Use of vitamins C and E as a prophylactic therapy to prevent postoperative atrial fibrillation.

Oxidative stress has been strongly involved in the underlying mechanism of atrial fibrillation, particularly in the arrhythmia occurring in patients undergoing cardiac surgery with extracorporeal circulation (postoperative atrial fibrillation). The ischemia/reperfusion injury thus occurring in the myocardial tissue contributes to the development of tissue remodeling, thought to be responsible for the functional heart impairment. Consequently, structural changes due to the cardiac tissue biomolecules attack by reactive oxygen and/or nitrogen species could account for functional changes in ion channels, transporters, membrane conductance, cytosolic transduction signals, and other events, all associated with the occurrence of arrhythmic consequences. The lack of success and significant side effects of anti-arrhythmic drugs have given rise to attempts aimed to develop alternative novel pharmacologic treatments. On this line, the biological properties of the antioxidant vitamins C and E suggest that they could decrease the vulnerability of the heart to the oxidative damage. Nevertheless, very few studies to assess their anti-arrhythmic effects have been reported in humans. The clinical and experimental evidence supporting the view that the pharmacological use of antioxidant vitamins could contribute to prevent postoperative atrial fibrillation is presented.

Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients.

Steatosis in obese nonalcoholic fatty liver disease (NAFLD) patients is a clinicopathological condition associated with depletion of n-3 polyunsaturated fatty acids (PUFA), a feature that may be related to PUFA desaturation. Liver Delta-6 and Delta-5 desaturase (Delta-6D and Delta-5D) activities, homeostasis model assessment of insulin resistance (HOMA(IR)), and ferric reducing ability of plasma (FRAP) were evaluated in 13 obese patients who underwent subtotal gastrectomy with gastro-jejunal anastomosis in Roux-en-Y and 15 nonobese patients who underwent laparoscopic cholecystectomy (controls). Liver Delta-6D and Delta-5D activities in obese patients were 87% and 66% lower than controls (P < 0.001), respectively, with a 62% diminution in the Delta-6D/Delta-5D activity ratio (P < 0.02). Delta-6D inversely correlated with both HOMA(IR) (r = -0.70, P < 0.0001) and oxidative stress assessed as the reciprocal value of FRAP (r = -0.40, P < 0.05). Delta-5D negatively correlated with HOMA(IR) (r = -0.48, P < 0.01) but not with FRAP(-1) (r = -0.13, not significant). In conclusion, liver PUFA desaturation is diminished in obese NAFLD patients, in association with underlying insulin resistance and oxidative stress, which may play a role in altering lipid metabolism favoring fatty infiltration.

Enhancement in liver SREBP-1c/PPAR-alpha ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion.

Sterol receptor element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) mRNA expression was assessed in liver as signaling mechanisms associated with steatosis in obese patients. Liver SREBP-1c and PPAR-alpha mRNA (RT-PCR), fatty acid synthase (FAS) and carnitine palmitoyltransferase-1a (CPT-1a) mRNA (real-time RT-PCR), and n-3 long-chain polyunsaturated fatty acid (LCPUFA)(GLC) contents, plasma adiponectin levels (RIA), and insulin resistance (IR) evolution (HOMA) were evaluated in 11 obese patients who underwent subtotal gastrectomy with gastro-jejunal anastomosis in Roux-en-Y and 8 non-obese subjects who underwent laparoscopic cholecystectomy (controls). Liver SREBP-1c and FAS mRNA levels were 33% and 70% higher than control values (P<0.05), respectively, whereas those of PPAR-alpha and CPT-1a were 16% and 65% lower (P<0.05), respectively, with a significant 62% enhancement in the SREBP-1c/PPAR-alpha ratio. Liver n-3 LCPUFA levels were 53% lower in obese patients who also showed IR and hipoadiponectinemia over controls (P<0.05). IR negatively correlated with both the hepatic content of n-3 LCPUFA (r=-0.55; P<0.01) and the plasma levels of adiponectin (r=-0.62; P<0.005). Liver SREBP-1c/PPAR-alpha ratio and n-3 LCPUFA showed a negative correlation (r=-0.48; P<0.02) and positive associations with either HOMA (r=0.75; P<0.0001) or serum insulin levels (r=0.69; P<0.001). In conclusion, liver up-regulation of SREBP-1c and down-regulation of PPAR-alpha occur in obese patients, with enhancement in the SREBP-1c/PPAR-alpha ratio associated with n-3 LCPUFA depletion and IR, a condition that may favor lipogenesis over FA oxidation thereby leading to steatosis.

