RESUMO
Secondary cold agglutinin syndrome (CAS) is autoimmune hemolytic anemia secondary to infections and lymphoid disorder. We here report the first Asian case of CAS secondary to novel coronavirus disease 2019 (COVID-19). A 72-year-old Japanese woman presented with a 2-week history of dyspnea and cough, and laboratory data revealed severe hemolytic anemia with a hemoglobin level of 4.7 g/dL. She was diagnosed with COVID-19, CAS, and monoclonal gammopathy of undetermined significance (MGUS). The anemia responded to corticosteroids administered for COVID-19 and required maintenance therapy. Although corticosteroids are not a standard therapy for CAS, they might be effective for CAS secondary to COVID-19 complicated with MGUS.
Assuntos
Anemia Hemolítica Autoimune , COVID-19 , Gamopatia Monoclonal de Significância Indeterminada , Corticosteroides/uso terapêutico , Idoso , Anemia Hemolítica Autoimune/complicações , Anemia Hemolítica Autoimune/tratamento farmacológico , COVID-19/complicações , Crioglobulinas , Feminino , Humanos , Imunoglobulina M , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Gamopatia Monoclonal de Significância Indeterminada/tratamento farmacológicoRESUMO
Homer is a postsynaptic scaffold protein, which has long and short isoforms. The long form of Homer consists of an N-terminal target-binding domain and a C-terminal multimerization domain, linking multiple proteins within a complex. The short form of Homer only has the N-terminal domain and likely acts as a dominant negative regulator. Homer2a, one of the long form isoforms of the Homer family, expresses with a transient peak in the early postnatal stage of mouse cerebellar granule cells (CGCs); however, the functions of Homer2a in CGCs are not fully understood yet. In this study, we investigated the physiological roles of Homer2a in CGCs using recombinant adenovirus vectors. Overexpression of the Homer2a N-terminal domain construct, which was made structurally reminiscent with Homer1a, altered NMDAR1 localization, decreased NMDA currents, and promoted the survival of CGCs. These results suggest that the Homer2a N-terminal domain acts as a dominant negative protein to attenuate NMDAR-mediated excitotoxicity. Moreover, we identified a novel short form N-terminal domain-containing Homer2, named Homer2e, which was induced by apoptotic stimulation such as ischemic brain injury. Our study suggests that the long and short forms of Homer2 are involved in apoptosis of CGCs.
Assuntos
Apoptose , Cerebelo/citologia , Proteínas de Arcabouço Homer/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Isquemia Encefálica/patologia , Proteínas de Arcabouço Homer/química , Proteínas de Arcabouço Homer/genética , Camundongos Endogâmicos ICR , Modelos Biológicos , N-Metilaspartato/metabolismo , Domínios Proteicos , Isoformas de Proteínas/metabolismoRESUMO
OBJECTIVE: Although thrombin-activatable fibrinolysis inhibitor (TAFI) has been implicated as a negative regulator of fibrinolysis, its pathophysiological significance remains to be unveiled. We performed the pharmacologic study to assess the effect of EF6265, a specific inhibitor of activated form of TAFI (TAFIa) on sepsis-induced organ dysfunction models. DESIGN: A controlled, in vivo laboratory study. SETTING: Company research laboratory. SUBJECTS: Wistar and Sprague-Dawley rats. INTERVENTIONS: Endotoxemia and sepsis models were induced by intravenous injection of lipopolysaccharide and Pseudomonas aeruginosa, respectively. MEASUREMENTS AND MAIN RESULTS: In the endotoxemia model, posttreatment (1 hour) with EF6265 reduced fibrin deposits in the kidney and liver accompanied by no significant changes in platelet count and fibrinogen concentration in plasma. This compound also significantly decreased levels of plasma lactate dehydrogenase and aspartate aminotransferase, markers of organ dysfunction. In the sepsis model, EF6265, simultaneously administered with ceftazidime (CAZ) 2 hours after Pseudomonas aeruginosa injection, showed no influence on the antibiotic activity of CAZ. Meanwhile, it dramatically potentiated the interleukin-6-reducing effect of CAZ in plasma, suggesting that inhibition of TAFIa leads to the reduction in systemic inflammatory response associated with bacterial infection. This combined treatment also lowered plasma lactate dehydrogenase and blood urea nitrogen more potently than single treatment with CAZ. CONCLUSIONS: These results clearly suggest that TAFI plays an important role in the deterioration of organ dysfunction in sepsis and the inhibitor of TAFIa protects against sepsis-induced tissue damage through regulation of fibrinolysis and inflammation.
