Clinical and prognostic usefulness of serum proteomic profile in hepatic colorectal metastases: a pilot prospective study.

PURPOSE: To analyze the use of proteomic profiles to discriminate healthy from patients with colorectal liver metastases (CLM) and to predict neoplastic recurrence after CLM resection. METHODS: From April 2005 to October 2008, 70 patients operated for first curative resection of CLM and 60 healthy controls underwent determination of preoperative serum proteomic profile. We performed a preliminary training with patients and controls and obtained a classification system based on these patients' proteomic profiles training. The system was then tested about the ability to predict the colon versus rectum origin, metachronous or synchronous appearance, risk of recurrence after CLM resection and whether a sample was from a control or a CLM patient. RESULTS: Sensitivity, specificity, positive and negative predictive values for detecting CLM patients were 75, 100, 100 and 54.6 %, respectively. Best CLM appearance time identification was 50 % and primary tumor origin identification was 62.5 %. Best classifications of neoplastic recurrence within the first year after CLM resection and during the follow-up period were 47.5 and 45 %, respectively. Larger training sets and prevalence-based training sets led to better classification of patients and characteristics. CONCLUSION: Proteomic profiles are a promising tool for discriminating CLM patients from healthy patients and for predicting neoplastic recurrence.

Increased serum hepcidin levels in patients with porphyria cutanea tarda.

BACKGROUND: Increased iron stores- are common in porphyria cutanea tarda (PCT) patients, but the pathophysiological pathways remain unknown. Down-regulation of hepcidin, a peptide which regulates systemic iron homeostasis, has been demonstrated in different conditions associated with PCT, such as haemochromatosis, chronic hepatitis C (CHC) and excessive alcohol intake. However, serum hepcidin levels have not yet been studied in PCT patients. OBJECTIVE: To measure the serum hepcidin levels in patients with PCT, CHC and control patients, and to assess the association of hepcidin with serum markers of inflammation, iron overload and oxidative stress. METHODS: Hepcidin levels were measured by a competitive enzyme-linked immunosorbent assay in serum samples of patients presenting PCT (n = 30), CHC (n = 31) and healthy volunteers (n = 52). RESULTS: The mean of serum hepcidin levels was significantly higher in the PCT group (129.6 ng/mL) in comparison with the mean values in the CHC (41.3 ng/mL) and control (70.8 ng/mL) groups. The serum concentration of ferritin and interleukin-6 (IL-6) was also significantly higher in the PCT group, and correlated strongly with the hepcidin levels. The PCT patients with hepatitis C virus (HCV) infection showed significantly higher hepcidin levels than the group of CHC patients without porphyria. CONCLUSION: Serum hepcidin levels are increased in patients with PCT suggesting that the mechanisms regulating iron homeostasis in PCT differ from those involved in other related disorders, such as haemochromatosis, HCV infection or alcohol abuse.

Moderate consumption of red wine, but not gin, decreases erythrocyte superoxide dismutase activity: a randomised cross-over trial.

BACKGROUND AND AIMS: Several studies have shown that moderate alcohol consumption reduces the risk of coronary heart disease, a disease related to oxidative stress. However, the effects of different alcoholic beverages on antioxidant status are not fully known. Our aim was therefore to compare the effects of a moderate intake of an alcoholic beverage with high polyphenol content (red wine) and another without polyphenol content (gin) on plasma antioxidant vitamins, lipid profile and oxidability of low-density lipoprotein (LDL) particles. METHODS AND RESULTS: Forty healthy men (mean age, 38 years) were included in a randomised cross-over trial. After a 15-day washout period, subjects received 30 g/ethanol/d as either wine or gin for 28 days. Diet and exercise were monitored. Before and after each intervention, we measured serum vitamins, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase activities, lipid profile, oxidized LDL and LDL resistance to ex-vivo oxidative stress. Compared to gin intervention, wine intake reduced plasma SOD activity [-8.1 U/gHb (95% confidence interval, CI, -138 to -25; P=0.009)] and MDA levels [-11.9 nmol/L (CI, -21.4 to-2.5; P=0.020)]. Lag phase time of LDL oxidation analysis also increased 11.0 min (CI, 1.2-20.8; P=0.032) after wine, compared to gin, whereas no differences were observed between the two interventions in oxidation rate of LDL particles. Peroxide concentration in LDL particles also decreased after wine [-0.18 nmol/mL (CI, -0.3 to-0.08;P=0.020)], as did plasma oxidized LDL concentrations [-11.0 U/L (CI,-17.3 to -6.1; P=0.009)]. CONCLUSION: Compared to gin, red wine intake has greater antioxidant effects, probably due to its high polyphenolic content.

