Hepatic Hypoxia Research Articles

Celiac Plexus Block Does Not Alter Hepatic Injury in Rats

We previously demonstrated that upper abdominal surgery on rats pretreated with phenobarbital and anesthetized with halothane caused centrilobular necrosis of the liver, which may be secondary to hepatic hypoxia induced by vasoconstriction. This study examined the possibility that celiac plexus blockade might decrease the degree of injury seen in the surgical model. Rats, pretreated with phenobarbital, were anesthetized with halothane, enflurane, isoflurane, or fentanyl with 100% oxygen. At the start of the hepatic artery dissection, the celiac plexus was blocked by injection of bupivacaine. Subsequently, the rat livers were evaluated for presence and degree of centrilobular necrosis. Animals anesthetized with halothane or fentanyl had a significantly greater incidence of centrilobular necrosis than controls (rats pretreated with phenobarbital who received no anesthesia or surgery). Hepatic injury in rats anesthetized with isoflurane or enflurane did not differ from that in controls. We conclude that celiac plexus blockade with bupivacaine provides no protection against hepatic necrosis in this model.

Alcohol potentiation of liver injury

Alcohol enhances the activity of many but not of all hepatotoxic agents. Not only high toxic doses but also amounts commonly consumed today by many people are active in this respect. An induction of the hepatic microsomal drug-metabolizing system leading to an increased metabolism of the hepatotoxic agents to toxic radicals is the best established cause for ethanol-induced potentiation of liver injury. In the case of CCl 4, hepatic hypoxia resulting from an ethanol-induced hypermetabolism may participate in the enhanced hepatotoxic response. Changes in the overall pharmacokinetics of the hepatotoxins, depletion of hepatic glutathione, and an increase of lipid peroxidation seem not to be implicated in potentiation of liver injury by ethanol. People regularly consuming alcohol may run a higher risk of being injured by hepatotoxic agents than abstainers. Thus, interactions between ethanol and other hepatotoxic agents should be envisaged as a possible additional factor in ethanol-induced human liver damage explaining, at least partially, the great variation in the sensitivity of man to the hepatotoxic effects of alcohol.

Alcohol Potentiation of Liver Injury

Alcohol Potentiation of Liver Injury. STRUBELT, O. (1984). Fundam. Appl. Toxicol. 4, 144–151. Alcohol enhances the activity of many but not of all hepatotoxic agents. Not only high toxic doses but also amounts commonly consumed today by many people are active in this respect. An induction of the hepatic microsomal drug-metabolizing system leading to an increased metabolism of the hepatotoxic agents to toxic radicals is the best established cause for ethanol-induced potentiation of liver injury. In the case of CCl4, hepatic hypoxia resulting from an ethanol-induced hypermetabolism may participate in the enhanced hepatotoxic response. Changes in the overall pharmacokinetics of the hepatotoxins, depletion of hepatic glutathione, and an increase of lipid peroxidation seem not to be implicated in potentiation of liver injury by ethanol. People regularly consuming alcohol may run a higher risk of being injured by hepatotoxic agents than abstainers. Thus, interactions between ethanol and other hepatotoxic agents should be envisaged as a possible additional factor in ethanol-induced human liver damage explaining, at least partially, the great variation in the sensitivity of man to the hepatotoxic effects of alcohol.

Effect of Oxygen Concentration, Hyperthermia, and Choice of Vendor on Anesthetic-Induced Hepatic Injury in Rats

Although hypoxic rats exposed to anesthetics may develop hepatic injury, divergent results have been obtained. These discrepancies might be due to different levels of hypoxia, hypothermia, or choice of vendor. Male Sprague-Dawley rats purchased from Zivic-Miller were pretreated with phenobarbital for 4 days. After 24 h without phenobarbital, they were exposed to 2 h of hypoxia and halothane, enflurane, isoflurane, thiopental, or fentanyl. Rectal temperature was kept between 36.5°C and 38.5°C. All agents given in 10% oxygen produced more hepatic injury than did control conditions (exposure to 10% oxygen alone) (P < 0.01). Only halothane given in 12% and 14% oxygen produced hepatic injury. No agent given in 20% or 100% oxygen demonstrated hepatotoxicity. In a separate study, rectal temperatures were kept between 32°C and 34°C during 2 h of exposure to 0.3 MAC halothane, enflurane, or isoflurane in 10% oxygen. Hypothermia prevented hepatotoxicity by enflurane and isoflurane, but not by halothane. Finally, although livers of rats obtained from Zivic-Miller were injured, specific pathogen-free rats from Charles River were not injured or were less injured by enflurane, thiopental, or fentanyl. Apparently, minor changes in experimental conditions can substantially affect results; hepatic hypoxia per se, anesthetic metabolism (especially that of halothane), and perhaps anesthesia itself may produce hepatic injury.

