Combined Hepatic Vein, Umbilicoportal Vein, and Superior Mesenteric Artery Catheterization in Portal Hypertension: Estimation of the Portal Fraction of Total Hepatic Blood Flow in Cirrhotic Patients

Hemodynamic data were obtained in 13 cirrhotic patients with severe portal hypertension, undergoing combined hepatic vein, umbilicoportal vein, and superior mesenteric artery catheterization. The relative clearance of indocyanine green, the portohepatic gradient (difference between the free portal venous pressure and the free hepatic venous pressure), and the estimated hepatic blood flow were measured. The portal fraction (PF) of total hepatic blood flow was calculated in all patients using indicator dilution curves obtained from the portal bifurcation, a right hepatic vein, and when possible a left hepatic vein (six cases) after injection of ⁵¹Cr-labeled red blood cells (⁵¹Cr RBC) into the superior mesenteric artery. Flows were overestimated because of loss of indicator through spontaneous portosystemic shunts; however, the ratio between hepatic and portal indicator dilution curves can be used to calculate the portal fraction of total hepatic blood flow since no extrahepatic shunts existed after the bifurcation of the portal vein (as shown on portography). In 10 patients, 15 series of curves were calculable and the PF varied between 30.1 and 100% (mean ± SE: 71.1 ± 6.2%). In the three other patients, only delayed activity from recirculation was detected from portal and hepatic vein samples and PF was 0%; in these three cases, portography and arteriography revealed spontaneous portacaval shunting with reverse and/or stagnant circulation in the portal vein. In the 13 patients, no correlation existed between PF and the relative clearance of indocyanine green or the portohepatic gradient, parameters generally used as indices of severity in cirrhosis. In 10 patients, no correlation was found between PF and the estimated hepatic blood flow.     

Altered proteinogram in short term portal vein stenosed rats

The electrophoretic pattern of serum proteins has been studied in short-term prehepatic portal hypertensive rats since atrophy is produced in the liver, which is the main origin of most of these proteins, during this postoperative period. After 28 days of evolution, rats (n = 9) with triple stenosing ligated portal vein showed hypoalbuminemia, hypo-alpha-globulinemia, hyper-alpha2-globulinemia and hyper-gamma-globulinemia, the albumin/globulin ratio decreased with respect to the control animals (n = 8). These alterations are associated with hepatic atrophy, portosystemic and portohepatic (44.4%) collateral circulation. The proteinogram alterations found in rats with short-term prehepatic portal hypertension suggest that hepatic failure exists in spite of potential portohepatic revascularization which is frequently originated by the development of portohepatic collateral circulation.     

Intravascular pressure profiles in elephant seals: hypotheses on the caval sphincter, extradural vein and venous return to the heart

In order to evaluate hemodynamics in the complex vascular system of phocid seals, intravascular pressure profiles were measured during periods of rest-associated apnea in young elephant seals (Mirounga angustirostris). There were no significant differences between apneic and eupneic mean arterial pressures. During apnea, venous pressure profiles (pulmonary artery, thoracic portion of the vena cava (thoracic vena cava), extradural vein, and hepatic sinus) demonstrated only minor, transient fluctuations. During eupnea, all venous pressure profiles were dominated by respiratory fluctuations. During inspiration, pressures in the thoracic vena cava and extradural vein decreased -9 to -21 mm Hg, and -9 to -17 mm Hg, respectively. In contrast, hepatic sinus pressure increased 2-6 mm Hg during inspiration. Nearly constant hepatic sinus and intrathoracic vascular pressure profiles during the breath-hold period are consistent with incomplete constriction of the caval sphincter during these rest-associated apneas. During eupnea, negative inspiratory intravascular pressures in the chest ("the respiratory pump") should augment venous return via both the venae cavae and the extradural vein. It is hypothesized that, in addition to the venae cavae, the prominent para-caval venous system of phocid seals (i.e., the extradural vein) is necessary to allow adequate venous return for maintenance of high cardiac outputs and blood pressure during eupnea.     

