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PubMed1997

Ectopic expression of the calcium-binding protein parvalbumin in mouse liver endothelial cells.

To elucidate the physiological role of the Ca2+ binding protein parvalbumin, we have generated transgenic mice carrying the full-length complementary DNA (cDNA) of rat parvalbumin under the control of the heavy-metal inducible metallothionein IIA promoter. Immunohistochemical and biochemical methods have been used to detect the presence of ectopic parvalbumin expression in different tissues. Here we show the expression of parvalbumin in endothelial cells lining the liver sinusoids in situ and after isolation in vitro. The hemodynamic effects of endothelin 1, a peptide hormone mediating potent vasoconstriction via calcium signalling, were investigated in the mouse liver perfused in situ. Vasoconstriction, thought to be mediated by the Ito cell, was not affected in the transgenic animals, whereas microvascular exchange, probed with the multiple indicator dilution technique, was markedly decreased in normal mice but virtually not affected in the transgenic animals. This suggests that ectopically expressed parvalbumin is involved in the regulation of Ca2+ signals in the sinusoidal endothelial cells. This animal model could be of interest to those working on the physiology of liver circulation.

Animals↗
PubMed2004

Patent ductus venosus in children: a case report and review of the literature.

A 10-year-old girl with a patent ductus venosus associated with multiple autoimmune disorders presented with hypoxia, cyanosis of her lips, and exertional dyspnea. Ultrasonography and abdominal computed tomography of the liver showed a communication between the portal vein and the inferior vena cava through a patent ductus venosus. Portography showed flow from the portal vein directly into the inferior vena cava via the portosystemic shunt. The portosystemic venous shunt ratio was estimated to be 71.8% by scintigraphy using 123I-IMP. Intraoperatively, the authors diagnosed this portosystemic shunt as patent ductus venosus because of the absence of the ductus venosus on real anatomic position. The portal venous pressure was 8.2 cm H2O, which increased to 17.7 cm H2O when the ductus venosus was temporarily occluded. After surgical ligation of the ductus venosus, the color of liver improved, indicating restored liver circulation. The postoperative course was uneventful, and the patient has been asymptomatic for 6 months.

Child↗
PubMed1996

Effects of isosorbide-5-mononitrate on variceal pressure and systemic and splanchnic haemodynamics in patients with cirrhosis.

BACKGROUND: Isosorbide-5-mononitrate is a long-acting nitrovasodilator which was introduced for the treatment of portal hypertension because of its capacity to reduce portal pressure. In contrast to vasoconstrictors, isosorbide-5-mononitrate acts primarily by decreasing portal-collateral resistance without deleterious effects on liver function, although at high doses, a reflex splanchnic vasoconstriction elicited by the fall in arterial pressure may further decrease portal pressure. However, there is no information on the effects of isosorbide-5-mononitrate on variceal pressure, which is thought to be a major determinant of variceal haemorrhage. METHODS: We investigated the effects of isosorbide-5-mononitrate (40 mg, orally; n = 12) or placebo (n = 10) on variceal pressure (non-invasive endoscopic gauge) and hepatic haemodynamics in 22 patients with cirrhosis. RESULTS: Placebo administration had no significant effects. In contrast, isosorbide-5-mononitrate significantly reduced variceal pressure (from 13.5 +/- 3.6 to 9.8 +/- 3.2 mmHg, p < 0.005). This was associated with a fall in wedged hepatic venous pressure (from 28 +/- 5.8 to 25.9 +/- 6.2 mmHg, p < 0.005), hepatic venous pressure gradient (from 20 +/- 4 to 18 +/- 4.7 mmHg, p < 0.005) and azygos blood flow (from 668 +/- 197 to 597 +/- 160 ml/min, p < 0.05), suggesting that the decrease in variceal pressure caused by isosorbide-5-mononitrate could be caused by both reductions in collateral resistance and collateral blood flow. Isosorbide-5-mononitrate moderately reduced mean arterial pressure (-13 +/- 16%; p < 0.005), its fall being directly related to the fall in hepatic venous pressure gradient (r = 0.6, p < 0.01). CONCLUSIONS: The results of this study show that isosorbide-5-mononitrate markedly and significantly reduces variceal pressure in patients with cirrhosis and provide further support for its clinical use in the pharmacological treatment of portal hypertension.

Aged↗
PubMed2003

Nitric oxide and portal hypertension: a nitric oxide-releasing derivative of ursodeoxycholic acid that selectively releases nitric oxide in the liver.

