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.     

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.     

Ermittlung ventrikulärer Druck-Geschwindigkeitskurven unter Berücksichtigung des enddiastolischen Druckes

Summary The effects of intravenous, intra-arterial and intraportal administration of glucagon on hepatic artery and portal vein flows were studied in anaesthetized dogs. Intravenous administration of glucagon (10 g/kg) increased hepatic arterial and portal venous flows by 155% and 176% of the control value respectively. Intraarterial injection of glucagon increased hepatic artery flow and decreased its resistance. The hepatic arterial effect of glucagon was dose-dependent and was not abolished after -adrenoceptor blockade by propranolol 1 mg/kg i.v., or after denervation. Intraportal injection of glucagon had no direct immediate (<15 sec) effect on portal venous flow or pressure. This was followed by an increase in portal vein flow and pressure reaching maximal response within 3–5 min. This late effect was most likely the result of the mesenteric vasodilator action of glucagon. It is concluded that glucagon posses a direct dilator action on the hepatic artery, and indirectly influences the portal venous circulation. Glucagon may have a physiological role in the hepatic vascular bed.This study was supported by NIH Grants HE-07739 and HL-05396 and Cardiology Research and Teaching Fund.Preliminary Communication of this work was presented at the Fall Meeting of the American Physiological Society, 16.–19. August 1971, and appeared as abstract in the Physiologist14, 108 (1971).     

The clinical anatomy of congenital portosystemic venous shunts

Congenital portosystemic venous shunts are rare. Their gross anatomy has not been well defined. Four different varieties of congenital portosystemic venous shunts are described in six children seen during a 10-year period, focusing on the anatomy of the shunt as determined by imaging studies and surgery. A detailed review of the literature indicates that congenital portosystemic venous shunts are best classified as: extrahepatic or intrahepatic. Extrahepatic shunts may be further subdivided into portocaval shunts (type 1 end-to-side and type 2 side-to-side) and others. Intrahepatic shunts are due to an abnormal intrahepatic connection between the portal vein and hepatic vein/inferior vena cava or a persistent patent ductus venosus. Additional congenital anomalies, particularly cardiac malformations, may be associated with any type. Some congenital intrahepatic portosystemic venous shunts close spontaneously in infancy; all other congenital portosystemic venous shunts tend to remain patent. To a variable extent, depending largely on the volume and duration of the shunt, affected individuals are at risk of developing hepatic encephalopathy and/or an intrahepatic tumor. The key to understanding the pathogenesis of these shunts lies in the normal developmental mechanisms underlying the formation of the portal vein and inferior vena cava in the embryo.     

血吸虫病性门静脉高压症兔肝脏微血管构筑变化的研究

目的:探讨血吸虫病门静脉高压症时肝脏微血管构筑的变化及其可能在全身高动力循环状态中的作用。方法:采用腹部敷贴法感染血吸虫尾蚴建立血吸虫病性肝纤维化模型,经插管检测心输出量(CO)、平均动脉压(MAP)、心率(HR)和肝静脉嵌塞压(WHVP),按公式计算心脏指数(CI)、外周血管阻力(SVR);通过血管铸型方法观察肝脏微血管构筑。结果:与正常兔比较,血吸虫病兔CO、CI明显增高,MAP和SVR显著降低,WHVP升高,两组间HR差异无统计学意义。肝脏微血管铸型观察,血吸虫病时肝内微血管形态和比例严重失常,肝窦显著膨大,门静脉主干增粗,肝内形成广泛的小吻合支,其间以门静脉终末支与肝静脉终末支、门静脉小分支直接引流入肝静脉多见。结论:血吸虫病性门静脉高压症兔存在肝内门-体分流病理改变,可能是形成全身高动力循环状态并维持门静脉高压的一个重要环节。     

On the Mechanisms Responsible for Selection of Hepatic Veins as Target for Thrombosis Following Injection of Endotoxin in Hyperlipemic Rats

