Folic acid ameliorates homocysteine-induced angiogenesis and portosystemic collaterals in cirrhotic rats.

INTRODUCTION AND OBJECTIVES: Liver cirrhosis is characterized by increased intrahepatic resistance, splanchnic vasodilation/angiogenesis, and formation of portosystemic collateral vessels. Collaterals can cause lethal complications such as gastroesophageal variceal hemorrhage. Homocysteine is linked to vascular dysfunction and angiogenesis and higher levels have been reported in cirrhotic patients. It is also known that folic acid supplementation reverses the effects of homocysteine. However, the treatment effect in cirrhosis has yet to be investigated. MATERIAL AND METHODS: Liver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (CBDL). The CBDL rats randomly received (1) vehicle; (2) dl-homocysteine thiolactone (1g/kg/day); (3) dl-homocysteine thiolactone plus folic acid (100mg/kg/day); or (4) folic acid. On the 29th day, hemodynamic parameters, liver and renal biochemistry, protein expressions of proangiogenic factors, mesenteric vascular density and portosystemic shunting were evaluated. RESULTS: In the cirrhotic rats, homocysteine increased mesenteric vascular density and the severity of shunting. It also up-regulated the protein expressions of mesenteric vascular endothelial growth factor (VEGF) and phosphorylated-endothelial nitric oxide synthase (p-eNOS). These effects were reversed by folic acid treatment (P<0.05). CONCLUSION: Folic acid ameliorated the adverse effects of homocysteine in the cirrhotic rats, which may be related to down-regulation of the VEGF-NO signaling pathway.

Angiogenesis and portal-systemic collaterals in portal hypertension.

In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.

Validação das diretrizes gerais de comunicação do enfermeiro com o cego / Validation of the general guidelines of communication between the nurse and the blind / Validación de las directrices generales de la comunicación entre la enfermera y el ciego

Objetivou-se validar as diretrizes gerais da comunicação do enfermeiro com o cego. Estudo quantitativo, realizado entre abril de 2008 e março de 2009 em Fortaleza-CE. Participaram 30 enfermeiros e 30 cegos divididos em grupo controle e experimental. Realizaram-se 30 consultas de enfermagem filmadas e analisadas por especialistas. O grupo experimental apresentou desempenho bom e excelente em todas as diretrizes para a comunicação verbal e não verbal com o cego, contrariamente ao grupo controle. Os resultados do estudo apontam para a urgência da adoção do ensino destas diretrizes gerais de comunicação com cegos nos cursos de enfermagem, além de capacitar enfermeiros no cuidado a pessoas cegas.

This quantitative study, conducted between 2008 April and 2009 March in Fortaleza-CE, Brazil, aimed to validate the general guidelines of the communication of the nurse with the blind. Thirty nurses and 30 blinds, divided into control and experimental groups, participated in the study. Thirty nursing consultations were videotaped and analyzed by experts. In contrast to the control group, the experimental group showed good and excellent performance in all guidelines for verbal and non-verbal communication with the blinds. The study results point to the urgency of adopting the teaching of these general guidelines for communicating with the blind in nursing courses, in addition to training nurses in caring for the blind people.

Estudio cuantitativo, realizado entre abril de 2008 y marzo de 2009, en Fortaleza-CE, Brasil, que tuvo como objetivo validar los lineamientos generales de la comunicación del enfermero con los ciegos. Los participantes fueron 30 enfermeros y 30 ciegos, divididos en grupos control y experimental. Fueran realizadas 30 consultas de enfermería, registradas y analizadas por expertos. El grupo experimental mostró un buen y excelente rendimiento en todas las directrices para comunicación verbal y no verbal con los ciegos, en contraste con el grupo de control. Los resultados del estudio apuntan a la urgencia de la adopción de la enseñanza de estas directrices generales para la comunicación con los ciegos en los cursos de enfermería, además de la formación de enfermeras en el cuidado de las personas ciegas.

The hemodynamic effects of zymosan in the perfused rat liver.