How to achieve more accurate comparisons in organ donation activity: time to effectiveness indicators.

We are used to comparisons of activity using donation or transplantation population (pmp) rates between regions or countries, without a further evaluation of the process. But crude pmp rates do not clearly reflect real transplantation capacity, because organ procurement does not finish with the donation step; it is also necessary to know the utilization of the obtained organs. The objective of this study was to present methods and indicators deemed necessary to evaluate the effectiveness of the process. We have proposed the use of simple definitions and indicators to more accurately measure and compare the effectiveness of the total organ procurement process. To illustrate the use and performance of these indicators, we have presented the donation and transplantation activity in Catalonia from 2002 to 2007.

[Prevalence of cardiovascular disease in uraemia and relevance of cardiovascular risk factors]. / Prevalencia de enfermedad cardiovascular en la uremia y relevancia de los factores de riesgo cardiovascular.

AIM: To evaluate the prevalence of cardiovascular disease (CVD) and its association with cardiovascular risk factors, as well as their control in end-stage renal disease (ESRD) patients under maintenance hemodialysis (HD). PATIENTS AND METHODS: A total of 265 patients with ESRD on maintenance HD from a University Hospital and 4 dialysis units were included in this multicenter and cross-sectional study that analyzed the prevalence of CVD and the possible association with classic and new cardiovascular risk factors. Usual biochemical and haemathological parameters were analyzed, as well as plasma levels of homocysteine, troponin-I, BNP, lipoprotein(a), C reactive protein, IL-6, fibrinogen, asymmetrical dimethylarginine (ADMA), advanced oxidation protein products (AOPP), malondialdehyde, adiponectin, osteoprotegerin, and fetuin. In a subset of patients an echocardiography and carotid artery Doppler echography were also performed. RESULTS: The prevalence of CVD was 52.8%. Factors positively associated with prevalent CVD were age, BMI, left ventricular hypertrophy, hypertension, dyslipidemia and diabetes mellitus, dialysis vintage, Charlson s comorbility index, levels of fibrinogen, osteoprotegerin, BNP and CRP, as well as carotid intima-media thickness, left ventricular mass and pulse pressure. Factors negatively associated with prevalent CVD were: previous renal transplant, ejection fraction or levels of LDL-c and phosphorous. In the multivariate analysis dyslipidemia, left ventricular hypertrophy, age and LDL-c (negatively) were associated with CVD. CONCLUSIONS: In HD patients the prevalence of CVD is high and is associated with the presence of cardiovascular risk factors and subclinical CVD.

Effect of the administration of an oral hyaluronan formulation on clinical and biochemical parameters in young horses with osteochondrosis.

The aim of this study was to evaluate the clinical and biochemical effects of the administration of oral hyaluronan (Hyal-Joint [HJ]) on young horses with osteochondrosis (OC). Our hypotheses were that HJ administration is safe, would decrease the degree of synovial effusion and the concentration of nitric oxide (NO) and prostaglandin E2 (PGE2) in synovial fluid, and would increase the concentration of hyaluronic acid (HA) in plasma and synovial fluid. Eleven young horses with tarsocrural OC were included in a randomised, double-blinded, placebo-controlled pilot clinical trial. Six horses received 250 mg/day HJ for 60 days (T60) and five horses received a placebo. The initial values of the degree of synovial effusion, NO, PGE2 and HA concentrations in synovial fluid and HA concentration in plasma were obtained. The horses were evaluated in terms of the same parameters at the end of treatment (T60) and 30 days thereafter (T90). The differences between the groups for each of the parameters evaluated at T0, T60 and T90 were not significant. Nevertheless, the horses treated with HJ tended to show a lower score for synovial effusion as well as higher HA, NO and PGE2 concentrations in synovial fluid, but these differences were non-significant. At a dose of 250 mg/day, HJ did not produce any adverse clinical effects and was well tolerated by the horses.

Perceived state of health is worse in kidney recipients younger than 60 years vs older than 60 years.

