8-epi-prostaglandin-f2alpha and Hypertension

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Arginine; Biomarkers; Deoxyguanosine; Dinoprost; Glycation End Products, Advanced; Humans; Hypertension; Lipid Peroxides; Lipoproteins, LDL; Lysine; Oxidative Stress

Obesity is becoming one of the leading risk factors of coronary heart disease, hypertension, cerebrovascular disease. Despite the presence of a large number of antihypertensive agents and scientific substantiation of antihypertensive treatment principles it would be wrong to assume that the problem is completely solved. Development of endothelial dysfunction is one of the key pathogenic mechanisms in hypertension. This process is proven to have contributed by immune inflammation activation which is mediated by pro-inflammatory cytokines and oxidative stress.. To investigate the additional benefits of the combined antihypertensive therapy with lacidipine and candesartan on the basis of studying their antioxidant properties, impact on endothelial function and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity.. A combination of a calcium channel blocker and angiotensin receptor blocker (lacidipine 2 mg, 4 mg, and candesartan 4mg, 8mg, 16mg) was prescribed to 30 patients with essential hypertension of grades 1-3, 30 to 65 years old (mean age - 54.7 ± 5.8 years), who previously have not been receiving regular antihypertensive therapy.. During the course of combined antihypertensive therapy with lacidipine and candesartan, a significant reduction in i-NOS activity, TNF-α to its type I soluble receptor ratio (TNF- α/sTNF-αRI), and oxidative stress marker - 8-iso-PgF2α has been observed. Activity of e-NOS, levels of SOD and catalase, in contrast, have increased by the end of observation period.. The improvement of endothelial function due to lower level of oxidative stress and a significant decrease of immune activation has been observed in hypertensive patients with overweight and obesity under the influence of combined antihypertensive therapy with lacidipine and candesartan.

Topics: Adult; Aged; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Case-Control Studies; Dihydropyridines; Dinoprost; Drug Therapy, Combination; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Tetrazoles; Tumor Necrosis Factor-alpha

Diet rich in fruits, vegetables, and dairy products, known as the Dietary Approaches to Stop Hypertension (DASH) diet, is known to reduce blood pressure (BP) in hypertensive patients. More recently, the DASH diet was shown to reduce oxidative stress in hypertensive and nonhypertensive humans. However, the main nutritional components responsible for these beneficial effects of the DASH diet remain unknown. Because the DASH diet is rich in potassium (K), magnesium (Mg), and alkali, we performed a randomized, double-blinded, placebo-controlled study to compare effects of potassium magnesium citrate (KMgCit), potassium chloride (KCl), and potassium citrate (KCit) to allow dissociation of the three components of K, Mg, and citrate on 24-hour ambulatory BP and urinary 8-isoprostane in hypertensive and prehypertensive subjects, using a randomized crossover design. We found that KCl supplementation for 4 weeks induced a significant reduction in nighttime SBP compared with placebo (116 ± 12 vs 121 ± 15 mm Hg, respectively, p <0.01 vs placebo), whereas KMgCit and KCit had no significant effect in the same subjects (118 ± 11 and 119 ± 13 mm Hg, respectively, p >0.1 vs placebo). In contrast, urinary 8-isoprostane was significantly reduced with KMgCit powder compared with placebo (13.5 ± 5.7 vs 21.1 ± 10.5 ng/mgCr, respectively, p <0.001), whereas KCl and KCit had no effect (21.4 ± 9.1 and 18.3 ± 8.4, respectively, p >0.1 vs placebo). In conclusion, our study demonstrated differential effects of KCl and KMgCit supplementation on BP and the oxidative stress marker in prehypertensive and hypertensive subjects. Clinical significance of the antioxidative effect of KMgCit remains to be determined in future studies.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Citrates; Cross-Over Studies; Dietary Supplements; Dinoprost; Double-Blind Method; Drug Combinations; Female; Humans; Hypertension; Linear Models; Magnesium Compounds; Male; Middle Aged; Oxidative Stress; Potassium; Potassium Chloride; Potassium Citrate; Potassium Compounds; Prehypertension; Vascular Stiffness