The actions of zymosan on hepatic microcirculation and on the cell membrane permeability were investigated using the multiple-indicator dilution technique. The experimental system was the perfused rat liver. [(3)H]Water, [(3)H]sucrose and [(14)C]urea or [(14)C]bicarbonate were simultaneously injected into the portal vein. Mean transit times, distribution spaces, variances, linear superpositions and transfer coefficients across the plasma membrane were calculated. Zymosan had no net effect on the great vessels space but increased the extracellular sucrose space and decreased the aqueous cell space. Zymosan impaired the flow-limited distribution and increased the normalized variances of all tracers. The increase in the portal pressure caused by zymosan results most probably from a constriction just after or at the exit of the sinusoids. Impairment of the flow-limited distribution of tracers in the sinusoidal bed indicates that zymosan induces the formation of permeability barriers, which could make the access of the solutes to transporters or enzymes located on the outer surface of the plasma membrane difficult.

Terlipressin is more effective in decreasing variceal pressure than portal pressure in cirrhotic patients.

BACKGROUND/AIMS: Terlipressin decreases portal pressure. However, its effects on variceal pressure have been poorly investigated. This study investigated the variceal, splanchnic and systemic hemodynamic effects of terlipressin. METHODS: Twenty cirrhotic patients with esophageal varices grade II-III, and portal pressure > or =12 mmHg were studied. Hepatic venous pressure gradient, variceal pressure and systemic hemodynamic parameters were obtained. After baseline measurements, in a double-blind administration, 14 patients received a 2mg/iv injection of terlipressin and six patients received placebo. The same measurements were repeated 60 min later. RESULTS: No demographic or biochemical differences were observed in basal condition between groups. Terlipressin produced significant decreases in intravariceal pressure from 20.9+4.9 to 16.3+/-4.7 mmHg (p<0.01, -21+/- 16%), variceal pressure gradient from 18.9+/-4.8 to 13.5+/-6.0 mmHg (p<0.01, -28+/-27%), estimated variceal wall tension from 78+/-29 to 59+/-31 mmHg x mm (p<0.01, -27+/-22%), and hepatic venous pressure gradient from 19.4+/-4.5 to 16.8+/-5 mmHg (p<0.01, -14+/-12%) at 60 min. The change in variceal pressure after 60 min of terlipressin administration was greater than the change in wedge hepatic venous pressure (-4.7 mmHg vs -0.5 mmHg, respectively, p<0.0001). Terlipressin also caused significant decreases in heart rate and cardiac index and increases in mean arterial pressure and peripheral vascular resistance. CONCLUSIONS: Our results demonstrate that terlipressin produces significant and prolonged decreases in variceal pressure and variceal wall tension and has intrinsic effects on portal pressure and systemic hemodynamics. Variceal pressure provides a better assessment of the effects of terlipressin administration on esophageal varices than hepatic venous pressure gradient.

Circulaçäo portal esplâncnica: reforço da intensidade da imagem radiológica e aumento da visibilizaçäo de colaterais com emprego da prostaglandina E1 / Splanchnic portal circulation: enhancement of the radiologic image intensity and of the visibility of collateral branches with the use of prostaglandin E1

Säo apresentados os resultados da comparaçäo entre mesentérico-portografias realizadas com e sem prostaglandina E1 (PGE1) injetada na artéria mesentérica superior como adjuvante à realizaçäo do exame angiográfico. Foram estudados 28 pacientes com variadas doenças hepáticas e biliopancreáticas nos quais, após cateterismo da artéria mesentérica superior, realizaram duas séries de arterio-mesentérico-portografias: a primeira só com contraste e a segunda com injeçäo prévia de 50 mug de prostaglandina E1 na forma de "bolus". Avaliaram-se, em cada série, a presença, a intensidade de opacificaçäo dos vários componentes do sistema portal e o tempo decorrido desde o início da injeçäo até o máximo da opacificaçäo. Observou-se que, com o uso da PGE1, houve opacificaçäo regular, acentuada e precoce da veia mesentérica superior, veia porta e ramos intra-hepáticos em todos os pacientes que apresentavam o eixo mesentérico-portal pérvio e/ou circulaçäo hepatópeta. Notou-se, também, a reduçäo significativa do tempo necessário para opacificar o sistema mesentérico-portal. Além disso, houve com o uso do fármaco, contrastaçäo das vias de circulaçäo colateral em maior número de doentes e aumento da sua intensidade. Devido aos bons resultados obtidos, à fugacidade da açäo do fármaco, à ausência de reaçöes colaterais cardiocirculatórias e/ou gerais é recomendado seu uso sistemático para estudo do sistema venoso portal esplâncnico.

