Hepatic arterial perfusion decreases intrahepatic shunting and maintains glucose uptake in the rat liver

Intrahepatic shunts have an important function in the regulation of portal venous pressure in the normal rat liver. The present study determined their location, the region of confluence between the hepatic arterial and portal venous vasculatures, regions within the liver that are bypassed and the effects of hepatic arterial perfusion upon the intrahepatic redistribution of portal venous flow. Livers of male Sprague-Dawley rats were excised and perfused in vitro. Hepatic bromosulphthalein (BSP) and glucose uptake were measured in hepatic venous samples. Diversion of the hepatic arterial supply into the portal venous vasculature opened the portal venous intrahepatic shunts and resulted in a 50% reduction in portal venous glucose uptake from 29.6+/-1.6% to 14.9+/-0.9% ( P<0.0001 Student's paired t-test). Portal venous injection of 15-microm-diameter microspheres also opened the intrahepatic shunts and reduced portal venous glucose uptake to 10% from 29.0+/-1.6% to 7.8+/-0.9% ( P<0.0001 Student's paired t-test). No significant reductions in portal venous BSP uptake (43.0+/-6.9 to 48.0+/-4.8%) or hepatic arterial glucose uptake, from an average value of 94.0%, occurred. Therefore, cessation of hepatic arterial perfusion or portal venous injection of microspheres reduced portal venous glucose uptake without affecting BSP uptake. It is concluded that intrahepatic shunts divert perfusate away from the perivenous, sinusoidal (zone III) regions and into the hepatic venous vasculature, distal to zone III. The microsphere data indicate that confluence between the hepatic arterial and portal venous vasculatures occurs mainly in sinusoidal zone II.     

Control of hepatic and intestinal blood flow: effect of isovolaemic haemodilution on blood flow and oxygen uptake in the intact liver and intestines.

1. Limited isovolaemic haemodilution was produced in cats by addition of dextran 75-Ringer solution to an extracorporeal blood reservoir connected in series with the cat. Total hepatic venous outflow was neasured using a hepatic venous long-circuit and hepatic arterial flow was measured with an electromagnetic flow probe. Oxygen uptake was monitored in the guts and liver. Na-pentobarbitone anaesthesia was used. 2. Following reduction of the haematocrit (from 31 to 22) the oxygen uptake of the gut segment and liver were maintained. Gut conductance increased to 125% of control while the oxygen extraction ratio increased to only 109%. The hepatic arterial conductance did not change in spite of a greatly reduced (to 68%) oxygen delivery. Hepatic extraction increased to 140% of control. 3. The hepatic artery did not dilate to maintain constant oxygen supply to the liver thus confirming our previous observation that blood flow is not coupled to hepatic metabolism. 4. Oxygen extraction in the gut correlated well with changes in portal blood flow but not with changes in vascular conductance, arterial blood pressure or oxygen delivery. 5. The blood flow of the gut (vascular beds draining into the portal vein in the splenectomized preparation) was controlled in a manner that prevented changes in portal venous PO2 in spite of a reduction in oxygen content. Local PO2 and perhaps pH, are suggested as the factors controlling gut blood flow following haemodilution. 6. Changes in portal blood flow correlated with changes in portal vascular (intrahepatic) conductance such that increased portal flow produced an increased portal conductance thereby maintaining portal venous pressure constant.     

The hepatic arterial blood flow response to portal vein occlusion in the dog

The acute effect of portal vein occlusion on hepatic arterial blood flow was studied in a group of nine anaesthetised dogs. The influence of hepatic artery denervation and total liver denervation on the hepatic arterial flow response was determined subsequently. Blood flows in the hepatic artery and portal vein were measured with electromagnetic flowmeters, and hepatic tissue perfusion with⁸⁵Krypton clearance. A side-to-side mesocaval shunt was constructed to provide a drainage channel for the mesenteric venous blood during the periods of portal vein occlusion.Occlusion of the portal vein produced an immediate and significant increase in hepatic arterial flow which was sustained at approximately 80% above control for the 6 min period of observation. Total liver blood flow and hepatic tissue perfusion were both significantly reduced by about 40%. Denervation either of the hepatic artery alone or the entire liver produced no change in the response, and it is concluded that there is no neurogenic component either initiating or modifying the early changes in hepatic arterial flow.     