Effects of weight loss on liver and erythrocyte polyunsaturated fatty acid pattern and oxidative stress status in obese patients with non-alcoholic fatty liver disease.

Our aim was to study the influence of weight loss on the fatty acid (FA) composition of liver and erythrocyte phospholipids and oxidative stress status in obese, non-alcoholic, fatty liver disease (NAFLD) patients. Seven obese NAFLD patients who underwent subtotal gastrectomy with a gastro-jejunal anastomosis in roux and Y were studied immediately and 3 months after surgery. Seven non-obese patients who underwent anti-reflux surgery constituted the control group. Serum F2-isoprostane levels were measured by GS/NICI-MS/MS and FA composition was determined by GC. At the time of surgery, controls and obese patients exhibited a hepatic polyunsaturated fatty acid (PUFA) pattern that correlated with that of erythrocytes. Three months after surgery, NAFLD patients lost 21% of initial body weight; serum F2-isoprostane levels decreased by 76%; total PUFA, long-chain PUFA (LCPUFA), n-3 PUFA, and n-3 LCPUFA increased by 22, 29, 81, and 93%, respectively; n-6/n-3 LCPUFA ratio decreased by 51%; docosahexaenoic acid/docosapentaenoic acid ratio increased by 19-fold; and the n-3 product/precursor ratio (20: 5 + 22: 5 + 22: 6)/18: 3 increased by 164% (p<0.05). It is concluded that weight loss improves the n-3 LCPUFA status of obese patients in association with significant amelioration in the biomarkers of oxidative stress, membrane FA insaturation, and n-3 LCPUFA biosynthesis capacity, thus representing a central therapeutic issue in the improvement of obesity-related metabolic alterations involved in the mechanism of hepatic steatosis.

Prevention of atrial fibrillation following cardiac surgery: basis for a novel therapeutic strategy based on non-hypoxic myocardial preconditioning.

Atrial fibrillation is the most common complication of cardiac surgical procedures performed with cardiopulmonary bypass. It contributes to increased hospital length of stay and treatment costs. At present, preventive strategies offer only suboptimal benefits, despite improvements in anesthesia, surgical technique, and medical therapy. The pathogenesis of postoperative atrial fibrillation is considered to be multifactorial. However oxidative stress is a major contributory factor representing the unavoidable consequences of ischemia/reperfusion cycle occurring in this setting. Considerable evidence suggests the involvement of reactive oxygen species (ROS) in the pathogenic mechanism of this arrhythmia. Interestingly, the deleterious consequences of high ROS exposure, such as inflammation, cell death (apoptosis/necrosis) or fibrosis, may be abrogated by a myocardial preconditioning process caused by previous exposure to moderate ROS concentration known to trigger survival response mechanisms. The latter condition may be created by n-3 PUFA supplementation that could give rise to an adaptive response characterized by increased expression of myocardial antioxidant enzymes and/or anti-apoptotic pathways. In addition, a further reinforcement of myocardial antioxidant defenses could be obtained through vitamins C and E supplementation, an intervention also known to diminish enzymatic ROS production. Based on this paradigm, this review presents clinical and experimental evidence supporting the pathophysiological and molecular basis for a novel therapeutic approach aimed to diminish the incidence of postoperative atrial fibrillation through a non-hypoxic preconditioning plus a reinforcement of the antioxidant defense system in the myocardial tissue.

Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension.

