Application of A. C.-polarography in a study of p-nitroanisole metabolism and its kinetic properties

Phase sensitive alternating current polarography was introduced for the simultaneous determination of p-nitroanisole and its metabolites p-nitrophenol and p-nitrocatechol in kinetic studies with rat liver microsomes. The substrate p-nitroanisole disappears rather rapidly while p-nitrophenol is formed. First traces of a second oxidation product, p-nitrocatechol, can be detected only after a few minutes after the initiation of the reaction. This suggest that O-demethylation of p-nitroanisole is the primary reaction which is followed by aromatic ortho hydroxylation of p-nitrophenol. After incubation times longer than 15 minutes, appreciable amounts of p-nitrocatechol are found which shows optical absorption characteristics similar to those of p-nitrophenol (absorption maximum at 440 nm). It is concluded from these kinetic experiments that optical determination of the primary metabolite during the initial reaction phase constitutes a reliable measure of microsomal O-demethylation activity. Phenobarbital induction differentially increases O-demethylation and ring-ortho-hydroxylation activities. From this and respective inhibition studies it is concluded that possibly multiple forms of cytochrome P-450 are involved in the metabolism of either p-nitroanisole or p-nitrophenol.     

Oxygen consumption and biosynthetic function in perfused liver from rats at different stages of development

Changes in mitochondrial function were studied in perfused liver from rats aged 24-365 days. Oxygen consumption together with the rates of gluconeogenesis, urea synthesis and ketogenesis were determined. Basal mitochondrial respiration as well as the ability of the liver to synthesize glucose, urea and ketone bodies declined from 24- to 365-day-old rats. On the other hand, on transition from 24 to 60 days the liver oxidation rate of hexanoate, sorbitol and glycerol is enhanced, but not of ketone bodies or palmitate. Our results show that the transition from weaning to middle age is accompanied by defined changes in hepatic substrate oxidation. From the observed time course of the decrease in basal and substrate-stimulated oxygen consumption, it is concluded that in rat liver cells a decline in respiratory chain function, long-chain fatty acid and ketone body metabolism, gluconeogenesis and ureogenesis occurs at a relatively early life stage.     

Effect of methionine on the metabolism of formate and histidine by rats fed folate/vitamin B-12-methionine-deficient diet

The metabolism of formate and histidine were compared in rats and in perfused livers of rats on diets deficient in vitamin B-12, methionine, and folic acid. Excretion of formate and formiminoglutamic acid, and the oxidation of [2-14C]histidine and [14C]formate to 14CO2 were measured. Liver folate levels decreased to 40% of normal on the vitamin B-12- and methionine-deficient diets but the rate of oxidation of histidine to CO2 in the whole animal decreased to 15% of normal. This indicated a reduction in the metabolic activity of the liver folates in vitamin B-12deficiency. Comparison of formate and histidine catabolism in folic acid deficiency showed that the oxidation of histine was decreased to 5% of normal but formate oxidation was decreased to only 30% of normal. This indicates that 25% of formate oxidation normally proceeds by a non-folate-dependent pathway.     

Delipidation and reactivation of UDPglucuronosyltransferase from rat liver

UDPglucuronosyltransferase was solubilized by treating Wistar rat liver microsomes with deoxycholate. Chromatography of this preparation on Bio-Gel P-30 resulted in extraction of 92% of phospholipids and complete loss of enzyme activity. UDPglucuronosyltransferase was reactivated by dialysing this delipidated preparation in the presence of lecithin, a mixture of liver microsomal lipids or microsomal preparations from livers of UDPglucuronosyltransferase-deficient Gunn rats. Virtually complete enzyme reactivation was obtained with regard to glucuronidation and glucosidation of bilirubin; however, the inactivation of UDPglucuronosyltransferase with p-nitrophenol as substrate was irreversible. These findings demonstrate that UDPglucuronosyltransferase with bilirubin as substrate is a lipid-requiring enzyme.     