Hepatic arterial perfusion regulates portal venous flow between hepatic sinusoids and intrahepatic shunts in the normal rat liver in vitro

Intrahepatic shunts regulate portal venous pressure during periods of acute portal hypertension when the transhepatic portal resistance is momentarily increased in the normal rat liver in vivo. Hepatic arterial inflow may also increase the transhepatic portal resistance and activate intrahepatic shunts. In the present study, the transhepatic portal resistance and the activity of intra-hepatic shunts were measured in vitro and the point of confluence between the hepatic artery and portal vein in the rat determined. Livers of male Sprague-Dawley rats were single-pass, dual-perfused in vitro. Total cessation or diversion of the hepatic arterial inflow to the portal venous vasculature, whilst maintaining total hepatic perfusate flow, decreased intrasinusoidal pressure, increased transhepatic portal venous resistance and opened the portal venous intrahepatic shunts in a manner similar to intraportal injection of 15-microm diameter microspheres. Injections of the microspheres into the hepatic arterial circulation increased hepatic arterial pressure dramatically, consistent with complete occlusion of the arterial vasculature. The intrahepatic shunts are located at a pre-sinusoidal level because no increases were detected in hepatic arterial pressure following intraportal injection of microspheres. The hepatic arterial vasculature, unlike the portal supply, does not possess a collateral shunt circulation and coalesces with the portal vein at an intrasinusoidal location     

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation.

In orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P < or = 0.02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment.     

Numerical simulation of the hepatic circulation

Availability of donor livers and the relatively short preservation time limit the success of liver transplantation. The use of hypothermic machine perfusion could pave the way for expansion of the donor pool. To better define optimal settings of such a device, the feasibility of using a numerical simulation model of the hepatic circulation is determined. Hemodynamics in the hepatic arterial, portal venous and hepatic venous compartments of the hepatic vascular tree was modelled using an electrical analogue. Calculated pressure and flow profiles throughout the liver were in accordance with physiologic profiles in the total circulatory system. Comparison of calculated flow values with normal control values showed a discrepancy that was explained by inaccurate diameter input data. Until more precise methods for determining vascular dimensions become available, redefining vessel diameter makes the simulation model perfectly suitable for predicting influences of temperature and/or viscosity on hepatic hemodynamics and is thereby an excellent tool in defining optimal settings for our hypothermic liver perfusion system.     

The hepatic haemodynamic response to acute portal venous blood flow reductions in the dog

The hepatic haemodynamic response to acute reductions in portal venous blood flow was investigated in 14 anaesthetized normal dogs. A side-to-side mesocaval anastomosis was constructed to enable varying degrees of portal flow to be diverted into the inferior vena cava by suitable manipulations of the shunt diameter. Measurements of portal venous and hepatic arterial blood flow were made with electromagnetic flowmeters.A linear relationship was observed between the degree of reduction in portal flow and the magnitude of the resulting hepatic arterial hyperaemic response. Hepatic arterial vascular resistance showed a decrease which became more pronounced the greater the degree of reduction in portal flow. For every 1.0 ml·min^–1 100 g^–1 decrease in portal flow, the hepatic arterial flow increased by a mean of 0.24 ml ·min^–1·100g^–1, a value representing the average compensatory capacity of the arterial response. Arterial flow improvement therefore provided some degree of protection against severe falls in total liver blood flow. However, it provided even more effective protection against any fall in total hepatic oxygen consumption, which showed only a very gradual decrease with reduced hepatic portal blood flow.     