OBJECTIVE: To evaluate the differences in perceived state of health (PSH) according to patient age younger or older than 60 years. PATIENTS AND METHODS: One hundred sixty-two patients were entered on the waiting list for renal transplantation from July 2003 at 4 hospitals in California and were observed prospectively for 2 years. Data were obtained at baseline and at 3 and 12 months after transplantation. All patients answered a generic Perceived State of Health (PSH) questionnaire, the 36-item Short-Form Health Survey (SF-36), and the EuroQol (EQ-5D) questionnaire. Data were analyzed using the t test for independent variables and the chi(2) test for contingency tables. RESULTS: Patients aged 60 years or older had higher PSH scores compared with those younger than 60 years on all dimensions of the SF-36 and on the 2 summary scores. Scores for the physical domains were significantly improved at all follow-up visits. After transplantation, scores for the EQ-5D were higher for older patients vs younger patients (mean [SD], 80 [16] vs 67 [14]; P = .01). The PSH score for the older patients was similar to that for the general population (>45 points). The PSH scores for the physical and mental health domains were worse for the younger patients compared with the general population; no differences were noted for clinical variables. CONCLUSION: Patients older than 60 years have higher PSH scores compared with patients younger than 60 years. However, scores for the younger patients were significantly improved at 1 year after transplantation.

Impact of health related quality of life in Catalonia liver transplant patients.

OBJECTIVE: Our aim was to study the changes in the Health Related Quality of Life (HRQoL) during the first year following liver transplantation. MATERIALS AND METHODS: Among 159 patients awaiting orthotopic liver transplantation (OLT) who were prospectively studied at 4 hospitals in Catalonia, 108 actually obtained an organ. HRQoL over time, namely, before, as well as at 3 and 12 months after transplantation, was recorded using the Short Form-36 (SF-36) and the Liver Disease Quality of Life (LDQOL 1.0). After we searched medical, clinical, and sociodemographic records to examine the studied variables on the HRQoL at each moment, the significance was explored using t tests and one-way analysis of variance (ANOVA). RESULTS: Comparison of the SF-36 dimensions before and at 3 months after transplantation revealed almost all domains to show significant improvements (P < .01), except bodily pain, role-physical, social functioning, and PCS. Comparisons between 3 and 12 months after transplantation showed only significant improvements in role-physical, physical functioning, and PCS (P < .05). The other dimensions showed similar or slightly better scores, but the differences were not significant. For LDQOL 1.0 before and 3 months after transplantation, the dimensions with significant differences (P < .01) were: effects of liver disease on activities of daily living; concentration; health distress; sleep problems; stigmata of liver disease; and sexual function. Comparing 3 and 12 months posttransplantation, no dimension showed a significant improvement. A negative correlation existed between hypertensive patients and PCS on the SF-36 (P < .001). The clinical diagnosis of alcoholic liver disease showed better scores in some dimensions of the LDQOL than the other diagnoses. Female subjects showed significantly worse HRQoL than men (P < .001). Child-Pugh and Model for End-Stage Liver Disease (MELD) classifications were not associated with the HRQoL either before or after transplantation. CONCLUSIONS: The most important finding in this study was that all domains showed significant improvements in HRQoL at 3 months after transplantation with only slight improvements at 12 months.

Health-related Quality of Life before and after a solid organ transplantation (kidney, liver, and lung) of four Catalonia hospitals.

INTRODUCTION AND AIMS: It has been described that patients who receive a transplant display a better Health Related Quality of Life (HRQoL). Our objective was to describe the HRQoL before and after a solid organ transplantation, comparing results among various transplantations. METHODS: This HRQoL study using the SF-36 was implemented before as well as at 3 and 12 months posttransplantation. Posttransplantation were compared with pretransplantation scores as well as with the general population. RESULTS: One hundred sixty-two renal, 159 liver, and 58 lung candidates were included before transplantation, among whom there were 126 renal, 108 liver, and 22 lung recipients. The median age of all transplant recipients was 53 years with 68% men. The various transplant types began with different HRQoL: lung showed the worst, followed by the liver, and then renal. The scores of the SF-36 before and 3 months posttransplantation showed significant improvements, except for "Pair." At 12 versus 3 months, mental health was somewhat better for renal, and almost all dimensions showed significant improvement for liver and lung patients. All subjects showed clear improvements after transplantation. CONCLUSION: All patients showed clear improvements after transplantation when mental health was compared with the general population, particularly lung transplant recipients who expressed the greatest improvement. However, they still showed deficits in physical health.

Living donor kidney transplantation in catalonia: comparison with cadaveric kidney donors.