Different accessibility from the artery and the portal vein of alpha- and beta-receptors involved in the sympathetic nerve action on glycogenolysis and hemodynamics in perfused rat liver

In perfused rat liver perivascular nerve stimulation (7.5 Hz, 20 V, 2 ms, 5 min) at the liver hilus caused an increase in glucose and lactate output and a decrease in flow. The influence of the alpha 1-receptor blocker prazosine and the beta-blocker propranolol on these nerve effects was studied in the isolated rat liver perfused classically via the portal vein only and, as developed recently, via both the hepatic artery and the portal vein. 1) In livers perfused via the portal vein only the nerve stimulation-dependent metabolic alterations were nearly completely inhibited by prazosine (5 microM), but not influenced by propranolol (10 microM). The hemodynamic changes were lowered to only 33% by prazosine and not altered by propranolol either. 2) In livers perfused via the hepatic artery (100 mm Hg, 20-40% of flow) and the portal vein (10 mm Hg, 80-60% of flow)--similar to portal perfusions--the nerve stimulation--dependent metabolic alterations were almost completely blocked by arterial, portal or simultaneously applied arterial and portal prazosine. However--in contrast to portal perfusions--the metabolic alterations were reduced to about 20% (glucose) and 50% (lactate) also by propranolol independently of its site of application. The decrease in flow was reduced by prazosine to about 60%, 50% and 30% when applied via the artery, the portal vein or via both vessels, respectively. The hemodynamic alterations were not influenced by propranolol. These results allow the following conclusions: A subpopulation of beta-receptors can play a permissive role in the alpha 1-receptor-mediated sympathetic nerve action on glucose and lactate metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

A novel canine model of portal vein stenosis plus thioacetamide administration-induced cirrhotic portal hypertension with hypersplenism

Current large animal models that could closely resemble the typical features of cirrhotic portal hypertension in human have not been well established. Thus, we aimed to develop and describe a reliable and reproducible canine cirrhosis model of portal hypertension. A total of 30 mongrel dogs were randomly divided into four groups: 1 (control; n = 5), 2 (portal vein stenosis [PVS]; n = 5], 3 (thioacetamide [TAA]; n = 5), and 4 (PVS plus TAA; n = 15). After 4-months modeling period, liver and spleen CT perfusion, abdominal CT scans, portal hemodynamics, gastroscopy, hepatic function, blood routine, the bone marrow, liver, and spleen histology were studied. The animals in group 2 (PVS) developed extrahepatic portosystemic collateral circulation, particularly esophageal varices, without hepatic cirrhosis and portal hypertension. Animals from group 3 (TAA) presented mild cirrhosis and portal hypertension without significant symptoms of esophageal varices and hypersplenism. In contrast, animals from group 4 (PVS + TAA) showed well-developed micronodular and macronodular cirrhosis, associated with significant portal hypertension and hypersplenism. The combination of PVS and TAA represents a novel, reliable, and reproducible canine cirrhosis model of portal hypertension, which is associated with the typical characteristics of portal hypertension, including hypersplenism.     

Simultaneous sampling of portal, hepatic and systemic blood during intragastric loading and tracer infusion in conscious pigs

A surgical model for catheterization at multiple sites has been developed for use in long-term metabolic studies. For blood sampling, catheters were inserted into the portal and hepatic veins and the common carotid artery. The hepatic vein catheter was inserted from the margin of a liver lobe and led through the venous system, until the tip was close to the bifurcation with the inferior vena cava. A new technique was developed to ensure correct placement of the hepatic vein catheter using the specific extraction of indocyanin-green over the liver during surgery. Gastrostomy was performed using a Pezzer catheter. Catheters in the artery and hepatic and portal veins were patent for blood withdrawal for up to 4 weeks, and thus allowed repeated metabolic studies. Studies were performed in conscious animals familiar with the experimental situation.     