Portal hypertension, a common consequence of chronic liver diseases, is directly responsible for most complications of cirrhosis. In liver microcirculation, nitric oxide is considered a major fine tuner of vascular tone by counterbalancing vasoconstrictors (sympathetic nervous activity, the renin-angiotensin system, and endothelin-1) in normal and cirrhotic livers. The deficiency of endothelial nitric oxide release is a key factor in the hemodynamic abnormalities associated with the dynamic component of portal hypertension. Conventional nitric oxide donors release nitric oxide into the blood stream, causing systemic hypotension and progression of vasodilatory syndrome in cirrhotic patients. NCX1000 is a nitric oxide-releasing derivative of ursodeoxycholic acid-derived compounds, being capable of selectively releasing nitric oxide into the liver circulation. Administration of NCX1000 to portal hypertensive rats decreases intrahepatic resistance providing a novel therapy for the treatment of portal hypertension.

Adipocytes↗
PubMed1999

The matrix metalloproteinase inhibitor batimastat inhibits angiogenesis in liver metastases of B16F1 melanoma cells.

Matrix metalloproteinases (MMPs) have been shown to contribute functionally to tumor metastasis. MMP inhibitors are thus being assessed for clinical utility as anti-metastatic therapeutics. Batimastat (BB-94) is a synthetic MMP inhibitor that has been shown to inhibit tumor growth and metastasis in mice. Here we assessed the ability of batimastat to inhibit liver metastases of murine B16F1 cells, after injection of cells in mice via mesenteric vein to target the liver. We then determined which of the sequential steps in metastasis were affected by batimastat, in order to identify its mechanism of action in vivo. Intravital videomicroscopy was used to assess the effect on extravasation, and a 'cell accounting' procedure was used to determine the effect on initial survival of cells. Stereological quantification of functional blood vessels was used to determine the effect on tumor vascularity, thereby avoiding problems associated with immunohistochemical detection of liver sinusoidal endothelial cells. We found that batimastat (50 mg/kg i.p. 5 h prior to and after cell injection, daily thereafter) resulted in a 23% reduction in mean diameter of liver metastases (equivalent to a 54% reduction in tumor volume), while not reducing the number of metastases. Extravasation of cells from the liver circulation was not affected: at 8, 24 and 48 h after injection of cells, the same proportion of cells had extravasated from treated vs. control mice. Batimastat also did not inhibit early survival of cells. However, batimastat-treated mice had a significantly reduced percentage vascular volume within liver metastases, indicating inhibition of angiogenesis. This study demonstrates in vivo that the mechanism by which batimastat limits growth of B16F1 metastases in liver is not by affecting extravasation, but by inhibiting angiogenesis within metastases. This finding suggests that MMP inhibitors may be appropriate for use in patients with metastatic cells that have already extravasated in secondary sites.

Animals↗
PubMedDate not supplied

[Early detection of hepatobiliary involvement in children with mucoviscidosis using duplex sonography of the portal system].

To investigate early signs of hepatobiliary disease in CF, we measured portal, splenic, superior mesenteric vein and hepatic artery diameters, maximal flow velocity (Vmax) and time average velocity (TAV) in 25 males and 17 females with CF. Hepatic artery resistance, regional blood flow and liver perfusion were calculated. According to liver enzyme data (aminotransferases raised greater than 30 U/l) and sonographic findings (nodular changes), there were 17 CF-patients (mean age 11.4 yrs; range 0.75-31) with and 25 CF-patients (mean age 7.8 yrs; range 0.25-32) without liver involvement (L+/L-). No patient had clinical signs of portal hypertension. 61 healthy children were studied for control. Diameter of portal vein (PVD) and flow data for portal vein showed consistent abnormalities (mean +/- SD): CF-L+ CF-L- Control PVC (mm/m2) 10.7 +/- 3.9*** 10.5 +/- 3.4*** 7.2 +/- 1.3 Vmax (m/sec) 0.23 +/- 0.06*** 0.30 +/- 0.06*** 0.40 +/- 0.14 TAV (m/sec) 0.12 +/- 0.04*** 0.16 +/- 0.04* 0.18 +/- 0.05 Differences were statistically significant (* p less than 0.05, *** p less than 0.001) for CF-patients versus controls. Data for splenic and mesenteric veins and for hepatic artery were moderately alterated, with a significant reduction in TAV and Vmax of splenic vein for CF-L+ versus controls. Liver perfusion and portal vein flow showed no relevant differences in CF-patients versus controls. It is concluded that portal system abnormalities, especially a decrease in Vmax and TAV of portal vein shown by duplex sonography, may be earlier indicators of CF liver disease than biochemical and clinical signs.