Effect of acute and chronic ethanol consumption on hepatic tissue oxygen tension in rats

In vivo hepatic tissue oxygenation was investigated in chronically ethanol-treated rats using micro oxygen electrode and reflectance spectrophotometry. Effect of acute ethanol administration was also studied. Hepatic oxygen tension of rats treated with ethanol chronically (daily ethanol intake, 9∼12 g/kg for 9 months) was very low as compared with that of normal rats, the decrease being comparable to that of rats treated with carbon tetrachloride. The hepatic oxygen tension in normal controls shortly after ethanol ingestion increased from basal level (median, 23 mmHg) to 40∼70 mmHg, while in chronically ethanol-treated rats, the hepatic oxygen tension decreased transiently, followed by a gradual increase, but it still remained low. In CCl 4-treated rats, the hepatic oxygen tension decreased further after the ethanol ingestion. It is concluded that chronic ethanol consumption in rats resulted in hepatic hypoxia with decreased liver blood flow and volume. Also acute ethanol administration does not induce hepatic hypoxia in normal rats, while in rats with injured liver it induces hypoxia.

Hepatic Blood Flow, Halothane, and Hypoxia

Hepatic Blood Flow, Halothane, and Hypoxia

Effect of ethanol on hepatic blood flow in unanesthetized dogs with chronic portal and hepatic vein catheterization.

A method of chronic portal and hepatic vein catheterization in the dog is described. Using this method, hepatic blood flow was measured by an indicator dilution technique and the effect of acute ethanol administration on hepatic blood flow was evaluated in unanesthetized dogs. Intravenous and intragastric ethanol administration (2.0 g.kg-1) resulted in a significant increase in hepatic blood flow. Splanchnic oxygen consumption was also increased following ethanol administration but this effect was offset by the rise in hepatic blood flow and the net result was an increase in hepatic vein oxygen content. These data demonstrate a significant effect of ethanol on hepatic blood flow but suggest that hepatic hypoxia does not occur following acute ethanol administration.

Influence of hypoxia on the hepatotoxic effects of carbon tetrachloride, paracetamol, allyl alcohol, bromobenzene and thioacetamide

Exposure of rats to a reduced oxygen tension (6% O 2, 94% N 2) for 6 h increased the serum enzyme and the histological lesions induced by carbon tetrachloride (CC1 4). Hypoxia did not enhance the hepatotoxic response to paracetamol, allyl alcohol, bromobenzene or thioacetamide. No correlation was found between the changes in hepatotoxicity induced by hypoxia and those after treatment with ethanol. Hepatic hypoxia therefore was not the pathogenetic mechanism responsible for ethanol-induced enhancement of hepatotoxicity.

Hepatic vein oxygenation, liver blood flow, and the rate of ethanol metabolism in recently abstinent alcoholic patients.

To determine whether hepatic hypoxia is associated with hepatocellular necrosis in alcoholics, oxygen tension in the hepatic vein and hepatic blood flow were determined in thirteen patients without overt clinical liver disease. Ethanol metabolic rate was also assayed as an index of liver metabolism. Hepatic blood flow and ethanol metabolic rate were also determined in six normal volunteers. According to liver histology patients were separated into two groups, with and without hepatocellular necrosis. Alcoholics with necrosis showed a higher (P less than 0.002) ethanol metabolic rate (4.05 +/- 0.23 mmol/kg/h) than those without necrosis (2.46 +/- 0.34). Hepatic blood flow in the total group of alcoholics was not significantly different from controls; in the group with necrosis it was lower (651.7 +/- 44.6 ml/min/m2) than in the group without necrosis (878.3 +/- 81.6; P less than 0.025). Hepatic vein pO2 was lower (P less than 0.01) in patients with hepatocellular necrosis (31.7 +/- 0.68 mmHg) than in patients without necrosis (35.7 +/- 0.99). In the whole group, a significant negative correlation (r = 0.76, P less than 0.003) was observed between hepatic vein pO2 and ethanol metabolic rate. Acute administration of ethanol (21.7 mmol/kg) did not alter hepatic blood flow in six normal individuals nor in five alcoholic patients, although an increase in hepatic vein pO2 was observed in the latter. The changes observed in hepatic vein pO2 functional hepatic blood flow, and ethanol metabolic rate which correlate with hepatocellular necrosis, may be of pathogenic importance in alcoholic liver disease.