Effects of hematocrit on oxygenation of the isolated perfused rat liver

The isolated perfused rat liver is used ubiquitously for metabolic and endocrine studies of hepatic function, yet few data are available regarding the inadequacy of the oxygenation of such preparations. Moreover, the isolated rat liver is usually deprived of its arterial supply and perfused via the hepatic portal vein with low-hematocrit or cell-free solutions. To investigate the efficacy of the oxygen supply, we determined the effect of hematocrit on the relation between oxygen consumption and perfusate flow. We then attempted to define a hematocrit at which hepatic oxygenation was maximal. Livers of male rats anesthesized with pentobarbital sodium were perfused via the portal vein with fresh canine red blood cells suspended in Krebs-Ringer-bicarbonate buffer. Perfusions were carried out at various flow rates, and the relation between perfusate flow and oxygen uptake was determined. At flow rates above 100 ml X min-1 X 100 g liver-1, oxygen uptake was independent of flow but below that value was flow limited, regardless of whether the hematocrit was 10, 20, or 40%. To determine the optimal hematocrit for hepatic oxygen uptake, hepatic portal venous and hepatic venous pressures were held at 10 and 0 mmHg, respectively. The hematocrit was lowered in steps from 80 to 10%. Blood flow increased exponentially as hematocrit fell while oxygen uptake increased to a maximum at approximately 20%. It is concluded that an hematocrit of approximately 20% provides the optimal combination of blood flow and oxygen-carrying capacity while maintaining physiological perfusion pressures, e.g., 10 mmHg.     

Non-invasive measurement of hepatic oxygenation by an oxygen electrode in human orthotopic liver transplantation

Precise evaluation of graft reperfusion is difficult in clinical liver transplantation. The oxygen electrode (OE) is a novel technique to detect blood flow indirectly by measuring the quantity of oxygen which can diffuse from the hepatic tissue to the surface electrode. Application of the surface OE does not influence the liver blood flow or parenchymal perfusion. Adequate graft oxygenation is essential to the outcome of organ transplantation and has not previously been analysed intra-operatively in liver transplant recipients. The OE was applied to the surface of the graft intra-operatively in 22 human liver grafts after restoring portal vein and hepatic artery inflow. OE readings were compared with liver blood flow using an electromagnetic flowmeter (EMF). Intra-operative haemodynamics and donor organ parameters known to influence graft function were correlated with the OE readings. There was a significant correlation (r=0.89; p<0.001, n=14) between tissue oxygenation using the OE and total liver blood flow measured by EMF. The tissue oxygenation measurements were reproducible with a coefficient of variation of 5%. The hepatic tissue oxygenation increased significantly from baseline following venous reperfusion of the graft (282+/-23 vs 3107+/-288 (+/-SE) nA, p<0.001). Hepatic arterial revascularisation resulted in a significant (p<0.001) increase of 41+/-7% in liver oxygen perfusion. There was significant negative correlation (r=0.80, p<0.001, n=22) between cold ischaemic time and graft tissue oxygenation. The OE provides a reliable, cheap and non-invasive method of monitoring liver graft oxygenation and perfusion during transplantation.     

A comparative histological and morphometric study of vascular changes in idiopathic portal hypertension and alcoholic fibrosis/cirrhosis

AIM: To examine the pathological changes of hepatic arteries in idiopathic portal hypertension (IPH) which is characterized by the obliteration of the intrahepatic portal vein branches and presinusoidal portal hypertension. METHODS AND RESULTS: Liver specimens (biopsied or surgically resected) from 20 patients with IPH, 20 patients with alcoholic fibrosis/cirrhosis (AF/C) and 20 histologically normal livers were used. The vascular lumina of arterial and venous vessels in portal tracts were morphometrically evaluated by an image analysis system. The ratio of portal venous luminal area to portal tract area (portal venous index) of IPH and that of AF/C were significantly reduced compared with normal liver. The portal venous index for IPH was significantly lower than that for AF/C. The ratio of hepatic arterial luminal area to portal tract area for AF/C was significantly higher than that in normal liver; however, that for IPH was similar to normal. The peribiliary vascular plexus was increased in AF/C but not in IPH. In AF/C, the number of mast cells and macrophages known to be the source of angiogenic substances was significantly increased in the portal tract compared with normal liver, while in IPH it was not increased. CONCLUSIONS: In AF/C, a reduction in portal venous lumen was associated with an increase of hepatic arterial lumen and of angiogenesis-related cells in portal tracts. However, such compensatory arterial changes were not evident in IPH, and this compensatory failure may be a feature of IPH.     

