Investigation of hepatic energy metabolism in normothermic hepatic ischemia--comparison between normal and cirrhotic rat liver]

The purpose of this study was to investigate the energy movement of the normothermic ischemic liver. Liver ischemia was induced in normal and cirrhotic rats, by cross-clamping portal vein and hepatic artery, bypassing the portal blood to the jugular vein through a shunt tube. The levels of ATP of the hepatic tissue was measured before and after hepatic ischemia, by HPLC and 31P-NMR. Before hepatic ischemia, the levels of ATP was greater in normal liver than in cirrhotic liver, but after ischemia it was significantly smaller in normal liver than cirrhotic liver. Generally they say that the greater is the ATP of the tissue, the greater is the viability of the tissue. But this experiment showed the contrary. Cirrhotic liver can't use glucose sufficiently, therefore acetyl-CoA, which is used in TCA-cycle, is derived from the resolution of fatty acid. As a result, free fatty acid and acyl-CoA increase in cirrhotic liver, and suppress Na(+)-K(+)-ATPase. I conclude that the cirrhotic liver can't effectively use ATP to maintain the potential of the liver cells, maybe, because of it's abnormal metabolism of glucose. Therefore, the levels of ATP was greater in cirrhotic liver than in normal liver after hepatic ischemia.     

Sepsis-induced failure of hepatic energy metabolism

HYPOTHESIS: Recent evidence suggests that sepsis may induce an uncoupling of oxidative phosphorylation. The purpose of this study was to quantify temporal changes in hepatic oxygen consumption and cellular energy state with increasing severity of sepsis and thus assess the interrelationship of these parameters as either primary defect or compensatory response. MAIN OUTCOME MEASURES: Pseudomonas aeruginosa was infused intravenously in eight instrumented anesthetized swine inducing a progressive severity of sepsis to shock. Eight other animals served as instrumented controls. Hepatic blood flow, oxygen use, and concentrations of ATP, ADP, AMP, NAD(+), and NADH were measured at baseline and then sequentially during the study. RESULTS: Except for an increase in heart rate, there were no temporal changes in measured values for the control animals. For swine receiving P. aeruginosa, hepatic oxygen delivery and consumption increased with early sepsis whereas there were no alterations in the concentrations of adenine nucleotides or NAD(+)/NADH within liver. Septic shock was notable for a decrease in oxygen delivery yet oxygen consumption remained elevated because of an increase in percent oxygen extraction. The hepatic concentrations of ATP and NADH decreased during septic shock. CONCLUSIONS: These findings suggest that any sepsis-induced limitation in phosphorylation may be initially compensated by an increase in oxygen use. This study also suggests that decreases in NADH availability may be a principal factor in the decompensation of sepsis to shock.     

Influence of colloidal carbon phagocytosis as a metabolic load on the hepatic energy metabolism in rats

The influence of phagocytosis on hepatic energy metabolism was investigated in rats injected with colloidal carbon. Following injection of 6 mg colloidal carbon per 100 g body wt (BW) the hepatic energy charge potential (ECP) remained unchanged. However, oxidative phosphorylation of the isolated mitochondria (PR) increased significantly to 120 and 124% of the control at 1 and 3 hr, respectively, and returned to the normal range at 6 hr. The pyruvate level rose to 195 and 150% at 3 and 6 hr. The lactate level was elevated to 195 and 143% at 3 and 6 hr. Following injection of 20 mg colloidal carbon per 100 g BW, the ECP decreased from 0.865 to 0.783 at 1 hr, but recovered to the normal range thereafter. The PR increased more markedly to 135% at 1 hr, concomitant with an elevation of the ketone body ratio. At 3 hr it remained elevated at 118%, but returned to the normal level at 6 hr. The pyruvate and lactate levels increased to more than 250% at 1 and 3 hr. At 6 hr, the lactate level returned to the control level, but the pyruvate level showed still higher level than the control. These results indicate that phagocytosis exerts an acute metabolic load on the total liver. It was tentatively proposed that parenchymal and nonparenchymal cells in the liver have interrelation in the energy metabolism, and that an enhancement of hepatocellular mitochondrial phosphorylative activity occurs to assist the accelerated metabolism due to phagocytosis.     