INTRODUCTION: We studied the renal transplantation results of living donor compared with cadaveric donor kidney transplantations. PATIENTS AND METHODS: One hundred thirty-six living donor transplantations performed during the period of 1990 to 2003 (group 1) were compared with a control group of 4304 cadaveric donor transplantations (group 2), paired 1:1 with group 1 patients, according to the period of transplantation, the primary renal disease, the transplant number, as well as the recipient and donor ages. RESULTS: There were no differences regarding patient or graft survival during a 10-year follow-up. CONCLUSIONS: The benefit of performing living donor kidney transplantations is the possibility of having the donor available even before beginning dialysis treatment.

Ischemic pre-conditioning in deceased donor liver transplantation: a prospective randomized clinical trial.

To assess the immediate and long-term effects of ischemic preconditioning (IPC) in deceased donor. liver transplantation (LT), we designed a prospective, randomized controlled trial involving 60 donors: control group (CTL, n = 30) or study group (IPC, n = 30). IPC was induced by 10-min hiliar clamping immediately before recovery of organs. Clinical data and blood and liver samples were obtained in the donor and in the recipient for measurements. IPC significantly improved biochemical markers of liver cell function such as uric acid, hyaluronic acid and Hypoxia-Induced Factor-1 alpha (HIF-1 alpha) levels. Moreover, the degree of apoptosis was significantly lower in the IPC group. On clinical basis, IPC significantly improved the serum aspartate aminotransferase (AST) levels and reduced the need for reoperation in the postoperative period. Moreover, the incidence of primary nonfunction (PNF) was lower in the IPC group, but did not achieve statistical significance. We conclude that 10-min IPC protects against I/R injury in deceased donor LT.

Nutritional determinants of plasma total homocysteine distribution in the Canary Islands.

OBJECTIVE: We sought to define plasma homocysteine reference values in healthy individuals in the Canary Islands and to determine its relations to folate and vitamin B12 intakes and concentrations. DESIGN: Cross-sectional study. SETTING: Population-based representative sample of 557 participants, aged 18-65 years, from the Canary Islands Nutrition Survey (ENCA). SUBJECTS: All participants completed two 24-h dietary recalls and a general questionnaire collecting socio-demographic and health-related lifestyle information. INTERVENTIONS: Plasma homocysteine and serum vitamin B12 levels were measured by immunoassay, whereas folate levels through an automated ionic capturing method. RESULTS: Median plasma homocysteine was 11.9 micromol/l, higher in men (13.1 micromol/l) than in women (10.9 micromol/l) (P<0.001) and positively associated with age in both sexes (P<0.001). The prevalence of hyperhomocysteinaemia (> or = 15 micromol/l), 21.4%, was also greater in men (32.2%) than in women (13.4%). There were significant negative correlations between plasma homocysteine and serum (r=-0.32, P<0.001) and erythrocyte (r=-0.26, P<0.001) folate, as well as serum vitamin B12 (r=-0.28, P<0.001) concentrations. When divided in quartiles of vitamin intakes or concentrations, men with the lowest vitamin B12 and folate serum values had significantly higher plasma homocysteine concentrations than those in the other three quartiles. In women, hyperhomocysteinaemia was higher in the lowest quartiles of folate intake and serum and erythrocyte folate concentrations. CONCLUSIONS: These data provide further evidence that hyperhomocysteinaemia is a sensitive marker of inadequate folate and vitamin B12 status, allowing for the identification of those with greatest need for nutritional interventions.

Improved preoperative iron status assessment by soluble transferrin receptor in elderly patients undergoing knee and hip replacement.

A poor preoperative haemoglobin (Hb) status is frequently encountered among adult patients scheduled for corrective surgery of the locomotive system, representing the main risk factor for blood transfusion. The soluble transferrin receptor (sTfR) has become a highly specific parameter for the detection of iron deficits as it can differentiate between iron deficiency anaemia and anaemia of chronic disease, because of the lack of effect by associated inflammation, unlike ferritin. The objectives of this study were to evaluate patients with the prevalence of risk for transfusion, the effect of inflammation on ferritin (F) values and functional iron deficiency in elderly patients with advanced degenerative arthropathy scheduled for hip or knee replacement. This observational, prospective study included patients over 50 years, operated for hip or knee replacements between April and June 2004. Of 218 patients studied, 87 (39%) presented with Hb levels between 10 and 13 g/dl. The prevalence of functional iron deficit was 27% (sTfR > 1.76 mg/l), while only 8.6% of patients displayed F levels below normal. As expected, C-reactive protein levels were elevated in 24.8% of patients and erythrocyte sedimentation rate was elevated in 50%. These inflammatory markers did not correlate with levels of either F or sTfR. Multiple factors can affect F levels, such as the inflammatory status of osteoarthritis in the elderly, obesity, nonsteroidal anti-inflammatory drugs therapy and low physical performance. As sTfR is not affected by inflammation, it has emerged as a primary parameter for the evaluation of iron status during preoperative assessment among patients scheduled for arthroplasty surgery. Our data strongly suggest that sTfR measurement contributes to improve patient management.