Oxidative stress has been associated with mechanisms of EH (essential hypertension). The aim of the present study was to test the hypothesis that the antioxidant properties of vitamins C and E are associated with a decrease in BP (blood pressure) in patients with EH. A randomized double-blind placebo-controlled clinical trial was conducted in 110 men with grade 1 EH (35-60 years of age without obesity, dyslipidaemia and diabetes mellitus, non-smokers, not undergoing vigorous physical exercise, without the use of any medication and/or high consumption of fruit and vegetables). Participants were randomly assigned to receive either vitamins C+E [vitamin C (1 g/day) plus vitamin E (400 international units/day)] or placebo for 8 weeks. Measurements included 24 h ambulatory BP and blood analysis of oxidative-stress-related parameters in erythrocytes (GSH/GSSH ratio, antioxidant enzymes and malondialdehyde) and plasma [FRAP (ferric reducing ability of plasma)], and levels of 8-isoprostane, vitamins C and E were measured at baseline and after treatment. Following administration of vitamins C+E, patients with EH had significantly lower systolic BP, diastolic BP and mean arterial BP and higher erythrocyte and serum antioxidant capacity compared with either placebo-treated patients with EH or the patients with EH at baseline prior to treatment. BP correlated positively with plasma 8-isoprostane levels and negatively with plasma FRAP levels in the vitamins C+E- and placebo-treated groups. In conclusion, the present study supports the view that oxidative stress is involved in the pathogenesis of EH, and that enhancement of antioxidant status by supplementation with vitamins C and E in patients with EH is associated with lower BP. This suggests intervention with antioxidants as an adjunct therapy for hypertension.

Effects of weight loss on liver and erythrocyte polyunsaturated fatty acid pattern and oxidative stress status in obese patients with non-alcoholic fatty liver disease

Our aim was to study the influence of weight loss on the fatty acid (FA) composition of liver and erythrocyte phospholipids and oxidative stress status in obese, non-alcoholic, fatty liver disease (NAFLD) patients. Seven obese NAFLD patients who underwent subtotal gastrectomy with a gastro-jejunal anastomosis in roux and Y were studied immediately and 3 months after surgery. Seven non-obese patients who underwent anti-reflux surgery constituted the control group. Serum F2-isoprostane levels were measured by GS/NICI-MS/MS and FA composition was determined by GC. At the time of surgery, controls and obese patients exhibited a hepatic polyunsaturated fatty acid (PUFA) pattern that correlated with that of erythrocytes. Three months after surgery, NAFLD patients lost 21 percent of initial body weight; serum F2-isoprostane levels decreased by 76 percent; total PUFA, long-chain PUFA (LCPUFA), n-3 PUFA, and n-3 LCPUFA increased by 22, 29, 81, and 93 percent, respectively; n-6/n-3 LCPUFA ratio decreased by 51 percent; docosahexaenoic acid/docosapentaenoic acid ratio increased by 19-fold; and the n-3 product/precursor ratio (20: 5 + 22: 5 + 22: 6)/18: 3 increased by 164 percent (p<0.05). It is concluded that weight loss improves the n-3 LCPUFA status of obese patients in association with significant amelioration in the biomarkers of oxidative stress, membrane FA insaturation, and n-3 LCPUFA biosynthesis capacity, thus representing a central therapeutic issue in the improvement of obesity-related metabolic alterations involved in the mechanism of hepatic steatosis.

Non-hypoxic preconditioning of myocardium against postoperative atrial fibrillation: mechanism based on enhancement of the antioxidant defense system.

Oxidative stress underlies postoperative atrial fibrillation and electrophysiological remodelling associated with rapid atrial pacing. An increasing body of evidence indicates that the formation of reactive oxygen species (ROS) released following extracorporeal circulation are involved in the structural and functional myocardial impairment derived from the ischemia-reperfusion cycle. ROS behave as intracellular messengers mediating pathological processes, such as inflammation, apoptosis and necrosis, thereby participating in the pathophysiology of atrial fibrillation. Thus, increased superoxide (O(2)(.-)) production has been found in isolated atrial cardiomyocytes from patients with atrial fibrillation. Therefore, it seems reasonable to assume that the reinforcement of the antioxidant defense system should protect the heart against functional alterations in the cardiac rhythm. On this line, antioxidant enzyme induction through in vivo exposure to moderate concentration of ROS is associated with a reduction in the susceptibility of myocytes to ROS-induced injury. This response could be due to a prevailing effect of survival over apoptotic pathway. Previously, tissue preconditioning caused by prior exposure to an ischemia/reperfusion cycle has been successfully applied in experimental models and clinical settings associated with oxidative damage by ROS. However, such hypoxic preconditioning method is harmful to be applied to many clinical conditions associated with oxidative stress. In turn, experimental studies have revealed that non-enzymatic antioxidants produce a significant functional amelioration in cardiomyocytes subjected to an oxidative challenge. Moreover, clinical studies with patients scheduled for primary coronary artery bypass graft surgery had a reduced incidence of postoperative atrial fibrillation. We present the hypothesis of non-hypoxic preconditioning based on the association of pretreatment with n-3 polyunsaturated fatty acids followed by ascorbate plus alpha-tocoferol supplementation diminishes the incidence of postoperative atrial fibrillation in patients subjected to cardiac surgery with extracorporeal circulation.