Derangement of hepatic energy metabolism in lead-sensitized endotoxicosis

Lead-sensitized endotoxicosis was investigated in rats in terms of hepatic energy metabolism. Lead acetate (Ld, 20 mg/kg BW) or endotoxin (Etx, 4 mg/kg BW) caused no deaths within 48 h. Ld plus Etx resulted in a lethality of 50 and 100% within 6 and 12 h respectively. Etx or Ld alone caused a slight but significant decrease in the hepatic tissue levels of total adenine nucleotides and/or ATP at 3 and 6 h after the application. The energy charge potential (ECP) remained normal. The ketone bodies acetoacetate and beta-hydroxybutyrate and the ratio AcAc/beta-OHB as well as the mitochondrial oxidative phosphorylation tended to increase; the hepatic tissue levels of pyruvate and lactate were increased after 3 h, indicative of an accelerated glycolysis. These alterations were no longer detectable after 6 h. In lead-sensitized endotoxemia (Ld + Etx), the total adenine nucleotides and ATP of the liver tissue decreased significantly to 84% (86%) and 71% (52%) of the controls within 3 and 6 h respectively, and the ECP had decreased from 0.865 to 0.684 at 6 h. The ketone bodies were increased, while the ratio AcAc/beta-OHB was significantly decreased at 6 h. The hepatic tissue lactate remained elevated. The mitochondrial activity was significantly reduced. A hyperglycemia (175 mg . dl-1) at 3 h changed into a hypoglycemia (50 mg . dl-1) at 6 h. It is suggested that Ld plus Etx causes a rapid impairment of hepatic mitochondria which leads to a drastic disturbance of the hepatic energy metabolism including hypoglycemia and contributes to an enhanced lethality in Ld-sensitized endotoxicosis.     

Effects of acute normovolemic hemodilution on splanchnic oxygenation and on hepatic histology and metabolism in anesthetized pigs.

Perioperative hemodilution (HD) has become an accepted means of reducing transfusion requirements. Therefore, the effects of limited (decrease in hematocrit [Hct] from 30 to 20%, "HD1") and severe (decrease in Hct from 20 to 14%, "HD2") acute normovolemic HD with 6% hydroxyethyl starch on splanchnic blood flows (electromagnetic flow probes), O2 uptakes and deliveries, surface O2 tensions (PO2) (Clark-type electrode), hepatic metabolism (organic acids), and hepatic histology (liver biopsies) were studied in nine pigs anesthetized and paralyzed with ketamine/flunitrazepam and pancuronium. HD1 caused significant (P less than 0.05) increases in cardiac output and all splanchnic flows. Only hepatic arterial blood flow increased twice as much as did cardiac output. Except for hepatic arterial O2 delivery, all splanchnic O2 deliveries decreased. Splanchnic O2 extractions increased, and O2 uptakes remained unchanged. There were no changes in mean surface PO2 values or in surface PO2 histograms of liver and small intestine; in portal or hepatic venous pH; and in hepatic uptake of pyruvate and lactate. In contrast, during HD2 (despite further increases in flows and O2 extractions) portal and hepatic venous pH decreased; mean surface PO2 of liver and small intestine decreased; and the liver surface PO2 histogram showed broadening and a shift to the left. However, hepatic uptake of lactate and pyruvate, and splanchnic O2 uptake remained unchanged, and histologic examination did not reveal significant cell injury. These data indicate that in this experimental model limited acute normovolemic HD was well tolerated by the splanchnic organs. After severe HD, gross liver function remained intact, but there was evidence that compensatory mechanisms (increases in flow and O2 extractions) were no longer fully able to counteract the decrease in splanchnic O2 delivery.     

