It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and β-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and β-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of β-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between β-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.

Animal studies and premarketing clinical trials have revealed hepatotoxicity of statins, primarily minor elevations in serum alanine aminotransferase levels. The combined chronic use of medicines and eventual ethanol abuse are common and may present a synergistic action regarding liver injury. Our objective was to study the effect of the chronic use of atorvastatin associated with acute ethanol administration on the liver in a rat model. One group of rats was treated daily for 5 days a week for 2 months with 0.8 mg/kg atorvastatin by gavage. At the end of the treatment the livers were perfused with 72 mM ethanol for 60 min. Control groups (at least 4 animals in each group) consisted of a group of 2-month-old male Wistar EPM-1 rats exposed to 10% ethanol (v/v) ad libitum replacing water for 2 months, followed by perfusion of the liver with 61 nM atorvastatin for 60 min, and a group of animals without chronic ethanol treatment whose livers were perfused with atorvastatin and/or ethanol. The combination of atorvastatin with ethanol did not increase the release of injury marker enzymes (alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase) from the liver and no change in liver function markers (bromosulfophthalein clearance, and oxygen consumption) was observed. Our results suggest that the combination of atorvastatin with ethanol is not more hepatotoxic than the separate use of each substance.

We have shown that tissue-type plasminogen activator (tPA) and plasma kallikrein share a common pathway for liver clearance and that the hepatic clearance rate of plasma kallikrein increases during the acute-phase (AP) response. We now report the clearance of tPA from the circulation and by the isolated, exsanguinated and in situ perfused rat liver during the AP response (48-h ex-turpentine treatment). For the sake of comparison, the hepatic clearance of a tissue kallikrein and thrombin was also studied. We verified that, in vivo, the clearance of 125I-tPA from the circulation of turpentine-treated rats (2.2 ± 0.2 ml/min, N = 7) decreases significantly (P = 0.016) when compared to normal rats (3.2 ± 0.3 ml/min, N = 6). The AP response does not modify the tissue distribution of administered 125I-tPA and the liver accounts for most of the 125I-tPA (>80%) cleared from the circulation. The clearance rate of tPA by the isolated and perfused liver of turpentine-treated rats (15.5 ± 1.3 µg/min, N = 4) was slower (P = 0.003) than the clearance rate by the liver of normal rats (22.5 ± 0.7 µg/min, N = 10). After the inflammatory stimulus and additional Kupffer cell ablation (GdCl3 treatment), tPA was cleared by the perfused liver at 16.2 ± 2.4 µg/min (N = 5), suggesting that Kupffer cells have a minor influence on the hepatic tPA clearance during the AP response. In contrast, hepatic clearance rates of thrombin and pancreatic kallikrein were not altered during the AP response. These results contribute to explaining why the thrombolytic efficacy of tPA does not correlate with the dose administered.

OBJETIVO. Revisão da filogênese e ontogênese hepáticas, do sistema microvascular hepático e da modulação do tônus deste sistema vascular por diferentes substâncias vasoativas. MÉTODO. Levantamento de artigos por meio do sistema MEDLINE e consulta a livros-texto. RESULTADO. Foram selecionados 52 trabalhos publicados entre 1949 e 1997, dos quais retiramos as informações a respeito de filogênese e ontogênese hepáticas, sistema microvascular hepático e mecanismos de controle do tônus vascular hepático. CONCLUSÃO. O fígado possui sistema vascular altamente especializado na promoção de mecanismos de troca entre hepatócitos e sangue. Diferentes fatores atuam continuamente sobre estruturas contrácteis deste sistema vascular adequando a perfusão do tecido hepático às necessidades homeostáticas de cada momento. O fígado é órgão eminentemente mantenedor do meio interno.