Hepatic circulation during sodium nitroprusside infusion in the dog.

Changes in the hepatic circulation and oxygen supply during sodium nitroprusside (SNP) infusion were studied in 14 dogs anesthetized with pentobarbital, 30 mg/kg. Portal and hepatic arterial blood flows were measured with electromagnetic flow-meters. Aortic, portal and hepatic vein pressures were recorded, and pH, PCo2, O2 content, and lactate and pyruvate concentrations of blood from these vessels were measured. Cardiac output was determined by thermodilution using a Swan-Ganz catheter. In half the dogs a surgical preparation permitted controlled portal blood flow. SNP, 3–5 μg/kg/min, decreased mean arterial blood pressure as much as 15 per cent with no significant change in hepatic circulation, Doses of 10–20 μg/kg/min decreased arterial blood pressure 40 per cent, portal pressure 44 per cent, and portal blood flow 25 per cent. Hepatic arterial blood flow increased 13 per cent. There was no significant change in oxygen content of arterial, portal or hepatic vein blood, in oxygen consumption of the liver, or in the ratio of Iactate to pyruvate produced by the liver. Concentrations of more than 25 μg/kg/min decreased arterial blood pressure more than 50 per cent from control level, decreased portal and hepatic arterial blood flows as much as 80 and 40 per cent, respectively, and decreased oxygen content of portal and hepatic vein blood as much as 5 ml oxygen/100 ml blood. In conditions of steady portal blood flow infusion of SNP led to a decrease in portal pressure by 18 per cent and a decrease in hepatic arterial blood flow. It is concluded that SNP in concentrations that decrease systemic blood pressure as much as 40 per cent of the baseline value does not lead to hepatic hypoxia in normal dogs. SNP decreases portal presinusoidal resistance and does not interfere with the ability of the liver to increase hepatic arterial blood flow in conditions of insufficient portal circulation.

The liver in congestive heart failure: a review.

AbstractCongestive heart failure may induce hepatic congestion with structural and functional derangements. The critical pathogenetic factor appears to be hepatic hypoxia which causes centrolobular damage. This lesion may evolve into cardiac cirrhosis wherein fibrous tissue bands from adjoining cent

Hepatic vein oxygenation, liver blood flow, and the rate of ethanol metabolism in recently abstinent alcoholic patients

Abstract. To determine whether hepatic hypoxia is associated with hepatocellular necrosis in alcoholics, oxygen tension in the hepatic vein and hepatic blood flow were determined in thirteen patients without overt clinical liver disease. Ethanol metabolic rate was also assayed as an index of liver metabolism. Hepatic blood flow and ethanol metabolic rate were also determined in six normal volunteers. According to liver histology patients were separated into two groups, with and without hepatocellular necrosis. Alcoholics with necrosis showed a higher (P < 0–002) ethanol metabolic rate (405±0–23 mmol/kg/h) than those without necrosis (2–46±0–34). Hepatic blood flow in the total group of alcoholics was not significantly different from controls; in the group with necrosis it was lower (651-7±44-6 ml/min/m2) than in the group without necrosis (878-3±81-6; P < 0025). Hepatic vein pO2 was lower (P < 001) in patients with hepatocellular necrosis (31-7±0–68 mmHg) than in patients without necrosis (35-7±0–99). In the whole group, a significant negative correlation (r= -0 76, P < 0–003) was observed between hepatic vein pO2 and ethanol metabolic rate. Acute administration of ethanol (21-7 mmol/kg) did not alter hepatic blood flow in six normal individuals nor in five alcoholic patients, although an increase in hepatic vein pO2 was observed in the latter. The changes observed in hepatic vein pO2, functional hepatic blood flow, and ethanol metabolic rate which correlate with hepatocellular necrosis, may be of pathogenic importance in alcoholic liver disease.

A dynamic and static study of hepatic arterioles and hepatic sphincters.

