Untargeted Metabolomics to Go beyond the Canonical Effect of Acetylsalicylic Acid.

Given to its ability to irreversibly acetylate the platelet cyclooxygenase-1 enzyme, acetylsalicylic acid (ASA) is successfully employed for the prevention of cardiovascular disease. Recently, an antitumoral effect of ASA in colorectal cancer has been increasingly documented. However, the molecular and metabolic mechanisms by which ASA exerts such effect is largely unknown. Using a new, untargeted liquid chromatography-mass spectrometry approach, we have analyzed urine samples from seven healthy participants that each ingested 100 mg of ASA once daily for 1 week. Of the 2007 features detected, 25 metabolites differing after ASA ingestion (nominal p < 0.05 and variable importance in projection (VIP) score > 1) were identified, and pathway analysis revealed low levels of glutamine and of metabolites involved in histidine and purine metabolisms. Likewise, consistent with an altered fatty acid ß-oxidation process, a decrease in several short- and medium-chain acyl-carnitines was observed. An abnormal ß-oxidation and a lower than normal glutamine availability suggests reduced synthesis of acetyl-Co-A, as they are events linked to one another and experimentally related to ASA antiproliferative effects. While giving an example of how untargeted metabolomics allows us to explore new clinical applications of drugs, the present data provide a direction to be pursued to test the therapeutic effects of ASA-e.g., the antitumoral effect-beyond cardiovascular protection.

Assessing Free-Radical-Mediated DNA Damage during Cardiac Surgery: 8-Oxo-7,8-dihydro-2'-deoxyguanosine as a Putative Biomarker.

Coronary artery bypass grafting (CABG), one of the most common cardiac surgical procedures, is characterized by a burst of oxidative stress. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), produced following DNA repairing, is used as an indicator of oxidative DNA damage in humans. The effect of CABG on oxidative-induced DNA damage, evaluated through the measurement of urinary 8-oxodG by a developed and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in 52 coronary artery disease (CAD) patients, was assessed before (T0), five days (T1), and six months (T2) after CABG procedure. These results were compared with those obtained in 40 subjects with cardiovascular risk factors and without overt cardiovascular disease (CTR). Baseline (T0) 8-oxodG was higher in CAD than in CTR (p = 0.035). A significant burst was detected at T1 (p = 0.019), while at T2, 8-oxodG levels were significantly lower than those measured at T0 (p < 0.0001) and comparable to those found in CTR (p = 0.73). A similar trend was observed for urinary 8-iso-prostaglandin F2α (8-isoPGF2α ), a reliable marker of oxidative stress. In the whole population baseline, 8-oxodG significantly correlated with 8-isoPGF2α levels (r = 0.323, p = 0.002). These data argue for CABG procedure in CAD patients as inducing a short-term increase in oxidative DNA damage, as revealed by 8-oxodG concentrations, and a long-term return of such metabolite toward physiological levels.

Role of thromboxane-dependent platelet activation in venous thrombosis: Aspirin effects in mouse model.

Recent trials suggest that Aspirin (ASA) reduces the incidence of venous thromboembolism in human. However, the molecular mechanisms underlying this effect are still unclear. In this study we assessed the effects of ASA in venous thrombosis mouse model induced by inferior vena cava (IVC) ligation and we investigated the mechanisms responsible for this effect. ASA (3mg/kg daily for 2 days) treatment decreased the thrombus size, the amounts of tissue factor activity in plasma microvesicles (TF-MP) and the levels of 2,3-dinor Thromboxane B2 (TXB-M) in urine compared to control mice. Interestingly, the thrombus size positively correlated with both TF-MP activity and TXB-M. In addition, positive correlation was observed between TF-MP activity and TXB-M. A reduced number of neutrophils and monocytes, and of TF-positive cells accompanied to a lower amount of fibrin and neutrophil extracellular traps (NETs) were also found in thrombi of ASA-treated mice. Similar results were obtained when mice were treated 24h before IVC ligation with SQ29548 (1mg/kg), a selective thromboxane receptor antagonist. In addition, transfusion of platelets in SQ29548 treated-mice excluded the likelihood of a redundant role of platelet-TP receptor in this context. Finally, incubation of macrophages and neutrophils with SQ29548 prevented TF activity and/or NETs formation induced by supernatant of activated platelets or by IBOP, a selective thromboxane analogue. In conclusion, ASA, suppressing TXA2, prevents macrophages and neutrophils activation and markedly reduces thrombus size with a mechanism most likely dependent of the inhibition of TF activity and NETs formation. These results provide a new link between platelet-produced thromboxane and the occurrence of venous thrombosis.