The feeding of a butter-rich diet, to sensitize rats for studying the phenomenon of hepatic vein thrombosis, is shown to produce severe liver steatosis leading to a sinusoidal barrage and portal hypertension. The portal pressure in these animals was 210 ± 4 mm of saline, as compared to 113 ± 3 mm in the normal rat. Blood circulation studies using carbon suspensions revealed production of a vascular stasis in the hepatic veins after 60 to 90 minutes, when endotoxin (Salmonella typhosa, 0.3 mg/kg) is introduced into the blood circulation to initiate hepatic vein thrombosis. Similar results were observed after 15 minutes with ellagic acid (1 mg/kg/min). The stasis was found in connection with an additional intrahepatic resistance to blood flow as evidenced by a rise in portal pressure and by a reduction in liver perfusion in relation with development of systemic hypotension. In contrast with this, endotoxin initiated only slight and transient changes in the normal rat. Thrombosis immediately followed production of stasis in the hepatic vein, whether the phenomenon was initiated by endotoxin or ellagic acid. Furthermore, inhibition of the vascular stasis of α-adrenergic blockade (phenoxybenzamine, 3 mg/kg) was accompanied by prevention of hepatic vein thrombosis. It is concluded that stasis in the hepatic veins resulting from a mechanical obstruction of the circulation by steatosis and by an additional reduction in blood flow initiated by endotoxin, is responsible for selection of hepatic veins as targets for thrombosis following injection of endotoxin in hyperlipemic rats.     

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.     

Afferent discharges from venous pressoreceptors in liver.

Afterent discharges were observed in dissected filaments or single nerve fibers of hepatic nerve in the guinea pig and the rabbit. Increasing the perfusion pressure of the portal vein in isolated liver preparation in the guinea pig caused an increase in afferent discharge rate. Discharge patterns were compatible with those of the slowly adapting type. Increasing the portal venous pressure by means of intravenous injection of Locke's solution into the left jugular vein in the rabbit in vivo caused an increase in afferent discharge rate. Increasing the hepatic arterial pressure was without effect. It is suggested that pressoreceptors are present in or near the venous wall of the portal venous system and that they send information about blood pressure in the portal vein to the central nervous system.     

Somatostatin-sensitive neural system in the liver

An intraportal bolus injection of cyclic somatostatin in a dose of 3.05 pmol significantly increased the vagal afferent discharge rate in the rat. The results indicate that somatostatin facilitates the vagal sensory nerve activity in the portal venous area. The present immunohistochemical examination of the rat hepatic neural system further disclosed the encapsulated corpuscles which showed intense staining for exogenous somatostatin. They were located beneath the endothelium of the large branches of the portal vein, protruded into the lumen and contained terminal nerve arborizations in the core.     

“肝脏反馈机制”并非门脉高压症高动力循环的发生机制

观察“肝脏反馈机制”在门脉高压症（ＰＨＴ）内脏高动力循环发生过程中的作用，检测了门静脉分支结扎（ＰＢＬ）大鼠和门静脉缩窄肝前型ＰＨＴ（ＰＶＬ）大鼠不同时期的血流动力学变化。结果显示：ＰＢＬ术后７天由于门静脉阻力增加，门静脉压力出现一过性增高，第５，７天出现类似于ＰＶＬ大鼠的短暂的全身高动力循环状态，整个实验过程中，尽管ＰＢＬ大鼠部分肝脏失去了门静脉血供，但未发现象ＰＶＬ大鼠所表现的内脏血管阻力下降     

Angiopoietin-1 causes reversible degradation of the portal microcirculation in mice: implications for treatment of liver disease