Adolescent↗
PubMed1983

Splanchnic galactose uptake in patients with cirrhosis during continuous infusion.

The galactose elimination capacity (GEC) is considered a test of functional liver cell mass. The main uncertainties of the method are the effects of extrahepatic elimination and of uneven distribution in the body on the calculated maximal elimination rate of galactose. This has been evaluated by hepatic and renal venous catheterization during continuous infusion of galactose at two arterial concentration levels (mean 6.0 and 8.7 mmol l-1) in 10 patients with reduced liver function. Hepatic and renal blood flow were measured by constant infusions of Indocyanine Green and 131I Hippuran. Hepatic galactose elimination rate was identical (mean 1.36 and 1.32 mmol min-1, P greater than 0.4) at the two arterial concentration levels studied, indicating that hepatic galactose elimination rate was maximal (Vmax). The total body galactose elimination rate, calculated as amount infused during steady state, was 1.4 times greater than the hepatic elimination rate, calculated as arterio-hepatic venous concentration difference times hepatic blood flow. Within the experimental error, the extrahepatic (i.e. total minus hepatic) galactose elimination could be accounted for by renal elimination. The steady state studies show that the galactose elimination capacity, estimated from single injection, overestimates the hepatic Vmax by about 25%. The reason for this is probably mainly distribution phenomena and insufficient correction for urinary loss, but extrahepatic metabolism of galactose cannot be excluded.

Catheterization↗
PubMed2000

Use of arginine vasopressin in the absence of diabetes insipidus: a case study.

This case study details the use of arginine vasopressin in a pediatric organ donor. Although arginine vasopressin is primarily administered for its antidiuretic effects in the treatment of diabetes insipidus, the study demonstrates the often overlooked vasoactive effect of arginine vasopressin and its use in a patient without diabetes insipidus.

Adolescent↗
PubMed1986

Gastrointestinal complications in critically ill patients: the intensivists' overview.

The critical care environment may be characterized by invasive monitoring, vasoactive drugs, and major interventions which may have adverse effects on gastrointestinal function. Furthermore, conditions such as heart failure or sepsis may compromise oxygen delivery to gastrointestinal organs. Life threatening illness from a variety of causes may produce endoscopically evident gastritis or ulceration in up to 100% of patients, and clinically evident bleeding in 20%. Clinical studies suggest that antacids or H2 receptor blockers may reduce the frequency of this complication. Other conditions are associated with a spectrum of hepatic dysfunction ranging from the cholestatic jaundice of reactive hepatopathy during sepsis to centrilobular necrosis and hepatitis of shock liver. Additionally, many drugs used in the critical care setting may adversely affect mesenteric oxygen delivery and result in ischemia or infarction of the bowel. An increased awareness and understanding of these and other gastrointestinal complications in critically ill patients will, it is hoped, lead to earlier detection and better therapy than is now available.

Animals↗
PubMed1997

Arteriovenous shunts in patients with hepatic tumors.

UNLABELLED: The study aimed to investigate the influence of tumor type, tumor size, tumor vascularity and treatment on arteriovenous shunts between the liver and lungs in patients with hepatic cancer. METHODS: Our previous assessment of the degrees of lung shunting using intra-arterial 99mTc-macroaggregated albumin in 125 patients with hepatocellular carcinoma (HCC) was extended to include 377 patients with HCC and 25 patients with colorectal liver metastases. Patients were given 111 MBq (3 mCi) of 99mTc-macroaggregated albumin during hepatic angiography. The lungs and the liver were localized as regions of interest on the digitized gamma scintigraphic image. The total counts taken over the lungs divided by the total counts taken over both the lungs and the liver gave the percentage of lung shunting. Tumor size was measured by computerized tomography or ultrasound scan. Tumor vascularity was assessed based on the degree of neovascularization. Linear regression and Wilcoxon rank test were used for statistical analysis. RESULTS: Patients with HCC had a higher median (7.6%) and a wider range (< 1-75.4%) of percentages of lung shunting when compared with those with colorectal liver metastases (median, 4.7%; range, < 1-23.9%). The lung shunting correlated with the tumor size in the 377 patients with HCC (r = 0.359; p < 0.0001). Excluding one outlier, we found a similar correlation in 24 patients with colorectal metastases (r = 0.686; p < 0.0001). In HCC, the mean lung shunting increased with increasing tumor size, up to 15 cm, and then remained almost unchanged, up to a size of > 20 cm. The mean lung shunting also increased with increasing vascularity grades, as assessed by hepatic angiography. The difference between any two vascularity grades was statistically significant (p = 0.0001-0.0148). Similar analysis by subgroups in colorectal liver metastases was impossible because of the small number of patients. Lung shunting decreased in HCC patients after the tumors were treated, but it might increase or decrease when the disease recurs. CONCLUSION: The lung shunting was influenced by the type, size and vascularity of the hepatic tumor. The change in lung shunting with the status of the tumor after treatment further suggests a neoplastic nature of the blood vessels involved in the arteriovenous shunt.