In Vivo Platelet Activation and Aspirin Responsiveness in Type 1 Diabetes.

Platelet activation is persistently enhanced, and its inhibition by low-dose aspirin is impaired in type 2 diabetes mellitus. We investigated in vivo thromboxane (TX) and prostacyclin (PGI2) biosynthesis and their determinants, as well as aspirin responsiveness, in young adult subjects with type 1 diabetes mellitus (T1DM) without overt cardiovascular disease and stable glycemic control. The biosynthesis of TXA2 was persistently increased in subjects with T1DM versus matched healthy subjects, with females showing higher urinary TX metabolite (TXM) excretion than male subjects with T1DM. Microalbuminuria and urinary 8-iso-PGF2α, an index of in vivo oxidative stress, independently predicted TXM excretion in T1DM. No homeostatic increase in PGI2 biosynthesis was detected. Platelet COX-1 suppression by low-dose aspirin and the kinetics of its recovery after drug withdrawal were similar in patients and control subjects and were unaffected by glucose variability. We conclude that patients with T1DM and stable glycemic control display enhanced platelet activation correlating with female sex and microvascular and oxidative damages. Moreover, aspirin responsiveness is unimpaired in T1DM, suggesting that the metabolic disturbance per se is unrelated to altered pharmacodynamics. The efficacy and safety of low-dose aspirin in T1DM warrant further clinical investigation.

8-Hydroxy-2-Deoxyguanosine Levels and Cardiovascular Disease: A Systematic Review and Meta-Analysis of the Literature.

SIGNIFICANCE: 8-Hydroxy-2-deoxyguanosine (8-OHdG) is generated after the repair of ROS-mediated DNA damages and, thus, is one of the most widely recognized biomarkers of oxidative damage of DNA because guanosine is the most oxidized among the DNA nucleobases. In several pathological conditions, high urinary levels of oxidized DNA-derived metabolites have been reported (e.g., cancer, atherosclerosis, hypertension, and diabetes). RECENT ADVANCES: Even if published studies have shown that DNA damage is significantly associated with the development of atherosclerosis, the exact role of this damage in the onset and progression of this pathology is not fully understood, and the association of oxidative damage to DNA with cardiovascular disease (CVD) still needs to be more extensively investigated. We performed a meta-analysis of the literature to investigate the association among 8-OHdG levels and CVD. CRITICAL ISSUES: Fourteen studies (810 CVD patients and 1106 controls) were included in the analysis. We found that CVD patients showed higher 8-OHdG levels than controls (SMD: 1.04, 95%CI: 0.61, 1.47, p < 0.001, I(2) = 94%, p < 0.001). The difference was confirmed both in studies in which 8-OHdG levels were assessed in urine (MD: 4.43, 95%CI: 1.71, 7.15, p = 0.001) and in blood samples (MD: 1.42, 95%CI: 0.64, 2.21, p = 0.0004). Meta-regression models showed that age, hypertension, and male gender significantly impacted on the difference in 8-OHdG levels among CVD patients and controls. FUTURE DIRECTIONS: 8-OHdG levels are higher in patients with CVD than in controls. However, larger prospective studies are needed to test 8-OHdG as a predictor of CVD.

Production of prostaglandin E2 induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells.

Cigarette smoke (CS) increases the incidence of atherothrombosis, the release of prostaglandin (PG) E2, and the amount of tissue factor (TF). The link between PGE2 and TF, and the impact of this interaction on CS-induced thrombosis, is unknown. Plasma from active smokers showed higher concentration of PGE2, TF total antigen, and microparticle-associated TF (MP-TF) activity compared with never smokers. Similar results were obtained in mice and in mouse cardiac endothelial cells (MCECs) after treatment with aqueous CS extracts (CSEs) plus IL-1ß [CSE (6.4 puffs/L)/IL-1ß (2 µg/L)]. A significant correlation between PGE2 and TF total antigen or MP-TF activity were observed in both human and mouse plasma or tissue. Inhibition of PGE synthase reduced TF in vivo and in vitro and prevented the arterial thrombosis induced by CSE/IL-1ß. Only PG E receptor 1 (EP1) receptor antagonists (SC51089:IC50 ∼ 1 µM, AH6809:IC50 ∼ 7.5 µM) restored the normal TF and sirtuin 1 (SIRT1) levels in MCECs before PGE2 (EC50 ∼ 2.5 mM) or CSE/IL-1ß exposure. Similarly, SIRT1 activators (CAY10591: IC50 ∼ 10 µM, resveratrol: IC50 ∼ 5 µM) or prostacyclin analogs (IC50 ∼ 5 µM) prevented SIRT1 inhibition and reduced TF induced by CSE/IL-1ß or by PGE2. In conclusion, PGE2 increases both TF expression and activity through the regulation of the EP1/SIRT1 pathway. These findings suggest that EP1 may represent a possible target to prevent prothrombotic states.