In many different liver diseases, such as cirrhosis, degradation of the microcirculation, including obliteration of small portal or hepatic veins contributes to disease-associated portal hypertension. The present study demonstrates the importance of angiogenesis in the establishment of arteriovenous shunts and the accompanying changes to the venous bed. One aspect of angiogenesis involves the branching of new vessels from pre-existing ones, and the molecular mechanisms controlling it are complex and involve a coordinated effort between specific endothelial growth factors and their receptors, including the angiopoietins. We modulated the hepatic vasculature in mice by conditionally expressing angiopoietin-1 in hepatocytes. In mice exposed to angiopoietin-1 during development, arterial sprouting, enlarged arteries, marked loss of portal vein radicles, hepatic vein dilation, and suggestion of arteriovenous shunting were observed. Most importantly, these phenotypic changes were completely reversed within 14 days of turning off transgene expression. Expression of excess angiopoietin-1 beginning in adulthood did not fully recapitulate the phenotype, but did result in enlarged vessels. Our findings suggest that controlling excessive angiogenesis during liver disease may promote the restoration of the portal vein circuit and aid in the resolution of disease-associated portal hypertension.     

Some aspects of the portal circulation in the liver in shock

Summary A study was made of the circulation in the portal vein of cats during shock resulting from current. To assess the circulation the author measured the blood pressure in the portal and posterior vena cavas, estimated the portocaval gradient and took repeated roentgenograms of the portal vein with the cardiotrast contrasting thereof. As revealed, the pressure in the portal vein and in the portocaval gradients was rather high even at the late phases of shock, when the arterial pressure had already undergone a considerable drop. This may be attributed to a marked resistance to the blood flow in the intrahepatic portion of the portal circulation, which is confirmed by the roentgeno grams.(Presented by Active Member AMN SSSR A. V. Lebedinskii) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 54, No. 10, pp. 51–54, October, 1962     

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.     

Increased sinusoidal resistance is responsible for the basal state and endothelin-induced venoconstriction in perfused cirrhotic rat liver

The localization of increased intrahepatic vascular resistance and the segmental vascular responsiveness to endothelin-1 are not well known in liver cirrhosis. We determined the segmental vascular resistances and their response to endothelin-1 of isolated portally perfused bile duct ligation (BDL)-induced cirrhotic rat livers. The portal occlusion pressure (Ppo) and the hepatic venous occlusion pressure (Phvo) were obtained by analyzing the profiles of the portal (Ppv) and hepatic venous (Phv) pressures during the double occlusion maneuver of simultaneous occlusions of the inflow and outflow perfusion lines. From the pressure gradients among Ppv, Ppo, Phvo, and Phv, the portal-hepatic venous resistance was assigned to three segments of the portal [Rpv = (Ppv − Ppo)/blood flow (Q)], sinusoidal [Rsinus = (Ppo − Phvo)/Q] and hepatic venous [Rhv = (Phvo − Phv)/Q] resistances. Rsinus, but not Rpv or Rhv, was significantly greater in BDL livers than in sham livers. Endothelin-1 (0.1–1 nM) increased Rpv and Rsinus to a similar magnitude, but not Rhv, in both sham and BDL. At 3 nM, the responsiveness of Rpv was smaller in BDL than in sham, but that of Rsinus were similar between in BDL and sham. In conclusion, increased sinusoidal resistance accounts for increased intrahepatic resistance of BDL-induced liver cirrhosis. Endothelin-1 contracts portal veins and sinusoids, but not hepatic veins, in both sham and cirrhotic livers. Sinusoidal contractility to endothelin-1 is not impaired in cirrhotic livers.     

肝循环门静脉系统的压力—流量关系

本文对兔离体肝脏的门静脉系统在门静脉狭窄、肝内阻塞、肝动脉压改变及对照状态下进行了血液动力学方面的动态测量和分析。得到肝脏门静脉系统的压力—流量曲线,通过回归分析,确定其回归方程为Q=a blnP。经数理统计,找出生理及各种病理模拟状态下具有显著性差异的指标b:在不同程度门静脉狭窄及不同程度肝内阻塞时,组内及各状态之间参数b的均数均有显著差异(P<0.01),在不同的肝动脉压状态下,参数b的均数在组内同样有显著差异(P<0.01)。     

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   

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.     