Carcinoma, Hepatocellular↗
PubMed1995

Induction of anaesthesia by propofol and hepatic blood flow in the rabbit.

Effects of propofol (12.5 mg kg-1, i.v. bolus injection) or 0.9% sodium chloride on arterial blood pressure, arterial blood gases and hepatic circulation (radio-labelled microsphere technique) were studied in 15 conscious and unpremedicated rabbits. No significant changes were observed after sodium chloride. Propofol resulted in anaesthesia, respiratory depression (-49 +/- 14% decrease in PaO2; mean +/- SD) and hypotension (-49 +/- 13% decrease in mean arterial pressure; mean +/- SD) but no changes in hepatic arterial and portal venous blood flows. We conclude that propofol does not affect the liver circulation despite marked depression of mean arterial pressure and respiration.

Anesthesia↗
PubMed1987

Autoantibodies against liver cell membrane antigens detected by enzyme-linked immunosorbent assay in acute and chronic liver disease.

An enzyme-linked immunosorbent assay was developed to detect serum antibody binding to liver membrane antigen derived from human hepatoma cell line SK-Hep-1. When we tested sera from 214 patients with this assay, IgM antibodies were detected in 100% of patients with acute type A, but not with type B or non-A, non-B hepatitis. IgM antibodies were also found in highest frequency (76%) and titer in patients with autoimmune chronic active hepatitis (CAH) among chronic liver disease groups. IgG antibodies occurred in over 50% of patients with acute type A hepatitis, type B chronic active liver disease (CALD), and autoimmune CAH. IgA antibodies were present in 43% of the patients with alcoholic liver disease, but were also seen in other patient groups. When freshly isolated rat hepatocytes were used as target cells, prevalences and titers similar to those obtained with SK-Hep-1 were found. The levels of serum membrane binding antibody were significantly reduced by the addition of human liver-specific membrane lipoprotein in all patient groups. In particular, IgM antibodies became negative in over 50% of patients with CALD (both type B and non-A, non-B) and autoimmune CAH, whereas in acute hepatitis over 50% lost their positivity for IgG antibody. These results indicate that circulating liver membrane binding autoantibodies are heterogeneous, occurring in hepatitis virus-induced acute and chronic liver disease as well as in autoimmune CAH.

Acute Disease↗
PubMed1993

Experimental evidence that the physiological position of the liver within the circulation is not a major determinant of zonation of gene expression.

Many enzymes are distributed heterogeneously within the liver lobule. The factors that play a determining role in the establishment and maintenance of these heterogeneous expression patterns have not yet been identified. To investigate whether the composition of the afferent hepatic blood plays a crucial role in the maintenance of the heterogeneity of gene expression of the parenchymal cells within the liver lobule, we changed the source of the afferent hepatic blood by microsurgical techniques. Three different groups of experimental animals were studied: rats with livers that are perfused with portal blood only (ligation of the hepatic artery), with caval blood only (portocaval transposition and ligation of the hepatic artery) and arterial blood only (portocaval shunt, arterialization of the distal end of the portal vein and ligation of the hepatic artery). To study differences in gene expression patterns, we chose enzymes that have a heterogeneous expression pattern within the liver lobule: the periportally located enzymes carbamoylphosphate synthase, succinate dehydrogenase, phosphoenolpyruvate carboxykinase and the pericentrally located enzymes glutamine synthase, glutamate dehydrogenase and NADPH-cytochrome P-450 reductase. To eliminate the potential interference of the long half-lives of some of these proteins on the interpretation of the results, we also studied the distribution of the mRNAs of carbamoylphosphate synthase, glutamine synthase, glutamate dehydrogenase and phosphoenolpyruvate carboxykinase. The animals were studied 2 wk after the operations. On the basis of their changes in body weight the animals were in steady state for at least a week. The patterns of gene expression of the enzymes studied did not change, regardless of the source of the altered afferent hepatic blood. The changes in gene expression that were observed in animals that did not regain their preoperative weight were shown to be caused by a limited intake of food. This study demonstrates that the physiological position of the liver within the circulation (i.e., between the gastrointestinal tract and the systemic circulation) is not as critical as is often stated and is certainly not essential for the maintenance of liver cell heterogeneity. The data suggest that the direction of the bloodstream (i.e., the existence of an upstream and a downstream compartment) is a major determinant of zonation of gene expression.