[Splanchnic portal circulation (enhancement of radiologic image intensity and of visibility of collateral branches with prostaglandin E1)]. / Circulação portal esplâncnica. (Reforço da intensidade da imagem radiológica e aumento da visibilização de colaterais com emprego da prostaglandina E1).

The authors present the results of a comparative study of mesenterico-portographies with and without the use of Prostaglandin E1 (PGE1) injected intrarterially into the superior mesenteric artery as an adjunct to the radiographic procedure. Twenty eight patients, with varied hepatic and biliopancreatic ailments, referred to the Radiologic Department for angiographic appraisal of the splanchnic circulation were studied. Two series of radiographies were realized after catheterization of the superior mesenteric artery: a first after the injection of the contrast only and a second after the injection of 50 micrograms of PGE1 as a bolus prior the contrast means. The difference in opacification of the various segments of the portal system and the lapse of time necessary to attain the maximum radiographic density were appraised. They observed that, with the use of PGE1 was attained a regular, intense and swift opacification of the superior mesenteric vein, portal vein and intrahepatic branches in all patients that had those segments previous and/or hepatotropic circulation. There was a significative reduction in the lapse of time necessary to attain the maximum opacification. Also they observed, with the use of the PGE1, the opacification of collateral branches of the portal system in more patients and intensification in those that were previously opacified. Because of the good results attained with the use of the PGE1, its transitory pharmacologic action and absence of collateral reactions with the dose used, they recommend its regular use when this investigation is performed.

Daily variation in portal blood flow and the effect of propranolol administration in a randomized study of patients with cirrhosis.

A nocturnal increase in portal pressure and blood flow was demonstrated in patients with cirrhosis, suggesting that these hemodynamic changes may contribute to the triggering of the hemorrhagic episodes observed during the night in these patients. It is known that propranolol reduces portal flow, thus reducing the risk of variceal bleeding. In a double-blind, placebo-controlled study, we evaluated the effect of long-term propranolol administration on the daily fluctuation of systemic and splanchnic hemodynamic parameters in 14 patients with cirrhosis. Cardiac output and portal blood flow were measured by the Doppler technique. A daily fluctuation of both cardiac output and portal blood flow was observed, peaking at midnight. beta-Adrenergic blockade was manifested by a significant reduction in heart rate (-21% +/- 4%, P < .01) and cardiac output (-12% +/- 2%, P < .05). A significant decrease in portal blood flow (-20% +/- 4%, P < .01) was also observed in these patients. Propranolol administration blunted the time-related changes in cardiac output and portal blood flow. In contrast, patients receiving placebo had a nocturnal peak of both parameters similar to that observed under basal conditions. Our study shows that chronic propranolol administration abolishes the nocturnal peak of portal blood flow in patients with cirrhosis and indicates a preventive effect of propranolol in these patients.

Vasodilatory effects of propylthiouracil in patients with alcoholic cirrhosis.