Concentration of hydroxyproline in blood: a biological marker in occupational exposure to asbestos and its relationship with Pi*Z and Pi*S polymorphism in the alpha-1 antitrypsin gene.

BACKGROUND: Hydroxyproline (OHP) is one of the most abundant amino acids in collagen and, in general, it provides a good measure of overall collagen catabolism. METHODS: Asbestos workers suffering from asbestosis (cases n = 85); asbestos exposed workers without asbestosis (exposed controls, EC, n = 86), and non-exposed population (non-exposed controls, NEC, n = 122) were studied. The concentration of free OHP in whole blood was measured following the Pico-Tag procedure. RESULTS: Concentration of OHP in blood was significantly different in the three groups studied (P < 0.001), being higher in cases (19.8 +/- 14.7 micromol/L) than in EC (16 +/- 12.4) and NEC (13.5 +/- 6.7). When all individuals were grouped and stratified by the Pi*S and Pi*Z polymorphisms in the alpha-1-antitrypsin gene, the highest OHP levels were detected in the Pi*S homozygotes, one of the asbestosis-at risk-genotypes (Pi*S homozygotes, x = 24.5 +/- 11.7; Pi*S heterozygotes, x = 16.6 +/- 10.0; wild type, wt, x = 15.9 +/- 11.8). CONCLUSIONS: Blood OHP concentration could be used for monitoring human exposure to asbestos, either as a marker for occupational monitoring or as an additional clinical parameter in diagnostic exploration of asbestosis.

Role of ischemic preconditioning and the portosystemic shunt in the prevention of liver and lung damage after rat liver transplantation.

BACKGROUND: This study evaluates whether surgical strategies such as the portosystemic shunt and ischemic preconditioning can protect against hepatic and pulmonary injury associated with liver transplantation. METHODS: The effect of the portosystemic shunt, ischemic preconditioning, and both surgical procedures together were evaluated in rat liver transplantation. Alanine aminotransferase, hyaluronic acid levels in plasma, adenosine triphosphate and nucleotide levels in liver and edema, malondialdehyde levels, and myeloperoxidase activity were measured 24 hr posttransplantation. Plasmatic tumor necrosis factor (TNF) levels were measured as a possible proinflammatory factor responsible for hepatic and pulmonary damage associated with liver transplantation. RESULTS: Hepatocyte and cell endothelial damage were observed in liver grafts subjected to 8 hr of cold ischemia. This was associated with increased plasma TNF levels and lung inflammatory response. Portosystemic shunt application in the recipient protected endothelial cells but did not confer an effective protection from hepatocyte damage or reduce the increased plasma TNF levels and lung damage after liver transplantation. However, preconditioning of the donor liver conferred protection against both the endothelial cell and hepatocyte damage observed after liver transplantation. Preconditioning also attenuated the increased plasma TNF release and pulmonary damage. The combination of both surgical strategies resulted in levels of liver injury, TNF, and lung damage similar to those seen after liver transplantation. CONCLUSIONS: These findings indicate that ischemic preconditioning could be a preferred treatment to reduce hepatic and pulmonary damage associated with liver transplantation. However, this strategy may not be effective in several clinical situations requiring a portosystemic shunt.

Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease.

