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The biological and pharmacological effects of BK (bradykinin) are mediated by two receptors: the constitutive B2R (B2 receptor) and the inducible B1R (B1 receptor). BK plays a role in the hepatic microcirculation by inducing the PHR (portal hypertensive response) via B2R, whereas DABK (des-Arg9-BK), a B1R agonist, does not elicit the response. During IRI (ischaemia/reperfusion injury), important changes occur in the microcirculation, and cell death by necrosis and apoptosis is involved in poor graft function. The aim of the present study was to analyse the role of B1R and B2R in liver cell death induced by IRI. Livers from Wistar rats were submitted to ischaemia (4°C) for 4 or 24 h. After this period, livers were reperfused ex vivo with Krebs-Henseleit solution (37°C). BK or DABK was then injected as a bolus during reperfusion in the absence or presence of HOE-140 (a B2R antagonist) or DALBK (des-Arg(9)-Leu(8)-BK) (a B1R antagonist) respectively. Liver viability was analysed by glucose release and bile secretion. The PHR to kinins did not change. Cell death was higher in the DABK group and its antagonist significantly decreased cell death. Interestingly, the B1R antagonist did not alter the number of necrotic cells, but it decreased the number of apoptotic cells. On the other hand, the B2R antagonist decreased the number of necrotic cells, but did not alter the number of apoptotic cells. Therefore B1R may participate in apoptotic cell death signalling, and B2R may be involved in necrotic cell death.

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Portal hypertension is the most common complication of chronic liver diseases, such as cirrhosis. The increased intrahepatic vascular resistance seen in hepatic disease is due to changes in cellular architecture and active contraction of stellate cells. In this article, we review the historical aspects of the kallikrein-kinin system, the role of bradykinin in the development of disease, and our main findings regarding the role of this nonapeptide in normal and experimental models of hepatic injury using the isolated rat liver perfusion model (mono and bivascular) and isolated liver cells. We demonstrated that: 1) the increase in intrahepatic vascular resistance induced by bradykinin is mediated by B2 receptors, involving sinusoidal endothelial and stellate cells, and is preserved in the presence of inflammation, fibrosis, and cirrhosis; 2) the hepatic arterial hypertensive response to bradykinin is calcium-independent and mediated by eicosanoids; 3) bradykinin does not have vasodilating effect on the pre-constricted perfused rat liver; and, 4) after exertion of its hypertensive effect, bradykinin is degraded by angiotensin converting enzyme. In conclusion, the hypertensive response to BK is mediated by the B2 receptor in normal and pathological situations. The B1 receptor is expressed more strongly in regenerating and cirrhotic livers, and its role is currently under investigation.

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Portal hypertension is the most common complication of chronic liver diseases, such as cirrhosis. The increased intrahepatic vascular resistance seen in hepatic disease is due to changes in cellular architecture and active contraction of stellate cells. In this article, we review the historical aspects of the kallikrein-kinin system, the role of bradykinin in the development of disease, and our main findings regarding the role of this nonapeptide in normal and experimentalmodels of hepatic injury using the isolated rat liver perfusion model (mono and bivascular) and isolated liver cells. We demonstrated that: 1) the increase in intrahepatic vascular resistance induced by bradykinin is mediated by B2 receptors, involving sinusoidal endothelial and stellate cells, and is preserved in the presence of inflammation, fibrosis, and cirrhosis; 2) the hepatic arterial hypertensive response to bradykinin is calcium-independent and mediated by eicosanoids; 3) bradykinin does not have vasodilating effect on the pre-constricted perfused rat liver; and, 4) after exertion of its hypertensive effect, bradykinin is degraded by angiotensin converting enzyme. In conclusion, the hypertensive response to BK is mediated by the B2 receptor in normal and pathological situations. The B1 receptor is expressed more strongly in regenerating and cirrhotic livers, and its role is currently under investigation.

Hipertensão portal é a complicação mais comum das doenças crônicas do fígado, tais como cirrose. A resistência intravascular aumentada observada na doença hepática é devida a alterações na arquitetura celular e contração ativa das células estreladas. Neste trabalho revisamos aspectos históricos do estudo do sistema calicreína-cinina e os resultados de nossos estudos do papel deste nonapeptídeo no controle do tono vascular intra-hepático em condições normais e modelos experimentais de agressão hepática usando a perfusão de fígado isolado de rato (mono e bivascular) e células hepáticas isoladas. Nós demonstramos que: 1) o aumento da resistência vascular intrahepática induzido pela bradicinina é mediado por receptores B2, envolve a participação de células endoteliais sinusoidais e células estreladas e não é alterada pela presença de inflamação, fibrose ou cirrose; 2) a resposta hipertensiva induzida pela bradicinina no sistema arterial hepático é cálcio-independente emediada por eicosanóides; 3) bradicinina não tem efeito dilatador na circulação intra-hepática; 4) após exercer efeito vasoconstritor intra-hepático, a bradicinina é degradada pela enzima conversora de angiotensina. Em conclusão, a resposta hipertensiva à bradicinina é mediada pelo receptor B2 em condições normais e patológicas. Receptor B1 é expresso mais fortemente nos fígados em regeneração e cirróticos e seu papel está sob investigação.