Overview of green tea interaction with cardiovascular drugs.

Sensitive to the massive diffusion of purported metabolic and cardiovascular positive effects of green tea and catechincontaining extracts, many consumers of cardiovascular drugs assume these products as a "natural" and presumably innocuous adjunctive way to increase their overall health. However, green tea may interfere with the oral bioavailability or activity of cardiovascular drugs by various mechanisms, potentially leading to reduced drug efficacy or increased drug toxicity. Available data about interactions between green tea and cardiovascular drugs in humans, updated in this review, are limited so far to warfarin, simvastatin and nadolol, and suggest that the average effects are mild to modest. Nevertheless, in cases of unexpected drug response or intolerance, it is warranted to consider a possible green tea-drug interaction, especially in people who assume large volumes of green tea and/or catechin-enriched products with the conviction that "more-is-better".

The red blood cell: a new key player in cardiovascular homoeostasis? Focus on the nitric oxide pathway.

RBCs (red blood cells) have a fundamental role in the regulation of vascular homoeostasis thanks to the ability of these cells to carry O2 (oxygen) between respiratory surfaces and metabolizing tissues and to release vasodilator compounds, such as ATP and NO (nitric oxide), in response to tissue oxygenation. More recently it has been shown that RBCs are also able to produce NO endogenously as they express a functional NOS (nitric oxide synthase), similar to the endothelial isoform. In addition, RBCs carry important enzymes and molecules involved in L-arginine metabolism, such as arginase, NO synthesis inhibitors and the cationic amino acid transporters. Altogether these findings strongly support the role of these cells as producers, vehicles and scavengers of NO, therefore affecting several physiological processes such as blood rheology and cell adhesion. Consequently, the importance of alterations in the L-arginine/NO metabolic pathway induced by specific conditions, e.g. oxidative stress, in different pathological settings have been investigated. In the present review we discuss the role of RBCs in vascular homoeostasis, focusing our attention on the importance of the NO pathway alterations in cardiovascular diseases and their relationship to major risk factors.

Nitric oxide synthetic pathway in patients with microvascular angina and its relations with oxidative stress.

A decreased nitric oxide (NO) bioavailability and an increased oxidative stress play a pivotal role in different cardiovascular pathologies. As red blood cells (RBCs) participate in NO formation in the bloodstream, the aim of this study was to outline the metabolic profile of L-arginine (Arg)/NO pathway and of oxidative stress status in RBCs and in plasma of patients with microvascular angina (MVA), investigating similarities and differences with respect to coronary artery disease (CAD) patients or healthy controls (Ctrl). Analytes involved in Arg/NO pathway and the ratio of oxidized and reduced forms of glutathione were measured by LC-MS/MS. The arginase and the NO synthase (NOS) expression were evaluated by immunofluorescence staining. RBCs from MVA patients show increased levels of NO synthesis inhibitors, parallel to that found in plasma, and a reduction of NO synthase expression. When summary scores were computed, both patient groups were associated with a positive oxidative score and a negative NO score, with the CAD group located in a more extreme position with respect to Ctrl. This finding points out to an impairment of the capacity of RBCs to produce NO in a pathological condition characterized mostly by alterations at the microvascular bed with no significant coronary stenosis.

Liquid chromatography-tandem mass spectrometry for simultaneous measurement of thromboxane B2 and 12(S)-hydroxyeicosatetraenoic acid in serum.