Influence of hepatic dysfunction on cyclosporine metabolism in the pig

Cyclosporine (CyA) is eliminated from the body via biliary excretion at a rate directly proportional to bile production and the functional status of the liver. Previous reports demonstrated that disturbances in the hepatic excretory function with a rise in the plasma bilirubin level are positively correlated with high blood concentrations of CyA and CyA plus metabolites (CyA + M). Less information is available about the blood concentrations of the CyA parental substance or CyA metabolites in the case of liver dysfunction when there was no elevation of serum bilirubin content. To answer this question, we compared the pharmacokinetic profile of CyA in a cholestatic and in a ischemic model in pigs. Our results show that in pigs receiving a single dose of CyA after liver ischemia, the blood concentrations of CyA and CyA + M are significantly increased independently of the serum bilirubin concentration, probably through a slow down of CyA metabolism by impairment of cytochrome P450 III A.     

Study of the ischemic effect on the hepatic energy metabolism

The changes of hepatic energy metabolism during normothermic and hypothermic ischemia were investigated using rats with portajugular shunt. In addition, some blood parameters were estimated as to whether they could reflect the changes in hepatic energy level (represented by energy charge, EC). In this study, [pyruvate]/[lactate] x 1/K(K = 1.11 x 10(-4)) and [2-oxoglutarate] x [ammonia]/[glutamate] x 1/K(K = 3.87 x 10(-3) mmole) were used as indexes of cytosolic and mitochondrial redox state, respectively. The following results were obtained. 1) Though hepatic EC recovered after 30 minutes of ischemia, it didn't recover after 60 minutes of normothermic ischemia. 2) The recovery of the hepatic EC even after 60 minutes of ischemia was observed in hypothermic condition. 3) Mitochondrial redox state changed like hepatic EC, however, some dissociations were observed between cytosolic redox state and hepatic EC in hypothermic ischemia. 4) The changes of mitochondrial and cytosolic redox state were reflected in those of arterial ammonia and lactate level, respectively. As a result, hypothermia can prolong the safe ischemic period due to its stabilizing effect on mitochondrial redox state. In addition, the changes of the hepatic EC are reflected in those of arterial ammonia and lactate level. In hypothermic condition, however, ammonia seemed a better parameter than lactate in assessing hepatic EC.     

Influence of aging on hepatic and peripheral glucose metabolism in humans

Mechanisms of glucose intolerance with aging were studied by comparing the metabolic response to glucose ingestion in 10 young (20-23 yr) and 10 elderly (73-80 yr) normal men with the simultaneous application of the forearm and double-isotope techniques. The latter technique consisted of a primed-constant infusion of [3-3H]glucose followed by the administration of an oral glucose load (mean +/- SE, 90.7 +/- 0.7 g) containing [1-14C]glucose. Fasting plasma glucose and insulin concentrations were similar in young and elderly subjects, but in the elderly, glucose tolerance was markedly impaired. Although in the elderly the initial rise in insulin levels (delta, i.e., the incremental area under the curve) from 0 to 30 min was delayed (P less than .02), the response from 0 to 45 min, 0 to 60 min, and thereafter equaled that in the young group, and from 90 to 240 min insulin concentrations in the elderly exceeded those in young subjects. Basal hepatic glucose output (HGO) was similar in young and elderly men (2.13 +/- 0.10 and 1.97 +/- 0.14 mg.kg-1.min-1, respectively). Similar proportional reductions in HGO from 0 to 270 min after glucose loading occurred in young (59.7 +/- 10.3%) and elderly (50.3 +/- 4.9%) subjects but was delayed in the elderly. Suppression of HGO was observed in the young 30 min after glucose ingestion (P less than .02), but not before 60 min in the elderly subjects (P less than .05). The systemic appearance of ingested glucose (0-270 min) was slowed with age (80.7 +/- 3.1 and 66.9 +/- 4.3% of the oral load in the young and elderly groups, respectively; P less than .02). Initial increments in both total glucose disappearance (Rd) and forearm glucose uptake (FGU) from 0 to 60 min after glucose loading were decreased in the elderly (Rd, 4.1 +/- 0.7 vs. 11.5 +/- 1.3 g, P less than .001; FGU, 17.2 +/- 1.4 vs. 24.6 +/- 2.5 md/dl forearm, P less than .02). The overall increment (delta, 0-270 min) in Rd was reduced with age (47.2 +/- 2.9 and 34.5 +/- 3.6 g, P less than .02 in the young and elderly, respectively), but the corresponding data for FGU were similar in the two groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of parathyroid hormone on myocardial energy metabolism in the rat