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UNLABELLED: We previously reported that in anicteric patients with the isolated form of schistosomiasis (without co-morbidities) an ursodeoxycholic acid-sensitive increase in serum gamma-glutamyltransferase activity (gammaGT) occurs. We now describe the presence of cholangiopathy in these patients. METHODS: Sixteen adult anicteric patients with the isolated form of schistosomiasis mansoni were carefully selected: nine with increased gammaGT and seven with normal gammaGT. High sensitive C-reactive protein (CRP), to exclude inflammatory status, hyaluronic acid (HA), and other laboratory parameters were determined. The ultrasonographic study measured spleen length, portal vein and splenic vein diameters, and the portal flow. Magnetic resonance cholangiopancreatography (MRCP) images were interpreted by a blind observer. MRCP was deemed abnormal when focal narrowing and/or paucity of second and third order biliary branches and/or irregularities in the contours of biliary pathways were identified. RESULTS: Both groups (normal and elevated gammaGT) have preserved hepatic function tests (HA, serum albumin, prothrombin time) and clinical significant portal hypertension (low platelet count and ultrasonographic parameters). MRCP was abnormal in all patients with elevated gammaGT but in only 3 of the 7 patients with normal gammaGT (p=0.003). CONCLUSION: Magnetic resonance cholangiopancreatography characterized a cholangiopatic disorder in anicteric patients with the isolated form of schistosomiasis, even preceding laboratory test alterations.

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UNLABELLED: Bradykinin elicits an intrahepatic vascular response (IHVR) mediated by the constitutive B(2) receptor (B(2)R). The biological effects of kinins may also be mediated by the inducible B(1) receptor (B(1)R). AIM: To verify if the hepatic B(1)R expression modulates IHVR to kinins. METHOD: We evaluated the ability of bradykinin and B(1)R agonists to elicit an IHVR in normal rats and in those submitted to acute or chronic inflammatory stimuli, fibrosis, cirrhosis, or hepatic regeneration. RESULTS: Bradykinin-induced IHVR was similar in all groups. B(1)R agonists did not elicit in any of them either a hypertensive or a hypotensive response. B(1) receptor induction was observed in all experimental groups (Western blot), except for the acute inflammatory group. CONCLUSION: B(1)R hepatic expression did not modulate IHVR to kinins.

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UNLABELLED: We have previously shown that tissue-type plasminogen activator (tPA) and rat plasma kallikrein (RPK) share a common, but not unique, pathway for liver clearance. AIM: To evaluate the hepatic clearance of both proteases in experimental liver fibrosis. METHODS: The hepatic clearance of these proteases was studied in porcine serum-induced liver fibrosis using the isolated and perfused rat liver model. To better interpret the results, we also studied four other experimental groups: the turpentine oil-induced acute-phase response (AP group), AP group followed by GdCl3 administration (AP/Gd group), CCl4-induced cirrhosis (CCl4 group) and normal group. RESULTS: The tPA clearance decreased significantly by both fibrotic and cirrhotic rat livers whereas the RPK clearance was not altered by the fibrotic rat liver. The hepatic clearance of tPA was reduced in the AP and AP/Gd groups; on the other hand, RPK clearance was increased in the AP group and, interestingly, this effect was neutralized by concomitant GdCl3 administration. CONCLUSIONS: We observed that tPA and RPK clearances were affected differently by fibrosis as well as by different stimuli of the acute-phase response, despite the fact that they share a common hepatic clearance mechanism in normal livers, and they were equally affected in cirrhosis.

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The liver is important for the kallikrein-kinin system modulation. This system plays a role in the inflammatory cascade with anticoagulant, profibrinolytic, and anti-adhesive attributes. The metalloendopeptidase EP24.15 is a major hepatic kininase. We studied the tissue distribution and subcellular localization of this enzyme in rat liver by cell fractionation and immunohistochemistry. Our results showed that EP24.15 is predominant in the soluble fraction of the liver homogenate and is present in the cytoplasm of hepatocytes, particularly in the perivenous zone (Z3). This localization is relevant because most hepatotoxin-induced necrosis, as well as ischemic hepatocellular injury, is predominant in Z3.