Assuntos
Aminoácidos/farmacologia , Carboxipeptidase B2/farmacologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Ácidos Fosfínicos/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Sepse/tratamento farmacológico , Análise de Variância , Animais , Análise Química do Sangue , Ceftazidima/farmacologia , Modelos Animais de Doenças , Fibrinogênio/efeitos dos fármacos , Fibrinogênio/metabolismo , Heparina/farmacologia , Interleucina-6/sangue , Contagem de Leucócitos , Lipopolissacarídeos/farmacologia , Masculino , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Contagem de Plaquetas , Probabilidade , Infecções por Pseudomonas/sangue , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Sensibilidade e Especificidade , Sepse/sangue , Células-TroncoRESUMO
OBJECTIVES: It is known that prophylaxis with imipenem reduces the risk of infection accompanying severe acute pancreatitis. In this study,we modified a rat experimental model of severe acute pancreatitis for antibiotic evaluation, and the effect of biapenem was compared with that of imipenem to determine the usefulness of biapenem. METHODS: Severe acute pancreatitis was induced by 5% sodium taurocholate. Antibiotics were subcutaneously administered at 3 and 6 hours and evaluated at 12 hours after the pancreatitis induction. For pharmacokinetic evaluation, antibiotics were subcutaneously administered at 3 hours after the pancreatitis induction. RESULTS: From 3 hours after the induction, bacteria were detected from the pancreas. The total bacterial count increased in a time-dependent manner for 12 hours. Biapenem administration reduced the total bacterial count in the pancreas, as observed in imipenem administration. The plasma concentration of biapenem was almost equivalent to that of imipenem; however, the pancreatic penetration of biapenem was approximately twice that of imipenem in this model. CONCLUSIONS: Biapenem was suggested to be effective in prophylactic treatment of infectious complications as much as imipenem because of its superior penetration to the pancreas in severe acute pancreatitis.
Assuntos
Antibacterianos/farmacocinética , Infecções Bacterianas/prevenção & controle , Imipenem/farmacocinética , Pâncreas/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Tienamicinas/farmacocinética , Doença Aguda , Animais , Antibacterianos/administração & dosagem , Ascite/microbiologia , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Imipenem/administração & dosagem , Injeções Subcutâneas , Intestinos/microbiologia , Linfonodos/microbiologia , Masculino , Pâncreas/metabolismo , Pâncreas/microbiologia , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Pancreatite/microbiologia , Ratos , Ratos Wistar , Índice de Gravidade de Doença , Ácido Taurocólico , Tienamicinas/administração & dosagemRESUMO
BACKGROUND/AIM: Plasma carboxypeptidase B is a physiological fibrinolysis inhibitor. In the present study, the effects of EF6265, a novel specific plasma carboxypeptidase B inhibitor, on renal dysfunction in a rat thrombotic glomerulonephritis model were examined. METHODS: The model was induced by injection of anti-glomerular basement membrane serum and lipopolysaccharide to rats. Renal microthrombosis was histologically evaluated by phosphotungstic acid-hematoxylin staining for fibrin thrombi. Renal dysfunction was evaluated on the basis of plasma levels of blood urea nitrogen as well as renal edemas and urine volume. RESULTS: The glomerular microthrombi observed in a positive control group were significantly reduced after a short-term treatment (4 h) with EF6265 at a dose which enhanced fibrinolysis. The elevation of blood urea nitrogen and renal edema formation decreased, and the reduction of the urine volume improved after a long-term treatment (21 h) with EF6265. In addition, EF6265 had a protective activity against multiple organ dysfunction, because it reduced plasma lactate dehydrogenase and alanine aminotransferase levels and mortality in this model. CONCLUSION: EF6265, which inhibits plasma carboxypeptidase B, showed a protective effect on thrombotic renal dysfunction in thrombotic glomerulonephritis through enhancing the fibrinolysis.