Relationship between (Na + K)-ATPase activity, lipid peroxidation and fatty acid profile in erythrocytes of hypertensive and normotensive subjects.

Oxidative stress may play a role in the pathogenic mechanism of essential hypertension. Lipid peroxidation can alter the cellular structure of membrane-bound enzymes by changing the membrane phospholipids fatty acids composition. We investigated the relationship between (Na + K)-ATPase activity, lipid peroxidation, and erythrocyte fatty acid composition in essential hypertension. The study included 40 essential hypertensive and 49 healthy normotensive men (ages 35-60 years). Exclusion criteria were obesity, dyslipidemia, diabetes mellitus, smoking, and any current medication. Patients underwent 24-h ambulatory blood pressure monitoring and blood sampling. Lipid peroxidation was measured in the plasma and erythrocytes as 8-isoprostane or malondialdehyde (MDA), respectively. Antioxidant capacity was measured as ferric reducing ability of plasma (FRAP) in the plasma and as reduced/oxidized glutathione (GSH/GSSG ratio) in erythrocytes. (Na + K)-ATPase activity and fatty acids were determined in erythrocyte membranes. Hypertensives had higher levels of plasma 8-isoprostane, erythrocyte MDA, and relative percentage of saturated membrane fatty acids, but lower plasma FRAP levels, erythrocyte GSH/GSSG ratio, (Na + K)-ATPase activity and relative percentage of unsaturated membrane fatty acids, compared with normotensives. Day-time systolic and diastolic blood pressures correlated positively with lipid peroxidation parameters, but negatively with (Na + K)-ATPase activity. These findings suggest that the modulation of (Na + K)-ATPase activity may be associated with changes in the fatty acid composition induced by oxidative stress and provide evidence of a role for this enzyme in the pathophysiology of essential hypertension.

Polyunsaturated fatty acid pattern in liver and erythrocyte phospholipids from obese patients.

OBJECTIVE: Our aim was to study the fatty acid (FA) composition of liver phospholipids and its relation to that in erythrocyte membranes from patients with obese nonalcoholic fatty liver disease (NAFLD), as an indication of lipid metabolism alterations leading to steatosis. RESEARCH METHODS AND PROCEDURES: Eight control subjects who underwent antireflux surgery and 12 obese patients with NAFLD who underwent subtotal gastrectomy with a gastro-jejunal anastomosis in Roux-en-Y were studied. The oxidative stress status of patients was assessed by serum F2-isoprostanes levels (gas chromatography/negative ion chemical ionization tandem mass spectrometry). Analysis of FA composition of liver and erythrocyte phospholipids was carried out by gas-liquid chromatography. RESULTS: Patients with NAFLD showed serum F2-isoprostanes levels 84% higher than controls. Compared with controls, liver phospholipids from obese patients exhibited significantly 1) lower levels of 20:4n-6, 22:5n-3, 22:6n-3 [docosahexaenoic acid (DHA)], total long-chain polyunsaturated FA (LCPUFA), and total n-3 LCPUFA, 2) higher 22:5n-6 [docosapentaenoic acid (DPAn-6)] levels and n-6/n-3 LCPUFA ratios, and 3) comparable levels of n-6 LCPUFA. Levels of DHA and DPAn-6 in liver were positively correlated with those in erythrocytes (r = 0.77 and r = 0.90, respectively; p < 0.0001), whereas DHA and DPAn-6 showed a negative association in both tissues (r = -0.79, p < 0.0001 and r = -0.58, p < 0.01, respectively), associated with lower DHA/DPAn-6 ratios. DISCUSSION: Obese patients with NAFLD showed marked alterations in the polyunsaturated fatty acid pattern of the liver. These changes are significantly correlated with those found in erythrocytes, thus suggesting that erythrocyte FA composition could be a reliable indicator of derangements in liver lipid metabolism in obese patients.