AbstractThe purpose of this investigation was to demonstrate the cytology of the sphincters of hepatic sinusoids, to elucidate further the pathway by which arterial blood is distributed to the sinusoids, and to study the hormonal and local regulation of arterial and portal venous blood flow through the sinusoids.The sphincters were found to consist of reticulo‐endothelial cells and were the primary site for the regulation of blood flow through the sinusoids. By contracting independently or in unison the flow of blood was regulated through individual sinusoids, through sinusoids supplying a portion of a lobule, or through sinusoids supplying a whole lobule. When the sphincter cells contracted, their nuclear region bulged into the lumen, thereby occluding it.Hepatic arterioles were found to wind around adjacent portal venules with an average curvature of 42° and communicated with sinusoids via arterio‐sinus twigs. No structural arterio‐portal anastomoses were observed; however, functional “arterioportal anastomoses” were formed by short twigs which terminated in sinusoids near their origins. No branches were found to terminate near central venules.The data suggest that the local regulation of blood flow through the hepatic sinusoids is mediated by vasodilator metabolites (adenosine and/or potassium) released from hypoxic hepatic cells as a result of the rapid glycogenolysis that accompanies hepatic cellular hypoxia.

EFFECTS OF HYPOXIA AND HYPERTHERMIA ON HEPATIC TISSUE OF THE DOG.

This work was done to evaluate the effects of hepatic hypoxia and hyperthermia in the dog. Hepatic temperature changes were produced by portal vein perfusion and hypoxia by hepatic arterial inflow occlusion. The extracorporeal circuit consisted of a heat exchanger, plastic tubing, pump, and heating jacket. Blood passed from the femoral artery or jugular vein through the extracorporeal circuit and returned to the portal vein. Forty-two animals were studied. Simple arterial inflow occlusion for 1 hr caused death in three of five animals. Perfusion of the liver with venous blood during hepatic artery occlusion was followed by death in all animals while survival was obtained when arterial blood perfusate was utilized. Death occurred if hepatic temperature exceeded 43 C, with one exception. Portal vein infusion without hepatic anoxia resulted in survival of animals following short periods of hepatic hyperthermia up to 46 C. The greatest increase in serum transaminase and alkaline phosphatase followed hepatic hyperthermia or anoxia, or both. Enzyme values gradually returned to normal within 21 days. It is concluded that hepatic anoxia augments the toxic effect of hepatic hyperthermia. The cause of death was not definitely identified.

Liver function following thermal injury.

Studies of acute changes in hepatic function utilizing the hepatic clearances of rose bengal (I131) and uric acid, and the determination of relative splanchnic oxygen consumption were performed in dogs following a 22 cal/cm2 30% body surface area burn in an attempt to determine the etiology of the hepatic pathologic changes which have been shown to occur following thermal injury. Although rose bengal clearance decreased following injury, arterial-hepatic venous oxygen difference rose sufficiently to increase relative splanchnic oxygen consumption. Plasma uric acid concentration increased following the burn but the arterial-hepatic venous uric acid difference indicated that the changes were not necessarily a result of hepatic dysfunction but could be explained on the basis of accelerated purine catabolism. The postburn administration of morphine effected a significant decrease in the relative splanchnic oxygen consumption. The infusion of dextran did not increase rose bengal clearance proportionate to the resulting increase in plasma volume. The data indicate that hepatic hypoxia does not contribute to the production of early hepatic injury following severe thermal trauma.

Altered liver function of chronic congestive heart failure

C HRONIC congestive heart failure is characterized by widespread, complex and interrelated changes in various functions of the human body. That the liver is involved in these changes has been shown by numerous anatomic and physiologic studies.1-‘0 There is, however, little agreement among investigators as to the basic mechanisms producing the hepatic alterations. Anoxia, venous hypertension, malnutrition and infection, acting singly or in combination, have all been suggested as factors in the pathogenesis of the process. The possibility that the hepatic disturbance may secondarily modify the heart failure state remains a matter for speculation. In an attempt to appraise responsible mechanisms and possible functional interrelationships between the liver and the cardiocirculatory system, in patients with chronic congestive heart failure, a series of studies has been undertaken. The present report considers the nature and severity of liver impairment in the presence of cardiac decompensation and as compensation is restored. It also provides information concerning the role of venous pressure and arterial or hepatic hypoxia in determining or influencing the hepatic impairment.