Arachidonic acid (AA) is metabolized in human platelets by two main pathways: via cyclooxygenase (COX-1) to prostaglandins and thromboxane (TX)A2 and via 12-lipoxygenase (12-LOX) to 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). While COX products are known to regulate platelet reactivity, the role of 12-LOX metabolites is still controversial. To better understand the platelet enzymatic pathways, we developed a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the simultaneous measurement of both platelet metabolites in human serum. After the addition of deuterated d4-TXB2 and d8-12(S)-HETE as internal standards and the solid-phase extraction of serum samples, analytes were resolved using reversed-phase C18 column and quantified using negative ion electrospray ionization-tandem mass spectrometry. Intra and interassay imprecisions were less than 10% for both analytes. The lower limits of quantification were 0.244ng/ml and 0.976ng/ml for TXB2 and 12(S)-HETE, respectively. This method was applied to measure platelet metabolites in healthy subjects (n=35). LC-MS/MS allows rapid, simultaneous, sensitive and accurate quantification of both platelet AA products in human serum with a small sample volume required and a minimal sample preparation.

Analysis, physiological and clinical significance of 12-HETE: a neglected platelet-derived 12-lipoxygenase product.

While the importance of cyclooxygenase (COX) in platelet function has been amply elucidated, the identification of the role of 12-lipoxygenase (12-LOX) and of its stable metabolite, 12-hydroxyeicosatretraenoic acid (12-HETE), has not been clarified as yet. Many studies have analysed the implications of 12-LOX products in different pathological disorders but the information obtained from these works is controversial. Several analytical methods have been developed over the years to simultaneously detect eicosanoids, and specifically 12-HETE, in different biological matrices, essentially enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA), high performance liquid chromatography (HPLC) and mass spectrometry coupled with both gas and liquid chromatography methods (GC- and LC-MS). This review is aimed at summarizing the up to now known physiological and clinical features of 12-HETE together with the analytical methods used for its determination, focusing on the critical issues regarding its measurement.

Oxidative stress and nitric oxide pathway in adult patients who are candidates for cardiac surgery: patterns and differences.

OBJECTIVES: We investigated whether oxidative stress and the arginine/nitric oxide pathway differ in control subjects and in adult patients who are candidates for the three most common cardiac surgical operations: coronary bypass surgery, aortic valve replacement for calcific non-rheumatic aortic stenosis or mitral valve repair for degenerative mitral insufficiency. METHODS: In this prospective observational study, we studied 165 consecutive patients undergoing surgery from January to June 2011 (coronary bypass surgery, n = 63; aortic valve replacement for calcific non-rheumatic aortic stenosis, n = 51; mitral valve repair for degenerative mitral insufficiency, n = 51). Thirty-three healthy subjects with cardiovascular risk factors similar to surgery patients were also studied (Controls). Oxidative stress (the ratio of reduced and oxidized glutathione and urinary isoprostane), antioxidants (alpha- and gamma tocopherol) and factors involved in nitric oxide synthesis (arginine, symmetric and asymmetric dimethylarginine) were measured before surgery. Analysis of variance general linear models and principal component analysis were used for statistical analysis. RESULTS: Surgical patients had increased levels of oxidative stress and decreased levels of antioxidants. Increased levels of nitric oxide inhibitor asymmetric dimethylarginine were detected in surgical candidates, suggesting arginine/nitric oxide pathway impairment. Concerning the differences among surgical procedures, higher oxidative stress and a major imbalance of the ratio between substrate and inhibitors of nitric oxide synthesis were evidenced in patients who were candidates for mitral valve repair with respect to coronary bypass surgery patients and patients with calcific non-rheumatic aortic stenosis. CONCLUSIONS: Patients undergoing cardiac surgery have increased oxidative stress and a trend towards an impaired arginine/nitric oxide pathway with respect to Controls. Patients affected by mitral valve regurgitation show more pronounced perturbations in these pathways. The clinical implications of these findings need to be investigated.

Nitric oxide synthetic pathway in red blood cells is impaired in coronary artery disease.