Liver Hemodynamics and Liver Function in Cats during Graded Hypoxic Hypoxemia

In 15 cats, anesthetized with chloralose and curarized, liver hernodynamics and liver function were followed during graded hypoxic hypoxemia. Hepatic arterial and intrahepatic portal venous conductance were not influenced by hypoxia, whereas severe hypoxemia increased gastrointestinal conductance. Total liver blood flow remained constant and hypoxemia was compensated for by an increase in hepatic extraction of oxygen approaching 100% Only when the hepatic venous PO₂ fell below 5–10 mmHg did hypoxemia decrease liver function. The results indicate that the sinusoidal perfusion is homogeneous.     

Intrahepatic distribution of portal and hepatic arterial blood flows in anaesthetized cats and dogs and the effects of portal occlusion, raised venous pressure and histamine

1. Radioactive microspheres were used to determine the distribution of arterial and portal flows within the liver. (141)Ce-microspheres and (51)Cr-spheres were given to allow two determinations of flow distribution in each animal and experiments are described to establish the accuracy and validity of the method.2. Mean flow/g to any lobe or segment of a lobe in a group of animals was not markedly different from the mean flow/g to the whole liver, and in general the liver was homogeneously perfused with both portal and arterial blood. However, in any one liver, some areas received a relatively greater flow (up to 300%) and some a relatively smaller flow (down to 50%) at the time the microspheres were given. The gall bladder received a much smaller portal flow/g than the parenchyma but its arterial flow/g varied widely in different animals.3. If portal flow to an area of parenchyma was reduced by occlusion of a branch of the portal vein, this area received a significantly increased arterial flow.4. An increase in hepatic venous pressure did not cause a significant change in the intrahepatic distribution of either arterial or portal flows in cats.5. In dogs, infusions of histamine into the portal vein caused a redistribution of portal flow away from the free ends of the lobes towards the hilar ends but the distribution between lobes did not change and there was no redistribution of arterial flow.     

Splanchnic clearance of plasma vasopressin in the dog: evidence for prehepatic extraction

It is generally considered that the liver is primarily responsible for the extraction of vasopressin from the circulating blood by the splanchnic viscera. To investigate this matter further, measurements were made in the anesthetized dog of the concentrations of vasopressin in arterial, portal venous, and hepatic venous plasma, and of total splanchnic plasma flow and hepatic arterial plasma flow. The total splanchnic vasopressin extraction ratio was 12.9 +/- 1.0%. However, the concentration of vasopressin in portal venous plasma was consistently lower than in arterial plasma, and there was a substantial prehepatic extraction of vasopressin, averaging 10.5 +/- 0.8%. A quantitative evaluation of the contribution of the "prehepatic" viscera, i.e., viscera with venous drainage into the portal vein, is provided by the relevant clearances of vasopressin. The prehepatic and total splanchnic vasopressin clearances were 1.58 +/- 0.20 and 3.04 +/- 0.31 ml X min-1 X kg-1, respectively. Thus, the splanchnic viscera other than the liver were responsible for approximately half of the splanchnic clearance of vasopressin; the remainder could be attributed to the liver. Immunoreactive vasopressin was not found in the bile. In splenectomized dogs, in which venous blood was collected from the superior mesenteric vein, the vasopressin extraction ratio was 14.6 +/- 2.3%, suggesting that the prehepatic clearance of vasopressin occurs largely in the mesenteric bed. A more specific localization of the prehepatic clearance sites has not as yet been made.     