This study examined the effect of parathyroid hormone (PTH) on myocardial energy production, transfer, and utilization. Rats (150 to 200 g) were injected with 1-84 PTH, 200 U/day i.p., or 1-34 PTH, 200 or 300 U/day i.p., for 4 days. Control animals received the vehicle only. The effect of the simultaneous administration of calcium channel blocker, verapamil, was also examined. Myocardial contents of Pi, ATP, and CP were significantly (P less than 0.01) lower in the 1-84 PTH-treated rats than in control animals. Both 1-84 PTH and 1-34 significantly (P less than 0.01) reduced mitochondrial oxygen consumption without altering ADP:O ratio indicating reduced phosphorylation. 1-84 and 1-34 PTH significantly (P less than 0.01) reduced the activities of mitochondrial and myofibrillar creatine phosphokinase and 1-84 PTH inhibited (P less than 0.01) the activities of mitochondrial Mg ATPase and those of myofibrillar Ca ATPase. There were significant (P less than 0.01) increments in myocardial 45Ca and in total calcium content in 1-84 PTH-treated rats. Verapamil abolished all the effects of 1-84 PTH. Similarly, inactivation of 1-84 PTH abolished its effects. Treatment with 1-84 PTH for 10 days was associated with a significant decrease in cardiac index and mean arterial pressure. Our data demonstrate that both 1-84 and 1-34 PTH impair energy production, transfer, and utilization. These biochemical derangements, if maintained, produce a decrease in cardiac index. It appears that the enhanced entry and the accumulation of calcium in the myocardium, either directly and/or indirectly, are responsible for the action of PTH on energy metabolism of the heart.     

Changes in hepatic energy metabolism in rats with acute necrotizing pancreatitis

In this study, changes of hepatic cellular ATP, ADP, and AMP, concentrations and mitochondrial oxidative phosphorylation were investigated in rats with experimental acute necrotizing pancreatitis (ANP). It was found that energy change (ATP + 1/2 ADP)/(ATP + ADP + AMP) of the liver decreased from 0.866 to 0.806 (P less than 0.05) 24 h after ANP, and to 0.769 (P less than 0.01) at 48 h. On the other hand, mitochondrial phosphorylative activity increased to 130% and 157% over the control at 12 h and 24 h respectively, and then rapidly dropped to 62% of normal value at 48 h. Blood ketone body ratio was positively correlated with hepatic energy charge level in ANP. The authors came to the following conclusions that: (1) In ANP, mitochondrial function damage resulted in decreased hepatic energy charge, which, in turn, led to hepatocellular impairment; (2) the measurement of blood ketone body ratio was a reliable indicator by which to assess the energy status of the liver in ANP.     

研究大鼠移植心脏组织中能量代谢模式的变化

目的分析大鼠移植心脏组织中与能量代谢相关酶的变化，探讨移植后心脏能量代谢模式的转变。方法建立大鼠心脏移植的Ono模型，采用蛋白质组学技术比较同基因移植组（供、受者均为Lewis大鼠）与异基因移植组（供者为Lewis大鼠，受者为Wistar大鼠）心脏移植后2周和8周时心脏组织中的蛋白质变化；通过基质辅助激光解吸电离飞行时间质谱（MALDFTOF-MS）法分析获得肽质量指纹图谱，经MatrixScience查询软件搜索获得匹配的蛋白质。结果同基因移植组与异基因移植组比较，发现了65个差异表达的蛋白质，其中与心肌能量代谢相关的酶有18个。结论异基因心脏移植后心肌能量代谢发生转变，线粒体三羧酸循环发生障碍，但线粒体电子传递和ATP跨线粒体外膜的跨膜转运能力增强，糖酵解增加，脂肪酸的氧化利用增强，支链氨基酸的氧化受抑制。     

Effects of dehydroepiandrosterone administration on rat hepatic metabolism following thermal injury