Effects of the nonsteroidal anti-inflammatory drug nimesulide on energy metabolism in livers from adjuvant-induced arthritic rats

The effects of nimesulide on energy metabolism and the hepatic metabolic alterations produced by adjuvant-induced arthritis were investigated in the perfused rat liver an in isolated liver mitochondria. Nimesulide, at therapeutic levels (20-50 microM), produced: (1) stimulation of oxygen consumption in the perfused rat liver and in isolated mitochondria, (2) inhibition of gluconeogenesis; (3) reduction of ADP/O ratio and the respiratory control ratio and stimulation of glycogenolysis in the livers from healthy rats, but not in livers from arthritic rats. These results indicate that nimesulide acts as a mitochondrial uncoupler. The main alterations produced by adjuvant-induced arthritis were: higher rates of oxygen consumption in both perfused livers and isolated mitochondria, with no decrease in the efficiency of mitochondrial energy transduction; (2) decreased gluconeogenesis and lack of glycogenolytic response to uncouplers, but not to alpha 1-agonists. These data allow to conclude that nimesulide-induced impairment of energy metabolism should worsen the hepatic disturbances that are already associated with the adjuvant disease.     

Microfluorometry using fluorescein diacetate reflects the integrity of the plasma membrane in UVA-irradiated cultured skin fibroblasts

Hepatic coenzyme A (CoA) plays an important role in cellular lipid metabolism. Because mitochondria and peroxisomes represent the two major subcellular sites of lipid metabolism, the present study was designed to investigate the specific impact of hepatic CoA deficiency on peroxisomal as well as mitochondrial beta-oxidation of fatty acids. CoA deficiency (47% decrease in free CoA and 23% decrease in total CoA) was produced by maintaining weanling male Sprague-Dawley rats on a semipurified diet deficient in pantothenic acid (the precursor of CoA) for 5 weeks. Hepatic mitochondrial fatty acid oxidation of short-chain and long-chain fatty acids were not significantly different between control and CoA-deficient rats. Conversely, peroxisomal beta-oxidation was significantly diminished (38% inhibition) in livers of CoA-deficient rats compared to control animals. Peroxisomal beta-oxidation was restored to normal levels when hepatic CoA was replenished. It is postulated that since the role of hepatic mitochondrial beta-oxidation is energy production while peroxisomal beta-oxidation acts mainly as a detoxification system, the mitochondrial pathway of beta-oxidation is spared at the expense of the peroxisomal pathway when liver CoA plummets. The present study may offer an animal model to investigate mechanisms involved in peroxisomal diseases.     

The role of cytokines in bacterial pneumonia: an inflammatory balancing act

The effect of 2 mM ethanol, a concentration indicative of daily alcohol consumption, was investigated on trichloroethylene (TRI) metabolism in perfused Wistar rat liver. The study consisted of two parts: The first part studied TRI administration with or without ethanol. In the second study chloral hydrate (CH), an intermediate in TRI metabolism, was administered in the absence or presence of ethanol to phenobarbital (PB) treated or non-PB-treated rats. The concentrations of the metabolites, total trichloroethanol (TCE), and trichloroacetic acid (TCA) were measured by gas chromatography and intracellular reduced pyridine nucleotides by surface fluorometry. In the first study, ethanol infusion significantly increased the TCE/TCA ratio, TCE production rate, and percentage of reduced pyridine nucleotides, and decreased TCA production rate without an associated change in the sum of TCE and TCA formation rates. In the second study, ethanol infusion in the absence or presence of PB produced similar significant increases in the TCE/TCA ratio, TCE production rate, and percentage of reduced pyridine nucleotides, accompanied by a decrease in TCA formation. The observed shift in TRI metabolism in the presence of ethanol, from oxidation to TCA to reduction to TCE, suggests that alcohol exerts alterations in hepatic intracellular oxidation-reduction (redox) states.     