Hepatic outflow obstruction created by balloon occlusion of the hepatic vein: induced hepatic hemodynamic changes and the therapeutic applications of hepatic venous occlusion with a balloon catheter in interventional radiology

Hepatic outflow obstruction created by balloon occlusion of the hepatic vein induces characteristic angiographic findings in the occluded area: prolonged enhancement on hepatogram followed by reversed portal opacification on the hepatic arteriogram and perfusion defect on the arterial portogram. The following induced hepatic hemodynamic changes are suggested: hepatic arterial flow increases, and the portal vein acts as a draining vein with slow reversed flow. These unique hemodynamic changes enhance the effect of hepatic interventional therapies. In transcatheter arterial infusion, increasing hepatic arterial flow and absence of portal inflow can bring about a high concentration of drugs, the presence of which is greatly protracted due to outflow blockage. In transcatheter arterial chemoembolization, reversed portal flow can allow portal embolization in addition to arterial embolization. In microwave coagulation therapy and radiofrequency ablation therapy, decreasing portal flow can cause larger areas of coagulation. Further, the technique of hepatic venous occlusion has potential therapeutic applications.     

Histological study of intrahepatic cavernous transformation in a patient with primary myelofibrosis and portal venous thrombosis

Summary Cavernous transformation in the liver was examined histologically by serial section observations, in an autopsy case of portal venous thrombosis and primary myelofibrosis. Cavernous transformation was present from the hepatic hilus to medium-sized portal tracts and was composed of dilated and thin-walled vessels. Serial sections disclosed that these vascular channels were anastomotic and occasionally communicated with occluded portal venous radicles. In places they entered directly into the hepatic parenchyma without accompanying biliary or arterial elements, and also drained into the patent portal venous branches beyond the occluded segment. The study demonstrated that cavernous transformation in the liver develops as hepatopetal collaterals secondary to the portal venous obstruction. Periportal and peribiliary capillary plexus may become cavernous in the presence of portal venous occlusion.     

Influence of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis

The influence of intravenous somatostatin infusion (7.6 micrograms/min) on systemic and splanchnic haemodynamics was examined in 10 patients with liver cirrhosis and portal hypertension. The hepatic vein catheter technique was employed and indocyanine green dye was injected to evaluate hepatic blood flow. Mean wedged hepatic venous pressure fell from 24.9 +/- 2.8 in the basal state to 21.4 +/- 3.2 mmHg (P less than 0.2) at 60 min of infusion and the mean arterial pressure decreased from 87 +/- 5 to 80 +/- 6 mmHg (P less than 0.05). The rate of indocyanine green dye disappearance decreased from 8.7 +/- 1.9 to 6.6 +/- 1.7%/min (P less than 0.001) during the infusion, indicating decreased hepatic blood flow. Arterial-hepatic venous oxygen differences rose from 69 +/- 11 to 78 +/- 11 ml/l. Blood glucose levels fell from 4.84 +/- 0.31 to 3.79 +/- 0.33 mmol/l at 60 min of infusion (P less than 0.005). It is concluded that a continuous infusion of somatostatin in patients with liver cirrhosis and portal hypertension causes a decreased hepatic blood flow with augmented hepatic oxygen extraction and a modest reduction in mean wedged hepatic venous pressure. In view of the magnitude of the observed haemodynamic changes the findings do not suggest an important role for somatostatin in the treatment of patients with bleeding oesophageal varices.     

Hepatic blood flow studies in the rat before and after portacaval transposition.

Portacaval transposition diverts portal blood from the liver and allows systemic venous blood from the caudal inferior vena cava to perfuse the portal bed. Measurement of hepatic tissue blood flow before and after portacaval transposition and its relationship to the liver atrophy seen after portacaval transposition is important. Sequential measurements of hepatic tissue blood flow carried out before and after portacaval transposition have been made using the clearance of the inert radioactive gas 85Krypton after injection into the portal bed. These measurements reveal that hepatic tissue blood flow is not diminished following the operation. The relative liver atrophy seen after portacaval transposition is therefore consequent on portal venous diversion but not on diminished hepatic perfusion.     