BACKGROUND: Severe burns cause dramatic alterations in liver and whole-body metabolism. Recently, there has been interest in using dehydroepiandrosterone (DHEA) as a treatment for trauma patients, and enhanced survival and immune function have been reported using DHEA in animal trauma models. The specific effects of DHEA on hepatic metabolism following burn injury have not been explored. MATERIALS AND METHODS: Male rats received either (1) a burn covering approximately 20% of the total body surface area or a sham burn or (2) burn injury followed by two intraperitoneal injections of DHEA or vehicle. After 4 days, the livers were isolated and perfused in vitro, and 28 metabolite fluxes were measured. Metabolic flux analysis was used to obtain the intracellular metabolic flux distribution and provide an overview of the metabolic state of the livers in each experimental group. RESULTS: Burn injury decreased the uptake of lactate and the production of beta-hydroxybutyrate and increased the deamination of glutamine to glutamate and asparagine to aspartate. DHEA, compared to vehicle treatment, decreased pentose phosphate pathway (PPP) fluxes and the uptake of several amino acids in burned rats. Furthermore, DHEA treatment restored liver metabolism in burned rats to a state that was very similar to that of the sham control group. CONCLUSIONS: DHEA administration appears to normalize hepatocellular metabolism in burned rats but also decreases the PPP flux, which may impair the liver's ability to recycle endogenous antioxidants. DHEA treatment combined with exogenous antioxidants should receive further consideration in the management of burn and trauma patients.     

不同程度血液稀释对家兔脑氧代谢的影响

目的 观察不同程度急性等容性血液稀释对常温下家兔脑氧代谢的影响.方法 32只成年家兔,随机均分为A、B、C、D四组,A、B、C三组的目标Hct分别为24%、18%、12%;D组为对照组,不行血液稀释.以20%乌拉坦行静脉麻醉后机械通气,并维持体温在37℃.监测血液稀释前后的动、静脉血气,并根据Fick's公式计算出脑氧代谢率(CERO2).结果 A组各时点CERO2与D组比较差异无统计学意义,B组CERO2在血液稀释后8 h较基础值增高,而C组CERO2在血液稀释后2、4、8 h均较基础值增高.结论 血液稀释目标Hct为24%时.对常温、有创条件下家兔脑氧代谢并无影响;日标Hct为18%时,在血液稀释后8 h可以出现CERO2增高,且血液pH值明显降低;血液稀释至Hct为12%时则不能满足脑氧代谢需求.     

Chronic alterations in energy metabolism in the burned rat

Growth rates and food consumption were measured in rats following a non lethal scald burn on 26–28 per cent body surface to develop an animal model for studies of chronic metabolic alterations in the post burn recovery period. The injury was produced by immersing the dorsum of 235–260 g rats in 90°C water for 10 seconds. The burned animals grew at an attenuated rate compared to controls. At 11 weeks post burn, prior to the wound healing of the first rat, the burned animals weighed only 394 ± 10 g v. 494 ± 9 g (mean ± s.e.) in controls. At 42 weeks, when half of the animals healed, the body weight of healed rats (547 ± 16 g) was lower (P<0·05) than that of controls (618 ± 14 g), but greater (P<0·001) than that of their unhealed counterparts (426 ± 13 g). During the period from 42 to 63 weeks the weight of healed rats gradually approached that of controls (P<0·3) while the growth of unhealed animals was virtually arrested. During the first 10 days post burn, food consumption was diminished. However, in the subsequent period food intake per unit of body weight or body surface, which were linearly related for the weight range studied, was elevated in burned rats. At 11 weeks the corrected food consumption of burned animals was elevated 30 per cent (P<0·001). At 42 and 63 weeks, unhealed rats consumed 32 per cent (P<0·001) and 43 per cent (P<0·001) more per unit body weight or surface than corresponding controls. During this later period, the relative food consumption of healed animals became equal to that of controls. The persistently elevated food consumption per unit of body weight or surface suggests the development of hypermetabolism in burned rats. This similarity to burned patients may permit elucidation of factors controlling energy metabolism after thermal injury.     