Assuntos
Aminoácidos/administração & dosagem , Carboxipeptidase B/antagonistas & inibidores , Carboxipeptidase B/sangue , Fibrinólise/efeitos dos fármacos , Glomerulonefrite/enzimologia , Rim/fisiopatologia , Ácidos Fosfínicos/administração & dosagem , Trombose/enzimologia , Animais , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Injeções Intravenosas , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Trombose/tratamento farmacológico , Trombose/patologiaRESUMO
BACKGROUND: Cocoa powder is rich in polyphenols such as catechins and procyanidins and has been shown in various models to inhibit LDL oxidation and atherogenesis. OBJECTIVE: We examined whether long-term intake of cocoa powder alters plasma lipid profiles in normocholesterolemic and mildly hypercholesterolemic human subjects. DESIGN: Twenty-five subjects were randomly assigned to ingest either 12 g sugar/d (control group) or 26 g cocoa powder and 12 g sugar/d (cocoa group) for 12 wk. Blood samples were collected before the study and 12 wk after intake of the test drinks. Plasma lipids, LDL oxidative susceptibility, and urinary oxidative stress markers were measured. RESULTS: At 12 wk, we measured a 9% prolongation from baseline levels in the lag time of LDL oxidation in the cocoa group. This prolongation in the cocoa group was significantly greater than the reduction measured in the control group (-13%). A significantly greater increase in plasma HDL cholesterol (24%) was observed in the cocoa group than in the control group (5%). A negative correlation was observed between plasma concentrations of HDL cholesterol and oxidized LDL. At 12 wk, there was a 24% reduction in dityrosine from baseline concentrations in the cocoa group. This reduction in the cocoa group was significantly greater than the reduction in the control group (-1%). CONCLUSION: It is possible that increases in HDL-cholesterol concentrations may contribute to the suppression of LDL oxidation and that polyphenolic substances derived from cocoa powder may contribute to an elevation in HDL cholesterol.
Assuntos
Cacau , HDL-Colesterol/sangue , Carboidratos da Dieta , Suplementos Nutricionais , Flavonoides/uso terapêutico , Lipoproteínas LDL/sangue , Fenóis/uso terapêutico , Bebidas , Biomarcadores/urina , Índice de Massa Corporal , Catequina/urina , Registros de Dieta , Gorduras na Dieta , Humanos , Lipoproteínas/sangue , Masculino , Oxirredução , Estresse Oxidativo , Polifenóis , SacaroseRESUMO
Human bone marrow-derived mesenchymal stem cells (hMSCs) have the potential to differentiate into several types of cells. Calcium ions (Ca(2+)) play an important role in the differentiation and proliferation of hMSCs. We have demonstrated that spontaneous [Ca(2+)](i) oscillations occur without agonist stimulation in hMSCs. However, the precise mechanism of its generation remains unclear. In this study, we investigated the mechanism and role of spontaneous [Ca(2+)](i) oscillations in hMSCs and found that IP(3)-induced Ca(2+) release is essential for spontaneous [Ca(2+)](i) oscillations. We also found that an ATP autocrine/paracrine signaling pathway is involved in the oscillations. In this pathway, an ATP is secreted via a hemi-gap-junction channel; it stimulates the P(2)Y(1) receptors, resulting in the activation of PLC-beta to produce IP(3). We were able to pharmacologically block this pathway, and thereby to completely halt the [Ca(2+)](i) oscillations. Furthermore, we found that [Ca(2+)](i) oscillations were associated with NFAT translocation into the nucleus in undifferentiated hMSCs. Once the ATP autocrine/paracrine signaling pathway was blocked, it was not possible to detect the nuclear translocation of NFAT, indicating that the activation of NFAT is closely linked to [Ca(2+)](i) oscillations. As the hMSCs differentiated to adipocytes, the [Ca(2+)](i) oscillations disappeared and the translocation of NFAT ceased. These results provide new insight into the molecular and physiological mechanism of [Ca(2+)](i) oscillations in undifferentiated hMSCs.