Druck-Stromst?rke-Beziehungen der Porta-Lebervenen-Strombahn bei Hunden und Katzen

Summary Pressure-flow relations of the intrahepatic venous pathways show—in dogs and cats—no autoregulatory responses but rather a purely passive pressure adjustment (Fig. 1, 4). Adrenaline and Papaverine have a smaller effect on the flow-pressure curves in the cat than in the dog (Fig. 3). The portal inflow seems to be regulated almost entirely by vasomotor responses (reflex and autoregulatory) of the splanchnic vessels. There is no evidence for any mechanism regulating the venous hepatic outflow in the cat, whereas the dog has a sometimes effectuous throttle mechanism situated in the hepatic veins. The most important factor for venous outflow appears to be (in both species) the caval pressure. The liver does not seem to play an important active hemodynamic role in body circulation at least in cats. The pressure-flow relations of the intrahepatic venous pathways of this species indicate a vascular organization, which, for purely metabolic reasons, allows the highest possible flow rate with the smallest possible portal pressure head.Our results would suggest that cats are preferable to dogs in animal-experiments performed to draw conclusions about the pressure-flow-relations in the human liver.     

Meal induced changes in hepatic and splanchnic circulation: a noninvasive Doppler study in normal humans

Summary The haemodynamic effects of a meal on the splanchnic and hepatic circulation were evaluated in 30 healthy volunteers, using Doppler ultrasonography. The resistance index (RI) of the superior mesenteric artery and of the left and right intrahepatic arteries, the portal vein blood flow as well as the ratio between maximal velocity in the left and right intrahepatic arteries and the adjacent portal vein were measured initially, then 15, 30, 45, and 60 min after the ingestion of a standard balanced liquid meal. Postprandial haemodynamic changes were maximal 30 min after the meal; at that time, mesenteric artery RI decreased significantly [mean –11% (SEM 14%)] whereas portal vein blood flow increased markedly [mean +79% (SEM 14%)]; a significant increase in hepatic artery RI was observed in both liver lobes. The ratio between maximal velocities of the intrahepatic artery and the intrahepatic portal vein was reduced significantly; this ratio decreased more markedly in the right lobe of the liver. These findings would suggest that there was an adaptation of hepatic artery to portal vein blood flow after a meal. The subsequent increase in intrahepatic portal vein flow velocity was found to be greater in the right lobe of the liver.     

The responses of the hepatic and splanchnic vascular beds to vasopressin in rats

Vasopressin, a vasoactive peptide, causes vasoconstriction via V1a vasopressin receptors. Unlike other vasoconstrictor agents, vasopressin also has vasodilatory properties. The purpose of this study was to determine the effect of vasopressin on hepatic and splanchnic circulation in Sprague- Dawley rats. The experiments were conducted in not only isolated blood- and constant flowperfused livers but also anesthetized spontaneously breathing rats. In anesthetized rats, portal venous pressure (Ppv), systemic arterial pressure (Psa), central venous pressure, and hepatic blood flow (HBF) of combined portal venous and hepatic arterial blood flow were continuously measured, and splanchnic vascular bed resistance (Rspl) defined by (Psa - Ppv) / HBF was determined. In perfused livers, vasopressin at 0.1-1,000 nM caused weak venoconstriction as evidenced by small increase in Ppv. In anesthetized rats, when vasopressin was injected into the portal vein as a bolus consecutively at 0.01-100 nmol/kg, Psa increased dose-dependently with the peak increment of 60 ± 18 mmHg at 100 nmol/kg. Ppv and HBF decreased, with resultant increase in Rspl, indicating splanchnic vasoconstriction. In conclusion, hepatic venoconstrictor action of vasopressin was weak in rats. Vasopressin causes splanchnic vasoconstriction, resulting in a decrease in HBF and Ppv in anesthetized rats.