The aim of this study was to investigate the usefulness of biochemical markers of bone turnover for monitoring treatment efficacy of Paget's disease of bone, and also to evaluate the utility of biological variation data in choosing the best markers for assessment of biochemical response to therapy. Thirty-eight patients with Paget's disease were included in a prospective study. All received 400 mg/day of oral tiludronate for 3 months. In 31 patients that completed treatment, biochemical markers were measured at baseline and at 1 and 6 months after treatment ended. In serum we determined the levels of total alkaline phosphatase (tAP), bone alkaline phosphatase (bAP), procollagen type I N-terminal propeptide (PINP), and C-terminal telopeptide of type I collagen (sCTx). Urine samples were analyzed for hydroxyproline (Hyp) and for C- and N-terminal telopeptides of type I collagen (CTx and NTx, respectively). Quantitative bone scintigraphy was performed at baseline and at 6 months after discontinuation of therapy. A ratio for monitoring response to treatment was obtained for each marker. This ratio reflected the size of treatment response of the marker in relation to the value of its critical difference. Thus, ratio values of >1 indicated a significant decrease of the marker after therapy. In addition, response to therapy was evaluated according to disease activity. Mean values of all markers of bone turnover decreased significantly after therapy. Serum bAP and PINP and urinary NTx showed the highest percentage reduction (between 58% and 68%). Furthermore, serum bAP and PINP showed the highest ratios for monitoring changes induced by treatment, followed by serum tAP and urinary NTx. sCTx and urinary CTx as well as Hyp showed mean ratios for monitoring changes of <1, indicating a low sensitivity for monitoring treatment. Patients with polyostotic disease showed a continuous decrease in mean values for all markers at 6 months from the end of therapy, whereas, in monostotic patients, there was a trend toward increased levels at this timepoint. In conclusion, serum bAP and PINP were the most sensitive markers for monitoring treatment efficacy in Paget's disease, although serum tAP and urinary NTx were also sensitive markers for monitoring changes. Data on biological variation are useful for assessing actual changes induced by treatment.

Hepatic xanthine levels as viability predictor of livers procured from non-heart-beating donor pigs.

BACKGROUND: The aim of the present study was to evaluate hepatic content of adenine nucleotides and their degradation products in non-heart-beating donor (NHBD) pigs and its relationship with recipient survival. METHODS: Thirty animals were transplanted with an allograft from NHBDs. After warm ischemia (WI) time (20, 30, or 40 min), cardiopulmonary bypass and normothermic recirculation (NR) were run for 30 min. Afterward, the animals were cooled to 15 degrees C and liver procurement was performed. RESULTS: Survival rate was 100% in the 20WI, 70% in the 30WI, and 50% in the 40WI. Livers from non-surviving animals had higher levels of xanthine after NR than livers from surviving animals. Logistic regression analysis revealed that xanthine at the end of NR was the only variable able to predict survival with a calculated sensitivity of 80% and a specificity of 60%. Prolongation of warm ischemic period leaded to a greater xanthine accumulation as well as increased plasma alpha-glutathione S-transferase levels at reperfusion. Xanthine at NR and alpha-glutathione S-transferase at reperfusion significantly correlated, indicating that donor xanthine contributes to some extent to the severity of the lesion by ischemia-reperfusion. CONCLUSIONS: It is suggested that xanthine content in the donor is able to predict survival after transplantation. Xanthine is significantly involved in the hepatic lesion elicited by warm ischemia and subsequent ischemia-reperfusion associated to liver transplantation from a NHBD.

Endogenous nitric oxide and exogenous nitric oxide supplementation in hepatic ischemia-reperfusion injury in the rat.

BACKGROUND: Although nitric oxide (NO) is thought to be beneficial in hepatic ischemia-reperfusion (I/R), the mechanisms for this effect are not well established. METHODS: To investigate the effects of endogenous NO and exogenous NO supplementation on hepatic I/R injury and their pathogenic mechanisms, serum ALT and hyaluronic acid (endothelial cell damage), and hepatic malondialdehyde and H2O2 (oxidative stress), myeloperoxidase activity (leukocyte accumulation), and endothelin (vasoconstrictor peptide opposite to NO) were determined at different reperfusion periods in untreated rats and rats receiving L-NAME, L-NAME+L-arginine, and spermine NONOate (exogenous NO donor). RESULTS: After reperfusion every parameter increased in untreated animals. Endogenous NO synthesis inhibition by L-NAME increased hepatocyte and endothelial damage as compared to untreated rats, which was reverted and even improved by the addition of L-arginine. Spermine NONOate also improved this damage. However, different mechanisms account for the beneficial effect of endogenous and exogenous NO. Oxidative stress decreased by both L-NAME and L-NAME+L-arginine, but remained unmodified by spermine NONOate. Myeloperoxidase increased by L-NAME and this effect was reverted by the addition of L-arginine, whereas no change was observed with spermine NONOate. Endothelin levels were not modified by L-NAME and L-NAME+L-arginine, but decreased with spermine NONOate. CONCLUSIONS: These results suggest that, although both endogenous and exogenous NO exert a protective role in experimental hepatic I/R injury, the mechanisms of the beneficial effect of the two sources of NO are different.