The molecular weight of human C5a AT was 17,500; its electrophoretic mobility at pH 8.5 was -1.7 x 10(-5) cm(2) V(-1) s(-1). The minimal effective concentration in vitro was 7.5 x 10(-10) M. The minimal effective doses of human C5a in producing a wheal and erythema in the human skin was 1 x 10(-15) mol. The results strongly suggest a biological function for both ATs and indicate that the expression of their activity is controlled by the AI of normal blood plasma.

Adsorption↗
PubMed1993

The effector roles of kringle 1 and kringle 2 in the enzymatic properties of recombinant tissue-type plasminogen activator as revealed by generation of recombinant molecules containing each kringle linked to the protease domain.

Recombinant DNA technology has been employed to construct and express in human kidney 293 cells cDNAs encoding deletion-mutant recombinant (r) tissue-type plasminogen activators (tPA) retaining only the kringle 1 ([K1tPA]) and serine protease (P) functional domains (r-[K1tPA]P), and the kringle 2 ([K2tPA]) and P domains (r-[K2tPA]P), along with a variant of r-tPA containing a W253S mutation (r-tPA/W253S). Of these mutants, only r-[K2tPA]P retained its ability to interact with omega-amino acid effector molecules. The Km for single-chain wild-type (wt) r-tPA toward the synthetic substrate H-D-Ile-L-Pro-L-Arg-p-nitroanilide (S2288) was decreased by approximately 3-fold in the presence of a saturating concentration of human fibrinogen (Fg), along with a small (1.14-fold) increase in the kcat for this same reaction. The kinetic activation (dissociation) constant (KA) for Fg was 2.4 microM. Fg did not influence the steady-state amidolytic properties of two-chain wtr-tPA. Similar effects of Fg on the Km for hydrolysis of S2288 were displayed for single-chain forms of r-[K1tPA]P, r-[K2tPA]P, and r-tPA/W253S, with additional small effects of Fg on the kcat of this reaction. The KA for Fg toward these proteins ranged from 2.4 microM for wtr-tPA to 5.2 microM for r-[K1tPA]P. The amidolytic properties of the two-chain forms of these variants were also unaffected by Fg. The activation rate of [Glu1]-plasminogen ([Glu1]Pg) by wtr-tPA was stimulated approximately 7-fold by Fg and approximately 139-fold by the same concentration (in Fg equivalents) of human fibrin (Fn) (Fn/Fg stimulatory ratio = 19.9). The Fn/Fg ratio was 10.6, 20.9, and 18.0 for r-[K1tPA]P, r-[K2tPA]P, and r-tPA/W253S, respectively. Quantitative [Glu1]Pg-enriched clot lysis assays revealed that r-[K1tPA]P, r-[K2tPA]P, and r-tPA/W253S were approximately 18, 72, and 54%, respectively, as effective as wtr-tPA in catalyzing the plasminogen activation event leading to lysis. The antifibrinolytic agent epsilon-aminocaproic acid, inhibited clot lysis with approximately equal effectiveness in [Glu1]Pg-enriched clots when wtr-tPA, r-[K1tPA]P, r-[K2tPA]P, or r-tPA/W253S were employed as the activators. These studies demonstrated that Fg- and Fn-based stimulatory effects on the enzymatic properties of r-tPA and its variants were generally not proportional to the macroscopic binding abilities of these proteins with omega-amino acids or with Fg and Fn.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed2002

The blockage of the high-affinity lysine binding sites of plasminogen by EACA significantly inhibits prourokinase-induced plasminogen activation.

Prourokinase-induced plasminogen activation is complex and involves three distinct reactions: (1) plasminogen activation by the intrinsic activity of prourokinase; (2) prourokinase activation by plasmin; (3) plasminogen activation by urokinase. To further understand some of the mechanisms involved, the effects of epsilon-aminocaproic acid (EACA), a lysine analogue, on these reactions were studied. At a low range of concentrations (10-50 microM), EACA significantly inhibited prourokinase-induced (Glu-/Lys-) plasminogen activation, prourokinase activation by Lys-plasmin, and (Glu-/Lys-) plasminogen activation by urokinase. However, no inhibition of plasminogen activation by Ala158-prourokinase (a plasmin-resistant mutant) occurred. Therefore, the overall inhibition of EACA on prourokinase-induced plasminogen activation was mainly due to inhibition of reactions 2 and 3, by blocking the high-affinity lysine binding interaction between plasmin and prourokinase, as well as between plasminogen and urokinase. These findings were consistent with kinetic studies which suggested that binding of kringle 1-4 of plasmin to the N-terminal region of prourokinase significantly promotes prourokinase activation, and that binding of kringle 1-4 of plasminogen to the C-terminal lysine158 of urokinase significantly promotes plasminogen activation. In conclusion, EACA was found to inhibit, rather than promote, prourokinase-induced plasminogen activation due to its blocking of the high-affinity lysine binding sites on plasmin(ogen).

Aminocaproates↗
PubMed1975

The inhibition of urokinase by aromatic diamidines.

1. Structure-activity relationships have been established for the inhibition of urokinase by aromatic diamidines. In an assay system employing purified urokinase and human plasminogen the most potent inhibitor was found in 4',4''-diamidino-2-hydroxy-1,4-diphenoxybutane which proved 5600 times more active on a molar bases than epsilon-aminocaproic acid (E-ACA). 2. 4',4''-diamidino-2-hydroxy-1,4-diphenoxybutane behaved as a competitive inhibitor of the urokinase catalyzed hydrolysis of N-alpha-acetyl-L-lysine methyl ester. At pH 7.85 and 37 degrees C the K-1 value was determined as 3.18 times 10-6 M which compares with a value of 6.79 times 10-5 M for p-aminobenzamidine and 3.57 times 10-2 M for E-ACA. 3. In two fibrinolytic tests including urokinase as activator the superiority of diamidines over E-ACA was less marked than in the pure plasminogen activation system. This was due to the presence of certain plasma proteins in the fibrinolysis assays which augmented the inhibitory strength of E-ACA. The order of effectiveness of diamidines in the lysis tests was also different from the one in the activation test. In a human fibrin clot lysis test the most active inhibitor was 3',3''-diamidino-2-hydroxy-1,4-diphenoxybutane which was 1700 times more effective on a molar basis than E-ACA. In a human plasma clot lysis test the strongest inhibitor, 2-hydroxy-stilbamidine, was 70 times more powerful than E-ACA.

Amidines↗