Assuntos
Trifosfato de Adenosina/fisiologia , Comunicação Autócrina/fisiologia , Sinalização do Cálcio/fisiologia , Células-Tronco Mesenquimais/metabolismo , Fatores de Transcrição NFATC/metabolismo , Comunicação Parácrina/fisiologia , Trifosfato de Adenosina/metabolismo , Adipogenia/fisiologia , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Junções Comunicantes/metabolismo , Humanos , Modelos Biológicos , Receptores Purinérgicos/fisiologia , Fatores de Transcrição/metabolismo , TransfecçãoRESUMO
BACKGROUND: Rosmarinic acid (RA) is a natural polyphenolic substance contained in many Lamiaceae herbs such as Perilla frutescens. Previous studies have shown RA has antioxidative and anti-inflammatory activity. However, little is known on the absorption, metabolism, degradation and excretion of RA. AIM OF THE STUDY: The aim of this study in healthy humans was to determine the absorption, metabolism, and urinary excretion of RA after a single intake of perilla extract (PE). METHOD: Six healthy men (mean age 37.2 +/- 6.2 y and mean body mass index 22.0 +/- 1.9 kg/m(2)) were enrolled in the study that was a crossover design involving single intakes of PE containing 200 mg RA and placebo with a 10 day interval between treatments. Blood samples were collected before intake and at designated time intervals, while urine samples were collected over the periods 0-6 h, 6-24 h and 24-48 h after intake. RA and its related metabolites in plasma and urine were measured by LC-MS. RESULTS: RA, methylated RA (methyl-RA), caffeic acid (CAA), ferulic acid (FA) and a trace of m-coumaric acid (COA) were detected in the urine after intake of PE. In plasma, RA, methyl-RA and FA were detected, with maximum levels obtained 0.5, 2 and 0.5 h after intake of PE, respectively. The majority of these components in both plasma and urine were present as conjugated forms (glucuronide and/or sulfated). The proportion of RA and its related metabolites excreted in the urine was 6.3 +/- 2.2% of the total dose, with approximately 75% of these components being excreted within 6 h after intake of PE. CONCLUSIONS: RA contained in PE was absorbed, conjugated and methylated following intake, with a small proportion of RA being degraded into various components, such as conjugated forms of CAA, FA and COA. These metabolites were then rapidly excreted in the urine.
Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Antioxidantes/metabolismo , Cinamatos/metabolismo , Perilla frutescens , Inibidores de Serina Proteinase/metabolismo , Adulto , Biomarcadores/metabolismo , Ácidos Cafeicos/metabolismo , Catecol O-Metiltransferase/efeitos dos fármacos , Catecol O-Metiltransferase/metabolismo , Cinamatos/urina , Ácidos Cumáricos/metabolismo , Estudos Cross-Over , Depsídeos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Metilação/efeitos dos fármacos , Pessoa de Meia-Idade , Perilla frutescens/metabolismo , Extratos Vegetais , Estruturas Vegetais , Valores de Referência , Inibidores de Serina Proteinase/urina , Ácido RosmarínicoRESUMO