Relationship between oxidative stress and essential hypertension.

This study investigated the association of blood pressure with blood oxidative stress-related parameters in normotensive and hypertensive subjects. A cross-sectional design was applied to 31 hypertensive patients and 35 healthy normotensive subjects. All subjects were men between the ages of 35 and 60 years. Exclusion criteria were obesity, dyslipidemia, diabetes mellitus, smoking and current use of any medication. All patients underwent 24-h ambulatory blood pressure monitoring and sampling of blood and urine. Antioxidant enzymes activity, reduced/oxidized glutathione ratio (GSH/GSSG), and lipid peroxidation (malondialdehyde) were determined in erythrocytes. Parameters measured in the plasma of test subjects were plasma antioxidant status, lipid peroxidation (8-isoprostane), plasma vitamin C and E, and the blood pressure modulators renin, aldosterone, endothelin-1 and homocysteine. Daytime systolic and diastolic blood pressures of hypertensives were negatively correlated with plasma antioxidant capacity (r=-0.46, p<0.009 and r=-0.48, p<0.007), plasma vitamin C levels (r=-0.53, p<0.003 and r=-0.44, p<0.02), erythrocyte activity of antioxidant enzymes, and erythrocyte GSH/GSSG ratio, with hypertensives showing higher levels of oxidative stress. Blood pressures showed a positive correlation with both plasma and urine 8-isoprostane. Neither plasma vitamin E nor the assessed blood pressure modulator levels showed significant differences between the groups or correlation with blood pressures. These findings demonstrate a strong association between blood pressure and some oxidative stress-related parameters and suggest a possible role of oxidative stress in the pathophysiology of essential hypertension.

Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is emerging as a major cause of chronic liver disease in association with the rising prevalence of obesity and type 2 diabetes in the population. Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of NAFLD and in the progression from steatosis to steatohepatitis. Recently, Houstis and colleagues reported that reactive oxygen species have a causal role in multiple forms of IR, a phenomenon that can further promote exacerbation of oxidative stress. The improvement of the knowledge of these interrelationships should contribute to elucidate pathogenic pathways and design effective treatments for NAFLD.

Relationship between in vivo chlorzoxazone hydroxylation, hepatic cytochrome P450 2E1 content and liver injury in obese non-alcoholic fatty liver disease patients.

The aim of the present study was to test the hypothesis that induction of cytochrome P450 2E1 (CYP2E1) in the liver of patients with non-alcoholic fatty liver disease (NAFLD) is correlated both with the in vivo activity of the cytochrome and with the development of liver injury. For this purpose, the liver content of CYP2E1 was determined by Western blot and the CYP2E1 activity by the in vivo hydroxylation of chlorzoxazone (CLZ). The study groups were obese women with an average body mass index (BMI) of 40.3kg/m(2), who underwent therapeutic gastroplasty or gastrectomy with a gastro-jejunal anastomosis. Further, the hepatic histology was determined to establish the pathological score grouping the subjects into three categories: control, steatosis and steatohepatitis. The liver CYP2E1 content and the CLZ hydroxylation of obese patients with steatosis and, particularly, with steatohepatitis were significantly higher than controls and correlated positively with both the severity of the liver damage. These data provide evidence that CYP2E1 would be involved in the mechanism of liver injury found in obese NAFLD patients. Also, the correlation between liver CYP2E1 content and in vivo CLZ hydroxylation would validate the latter as a reliable indicator of liver injury in NAFLD, thus providing a simple and not invasive method to study these patients.

Oxidative stress and depletion of hepatic long-chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease.