Animals↗
PubMed1992

Hemodynamic and sympathetic responses to human atrial natriuretic peptide infusion in patients with cirrhosis.

To determine the potential usefulness of atrial natriuretic peptide (ANP) in patients with cirrhosis, we examined the effects of the infusion of a low dose of alpha-human ANP (alpha hANP, 25 ng.kg-1.min-1 for 30 min) on renal, splanchnic, systemic hemodynamics and sympathetic outflow in eight patients. Pulmonary arterial plasma ANP concentrations increased from 59 +/- 9 to 328 +/- 41 pg/ml (mean +/- S.E., p less than 0.05). Mean values of glomerular filtration rate and renal plasma flow were not significantly changed. Individual renal plasma flow responses differed from one patient to another. Renal plasma flow increased in two patients, decreased in three and did not change in the other patients. Renal plasma flow changes were correlated with basal renal plasma flow values (r = -0.938, p less than 0.05) but not with arterial pressure changes or renal vein plasma norepinephrine concentration changes. Azygos blood flow increased from 0.43 +/- 0.10 to 0.63 +/- 0.13 l/min (p less than 0.05) and the hepatic-venous pressure gradient decreased from 19.9 +/- 1.5 to 17.5 +/- 2.9 mmHg in post-infusion (p less than 0.05). Mean arterial pressure decreased significantly by 18% and cardiac output by 12%. Systemic vascular resistance and pulmonary arterial plasma norepinephrine concentrations were not significantly modified. Thus, in patients with cirrhosis, alpha hANP appears to have a direct vasodilating action on renal arterioles when basal renal vascular tone is high. In addition, although alpha hANP might exert a portal hypotensive action, alpha hANP induced arterial hypotension as a result of both low cardiac output and a lack of increased sympathetic vascular tone. The arterial hypotensive action may, thus, limit the therapeutic use of low doses of alpha hANP in cirrhotic patients.

Aldosterone↗
PubMed2006

Liver regeneration and hemodynamics in pigs with mesocaval shunt.

BACKGROUND: A surgical technique using a mesocaval shunt and downstream ligation of the superior mesenteric vein has been recently proposed to overcome the size limitations that restrict the use of partial liver grafts. We designed an experimental study in pigs to evaluate the capacities of liver regeneration and hemodynamic changes after completion of this procedure. MATERIAL AND METHODS: Liver regeneration after left hepatectomy was compared between two groups of five pigs, with or without mesocaval shunt, sacrificed 11 to 14 days after surgery. A third group of five animals was used for hemodynamic studies. RESULTS: Liver regeneration in study animals was 45.3% of controls. This was obtained despite a reduction of the venous inflow to 15.6% of the control, resulting in a net decrease of the total blood inflow to 56% of the control, despite a compensatory increase in the arterial inflow. There was no significant difference in mitotic index, hepatocellular size, and glycogen content between study and control animals. CONCLUSION: Our experimental study confirms that the regenerative capacities of the pig liver are largely preserved despite the dramatic reduction of the venous blood inflow, reduced to its gastroduodenosplenopancreatic component. This lends further support to the hypothesis that the gastroduodenosplenopancreatic blood is enriched in hepatotrophic factors, likely to originate from the pancreas and duodenum.

Anastomosis, Surgical↗
PubMed1987

Long-term effects of beta-adrenergic blockade with nadolol on hepatic and renal haemodynamics and function in cirrhotics.

Non-cardioselective beta-blockers are used for prevention of re-bleeding from oesophageal varices in cirrhotics with portal hypertension. Nadolol, a non-cardioselective beta-blocker with a low liposolubility and a low hepatic metabolism, has been demonstrated to decrease portal pressure in cirrhotic patients. Since cirrhotics need long-term treatment, we investigated long-term effects of beta-adrenergic blockade with nadolol on hepatic and renal haemodynamics and function in a group of patients with cirrhosis and portal hypertension. In 19 patients with cirrhosis, after one and six months of treatment with nadolol hepatic venous pressure gradient showed a significant and persistent decrease, averaging 19% and 22%, respectively. Hepatic function and renal haemodynamics and function remained unaffected. Oesophageal varices severity was lowered in 11/19 patients after one month, in 9/16 after six months, in 8/14 after 12 months and in 5/10 after 18 months. Our results showed that, also after long-term treatment, nadolol decreases portal pressure and, in approximately 50% of patients, oesophageal varices severity, without side-effects on liver and renal function.

Adult↗