BACKGROUND/AIMS: An experimental study has shown that propylthiouracil increases portal blood flow in normal rats. Whether propylthiouracil has a similar effect in patients with alcoholic cirrhosis remains to be demonstrated. The aim of this study was to evaluate the effects of oral propylthiouracil (300 mg) on systemic and portal hemodynamics in patients with alcoholic cirrhosis. METHODS: Plasma propylthiouracil levels were also measured by high performance liquid chromatography in five patients with alcoholic cirrhosis. In eight patients with cirrhosis, mean arterial pressure, cardiac output and portal blood flow were evaluated before and after placebo and propylthiouracil administration. Hemodynamic measurements were performed by the Doppler technique. The plasma peak level of propylthiouracil was achieved at 1.4 +/- 0.1 h in patients with alcoholic cirrhosis. This time was chosen to express hemodynamic changes. RESULTS: Propylthiouracil administration caused a significant increase in portal blood flow (+16.5%, p < 0.05) in patients with alcoholic cirrhosis. This effect was associated with a mild and significant rise in cardiac output (from 5.8 +/- 0.2 to 6.1 +/- 0.3 l/min, p < 0.05) and a decrease in peripheral vascular resistance (from 1171 +/- 69 to 1070 +/- 67 dyn . s-1 . cm-5, p < 0.01). A significant correlation was observed between changes in portal blood flow and peripheral vascular resistance (r = 0.79, p < 0.05). No significant changes were observed after placebo. CONCLUSIONS: Our findings show that propylthiouracil has a vasodilatory effect in patients with alcoholic cirrhosis. We postulate that this effect could be the mechanism by which propylthiouracil decreases hypermetabolic state, and increases oxygen delivery to the liver, in patients with alcoholic liver diseases.

Effect of the somatostatin analogue octreotide (SMS201-995) on portal and mesenteric blood flow in rats

Várias investigaçöes revelaram que a somatostatina e análogas baixam o fluxo sanguíneo esplâncnico e portal em cirróticos e em modelos experimentais de hipertensäo portal. Tem sido experimentado habitualmente no tratamento de varizes sangrantes. O mecanismo pelo qual o hormônio age permanece obscuro. No presente estudo investigou-se o efeito da açäo prolongada do octreotide, somatostatina análoga, no fluxo sanguíneo mesentérico e portal, em ratos sadios. A administraçäo intravenosa do octreotide näo teve efeito significante na circulaçäo esplânic. Em alguns animais registrou-se, após a infusäo inicial da droga, queda pequena no fluxo venoso portal. Infusöes adicionais näo alteraram o fluxo portal. O fluxo sangüíneo mesentérico superior permaneceu inalterado. Conclui-se que o octreotide näo influiu na circulaçäo espâncnica, em ratos sadios, e que novos estudos se fazem necessários para explicar os seus efeitos em modelos de hipertensäo portal

Postprandial vascular response in patients with cirrhosis. Short-term effects of propranolol administration.

Systemic and portal hemodynamic parameters were evaluated in eight cirrhotic patients in basal conditions and after food intake and placebo. Following seven days of oral propranolol administration, hemodynamic parameters were reevaluated in the fasting and postprandial states under similar conditions. Cardiac output and portal blood flow were measured by Doppler technique. Intraobserver variability of repeated measurements was less than 10%. Food intake caused a significant increase of portal blood flow (+28%, P < 0.05). No significant changes were observed in the other hemodynamic parameters studied. Propranolol at doses achieving effective beta blockade (84 +/- 14 mg/day) (mean +/- SD) reduced portal blood flow (-24%, P < 0.05). Food intake caused a significant increase in portal blood flow (+35%, P < 0.05) in propranolol treated patients. However, in absolute values, postprandial portal blood flow during propranolol treatment was significantly lower (986 +/- 402 ml/min) than that obtained after the initial food intake (1214 +/- 537 ml/min, P < 0.05). Placebo administration had no significant hemodynamic effects in either group. This study demonstrates that chronic propranolol administration could protect from portal hemodynamic changes following food intake. Doppler technique is a reliable technique to evaluate changes on portal and systemic hemodynamic parameters during a short period of time in patients with cirrhosis.