Insulin resistance in patients with cirrhosis and portal hypertension

Insulin resistance (IR) is involved in the pathogenesis of endothelial dysfunction and is also present in patients with cirrhosis. Intrahepatic endothelial dysfunction plays a major role, increasing hepatic vascular resistance and promoting portal hypertension (PH). In addition, β-adrenergic agonists and insulin share several intracellular signaling pathways. Thus IR may influence the response to β-blockers. This study aimed at evaluating the relationship between IR and hepatic hemodynamics in patients with cirrhosis and with the portal pressure response to acute β-blockade. Forty-nine patients with cirrhosis and PH were included. Hepatic and systemic hemodynamics were measured, and IR was estimated by using the updated homeostasis model assessment (HOMA)-2 index. Patients with HOMA-2 > 2.4 were considered IR. In patients with hepatic venous pressure gradient (HVPG) ≥ 10 mmHg) [clinically significant PH (CSPH)], hemodynamic measurements were performed again 20 min after intravenous propranolol. Mean HOMA-2 index was 3 ± 1.4. Fifty-seven percent of patients had IR. A weak correlation between HOMA-2 index and HVPG was observed. Eighty-six percent of patients had CSPH. HOMA-2 index was an independent predictor of CSPH. However, in patients with CSPH, the correlation between HOMA-2 index and HVPG was lost. HVPG, but not IR, predicted the presence of esophageal varices. Response to propranolol was not different between patients with or without IR. In nondiabetic patients with cirrhosis, HOMA-2 index is directly associated with the presence of CSPH and indirectly with varices, but does not allow either grading HVPG or predicting its response to propranolol.     

In vivo uptake of ethanol and release of acetate in rat liver and GI

The concentration gradients of ethanol and acetate across liver and Gl were determined in overnight starved rats infused with ethanol at a rate (15 μmol/min/rat) below and a rate (30 μmol/min/rat) exceeding the rate of ethanol disposal in the animals. Plasma concentrations of ethanol in the systemic circulation reached steady-state levels of ∼0.6 mM between 30 and 60 min during low rate of infusion; increased steadily from 3.5 mM at 30 min to 6.4 mM at 2 h during high rate of infusion. Gl metabolism was determined by concentration differences in aorta and portal vein; hepatic metabolism by differences in hepatic influx and hepatic veins. Hepatic influx was the sum of the concentrations in aorta and portal vein, each multiplied by their fractional contributions to heoatic blood supply. At low rate of infusion, hepatic extraction of ethanol was nearly complete and could be accounted for entirely by the acetate released from liver. The concentrations of ethanol in aorta were greater but not significantly than that in portal vein. At high rate of infusion, hepatic and Gl gradients of ethanol remained constant despite changes in circulating concentrations of ethanol. The concentration gradients of ethanol and acetate across liver, though different in signs, were identical in magnitude. Gl gradient indicating uptake of ethanol was statistically significant and was about 30 % of hepatic gradient. Enzyme activity of alcohol dehydrogenase in stomach was found to be about 10 % of that in liver. Our results thus show that acetate generated during ethanol oxidation is completely released from liver in rats, in either conscious or anesthetized state under submaximal or maximal condition of ethanol disposal, and that Gl metabolism of circulating ethanol can be as high as one third of the metabolism in liver.     

Effect of isosorbide dinitrate,verapamil, and labetalol on portal pressure in cirrhosis.

The effects on portal pressure of the vasodilatory drugs isosorbide dinitrate and verapamil and of an alpha and beta blocking agent, labetalol, were assessed in 21 patients with cirrhosis and portal hypertension. The wedged hepatic venous pressure gradient (wedged minus free hepatic venous pressures) was used as an index of portal pressure and was not significantly changed by treatment with labetalol (n = 5) but was significantly decreased by verapamil (n = 6; p less than 0.05) and isosorbide dinitrate (n = 10; p less than 0.01). Long term administration of isosorbide dinitrate also had a significant effect (p less than 0.01).     