To investigate whether (i) angiotensin receptor occupying profiles of angiotensin II receptor blockers (ARBs) vary among the drugs and (ii) such differences contribute to the degree of their pleiotropic effects.. In a randomized, three phase crossover study, nine hypertensive patients received repeated doses (each recommended starting dose for 7 days and then each maximum recommended dose for 20 days) of irbesartan, valsartan and candesartan. The time course profiles and trough level of receptor occupancy were determined on days 7 and 28, respectively. The pleiotropic effect related parameters were measured on days 0 and 28 in each trial.. Of the pleiotropic effect related parameters investigated, urinary 8-isoprostane, fasting serum insulin and homeostasis model assessment of insulin resistance index were more suppressed after 4 weeks treatment with irbesartan than after candesartan and valsartan therapy, respectively. The maximum, area under the curve and trough values of receptor occupancy significantly differed between the ARBs [geometric mean (and 95% CI) of trough value 18.1 (12.9, 25.3) for irbesartan, 9.6 (6.0, 15.3) for valsartan and 5.5 (2.8, 10.8) for candesartan, respectively] and were negatively correlated with the change in urinary 8-isoprostane (r = -0.46 - -0.55, P < 0.05), but not the markers of insulin resistance (r = 0.02-0.15, P = 0.46-0.94).. Our results demonstrate that the receptor occupying profiles are different among the ARBs. This class of drugs might have both receptor occupancy dependent and independent pleiotropic effects.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Area Under Curve; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cross-Over Studies; Dinoprost; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Humans; Hypertension; Insulin; Insulin Resistance; Irbesartan; Luminescent Measurements; Male; Middle Aged; Oxidative Stress; Radioligand Assay; Receptors, Angiotensin; Tetrazoles; Time Factors; Valine; Valsartan; Young Adult

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease, largely as a result of defective production of cardioprotective nitric oxide and a concomitant rise in oxidative stress. Dietary interventions that could reverse this trend would be extremely beneficial. Here we investigated whether dietary n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation positively affected platelet nitroso-redox imbalance.. We randomized hypertensive T2DM patients (T2DM HT; n = 22) and age-and-sex matched hypertensive study participants without diabetes (HT alone; n = 23) in a double-blind, crossover fashion to receive 8 weeks of n-3 PUFAs (1.8 g eicosapentaenoic acid and 1.5 g docosahexaenoic acid) or identical olive oil capsules (placebo), with an intervening 8-week washout period. Platelet nitrite and superoxide were measured and compared before and after treatment; 8-isoprostane was determined by ELISA and subcellular compartmentalization of the NAD(P)H oxidase subunit p47-phox examined by Western blotting.. The n-3 PUFA supplementation reduced 8-isoprostane and superoxide levels in platelets from T2DM HT, but not HT alone, participants, without effect on nitrite production. This coincided with a significant decrease in p47-phox membrane localization and a similar reduction in superoxide to that achieved with apocynin. At baseline, a subcohort of T2DM HT and HT alone participants showed evidence of nitric oxide synthase (NOS)-derived superoxide production, indicating defective enzymatic activity. This was reversed significantly in T2DM HT participants after treatment, demonstrating improved NOS function.. Our finding that n-3 PUFAs diminish platelet superoxide production in T2DM HT patients in vivo suggests a therapeutic role for these agents in reducing the vascular-derived oxidative stress associated with diabetes.

Topics: Aged; Blood Platelets; Cross-Over Studies; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Fatty Acids, Omega-3; Female; Humans; Hypertension; Male; Middle Aged; Oxidation-Reduction; Superoxides

The antihypertensive effects of angiotensin-converting enzyme inhibitors (ACEi) are explained, at least in part, by enhanced bradykinin-dependent nitric oxide (NO) formation and decreased angiotensin II-induced oxidative stress and vasoconstriction. We examined for the first time whether treatment with enalapril increases the plasma levels of markers of NO formation and decreases oxidative stress in mild to moderate hypertensive patients.. Eighteen untreated hypertensive patients were treated with enalapril 10 mg/day (n=10) or 20 mg/day (n=8) for 60 days. Eighteen normotensive healthy controls were followed for the same period. Venous blood samples were collected at baseline and after 30/60 days of treatment with enalapril. Plasma NOx (nitrites + nitrates) concentrations were determined by using the Griess reaction. Plasma nitrite and whole blood nitrite concentrations were determined by using an ozone-based chemiluminescence assay. Plasma thiobarbituric acid-reactive species (TBARS) and 8-isoprostane concentrations were determined by a fluorimetric method and by ELISA, respectively.. Treatment with enalapril decreased blood pressure in hypertensive patients. However, we found no significant changes in plasma NOx, nitrite, whole blood nitrite, and in the levels of markers of oxidative stress in both normotensive controls and hypertensive patients treated with enalapril.. Our data show that enalapril 10-20 mg/day does not affect the concentrations of relevant markers of NO formation or markers of oxidative stress in mild to moderately hypertensive subjects, despite satisfactory blood pressure control. Our findings do not rule out the possibility that ACEi may produce such effects in more severely hypertensive patients treated with higher doses of ACEi.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Biomarkers, Pharmacological; Blood Pressure; Dinoprost; Enalapril; Humans; Hypertension; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Oxidative Stress; Thiobarbituric Acid Reactive Substances