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Schistosomiasis mansoni is a non-cirrhotic fibrogenic disease model. The mild form shows normal liver function with slight or no liver fibrosis whereas in the periportal fibrosis form the manifestations of portal hypertension prevail over hepatocellular failure. We assessed serum hyaluronic acid as a marker of the course of the disease. We studied 24 patients presenting with pure chronic forms of schistosomiasis and seven with cirrhosis. In order to measure serum hyaluronic acid we developed a sandwich fluorescent ELISA-like assay. alpha2-Macroglobulin, prothrombin index, gamma-glutamyltransferase, platelets and ultrasound parameters were also assessed. The 20 micro g/l (ROC plot) hyaluronic acid level differentiated patients with the mild form (with no portal hypertension) from those with the severe form of schistosomiasis with 78% diagnostic efficacy. The 80 micro g/l cut-off value differentiated patients with the severe form of schistosomiasis from the cirrhotic group with similar diagnostic efficacy. alpha2-Macroglobulin provided no distinction between the groups studied. The hyaluronic acid serum concentration correlated positively with the splenic vein diameter (P=0.004) and marginally with alpha2-macroglobulin (P=0.059). Serum hyaluronic acid is a good marker for the initial phase of hepatic fibrosis and it was able to assess severity of liver disease in schistosomiasis.

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BACKGROUND: In severe forms of cirrhosis reduced liver synthesis of thrombopoietin (Tpo) can contribute to thrombocytopenia. In the hepatosplenic form of schistosomiasis, portal hypertension is the most evident clinical complication, although a deficiency of protein synthesis may be detected early. Our aim was to determine, for the first time in schistosomiasis, Tpo serum concentrations in patients with chronic forms of the disease. METHOD: Twenty-four patients with the pure form of schistosomiasis were studied; 13 had the hepatosplenic form (HE, with portal hypertension) and 11 had the hepatointestinal form (HI, without portal hypertension). Patients were HBsAg, anti-HBc and anti-HCV negative, and reported alcohol ingestion below 160 g/week. RESULTS: The Tpo serum concentration, determined in 10 healthy volunteers, varied from undetectable (< 15 pg/mL) to 489 pg/mL (median 208 pg/mL). The HE and HI groups differed (p = 0.004) in regard to the prothrombin index, thrombocytemia and gamma-glutamyltransferase but not in regard to Tpo (p = 0.622). No significant correlation was found between Tpo and the other parameters (p > 0.05). CONCLUSIONS: The results suggest that Tpo serum concentration does not mirror and/or has no significant participation in the mechanisms responsible for the thrombocytopenia observed in schistosomiasis patients with splenomegaly and portal hypertension.

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A concentraçåo das substâncias presentes no plasma é o resultado de um balanço entre as velocidades com que elas entram e deixam o espaço intravascular. Este artigo é atualizaçåo de importante mecanismo pelo qual o fígado remove glicoproteínas da circulaçåo: a endocitose mediada por receptor

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A proteína C (PC) do sistema plasmático de anticoagulaçäo pode estar diminuída em portadores da forma hepatoesplênica da esquistosomose (EHE), o que constitui fator de risco trombótico. Para avaliar o efeito de cirurgia da hipertensåo portal (HP) sobre a PC, determinamo-la (teste imuno-enzimático, Boehringer Mannheim Diagnostica) em 9 portadores da EHE antes e, em 5 deles, 6 dias após cirurgia que inclui a esplenectomia. Como controle estudamos 11 doadores de sangue sadios e 8 indivíduos eletivamente à colecistectomia. Os 28 indivíduos estudados eram HBsAg-negativos, nåo-alcólatras e nåo-transfundidos. A concentraçåo plasmática média da PC nos sadios (1,1 +- 0,1 U/mL) nåo diferiu das médias obtidas no pré (1,1 +- 0,1 U/mL) e no 6§ dia pós-operatório (1,1 +- 0,2 U/mL) dos colecistectomizados. Por outro lado, a média do grupo EHE (0,7 +- 0,1 U/mL) foi anterior (p<0,001) à grupos de controle. Em nenhum dos 19 controles a PC foi inferior a 0,6 U/mL, o que ocorreu em 33 por cento dos EHE, diminuiçåo esta acompanhada de hipoalbuminemia. Assim como a colecistectomia, a cirurgia de HP nåo alterou a PC diminuída (<0,6 U/mL) no pré-operatório näo a tiveram normalizada no pós-operatório. Os resultados evidenciam que atos cirúrgicos, per se, näo modificam a concentraçåo plasmática da PC e sugerem que a diminuiçåo desta reflete síntese hepática insuficiente e nåo consumo crônico. Na EHE, consumo crônico pode, como no caso da protrombina, ser corrigido pela esplenectomia.

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Alcoólatras assintomáticos (ingestäo média de 109 gramas de etanol por dia) assim como näo alcoólatras (grupo controle) foram submetidos ao teste de estímulo com infusäo de arginina I.V. e ao estímulo com glicose administrada por via oral. O teste de estímulo com glicose näo discriminou o grupo alcoólatra enquanto o teste com arginina mostrou: a) hiperglicemia no grupo alcoólatra durante o período de pós-infusäo; e b) hipoinsulinemia no grupo alcoólatra durante o período de infusäo do aminoácido. A resposta das células alfa (secreçäo de glucagon) a este estímulo foi semelhante nos dois grupos estudados. Sugerimos que alcoólatras assintomáticos e com resposta insulinêmica normal ao estímulo com glicose per os devam ser submetidos ao teste de infusäo de arginina antes que sua funçäo pancreática endócrina possa ser considerada normal

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