Plasma procarboxypeptidase B, also known as thrombin-activatable fibrinolysis inhibitor (TAFI), is converted by thrombin into the active enzyme, carboxypeptidase B (CPB)/activated TAFI. Plasma CPB down-regulates fibrinolysis by removing carboxy-terminal lysines, the ligands for plasminogen and tissue-type plasminogen activator (tPA), from partially degraded fibrin. To target thrombosis in a new way, we have identified and optimized a phosphinic acid-containing inhibitor of CPB, EF6265 [(S)-7-amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino) propyl]hydroxyphosphinoyl]methyl]heptanoic acid] and determined both the pharmacological profile and pathophysiological role of CPB in rat thrombolysis. EF6265 specifically inhibited plasma CPB activity with an IC(50) (50% inhibitory concentration) of 8.3 nM and enhanced tPA-mediated clot lysis in a concentration-dependent manner. EF6265 decreased detectable thrombi (percentage of glomerular fibrin deposition; control, 98 +/- 1.1; EF6265, 0.1 mg/kg, 27 +/- 9.1) that had been generated by tissue factor in a rat microthrombosis model with concomitant increases in plasma D-dimer concentration (control, <0.5 microg/ml; EF6265, 0.1 mg/kg, 15 +/- 3.5 microg/ml). EF6265 reduced plasma alpha2-antiplasmin activity to a lesser extent than tPA. In an arteriovenous shunt model, EF6265 (1 mg/kg) enhanced exogenous tPA-mediated thrombolysis under the same conditions that neither EF6265 nor tPA (600 kIU/kg) alone reduced thrombi. EF6265 (1 and 30 mg/kg) did not affect the bleeding time in rats. Moreover, it did not prolong the bleeding time evoked by tPA (600 kIU/kg). These results confirm that circulating procarboxypeptidase B functions as a fibrinolysis inhibitor's zymogen and validates the use of CPB inhibitors as both an enhancer of physiological fibrinolysis in microcirculation and as a novel adjunctive agent to tPA for thromboembolic diseases while maintaining a small effect on primary hemostasis.
Assuntos
Aminoácidos/farmacologia , Carboxipeptidase B2/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fibrinólise/efeitos dos fármacos , Ácidos Fosfínicos/farmacologia , Aminoácidos/farmacocinética , Aminoácidos/uso terapêutico , Animais , Derivação Arteriovenosa Cirúrgica , Tempo de Sangramento , Carboxipeptidase B2/metabolismo , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Injeções Intravenosas , Masculino , Modelos Biológicos , Ácidos Fosfínicos/farmacocinética , Ácidos Fosfínicos/uso terapêutico , Ratos , Ratos Wistar , Tromboplastina , Trombose/induzido quimicamente , Trombose/tratamento farmacológicoRESUMO
Ion channels and receptors are targeted and localized at specific postsynaptic sites to mediate neurotransmission. Receptors clustering at postsynaptic sites has been extensively studied; however, the molecular mechanisms underlying intracellular trafficking of receptors to their specific destinations remain unclear. In the present study, we found that glutamate receptor delta2 interacted directly with AP-4, a newly identified adaptor protein complex-4 that mediates protein sorting in mammalian cells. The interaction between mu4 subunit of AP-4 and the delta2 C-terminal involved multiple amino acid sequence motifs other than the classical tyrosine-based signals. AP-4 complex is expressed ubiquitously in many regions of brain, with localization on the Golgi-like structures in the cell bodies and dendrites of neurons. In addition, overexpression of mu4 substantially altered the distribution pattern of delta2 in heterologous cells. These results suggest a potential involvement of AP-4 in the trafficking of delta2 in the brain.