Human nonalcoholic fatty liver disease (NAFLD) associated with obesity is characterized by depletion of hepatic n-3 long-chain polyunsaturated fatty acids (LCPUFA), with lower LCPUFA product/precursor ratios and higher 18:1n-9 trans levels in adipose tissue, both in patients with steatosis and in those with steatohepatitis. These changes point to modification of gene expression, with decreased fatty acid oxidation and triacylglycerol export and enhanced lipid synthesis, thereby leading to fat accumulation in the liver. Changes in oxidative stress-related parameters indicate a moderate enhancement in the pro-oxidant status of the liver in steatosis, which is further exacerbated in steatohepatitis. It is proposed that oxidative stress plays a dual role in NAFLD by contributing to steatosis due to higher peroxidation of LCPUFA, in addition to defective fatty acid desaturation and diet imbalance, and by promoting progression of steatosis to steatohepatitis, features that might involve changes in the activity of transcriptional mediators.

Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease.

Hepatic steatosis is a major feature associated with NAFLD (non-alcoholic fatty liver disease). The aims of the present study were to assess the levels of PUFA (polyunsaturated fatty acids) in liver total lipids, triacylglycerols (triglycerides) and phospholipids of NAFLD patients in relation to those in adipose tissue and hepatic indexes related to oxidative stress as factors contributing to hepatic steatosis. Eleven control subjects and 19 patients with NAFLD were studied. Analysis of liver and abdominal adipose tissue fatty acids was carried out by GLC. The liver content of protein carbonyl groups and malondialdehyde were taken as indexes related to oxidative stress. NAFLD patients had a depletion in LCPUFA (long-chain PUFA) of the n -6 and n -3 series in liver triacylglycerols, with decreased 20:4, n -6/18:2, n -6 and (20:5, n -3+22:6, n -3)/18:3, n -3 ratios, whereas liver phospholipids contained higher n -6 and lower n -3 LCPUFA. These findings were accompanied by an enhancement of (i) n -6/ n -3 ratio in liver and adipose tissue, (ii) 18:1, n -9 trans levels in adipose tissue, and (iii) hepatic lipid peroxidation and protein oxidation indexes. It is concluded that a marked enhancement in LCPUFA n -6/ n -3 ratio occurs in the liver of NAFLD patients, a condition that may favour lipid synthesis over oxidation and secretion, thereby leading to steatosis. Depletion of hepatic LCPUFA may result from both defective desaturation of PUFA, due to inadequate intake of precursors, such as 18:3, n -3, and higher intake of the 18:1, n -9 trans isomer leading to desaturase inhibition, and from an increased peroxidation of LCPUFA due to oxidative stress.

Homocysteine and essential hypertension.

The authors examine the available clinical and experimental data supporting the view that homocysteine, an alternative risk factor of cardiovascular disease, may play a role in the pathogenesis of essential hypertension. The mechanism of this disease has not been elucidated, but it may be related to impairment of vascular endothelial and smooth muscle cell function. Therefore, the occurrence of endothelial dysfunction could contribute to alterations of the endothelium-dependent vasomotor regulation. Elevated homocysteinemia diminishes the vasodilation by nitric oxide, increases oxidative stress, stimulates the proliferation of vascular smooth muscle cells, and alters the elastic properties of the vascular wall. Thus, homocysteine contributes to elevate the blood pressure. Also it is known that elevated plasma levels of homocysteine could lead to oxidant injury to the endothelium. The correction of elevated homocysteinemia by administration of vitamins B12 and B6 plus folic acid, could be a useful adjuvant therapy of hypertension. However, further controlled randomized trials are necessary to establish the efficacy and tolerability of these potentially therapeutic agents.

Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension.

The present review examines the clinical and experimental data to support the view that homocysteine and oxidative stress, two alternative risk factors of vascular disease, may play a role in the pathogenesis of primary or essential hypertension. Although the precise mechanism of this disease has not been elucidated, it may be related to impairment of vascular endothelial and smooth muscle cell function. Thus, the occurrence of endothelial dysfunction could contribute to alterations of the endothelium-dependent vasomotor regulation. Hyperhomocysteinemia limits the bioavailability of nitric oxide, increases oxidative stress, stimulates the proliferation of vascular smooth muscle cells, and alters the elastic properties of the vascular wall. The link between oxidative stress and hyperhomocysteinemia is also biologically plausible, because homocysteine promotes oxidant injury to the endothelium. Cumulated evidence suggests that the diminution of oxidative stress with antioxidants or the correction of hyperhomocysteinemia with vitamins-B plus folic acid, could be useful as an adjuvant therapy for essential hypertension. Further studies involving long-term trials could help to assess the tolerability and efficacy of the use of these therapeutic agents.