An in vitro study on methotrexate hydroxylation in rat and human liver

Methotrexate (MTX) was investigated for possible effect on the metabolism of ethoxyresorufin, pentoxyresorufin and ethoxycoumarin, the model substrates of cytochrome P450. The investigation was carried out in liver microsomes of rats pretreated with classical inducers of cytochrome P450 as well as in microsomes of two human livers. Furthermore, we measured the conversion of MTX (100microM) to its main metabolite, 7-hydroxymethotrexate (7-OHMTX), in microsomes and cytosolic fractions of rat and human livers. The inhibition of 7-OHMTX formation by menadion (inhibitor of aldehyde oxidase) and allopurinol (inhibitor of xanthine oxidase) was studied in the cytosol of rat and human livers. In both species, MTX in the concentration range 0.5-500 microM exerted no inhibitory effect on enzymatic activities associated with cytochrome P450. Moreover, we did not observe any measurable formation of 7-OHMTX in liver microsomes. MTX was metabolized at a similar rate in the cytosol of rat and human liver. Allopurinol (100 microM) reduced the rate of MTX hydroxylation by 31.5% in the cytosol of human livers but had no effect in the rat. Menadion (100 microM) decreased the rate of 7-OHMTX formation in the cytosol of human and rat liver by 69% and 94%, respectively. Our results confirmed that MTX is oxidized by a soluble enzymatic system in both the rat and human liver. In human tissues, both aldehyde oxidase and xanthine oxidase may play an important role in the metabolism of MTX. Depression of cytochrome P450 and related enzymatic activities observed in vivo cannot be explained by a direct inhibitory action of MTX on cytochrome P450.     

Effect of lipid-free total parenteral nutrition on hepatic drug conjugation in rats

The effect of total parenteral nutrition (TPN) on drug conjugation in male Sprague-Dawley rats was examined using a nutrition solution composed of amino acids and glucose. The overall disposition of acetaminophen including the formation kinetics of the sulfate and glucuronide metabolites was used as an in vivo probe. Selected drug metabolizing enzyme activities also were examined in vitro. TPN, 200 kcal/kg/day, was administered by continuous i.v. infusion for 14 days and changes elicited were compared to control animals allowed free access to rat chow. TPN decreased the total clearance of acetaminophen by 34% and the formation clearance to acetaminophen sulfate by 47%. The formation clearance of acetaminophen to acetaminophen glucuronide was unaffected by TPN. Cytochrome P450 concentration and oxidative demethylase activity toward p-nitroanisole were decreased in parallel, 47 and 53%, respectively, and UDP-glucuronosyltransferase activity with p-nitrophenol and acetaminophen as the acceptor aglycones was decreased 44 and 25%, respectively in the animals receiving TPN. Sulfotransferase activity toward both p-nitrophenol and acetaminophen decreased 28% in animals receiving TPN vs. ad libitum rat chow. Administration of the parenteral nutrition solution as a continuous enteral infusion via a doudenal catheter slightly decreased p-nitroanisole demethylase activity (26%), but had no other significant effects on either cytochrome P450 concentration or on drug conjugating enzyme activities determined in vitro. These results show that parenteral nutrition administered i.v. depresses drug conjugation and suggest that alterations in both hepatic oxidative and conjugative biotransformation arising from total parenteral nutrition are largely attributable to bypassing the intestinal route for nutrient intake.     

Complement C6 and C2 biosynthesis in syngeneic PVG/c- and PVG/c+ rat strains

A PVG rat with total deficiency of C6 and partial deficiency of C2 (PVG/c-), and a syngeneic control strain (PVG/c+), were used to study the production of extrahepatically synthesized complement. Livers of complement deficient rats were transplanted in sufficient rats (Tx-L). The C6 and C2 levels in Tx-L rats declined within 2 days to 25% and 30%, respectively, and remained stable for more than 6 weeks. To investigate the contribution of C6 synthesis by the liver, C6 sufficient livers were grafted in deficient rats (Tx + 1). After an initial increase, with maximum C6 levels of 119% at 10 days following transplantation, the C6 levels decreased gradually and C6 was no longer detectable 28 days after transplantation. This decline in C6 levels was dependent on antibody production against C6. No significant change in the C3, C4, factor H and factor B levels was observed. Expression of C6 mRNA in the grafted PVG/c+ sufficient liver was comparable to the expression of C6 mRNA in control PVG/c+ livers while C6 mRNA expression in the transplanted PVG/ c- liver and the control PVG/c- liver was lower. In conclusion, it was demonstrated in vivo that not only C6 but also C2 is synthesized extrahepatically in PVG/c rats.     