Assuntos
Complexo 4 de Proteínas Adaptadoras/biossíntese , Regulação da Expressão Gênica/fisiologia , Neurônios/metabolismo , Receptores de Glutamato/metabolismo , Complexo 4 de Proteínas Adaptadoras/genética , Complexo 4 de Proteínas Adaptadoras/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Sistema Nervoso Central/metabolismo , Chlorocebus aethiops , DNA Complementar/genética , Humanos , Dados de Sequência Molecular , Ratos , Ratos Wistar , Receptores de Glutamato/genética , Homologia de Sequência de AminoácidosRESUMO
Receptors and various molecules in neurons are localized at precise locations to perform their respective functions, especially in synaptic sites. Among synaptic molecules, PDZ domain proteins play major roles in scaffolding and anchoring membrane proteins for efficient synaptic transmission. In the present study, we isolated CIP98, a novel protein (98 kDa) consisting of three PDZ domains and a proline-rich region, which is widely expressed in the central nervous system. In situ hybridization and immunohistochemical staining patterns demonstrate that CIP98 is expressed strongly in certain types of neurons, i.e. pyramidal cells in layers III-V of the cerebral cortex, projecting neurons in the thalamus and interneurons in the cerebellum. The results of immunocytochemical staining and electron microscopy revealed that CIP98 is localized both in dendrites and axons. Interestingly, CIP98 interacts with CASK (calmodulin-dependent serine kinase), a member of the membrane-associated guanylate kinase (MAGUK) family that plays important roles in the molecular organization of proteins at synapses. CIP98 was shown to co-localize with CASK along the dendritic processes of neurons. In view of its direct association with CASK, CIP98 may be involved in the formation of CASK scaffolding proteins complex to facilitate synaptic transmission in the CNS.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Sistema Nervoso Central/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Núcleosídeo-Fosfato Quinase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Proteínas de Transporte/genética , Células Cultivadas , Proteínas de Fluorescência Verde , Guanilato Quinases , Humanos , Hibridização In Situ , Proteínas Luminescentes/genética , Masculino , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Neurônios/metabolismo , Núcleosídeo-Fosfato Quinase/genética , Especificidade de Órgãos , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína/fisiologia , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Homologia de Sequência de Aminoácidos , Técnicas do Sistema de Duplo-HíbridoRESUMO
Inside cells, membrane proteins are localized at particular surface domains to perform their precise functions. Various kinds of PDZ domain proteins have been shown to play important roles in the intracellular trafficking and anchoring of membrane proteins. In this study, we show that delta2 glutamate receptor is interacting with S-SCAM/MAGI-2, a PDZ domain protein localized in the perinuclear region and postsynaptic sites of cerebellar Purkinje cells. The binding is regulated by PKC (protein kinase-C) mediated phosphorylation of the receptor with a unique repetitive structure in S-SCAM/MAGI-2. Co-expression of both proteins resulted in drastic changes of the receptor localization in COS7 cells. These results show a novel regulatory mechanism for the binding of PDZ domain proteins and suggest that the interaction between delta2 receptor and S-SCAM/MAGI-2 may be important for intracellular trafficking of the receptor.
Assuntos
Proteínas de Transporte/metabolismo , Proteína Quinase C/metabolismo , Receptores de Glutamato/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Células COS , Proteínas de Transporte/genética , Linhagem Celular , Cerebelo/metabolismo , Guanilato Quinases , Humanos , Técnicas In Vitro , Masculino , Dados de Sequência Molecular , Mutagênese , Ligação Proteica , Proteína Quinase C/genética , Estrutura Terciária de Proteína , Células de Purkinje/metabolismo , Ratos , Ratos Wistar , Receptores de Glutamato/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Técnicas do Sistema de Duplo-HíbridoRESUMO
Procarboxypeptidase B (also known as thrombin-activatable fibrinolysis inhibitor) is a recently described plasma zymogen known to be activated by thrombin in plasma. Carboxy-terminal lysine residues from partially degraded fibrin are important for the binding and activation of plasminogen, and carboxypeptidase B, an active form of procarboxypeptidase B, has been shown to inhibit fibrinolysis by eliminating these residues. The present paper investigates the effects of carboxypeptidase B inhibitors, DL-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGPA) and potato-derived carboxypeptidase inhibitor (CPI), on tissue factor (TF)-induced microthrombosis in rats. Intravenous injection of MGPA (3 mg/kg and higher) or CPI (0.3 mg/kg and higher) after microthrombi formation dramatically attenuated TF-induced glomerular fibrin deposition with an increase in plasma levels of D-dimer. These results indicate that carboxypeptidase B inhibitors can enhance endogenous fibrinolysis and reduce thrombi in the TF-induced microthrombosis model after systemic administration even after thrombi formation.