Effect of infusion of salmon calcitonin on the secretion of somatostatin and gastrin in man

In vitro and animal studies have pointed out complex interrelations between gastrointestinal hormones and calcitonin. To analyse the acute effects of calcitonin in more detail, patients undergoing surgery were infused intravenously with synthetic salmon calcitonin, a potent analog of the human hormone. Samples were taken after 0, 30 and 60 minutes from the hepatic, portal and a peripheral vein. Somatostatin and gastrin were determined by radioimmunoassay. The mean basal levels of somatostatin in peripheral and hepatic venous plasma (14.2 and 15.6 pg/ml) were significantly lower than in portal plasma (45.6 pg/ml), indicating effective removal by the liver. After infusion of calcitonin there was a general rise in somatostatin levels and an increase in the gradient between hepatic and portal blood. Basal gastrin levels were highest in the portal vein when compared intraindividually. The differences disappeared after calcitonin infusion with a concomitant systemic reduction of gastrin levels. Thus, calcitonin is able to stimulate the secretion of somatostatin from the gastrointestinal tract and does reduce gastrin secretion, possibly via the stimulation of somatostatin secretion.     

Epinephrine-induced hepatic potassium movements before and after adrenergic blockade.

The epinephrine-induced loss and subsequent uptake of K+ by the liver was studied by measuring hepatic arterio-venous K+ differences and splanchnic blood flows in anesthetized dogs with chronically implanted portal vein catheters and celiac and superior mesenteric artery flow probes. When epinephrine was administered intraportally, neither alpha- nor beta-adrenergic blockade, singly or in combination, had significant effects upon the hyperkalemic or the hypokalemic phases in either hepatic venous or systemic arterial blood. It was concluded that the movements of K+ into and out of the liver caused by epinephrine are not mediated by the classical adrenergic receptors as defined by inhibition by specific blocking agents.     

Hemorrhagic shock primes the hepatic portal circulation for the vasoconstrictive effects of endothelin-1

To test whether hemorrhagic shock and resuscitation (HSR) alters the vascular responsiveness of the portohepatic circulation to endothelins (ETs), we studied the macro- and microcirculatory effects of the preferential ET(A) receptor agonist ET-1 and of the selective ET(B) receptor agonist sarafotoxin 6c (S6c) after 1 h of hemorrhagic hypotension and 5 h of volume resuscitation in the isolated perfused rat liver ex vivo using portal pressure-flow relationships and epifluorescence microscopy. Although HSR did not cause major disturbances of hepatic perfusion per se, the response to ET-1 (0.5 x 10(-9) M) was enhanced, leading to greater increases in portal driving pressure, total portal resistance, and zero-flow pressures and more pronounced decreases in portal flow, sinusoidal diameters, and hepatic oxygen delivery compared with time-matched sham shock controls. In sharp contrast, the constrictive response to S6c (0.25 x 10(-9) M) remained unchanged. Thus HSR primes the portohepatic circulation for the vasoconstrictive effects of ET-1 but does not alter the effects of the ET(B) receptor agonist S6c. The enhanced sinusoidal response may contribute to the subsequent development of hepatic microcirculatory failure after secondary insults that are associated with increased generation of ET-1.     

Contribution of the umbilical and portal veins to the hepatic blood supply of guinea pig fetuses--an angiographic study.

The interlobular distribution of the umbilical and portal venous blood flow within the liver was examined in 35 guinea pig fetuses between 59 and 65 days of gestation. Contrast medium was injected into the umbilical or vitelline vein, and its passage through the liver was monitored by serial angiography. In four experiments, injections were made into both the umbilical and vitelline veins of the same fetus. To ease interpretation of the angiograms obtained in vivo, we also made a postmortem examination of livers in which the venous system had been filled with an aqueous suspension of barium sulphate in gelatin. These combined experiments demonstrated no passage of contrast medium from the placenta to the inferior vena cava, which is in accordance with independent evidence that the term guinea pig fetus lacks a functional ductus venosus. The area supplied by the umbilical and portal veins was clearly and consistently delineated. The umbilical vein supplied the left lobe and the left sublobe of the quadrate lobe. The portal vein supplied the right lobe, the smaller caudate lobe, and all or most of the right sublobe of the quadrate lobe. This pattern of distribution appears to be determined by flow and pressure gradients within the hepatic circulation.     