The effects of intraportl infusions of glucagon on the hepatic arterial and portal venous vascular beds of the dog: Inhibition of hepatic arterial vasoconstrictor responses to noradrenaline

The sympathetically-innervated hepatic arterial and portal venous vascular beds of the dog were perfused simultaneously in situ. Glucagon was infused into the hepatic portal vein (1–10 g/min); it caused increases in hepatic portal vascular resistance and tended to reduce the hepatic arterial vascular resistance. Extrahepatic effects of intraportal infusions of glucagon included increases in superior mesenteric blood flow and heart rate and falls in systemic arterial pressure.A test dose of noradrenaline (10 g) injected into either the hepatic artery or the portal vein caused both hepatic arterial and portal venous vasoconstriction. The hepatic arterial constrictor responses to noradrenaline were antagonized intraportal infusions of glucagon. In contrast, intraportal glucagon did not antagonize the portal constrictor responses to intraarterial or intraportal noradrenaline.Elevated portal blood glucagon concentrations may protect the hepatic arterial blood flow from vasoconstriction due to elevated systemic levels of vasoactive substances including catecholamines.     

A model of dual circulation in liver acini with hypoxia regulated adenosine secretion

It was postulated by W.W. Lautt that the hepatic artery flow compensation for changes in portal vein flow (the 'hepatic arterial buffer response') is regulated through the portal blood washout of adenosine from the small fluid compartment that surrounds the hepatic arterial resistance vessels. It is presumed that the adenosine secretion there is constant and independent of oxygen supply or liver demand. It was reported by others that liver secretes variable quantities of adenosine and that secretion is related to the level of liver hypoxia. This paper is an attempt to describe a model of acinar circulation without sources of constant adenosine secretion. The presented model is based on the fact that portal blood enters acinar space near the vascular stalk in the zone 1, while most of the arterial branches empty one-third from the interlobular septa, at the beginning of the zone 2, just downstream from the zone 1. Another important characteristic of liver architecture is that near 5/9 of lobular volume is in the zone 1. Liver cells in zone 1 are well oxygenated by the portal blood and they have low adenosine secretion that might seem almost constant. Since most arterial branches empty more peripherally, the zone 1 normally does not depend on the arterial circuit and most of arterial branches are governed by the adenosine secretion from the upstream zone 1. Low portal flow, would increase adenosine secretion from the zone 1 and thus dilate numerous downstream arterial resistance vessels. An increased flow from these arterial vessels would compensate any decrease in the portal flow. Zones 2 and 3 probably have higher adenosine secretion rates since the oxygenation depends on the amount of added arterial blood and on the liver cell metabolism. Some of the arterial branches in those zones are probably open all the time, preserving them zones from hypoxic injury. Since the main point for arterial inflow is concentrated downstream from the zone 1, in cases of low portal pressures, or elevated upstream resistance, some of the arterial blood might leave the acinus in retrograde direction via the portal branch and enter some other acinus as a part of portal blood. These arterio-portal communications might be important in cases of low or none portal flow when zone 1 is in hypoxia. In the 3D liver space with tightly packed acini, very complex and ever-changing patterns of combined antegrade and retrograde flows can be expected.     

Re-investigation of the effect of adrenaline and noradrenaline on renal function in situ

1. Adrenaline or noradrenaline in single doses (0.01-0.10 mug/kg) or by continuous infusion (0.3-3.0 mug.kg(-1) min(-1)) into anaesthetized dogs has been administered by different routes. The changes in femoral arterial B.P., hepatic portal venous pressure, renal venous pressure, intrarenal venous pressure, kidney volume, renal plasma flow (RPF), glomerular filtration rate, urine flow and plasma protein concentration have been followed. The effects varied with route of administration, with dose and time.2. Direct injection of single doses of these drugs (相似文献