Studies on transmembrane and paracellular phenomena in the foot of the slug agriolimax reticulatus (Mü)

Employing livers from rats fed on a protein-free diet for two weeks, the effects of protein deficiency on both biosynthesis and degradation of rRNA were investigated and the following results were obtained. 1. Protein deficiency led to a decrease of total liver RNA content per DNA to about 80% of that in normal rat liver. 2. From the kinetics of rRNA labelling with [14C]orotic acid in vivo, the half-lives of cytoplasmic rRNA's of normal and protein-deficient rat livers were determined to be 6.2 and 5.1 days, respectively. Furthermore, considering the pool size of rRNA in rat liver, the turnover rate of cytoplasmic rRNA was calculated to be 0.212 pmole/min/mg of nuclear DNA in normal rats and 0.240 pmole/min/mg of nuclear DNA in protein-deficient rats. 3. From the electrophoretic patterns of nucleolar RNA's of both groups of rat livers labeled with [14C]orotic acid, the time courses of the specific activities of nucleolar 45S, 32S, and 28S rRNA's were analysed and the half-life of each nucleolar RNA in both groups of rat livers was determined. Nucleolar 45S, 32S, and 28S RNA's had half-lives of 6.0, 15.9, and 26.5 min in normal rats, respectively, and 5.5, 19.4, and 22.9 min in protein-deficient rats, respectively Considering the pool size of each nucleolar RNA obtained from the leectrophoretic pattern, the turnover rates of 45S, 32S, and 28S RNA's were calculated to be the same, i.e., o.189 pmoles/min/mg of nuclear DNA, in normal rat liver and 0.372, 0.372, and 0.358 pmoles/min/mg of nuclear DNA in protein-deficient rat liver, respectively. 4. These results indicate that protein deficiency increased both the rate of degradation of cytoplasmic rRNA and that of nucleolar rRNA synthesis in rat liver. While in normal rat liver the rates of rRNA synthesis and degradation were rather similar, the rate of rRNA synthesis in protein-deficient rats was about 1.5 times higher than that of its degradation. Therefore, the decrease of total liver RNA content in protein deficiency might be accounted for by stimulated degradation of rRNA in the nucleus. 5. The activities of RNase in nuclear fractions of both groups of rat livers were compared. Both activities of nuclear acid RNase and especially that of the free form of alkaline RNase in protein-deficient rat liver were higher than those in normal rat liver.     

Effect of glycerol on lipogenic enzyme activities and on fatty acid synthesis in the rat and chicken

The influence of glycerol on the rates of fatty acid snythesis in liver slices from rats and chickens in pieces of adipose tissue from rats was first studied. Then the effect of dietary glycerol on lipid metabolism in rats and cheickens was examined. Media containing 3 or 10 mM glycerol depressed the rate of glucose conversion to fatty acids in rat liver slices. However, media containing up to 25 mM glycerol did not influence the rate of fatty acid synthesis in chick liver slices. The inhibitory action of glycerol in rat liver slices might occur at the level of glucose (or glycogen) conversion to pyruvate because glycerol did not inhibit pyruvate or acetate conversion to fatty acids. Rats and chickens were fed glycerol containing diets for either 3 days or 3 weeks. Feeding diets containing 20.5 parts glycerol (22% of dietary energy) to rats or chickens did not influence the growth rate of the animals. However, substitution of 42.2 parts glycerol (43% of dietary energy) for glucose in the diet significantly depressed food intake and growth rate in both rats and chickens. The activities of citrate cleavage enzyme, fatty acid synthetase and malic enzyme in livers of rats fed the glycerol-containing diets were dramatically increased. However, this stimulation of enzyme activity occurred without a concomitant increase in the in vivo rate of fatty acid synthesis in the rat liver. In the chicken, unlike the rat, dietary glycerol did not stimulate but instead decreased hepatic malic enzyme and fatty acid synthetase activities. No significant differences in adipose tissue lipogenic enzyme activities or in the rates of fatty acid synthesis were observed in rats fed glycerol-containing diets. The lipogenic response to glycerol feeding depends on the species as well as the organ.     

Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol

OBJECTIVE: This study was designed to investigate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism. METHODS: The extent of tramadol O- and N-demethylation was calculated by determining the amounts of tramadol and O- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The O- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O- and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe. RESULTS AND CONCLUSION: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (rs = 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.     