BACKGROUND: All the enzymatic factors/cofactors involved in nitric oxide (NO) metabolism have been recently found in red blood cells. Increased oxidative stress impairs NO bioavailability and has been described in plasma of coronary artery disease (CAD) patients. The aim of the study was to highlight a potential dysfunction of the metabolic profile of NO in red blood cells and in plasma from CAD patients compared with healthy controls. METHODS: We determined L-arginine/NO pathway by liquid-chromatography tandem mass spectrometry and high performance liquid chromatography methods. The ratio of oxidized and reduced forms of glutathione, as index of oxidative stress, was measured by liquid-chromatography tandem mass spectrometry method. NO synthase expression and activity were evaluated by immunofluorescence staining and ex-vivo experiments of L-[(15)N2]arginine conversion to L-[(15)N]citrulline respectively. RESULTS: Increased amounts of asymmetric and symmetric dimethylarginines were found both in red blood cells and in plasma of CAD patients in respect to controls. Interestingly NO synthase expression and activity were reduced in CAD red blood cells. In contrast, oxidized/reduced glutathione ratio was increased in CAD and was associated to arginase activity. CONCLUSION: Our study analyzed for the first time the whole metabolic pathway of L-arginine/NO, both in red blood cells and in plasma, highlighting an impairment of NO pathway in erythrocytes from CAD patients, associated with decreased NO synthase expression/activity and increased oxidative stress.

Circulating levels of dimethylarginines, chronic kidney disease and long-term clinical outcome in non-ST-elevation myocardial infarction.

BACKGROUND: Mechanisms linking chronic kidney disease (CKD) and adverse outcomes in acute coronary syndromes (ACS) are not fully understood. Among potential key players, reduced nitric oxide (NO) synthesis due to its endogenous inhibitors, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine could be involved. We measured plasma concentration of arginine, ADMA and SDMA and investigated their relationship with CKD and long-term outcome in non-ST-elevation myocardial infarction (NSTEMI). METHODOLOGY/PRINCIPAL FINDINGS: We prospectively measured arginine, ADMA, and SDMA at hospital admission in 104 NSTEMI patients. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). We considered a primary end point of combined cardiac death and re-infarction at a median follow-up of 21 months. In CKD (n = 33) and no-CKD (n = 71) patients, arginine and ADMA were similar, whereas SDMA was significantly higher in CKD patients (0.65±0.23 vs. 0.42±0.12 µmol/L; P<0.0001). Twenty-four (23%) patients had an adverse cardiac event during follow-up: 12 (36%) were CKD and 12 (17%) no-CKD patients (P = 0.02). When study population was stratified according to arginine, ADMA and SDMA median values, only SDMA (median 0.46 µmol/L) was associated with the primary end-point (P = 0.0016). In models adjusted for age, hemoglobin and left ventricular ejection fraction, the hazard ratio (HR) for CKD and SDMA were high (HR 2.93, interquartile range [IQR] 1.15-7.53; P = 0.02 and HR 6.80, IQR 2.09-22.2; P = 0.001, respectively) but, after mutual adjustment, only SDMA remained significantly associated with the primary end point (HR 5.73, IQR 1.55-21.2; P = 0.009). CONCLUSIONS/SIGNIFICANCE: In NSTEMI patients, elevated SDMA plasma levels are associated with CKD and worse long-term prognosis.

Direct glutathione quantification in human blood by LC-MS/MS: comparison with HPLC with electrochemical detection.

Glutathione plays a central role in the defence against oxidative damage and in signaling pathways. Upon oxidation the reduced glutathione (GSH) is transformed to glutathione disulfide (GSSG). The concentration of GSH and GSSG in whole blood samples and their ratios is useful indicator of the oxidative stress status and/or disease risk. Here we describe a liquid-chromatographic method coupled with tandem mass spectrometry (LC-MS/MS) and we present the results of its comparison with a high-performance liquid-chromatographic method with electrochemical detection (HPLC-ECD). The method performed well in terms of validation parameters, i.e. linear range (0.01-50µM for both GSH and GSSG), precision (intra- and inter-day coefficients of variation were less than 10% for both GSH and GSSG), accuracy (bias% varied between -2.1 and 7.9% for both analytes), quantification limits (LLOQs were 0.5µM and 0.0625µM for GSH and GSSG respectively). Furthermore the LC-MS/MS method showed a good agreement with the HPLC-ECD assay. However, major benefits of LC-MS/MS are the improved selectivity, precision and accuracy, the higher sensitivity and the unaltered capacity of detection with time in contrast to ECD.

Quantification of arginine and its metabolites in human erythrocytes using liquid chromatography-tandem mass spectrometry.

Erythrocytes may affect several physiological processes because they are scavengers, vehicles, and (as recently highlighted) a producer of nitric oxide (NO). NO bioavailability is linked to arginine, its metabolic products ornithine and citrulline, and methylarginines. Here we describe a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of analytes involved in the Arg/NO metabolic pathway in erythrocytes. Calibration functions were linear, and the interday coefficients of variation were less than 10%. Limit of quantification values make this method suitable for low concentration samples. The method presented here allows easy sample preparation and provides a valuable tool for the evaluation of the Arg/NO metabolic pathway in erythrocytes.