Evidence for impairment of hepatic energy homeostasis in head-injured rat

Traumatic brain injury (TBI) is known to induce a metabolic adaptation characterized by a nitrogen transfer from the periphery to the liver. However, the consequences of TBI on liver energy status are poorly documented. We evaluated the consequences of TBI on liver energy homeostasis in rats. In a first set of experiments, rats were randomized into two groups: a TBI group traumatized by fluid percussion, and an ad libitum fed group (AL) of healthy rats. The rats were sacrificed at 2, 3, or 4 days (D2, D3, and D4, respectively to determine the kinetic of hepatic energy changes). Since TBI leads to a profound anorexia, in a second set of experiments TBI rats received enteral nutrition (TBI-EN group) for 4 days to specifically assess the role of anorexia in the hepatic disturbances. TBI led to a decrease in hepatic glycogen (D2: TBI 3.9 +/- 1.9 vs. AL 18.9 +/- 2.6 mg/g, p < 0.05) and ATP (D2: TBI 540 +/- 57 vs. AL 850 +/- 44 nmol/g, p < 0.05) contents. These effects were not linked to anorexia, since they were observed when rats were fed using continuous enteral nutrition. Interestingly, there was no adaptation of the mitochondrial oxidative capacity to compensate for the increase in energy requirements (cytochrome C oxidase activity: AL, 82 +/- 5; TBI, 82 +/- 4; and TBI-EN, 87 +/- 3 micromol/min/g, NS). These findings demonstrate that TBI is responsible for an impairment of liver energy homeostasis. Moreover, these alterations are related neither to anorexia nor to decreased mitochondrial oxidative capacity.     

高容血液稀释联合控制性降压对腰椎手术病人血液动力学和氧代谢的影响

目的 探讨术前急性高容血液稀释联合术中控制性降压对腰椎手术病人血液动力学和氧代谢的影响。方法 择期行腰椎骨折椎板减压切开复位内固定术病人30例,随机分为二组:术前急性高容血液稀释联合术中控制性降压组(联合组)和单纯控制性降压组(对照组),每组15例。联合组术前输入6％羟乙基淀粉20 ml/kg和乳酸林格氏液20 ml/kg,行急性高容血液稀释;术中微量泵输注硝普钠0.5-6 μg·kg-1·min-1实施控制性降压,平均动脉压(MAP)控制在55-65 mm Hg;对照组术中控制性降压同联合组。观察联合组插管后稀释前即刻(T0)、稀释后降压前即刻(T1)、降压后30 min(T2)和停降压后30 min(T3)时,对照组插管后降压前即刻(T1)、降压后30 min(T2)和停降压后30 min(T3)时心率(HR)、MAP、中心静脉压(CVP)、心输出量(CO)、氧供(DO2)氧耗(VO2)以及动脉血乳酸(LA)的变化。结果 HR:联合组T1低于T0,对照组T2、T3高于T1,T3 低于 T2;联合组 T2、T3低于对照组。MAP:与T0比较,联合组T1、T3升高、T2降低;T2低于T1,T3高于T2;与T1比较,对照组T2降低、T3升高;与对照组比较,联合组T3降低。CVP:联合组T1高于T0,T2低于T1;对照组T2、T3低于T1;与对照组比较,联合组T1、T2升高。CO:联合组T1、T2高于T0,T3低于T2;联合组T1、T2高于对照组。D02:联合组T1、T3     

半肝血流阻断下肝能量代谢变化的研究

目的　探讨全肝及半肝血流阻断时对肝脏能量代谢的影响。方法　作者对105例肝细胞性肝癌行肝叶切除术的病例进行了术中动脉血酮体比率(AKBR)连续监测。结果　发现全入肝血流阻断组复流时AKBR为0.53±0.10,半肝血流阻断组为0.74±0.06,差异有显著意义(P＜0.05),且合并有肝硬化的病例全入肝血流阻断后AKBR下降更明显达0.42±0.10。复流后全入肝血流阻断组AKBR回升缓慢,术后并发症率较高。结论　作者认为肝叶切除术时采用半肝血流阻断技术是一种简便、安全的方法,特别适用于原发性肝癌合并肝硬化的病例。