Anti-IL-4 antibody inhibits antigen specific IgE response but fails to prevent chicken gamma globulin-induced active systemic anaphylaxis: evidence for the involvement of IgG antibodies

Liver core temperature during organ procurement, storage, and rewarming has not been reported in human orthotopic liver transplantations (OLT). We have shown in the rat that optimal temperature for liver storage is not 4 degrees C but 0 degree C to 1 degree C. Therefore, a study was undertaken in humans and in pigs to determine the pattern of temperature change during OLT. The porcine studies were performed, because it was not possible to follow human grafts during the period that they were sterilely packaged. Temperature depression in humans was rapid during organ perfusion, remained stable during organ dissection, and decreased again slightly, when after excision, the organ was perfused again. Temperature depression during the period of perfusion with University of Wisconsin (UW) solution was curvilinear with the initial rapid temperature depression followed by a period of slower temperature depression. Volume perfused versus time was linear during these periods and the relationship between temperature depression and volume infused was curvilinear. At the time of packaging, 65 +/- 12 minutes after start of cold perfusion, the liver core temperature was 5.7 degrees C +/- 1.3 degrees C. Studies in the pig showed that it took 75 to 100 minutes for liver core temperature to decrease below 5 degrees C, and core temperature reached a plateau at 1 degree C at 195 +/- 75 minutes after packaging. During the rewarming period in humans, while vascular anastomoses were being constructed, there was a rapid linear increase in temperature from 0.8 degree C, when the graft was removed from the cold, to 17.2 degrees C +/- 3.1 degrees C at 45.5 +/- 4.4 minutes later, just before portal reperfusion commenced. These studies show that it takes only a short time to cool livers down to 10 degrees C, but after flushing is stopped, temperature depression is markedly reduced, and ideal temperatures are not reached before packaging. Rewarming of livers during performance of vascular anastomoses is rapid and reaches temperatures at which substantial hepatic metabolism is occurring.     

Lipid changes in hepatic microsomes and its relationship to P-nitrophenol glucuronidation in an experimental model of portal hypertension

The liver is responsible for the most important metabolic pathway of non polar compounds. The aim of the present work was to study the p-nitrophenol glucuronidation and its relationship with lipidic composition of microsomal membrane in a model of hepatic portal hypertension and hepatocellular damage induced by monocrotaline. A global increment in liver microsomal phospholipids as well as changes in the phospholipid pattern (phosphatidylethanolamine and sphingomyelin increased up to 156 +/- 13 and 195 +/- 14% respectively) were detected in monocrotaline intoxicated rats when it were compared to control rats. The microsomal cholesterol content showed a decrease in monocrotaline intoxicated rats. (4.1 +/- 0.7 against 6.6 +/- 1.5 micrograms/mg of microsomal protein, in control rats). When p-nitrophenol activity was measured, Km from monocrotaline intoxicated rats was 0.137 mM, and Vmax was 2.9 nmol of p-nitrophenol/mg microsomal protein since in control group Km was 0.322 mM, and Vmax was 4.5 nmol of p-nitrophenol/mg microsomal protein. It is concluded that monocrotaline intoxicated rats showed a different behavior in the kinetics of p-nitrophenol UDP-glucuronyltransferase, as well as a different microsomal lipidic profile, when compared to control group.     

Effects of maternal ethanol consumption on hepatic lipid biosynthesis in foetal and neonatal rats

Effects of prolonged maternal ethanol consumption were studied on hepatic lipid content, on the rates of fatty acid synthesis and on the activities of enzymes involved in fatty acid synthesis in the livers of foetal and suckling neonatal rats. Prolonged maternal ethanol consumption resulted in a significant increase in the contents of hepatic total lipids, triacylglycerols and plasma unesterified fatty acids in foetal and neonatal rats. Studies in vitro with 3H2O showed that maternal ethanol consumption did not result in a significant change in its rate of incorporation into lipid fractions of foetal and neonatal livers. The rates of fatty acid synthesis showed a pronounced decrease immediately after birth, compared with the foetal stage, but increased in the adult animals. On the other hand, the highest rates of lipid oxidation were observed in the neonatal stage. Maternal ethanol consumption resulted in a significant decrease in the rates of [14C]palmitate oxidation to 14CO2 by both the foetal and neonatal livers. Maternal ethanol consumption did not result in an increase in the activities of any of the lipid-synthesizing enzymes tested throughout the period of development. Although increased fatty acid synthesis does not seem to be the mechanism for the accumulation of these lipids, decreased oxidation of the lipids may be partly responsible for the lipid accumulation.     