Simultaneous quantification of 8-iso-prostaglandin-F(2alpha) and 11-dehydro thromboxane B(2) in human urine by liquid chromatography-tandem mass spectrometry.

Both F(2)-isoprostanes (8-iso-PGF(2alpha)), a well-known marker of oxidative stress, and thromboxanes A(2) (TXA(2)) are involved in atherosclerosis through LDL oxidation and platelet activation. Different aspects of the pathology can be described by 8-iso-PGF(2alpha) and TXA(2) so it is important to determine both their concentrations to monitor the disease progression and/or therapy effects. We developed a simple and sensitive method based on liquid chromatography-tandem mass spectrometry, using electrospray ionization in negative-ion mode, for the simultaneous measurement of the concentration of 8-iso-PGF(2alpha) and 11-dehydro thromboxane B(2) (11-DH-TXB(2)), a TXA(2) metabolite. This method was applied to analyze urine samples collected overnight from 15 atherosclerotic patients, with documented carotid artery sclerosis (CAS), and from 20 controls. The detection limit was 0.097pg/microL for 8-iso-PGF(2alpha) and 0.375pg/microL for 11-DH-TXB(2), with a linear range of 0.78-25pg/microL; the inter- and intraday imprecision was <5% for both metabolites. These analytes were higher in CAS (P<0.005 vs controls) and were positively correlated in patients but not in controls, even after adjustment for age and gender (r=0.60; P=0.032). This highly sensitive, precise, and rapid method allows for the simultaneous determination of 8-iso-PGF(2alpha) and 11-DH-TXB(2) in human urine samples in order to evaluate oxidative stress and platelet aggregation.

Assessment of oxidative stress in coronary artery bypass surgery: comparison between the global index OXY-SCORE and individual biomarkers.

The performances of the OXY-SCORE, a summary index of oxidative stress, and of its individual components (plasma malondialdehyde (MDA), oxidized and reduced glutathione, individual antioxidant capacity, alpha- and gamma-tocopherol and urinary isoprostanes) were assessed in 47 patients undergoing coronary surgery, randomly assigned to cardiopulmonary bypass (CPB) or off-pump procedure (OPCAB) associated with less oxidative stress. The ability of the OXY-SCORE to classify correctly the patients was high (area under the ROC curve 0.90). Only free MDA showed a similar performance, but it was insensitive to the minor variations of the oxidative balance in the OPCAB group.

Anesthetic propofol enhances plasma gamma-tocopherol levels in patients undergoing cardiac surgery.

BACKGROUND: Propofol (2,6-diisopropylphenol) is an anesthetic drug with antioxidant and antiinflammatory properties, documented both in vitro and in experimental models of ischemia-reperfusion injury and septic shock. These properties have been related to the similarity of its chemical structure to that of endogenous tocopherols, which are phenol-containing radical scavengers. This study evaluated the effects of propofol on alpha- and gamma-tocopherol (alpha- and gamma-T) levels and on selected markers of oxidant-antioxidant and inflammatory status in patients undergoing cardiac surgery. METHODS: Patients were randomly assigned for anesthesia with either propofol (propofol group, n = 22) or sevoflurane (control group, n = 21). Plasma levels of alpha- and gamma-T, individual antioxidant capacity, malondialdehyde, and interleukin 10 were measured before, during, and after anesthesia. In addition, levels of the proinflammatory prostaglandin E2 as a marker of cyclooxygenase-2 activity and those of interleukin 10 were measured in whole blood cultured with bacterial lipopolysaccharide. RESULTS: Gamma-T levels increased significantly during surgery in propofol group (P < 0.0001 vs. control group). By contrast, alpha-T similarly decreased in both groups. Malondialdehyde and interleukin 10 increased markedly and individual antioxidant capacity decreased, without differences between groups. Prostaglandin E2 levels measured 24 h after anesthesia induction were significantly lower in the propofol than in the control group. In vitro studies highlighted the different capacity of gamma- and alpha-T to impair prostaglandin E2 synthesis by human monocytes challenged with bacterial lipopolysaccharide. CONCLUSIONS: The antiinflammatory properties of propofol that may be linked to its effect on gamma-T levels could be relevant in controlling the inflammatory response that accompanies tissue injury during reperfusion.