Effects of red wine consumption on kidney FA composition.

We studied the effects of red wine consumption on the FA composition of rat kidney. Four groups of adult male rats were fed a balanced diet for 10 wk. The drinking fluid was water (control), red wine, alcohol-free red wine, or ethanol (12.5%, vol/vol). FA composition, lipid peroxidation, and cytochrome P450 content were determined in the kidney. The antioxidant capacity of plasma was also measured. Ethanol decreased the content of long-chain PUFA, whereas red wine maintained the levels of arachidonic (20:4n-6) and eicosapentaenoic (20:5n-3) acids and alcohol-free red wine significantly increased the levels of 20:4n-6. Lipid peroxidation in the red wine and alcohol-free red wine groups was significantly lower than that of both the control and ethanol groups. The diminished renal lipid peroxidation was associated with an increased antioxidant capacity of plasma. Renal cytochrome P450 was elevated by 50% in the ethanol group and diminished by 20% in the alcohol-free red wine group. These data suggest that moderate red wine consumption could contribute to the preservation of the contents of n-3 and n-6 PUFA, particularly 20:4n-6, in rat kidney. Although ethanol increased the content of cytochrome P450 in the kidney, this effect was eliminated by the nonalcoholic components of red wine.

Rat kidney antioxidant response to long-term exposure to flavonol rich red wine.

This study evaluated the antioxidant defense system of the rat kidney following chronic exposure to red wine rich in flavonols. Both ethanol and antioxidant non-alcoholic wine components, mainly polyphenols, could contribute to the antioxidant status of kidney. Adult rats were given separately, water, ethanol (12.5%), red wine or alcohol-free red wine. After ten weeks of treatment, blood samples were obtained to determine plasma antioxidant capacity (FRAP, ferric reducing ability of plasma), uric acid and ethanol levels. Kidney tissues (cortex and papilla) were separated to perform measurements of reduced glutathione (GSH), glutathione disulfide (GSSG), lipid peroxidation (malondialdehyde, MDA) and the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). The activity of (Na + K)-ATPase, a membrane-bound enzyme, was also assessed. Red wine in plasma, elevated the FRAP without changing the concentration of uric acid; in kidney, it diminished the MDA production and elevated the GSH/GSSG ratio and the activity of CAT and GSH-Px. The activity of SOD did not change. Despite the finding that renal (Na + K)-ATPase activity was upregulated by ethanol, it was not altered by either red wine or alcohol-free red wine. The effects on the antioxidant enzymes could be attributed to ethanol, but the increase in the FRAP and GSH/GSSG ratio is attributed to the non-alcoholic components of red wine. These data suggest that there is an enhancement of the antioxidant defense potential in kidney and plasma, after chronic red wine consumption. Both ethanol and the non-alcoholic antioxidant constituents of red wine could be responsible for these effects.

Modulation of cytochrome P450 activity in the kidney of rats following long-term red wine exposure.

Cytochrome P450 (CYP)-dependent oxidation of lauric acid, p-nitrophenol and ethanol by microsomal fractions of kidney were studied in control rats and in animals given either ethanol, red wine, or alcohol-free red wine for 10 weeks. Ethanol increased the total CYP content and specifically CYP 2E1, as well as p-nitrophenol and ethanol oxidation. The effects of ethanol treatment on the content and activity of CYP 2E1 were attenuated when red wine was administered, while the alcohol-free red wine values were similar to those of the control group. Although lauric acid hydroxylation was decreased by red wine treatment, the content of CYP 4A1 was not influenced by drinking fluids. We conclude that red wine administration attenuates the ethanol-induced enhancement of microsomal activities dependent on CYP 2E1 of rat kidney. Our results suggest that the non-alcoholic constituents of red wine could account for this modulation.