The role of hepatic arterial flow on portal venous and hepatic venous wedged pressure in the isolated perfused CCl4-cirrhotic liver

In cirrhosis, hepatic venous pressure gradient is used to measure portal venous and sinusoidal pressures, as well as drug-induced decreases of elevated pressures. The aim of this study was to investigate the influence of hepatic arterial flow (HAF) changes on portal venous perfusion (PVPP) and wedged hepatic venous pressure (WHVP). Normal and CCl4-cirrhotic rats were subjected to a bivascular liver perfusion with continuous measurements of PVPP, WHVP, and hepatic arterial perfusion pressure. Flow-pressure curves were performed with the use of different flows either through the portal vein (PVF: 20-32 ml/min) or HAF (5-15 ml/min). Increases in HAF lead to significant absolute and relative increases in PVPP (P = 0.002) and WHVP (P < 0.001). Absolute changes in HAF correlated to absolute changes in PVPP (cirrhosis: r = 0.64, P < 0.001; control: r = 0.67, P < 0.001) and WHVP (cirrhosis: r = 0.71, P < 0.001; control: r = 0.82, P < 0.001). Changes in PVPP correlated to changes in WHVP due to changes in PVF only in cirrhosis (r = 0.75, P < 0.001), whereas changes in HAF correlated in both cirrhosis (r = 0.92, P < 0.001) and control (r = 0.77, P < 0.001). In conclusion, increases and decreases in HAF lead to respective changes in PVPP and WHVP. This suggests a direct influence of HAF on PVPP and WHVP most likely due to changes in sinusoidal perfusion.     

Diminished hyperaemic response of the hepatic artery to portal venous occlusion (the buffer response) in Asian hybrid minipigs: a comparison of the response to that observed in dogs

The hyperaemic response of the hepatic artery to portal vein occlusion (the buffer response) and the action of exogenous adenosine upon hepatic artery blood flow was studied in Asian hybrid minipigs as a potential alternative experimental model to that previously developed in dogs. Adenosine produced a dose-dependent hepatic artery vasodilatation, but of lesser extent than that observed in dogs. A greatly diminished buffer response was observed in the pigs compared to that seen in dogs, and could not be replicated consistently. The adenosine uptake inhibitor dipyridamole did not potentiate responses to adenosine or the buffer response. It is concluded that the minipig is an unsuitable alternative model for the study of the hepatic artery buffer response.Abbreviations bw body weight - DPD dipyridamole - GDV gastroduodenal vein - HA hepatic artery - PV portal vein - PVO portal venous occlusion - PVP portal venous pressure - SE standard error     

A simple technique for experimental hepatic vein catheterization in swine

Hepatic vein catheterization is a valuable technique in studies of hepatic physiology and metabolism. A new technique for hepatic vein catheterization in swine is described which avoids fluoroscopy, incision, or puncture of the hepatic parenchyma. Experience with this new technique in over 40 studies of young pigs has confirmed the reliability of the technique. Management of hepatic vein catheters after insertion and potential sources of error in hepatic venous sampling are discussed.     

大鼠门静脉分支残端置管模型构建及细胞移植途径的评价

目的：大鼠肝部分切除模型被广泛的应用于肝脏疾病的研究,随着干细胞治疗肝损伤及护肝药物研究的发展,对大鼠肝损伤模型也提出了很多新的要求。本实验拟在大鼠肝部分切除术的基础上改进以建立大鼠肝断面门静脉分支残端的静脉置管模型,并进行细胞移植实验,对比分析新模型的优劣。方法：60只F344大鼠分为三组。A、B组行行85％肝切除术;C组行85％肝切除术＋肝断面门静脉分支残端置管术。术中B组经门静脉注入4×105个表达GFP（greenfluorescenceprotein,GFP）的胎肝干细胞（fetalliverstern／progenitorcells,FLSPCs）。c组经留置导管注射入同等量的FLSPCs,A组注射同等剂量的培养液。72小时取血清,测定肝功能ALT、AST,统计死亡率;取肝脏组织切片观察其修复情况。统计学采用方差分析和LSD—t检验。结果：B、C组F344大鼠72小时肝功指标（ALT、AST）均明显优于A组;B组、C组肝脏组织学的病理损伤的恢复分别较A组快。B、C组间肝功指标无统计学意义。结论：经门静脉分支残端置管途径移植FLSPCs效果等同于经门静脉穿刺途径,且该模型具有可反复、可选时、减少创伤等优点。     