Oxidative stress and inflammation are common manifestations and major mediators of cardiovascular and many other complications of end-stage renal disease (ESRD). Oxidative stress and inflammation are intimately interrelated as each can cause the other. The present study tested the hypothesis that antioxidant therapy may alleviate oxidative stress and improve inflammation in ESRD patients. We studied 37 hemodialysis patients, of whom 20 were treated daily with a combination of vitamin E, 800 lU; vitamin C, 250 mg; vitamin B6, 100 mg; vitamin B12, 250 microg; and folic acid, 10 mg; whereas 17 patients were given placebo for 8 weeks. Predialysis levels of f-2 isoprostane and protein carbonyl (markers of oxidative stress), C-reactive protein (CRP) and IL6 (markers/ mediators of inflammation) were measured prior to and at 4 and 8 weeks after the onset of therapy. Kt/V, predialysis and postdialysis blood pressure, blood hemoglobin, erythropoietin requirement, plasma ferritin and transferrin saturation, and nutritional indexes were similar among the 2 groups at baseline and remained virtually unchanged throughout the study period. Likewise, plasma f-2 isoprostane, protein carbonyl, CRP, and IL-6 levels remained unchanged and were unaffected by antioxidant administration. In conclusion, the addition of a potent antioxidant cocktail to conventional vitamin supplements had no effect on severity of ESRD-induced oxidative stress, inflammation, hypertension, anemia, or nutritional disorders in hemodialysis patients. Thus, high doses of vitamins beyond the routinely prescribed vitamin supplements do not appear to be indicated in this population.

Topics: Anemia; Antioxidants; C-Reactive Protein; Dinoprost; Double-Blind Method; Female; Humans; Hypertension; Inflammation; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Protein Carbonylation; Renal Dialysis; Vitamins

Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated.. In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostanes).. In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosis-related diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostane levels were measured.. In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P < .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group.. Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure-lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Carotid Arteries; Carotid Stenosis; Dinoprost; Enalapril; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Tunica Intima; Tunica Media; Ultrasonography

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.

Topics: Adult; Analysis of Variance; Antioxidants; Ascorbic Acid; Blood Pressure Determination; Dinoprost; Double-Blind Method; Erythrocytes; Humans; Hypertension; Iron; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Treatment Outcome; Vitamin E; Vitamins

Endothelial function is impaired in hypertensive patients. Decreased nitric oxide production and increased oxidative stress are involved in this abnormality. The aim of the present study was to evaluate whether endothelial function and oxidative stress differ following long-term antihypertensive treatment with an angiotensin type 1 receptor blocker, valsartan, or a calcium channel blocker, amlodipine, in patients with essential hypertension. Hypertensive patients were treated with valsartan (80-160 mg/day) or amlodipine (5-10 mg/day) for one year (n = 9 for each). The baseline blood pressure was similar between groups, and the magnitude of the decreases in blood pressure did not differ during treatment at three months, six months, or one year. Endothelial function and oxidative stress markers were examined before and after treatment. Endothelial function, assessed by flow-mediated vasodilation, was significantly improved in hypertensive patients treated with valsartan (5.8 +/- 1.2 to 10.7 +/- 1.4 %, p < 0.01) but not in those treated with amlodipine. The percent increase in vasodilation induced by sublingual nitroglycerin did not differ between the two groups. As markers of oxidative stress, urinary excretion of 8-isoprostane and 8-hydroxy-2'-deoxyguanosine was significantly reduced in patients treated with valsartan, but not in those treated with amlodipine. These findings suggest that the treatment of hypertensive patients with valsartan for at least one year improves endothelial function in association with reduced oxidative stress. The improved endothelial function and reduced oxidative stress might be involved in the benefits of anti-hypertensive treatment beyond simply lowering blood pressure, although the effects of treatment with valsartan or amlodipine over a much longer period are unknown.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Asian People; Biomarkers; Blood Pressure; Brachial Artery; Calcium Channel Blockers; Deoxyguanosine; Dinoprost; Endothelium, Vascular; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Regional Blood Flow; Tetrazoles; Valine; Valsartan; Vasodilation