Alterations in adriamycin efficacy by phenobarbital

Adriamycin dosage should be reduced in patients with impaired liver function, since adriamycin disposition is influenced by liver metabolism and biliary excretion. It follows that drugs that increase the metabolism or excretory capacity of the liver may decrease adriamycin concentrations to suboptimal values. Adriamycin metabolism was therefore studied in mice pretreated with phenobarbital (75 mg/kg i.v.) by injection. After an i.v. dose of adriamycin (30 mg/kg i.v.), plasma fluorescence due to drug and metabolites was less and disappeared at a greater rate in phenobarbital-pretreated mice than control animals. When extracted with chloroform: isoprophyl alcohol (1:1), the livers from the phenobarbital-pretreated group yielded a greater concentration of glycones. Experiments with liver microsomes confirmed that aglycone production occurred at a more rapid initial rate in phenobarbital-induced livers. No increase in aldoketo reductase (daunorubicin reductase) activity was noted. Phenobarbital-pretreated mice, inoculated i.p. with 1 million L1210 cells and then treated with adriamycin (6 mg/kg i.v.), had significantly lower survival than did controls (p less than 0.01). These findings show that phenobarbital affects the disposition of adriamycin by microsomal enzyme induction and suggest that drugs that induce microsomal enzymes should not be used concurrently with adriamycin if optimal drug efficacy is desired.     

Effects of rho-chloroamphetamine on locomotor activity and brain 5-hydroxyindoles

The conversion of 14C-maltose into glucose, lactate and 14 CO2 was studied in perfused livers from fed and fasted rats and in isolated hepatocytes. Maximal glucose production was 30 mM x g-1 x h-1; half-maximal rates were found with 3 mM maltose. About 0.01 % of the radioactivity infused was recovered as 14CO2. The addition of maltose had no effect on rates of oxygen consumption, lactate production or ketogenesis. The data suggest that maltose did not serve as a major substrate for biosynthetic or energy producing processes under the conditions of the perfused rat liver.     

Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats

Increased intrahepatic resistance in cirrhotic livers is in part caused by increased vascular tone. Several morphological abnormalities have been described in the sinusoidal endothelial cells of cirrhotic livers, but the functional impact of these abnormalities on the intrahepatic vascular tone has not been studied. The aim of this study was to investigate the intrahepatic endothelial function and the role of nitric oxide (NO) with regard to vascular tone in cirrhotic livers. Isolated rat liver perfusions were performed in cirrhotic rats (induced by chronic carbon tetrachloride inhalation) and weight-matched normal controls. After preconstricting the intrahepatic microcirculation with methoxamine (10(-4) mol/L), response to cumulative doses of receptor-mediated endothelial agonist, acetylcholine (10(-7) mol/L-10(-5) mol/L), was obtained. In another series, response to the receptor-independent endothelial agonist, calcium ionophore A23187 (10(-7) mol/L and 3 x 10(-7) mol/L), was obtained in the absence and presence of Nomega-nitro-L-arginine (NNA) and indomethacin. In a third series of rats, nitrate and nitrite production was measured in the perfusate of perfused normal and cirrhotic livers. There was significantly less vasorelaxation in cirrhotic livers as compared with normal livers in response to acetylcholine and calcium ionophore A23187 (P < .0001). The impaired vasorelaxation was a result of a decrease in both NO-mediated and non-NO-mediated components of vasorelaxation. Cirrhotic livers from ascitic rats had significantly less vasorelaxation as compared with livers from nonascitic rats (P < .005). There was significantly less production of nitrates and nitrites in cirrhotic livers (P < .05). The liver microcirculation of cirrhotic livers is characterized by endothelial dysfunction that results in impaired release of endothelial relaxing factors including NO.