Visualization and Analysis of Blood Flow and Oxygen Consumption in Hepatic Microcirculation: Application to an Acute Hepatitis Model

There is a considerable discrepancy between oxygen supply and demand in the liver because hepatic oxygen consumption is relatively high but about 70% of the hepatic blood supply is poorly oxygenated portal vein blood derived from the gastrointestinal tract and spleen. Oxygen is delivered to hepatocytes by blood flowing from a terminal branch of the portal vein to a central venule via sinusoids, and this makes an oxygen gradient in hepatic lobules. The oxygen gradient is an important physical parameter that involves the expression of enzymes upstream and downstream in hepatic microcirculation, but the lack of techniques for measuring oxygen consumption in the hepatic microcirculation has delayed the elucidation of mechanisms relating to oxygen metabolism in liver. We therefore used FITC-labeled erythrocytes to visualize the hepatic microcirculation and used laser-assisted phosphorimetry to measure the partial pressure of oxygen in the microvessels there. Noncontact and continuous optical measurement can quantify blood flow velocities, vessel diameters, and oxygen gradients related to oxygen consumption in the liver. In an acute hepatitis model we made by administering acetaminophen to mice we observed increased oxygen pressure in both portal and central venules but a decreased oxygen gradient in the sinusoids, indicating that hepatocyte necrosis in the pericentral zone could shift the oxygen pressure up and affect enzyme expression in the periportal zone. In conclusion, our optical methods for measuring hepatic hemodynamics and oxygen consumption can reveal mechanisms related to hepatic disease.     

Hepatic potassium movements induced by sympathomimetic amines before and after adrenergic blockade.

The hepatic K+-mobilizing effects of phenylephrine and isoproterenol were studied in dogs equipped with chronic indwelling portal vein catheters. Animals anesthetized with sodium pentobarbital, received intraportal injections of these sympathomimetic amines, alone or in combination, before and after alpha, or beta, or combined adrenergic blockade. Hepatic K+ movements were assessed by measuring systemic arterial and hepatic venous K+ levels. It was concluded that adrenergic blockade exerted no significant influence on the ability of these agents to provoke the initial release and subsequent uptake of K+ by the liver.     

Comparison of Invasive Blood Pressure Measurements from the Caudal Ventral Artery and the Femoral Artery in Male Adult SD and Wistar Rats

Background and Purpose

Studies have suggested that the caudal ventral artery is a potential site for continuous arterial blood pressure monitoring in rats. However, the agreement of mean arterial pressure values between the femoral artery and the caudal ventral artery has not been investigated. This study was performed to identify whether the caudal ventral artery could be safely used for continuous blood pressure monitoring as an alternative site to the femoral artery.

Methods

Rats were randomized into four groups: Sprague Dawley rats under normothermia; Wistar rats under normothermia; Sprague Dawley rats under hypothermia; Wistar rats under hypothermia. Each rat underwent simultaneous monitoring of blood pressure using femoral artery and caudal ventral artery catheterization during a stable hemodynamic state and three periods of acute severe hemodynamic changes. The effects of rat strain, rectal temperature, experimental time course and hemodynamic factors on pressure gradients, the concordance of mean arterial pressure values between the femoral artery and the caudal ventral artery, and the rates of distal ischemia after surgery were determined.

Results

There was a significant difference in the rate of distal ischemia between femoral and caudal ventral arteries after catheterization (25% vs 5%, P<0.05). The overall mean gradient and the mean gradient under a steady hemodynamic state were 4.9±3.7 mm Hg and 5.5±2.5 mm Hg, respectively. The limits of agreement (bias±1.96 SD) were (−2.5 mm Hg, 12.3 mm Hg) and (-0.5 mm Hg, 10.5 mm Hg), respectively. Although the concordance decreased during the first 30 sec of each period of severe hemodynamic changes, the degree of agreement was acceptable regardless of the effects of rat strain and rectal temperature.

Conclusions

Based on the degree of agreement and the safety of catheterization, the caudal ventral artery may be a preferred site for continuous arterial blood pressure monitoring without acute severe hemodynamic changes.