PURPOSE. To review some aspects of the hepatic phylogeny and ontogeny, the hepatic microvascular system, and the modulation of the tonus on this vascular system by different vasoactive substances. METHOD. Text books and articles from MEDLINE-indexed journals were consulted. RESULTS. Fifty-two articles, that were published between 1949 and 1997, were selected. They provided us with information concerning hepatic phylogeny and ontogeny, the hepatic microvascular system, and the modulation of the tonus in this vascular system. CONCLUSION. The architecture of the hepatic microvascular system, a unique and complex vascular system, is well suited to the functions of the organ. Different factors, including endothelial vasoactive substances, participate in the modulation of the vascular resistance through the liver adequating the liver perfusion to the homeostatic needs. The liver is eminently a maintainer of internal stability.

OBJETIVO: - O fígado inativa quantidades consideráveis de bradicinina; a principal enzima hepática cinino-inativadora (BIE, bradykinin inativating endopeptidase) hidrolisa especificamente a ligação Phe5-Ser6 do nonapeptídio e foi caracterizada como sendo a oligoendopeptidase EC 3.4. 24.15. No transplante ortotópico de fígado existe correlação entre aumento da concentração de aminoácidos no líquido de preservação (conseqüência de proteólise) e falência do enxerto. O objetivo deste trabalho é verificar se ocorre liberação da BIE de fígados preservados ex-vivo no líquido Braun-Collins ou em solução de Krebs-Henseleit bicarbonato (Krebs). MÉTODO: Fígados de ratos Wistar (180-220g) foram exsangüinados e após remoção foram preservados em líquido Braun Collins ou em solução Krebs, a 4oC. Foram retiradas alíquotas do líquido de preservação nos tempos 0, 4, 8 e 24 horas, para dosagem de ALT, AST, DHL e BIE. A atividade fluorimétrica da BIE foi ensaiada com o substrato Abz-RPPGFSPFRQ-EDDnp (análogo sintético da bradicinina) e sua presença confirmada por immunoblotting, revelado com anticorpo específico anti-EC 3.4.24.15. RESULTADOS: A liberação de ALT, AST, DHL e BIE é significativa no período 8-24hs. Nas alíquotas de 24 hs, em relação ao tempo zero, a concentração das quatro enzimas aumentou, respectivamente, no líquido Braun Collins, 8, 7, 19 e 10 vezes e, na solução de Krebs, 21, 17, 27 e 21 vezes; a relação ALT/DHL foi sempre inferior a um. CONCLUSÃO: Ocorre liberação de BIE durante a preservação ex-vivo do fígado, o que poderá servir como indicação da condição de preservação do enxerto; diminuição da capacidade cinino-inativadora do fígado poderá afetar sua reatividade vascular.

BACKGROUND: The liver inactivates considerable amounts of bradykinin; the main liver kinin-inactivating enzyme (BIE, bradykinin inactivating endopeptidase) hydrolyses specifically the Phe5-Ser6 bond of the nonapeptide and it has been characterized as the oligoendopeptidase E.C. 3.4.24.15. When orthotopic liver transplantation is performed there is a correlation between the increase of amino acid concentration in the preservation fluid (as a consequence of proteolysis) and graft dysfunction. AIM: Verify if BIE is released from livers stored ex vivo. METHOD: Wistar rats (180-220g) livers were exsanguinated and after removal were preserved in Braun Collins fluid or Krebs solution at 4o C. Aliquots were collected from the preservation fluid at 0, 4,8,24h, for ALT, AST, LDH and BIE assays. The fluorimetric activity of BIE was assayed upon Abz-RPPGFSPFRQ-EDDnp (synthetic BK analogue) and its presence was confirmed by immunoblotting, revealed with specific antibody anti-E.C.3.4.24.15. RESULTS: The release of ALT, AST, LDH and BIE is significant between 8-24h. In the 24h aliquots the four enzymes concentration increased in the Braun Collins fluid 8,7,19 and 10 respectively, and in the Krebs solution 21, 17, 27, 21 respectively, when compared to the zero time aliquot activities. The ratio ALT/LDH was always < 1. CONCLUSION: There is BIE release during ex vivo liver storage; this information may be useful as an indicator of the graft preservation condition; a decrease of the liver kinin-inactivating capability could affect the graft vascular reactivity.