Functional modifications evoked by physical training in rats

Se investigaron los efectos del entrenamiento físico (natación, 5 veces/semana durante lapsos de 2 a 60 min, durante 4 meses) sobre la actividad funcional de segmentos vasculares aislados, peso corporal y presión arterial sistólica en ratas macho. Después de 75 días, el peso corporal del grupo entrenado (E) fue significativamente menor que el del grupo control (C). La presión arterial sistólica decayó significativamente en E (p < 0.001 vs. C) a los 60 días. La tensión contráctil isométrica de la vena porta aislada al final del período de entrenamiento e incubada en medio de Krebs-Ringer-bicarbonato fue similar en ambos grupos (E: 15.36ñ0.82 mN, n=15; C:16.15ñ1.9 mN, n=10). Los componentes fásico y tónico de las contracturas inducidas por norepinefrina fueron mayores en E y la EC50 menor en C. No hubo, en cambio, diferenciais significativas en las respuestas contráctiles a ClK. La reactividad farmacológica de la arteria caudal ventral a los mismos agentes fue significativamente mayor en E. Nuestros hallazgos indican que el entrenamiento físico en ratas induce cambios funcionales adaptativos que incluyen modificaciones del peso corporal y la presión arterial sistólica. Los resultados obtenidos en músculo liso vascular aislado pueden ser explicados por incremento en la población de receptores adrenérgicos con disminución simultánea de su afinidad, como lo sugieren los valores de la EC50. Otros fenómenos adaptativos celulares (modificaciones en la fosforilación de proteínas, metabolismo...

Functional modifications evoked by physical training in rats

Se investigaron los efectos del entrenamiento físico (natación, 5 veces/semana durante lapsos de 2 a 60 min, durante 4 meses) sobre la actividad funcional de segmentos vasculares aislados, peso corporal y presión arterial sistólica en ratas macho. Después de 75 días, el peso corporal del grupo entrenado (E) fue significativamente menor que el del grupo control (C). La presión arterial sistólica decayó significativamente en E (p < 0.001 vs. C) a los 60 días. La tensión contráctil isométrica de la vena porta aislada al final del período de entrenamiento e incubada en medio de Krebs-Ringer-bicarbonato fue similar en ambos grupos (E: 15.36ñ0.82 mN, n=15; C:16.15ñ1.9 mN, n=10). Los componentes fásico y tónico de las contracturas inducidas por norepinefrina fueron mayores en E y la EC50 menor en C. No hubo, en cambio, diferenciais significativas en las respuestas contráctiles a ClK. La reactividad farmacológica de la arteria caudal ventral a los mismos agentes fue significativamente mayor en E. Nuestros hallazgos indican que el entrenamiento físico en ratas induce cambios funcionales adaptativos que incluyen modificaciones del peso corporal y la presión arterial sistólica. Los resultados obtenidos en músculo liso vascular aislado pueden ser explicados por incremento en la población de receptores adrenérgicos con disminución simultánea de su afinidad, como lo sugieren los valores de la EC50. Otros fenómenos adaptativos celulares (modificaciones en la fosforilación de proteínas, metabolismo... (AU)

Efeito do propranolol na pressäo portal medida através de punçäo da veia esplênica em 27 pacientes com hipertensäo porta / Effect of propranolol on portal pressure measured by puncturing the splenic vein of 27 patients with portal hypertension

Os autores estudaram o efeito do propranolol sobre a pressäo no sistema porta, realizado através de medida da pressäo na veia esplênica em 27 pacientes com hipertensäo porta. Doze pacientes (44,4%) reduziram a pressäo porta em mais de 10% da inicial utilizando dose média de 101mg. Quando compararam indivíduos com esquistossomose hepatosplênica e cirrose hepática, o grau de resposta foi semelhante, com reduçäo da pressäo em cerca de 50% dos casos. Discutem os autores os diversos métodos de avaliaçäo da resposta hemodinâmica ao propranolol e a necessidade de correlaçäo entre resposta clínica favorável e resposta hemodinâmica. Por fim, sugerem a necessidade de seleçäo adequada dos pacientes que faräo uso da droga, através de métodos näo invasivos como a ultra-sonografia associada ao doppler, já que em nosso estudo nenhum dado clínico ou hemodinâmico previa uma resposta positiva ao propranolol