A deficiência de antitrombina III (ATIII) é observada na hepatopatia grave e pode ser decorrente da redução de síntese ou de consumo aumentado, o que poderia ser compensado com o uso de concentrado de ATIII. OBJETIVO. Avaliar a eficiência da administração de uma dose fixa de concentrado de ATIII, em pacientes com hepatopatia descompensada com distúrbio da hemostasia. CASUÍSTICA E MÉTODO. Foram avaliados seis pacientes, com idade média de 44 anos, variando de 14 a 63 anos, portadores de cirrose (quatro de etiologia alcoólica, um viral e um doença de Wilson), com alteração de pelo menos dois dos parâmetros da hemostasia (TP > 1,40, TTPA > 1,25, fibrinogênio < 1,5g/L, plaquetas < 80.000/mm³). A média do nível de albumina foi de 2,6g/dL (1,9 a 3,8g/dL). O concentrado de ATIII (Kybernin®) foi administrado na dose de 50U/kg, em dias alternados. Foi colhido sangue antes da primeira infusão, 4 horas após e, depois, diariamente, antes da infusão do dia, para medida da ATIII plasmática (amidolítico). Nenhum paciente recebeu hemoderivados. RESULTADOS.As médias da dosagem de ATIII foram: inicial = 35,8%, 4 horas = 56,2%*, 2 dias = 48,7%*, 4 dias = 45,7%* e 8 dias = 42,3%. Após a infusão houve elevação significante dos níveis de ATIII (* = p < 0,02, teste de Friedman), que se manteve até o 4º dia. Não houve alteração dos demais parâmetros de coagulação. CONCLUSÕES. O uso de concentrado de ATIII na dose utilizada é suficiente para elevar os níveis desse inibidor na hepatopatia; entretanto, com essa dose não se obteve normalização de seus níveis. Esses dados sugerem que doses mais elevadas devem ser usadas em pacientes com hepatopatias graves, que apresentam não apenas redução de síntese, mas aumento de consumo dos fatores da coagulação e de seus inibidores.

BACKGROUND. Patients with severe hepatic failure present acquired deficiency of antithrombin III (ATIII) owing to reduced synthesis associated with intravascular activation of blood coagulation, which may be corrected by ATIII infusion. OBJECTIVE. The aim of this uncontrolled trial was to verify the effect of a standard dose of ATIII concentrate (Kybernin™ ), that is, 50U/kg of body weight per day, every 2 days, on ATIII levels in patients with severe hepatic failure and hemostatic imbalance. PATIENTS AND METHODS. Six cirrhotic patients were studied: mean age of 44 years (14 to 63 years), who presented at least 2 abnormal coagulation tests (PT > 1.40, APTT > 1.25, Fibrinogen < 1.5g/dL, Platelet count < 80,000/mm³). Mean serum albumin was 2.6g/dL (1.9 to 3.8g/dL). Blood was drawn before infusion, 4h after the first infusion, and just before the next infusion. ATIII levels were measured by amidolytic method. RESULTS. Mean ATIII levels were: initial = 35.8%, 4th h = 56.2%*, 2th d = 48.7%*, 4 d th = 45.7%*, and 8th d = 42.3%. ATIII levels increased significantly after infusion of this standard dose in all patients, although they have not been fully corrected (Friedman test, * p < 0.02), which has been sustained till the 4th day. There was no improvement on the clinical outcome. CONCLUSIONS. These findings suggest that doses of ATIII concentrate higher than 50U/kg/infusion must be administered to patients with severe hepatic failure, to guarantee normal levels of the inhibitor, in order to verify its influence on the hemostatic mechanism.