Renin-angiotensin system blockade reduces proteinuria and prevents nephropathy progression in patients with type 2 diabetes mellitus (T2D). Experimental evidence demonstrates that angiotensin receptor blockers (ARBs) possess anti-inflammatory potential, which might contribute to reducing proteinuria and providing renoprotection.. We conducted a multicentre, double-blind, prospective, parallel-group non-inferiority study of 885 hypertensive [systolic blood pressure/diastolic blood pressure (SBP/DBP) >130/80 mmHg] patients with T2D, proteinuria (> or =900 mg/24 h) and serum creatinine (< or =3.0 mg/dl) who were randomized to once-daily telmisartan 80 mg or valsartan 160 mg; additional antihypertensive therapy was permitted. The primary endpoint was the change from baseline in the 24-h proteinuria after 12 months. Secondary endpoints included changes in 24-h albuminuria, estimated glomerular filtration rate (eGFR) and inflammatory parameters asymmetrical dimethylarginine (ADMA), high-sensitivity C-reactive protein (CRP) and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)).. Telmisartan and valsartan produced comparable reductions in 24-h urinary protein excretion rates: geometric mean reduction (95% confidence interval) [telmisartan, 33% (27-39%); valsartan, 33% (27-38%)]. No significant differences between treatments were seen in changes from baseline in 24-h urinary albumin excretion rate and eGFR at 12 months. With both treatments, greater renoprotection was seen among patients with better blood pressure control. No significant changes in ADMA or CRP were noted in either group after 12 months, but urinary 8-iso-PGF(2alpha) levels decreased by 14% with telmisartan and by 7% with valsartan (P = 0.040).. In patients with T2D, hypertension and overt nephropathy, the renoprotection afforded by telmisartan and valsartan appears similar, and the study was unable to show any effect beyond that due to blood pressure control. At doses used to treat hypertension, there is no evidence of inflammatory parameters being modified by ARBs in patients with more advanced kidney disease due to T2D.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Arginine; Benzimidazoles; Benzoates; Blood Pressure; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System; Telmisartan; Tetrazoles; Valine; Valsartan

It has been shown that angiotensin-converting enzyme inhibition or angiotensin receptor blockade may improve endothelial dysfunction, an early manifestation of atherosclerosis, in patients with diabetes. Whether this protective effect is mediated through blood pressure-lowering effects or other specific mechanisms such as a reduction in oxidative stress is not clear. We investigated the influence of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension.. Thirteen patients were included in this randomized, double-blind, crossover study; they received losartan 50 mg twice daily for 4 weeks followed by atenolol 50 mg twice daily or vice versa. Concomitant medication with renin-angiotensin blocking agents or beta-blockers was withdrawn, whereas other medication remained unchanged. At baseline and after each treatment period, flow-mediated dilation of the brachial artery and oxidative stress were measured in serum samples.. Flow-mediated dilation was increased significantly after 4 weeks' treatment with losartan (3.4 +/- 0.44%) compared with atenolol (2.58 +/- 0.42%; P = 0.01). 8-Isoprostanes, a marker of oxidative stress, were significantly reduced in the losartan group compared with baseline (0.039 +/- 0.007 versus 0.067 +/- 0.006 ng/ml; P = 0.01), but did not differ from baseline with atenolol. Glucose, hemoglobin A1c, highly sensitive C-reactive protein, lipids and systolic blood pressure remained unaltered, whereas diastolic blood pressure tended to be lower in the atenolol group.. This study demonstrates that losartan significantly improved endothelial function in type 2 diabetes patients with hypertension compared with atenolol. This must be independent of the blood pressure-lowering effect of losartan and is probably caused by an antioxidative effect of the angiotensin receptor blocker.

Topics: Antihypertensive Agents; Atenolol; Blood Pressure; Brachial Artery; Cross-Over Studies; Diabetes Mellitus, Type 2; Dinoprost; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Insulin Resistance; Losartan; Male; Middle Aged; Oxidative Stress; Regional Blood Flow; Research Design; Treatment Outcome; Vasodilation

Regular intake of cocoa-containing foods is linked to lower cardiovascular mortality in observational studies. Short-term interventions of at most 2 weeks indicate that high doses of cocoa can improve endothelial function and reduce blood pressure (BP) due to the action of the cocoa polyphenols, but the clinical effect of low habitual cocoa intake on BP and the underlying BP-lowering mechanisms are unclear.. To determine effects of low doses of polyphenol-rich dark chocolate on BP.. Randomized, controlled, investigator-blinded, parallel-group trial involving 44 adults aged 56 through 73 years (24 women, 20 men) with untreated upper-range prehypertension or stage 1 hypertension without concomitant risk factors. The trial was conducted at a primary care clinic in Germany between January 2005 and December 2006.. Participants were randomly assigned to receive for 18 weeks either 6.3 g (30 kcal) per day of dark chocolate containing 30 mg of polyphenols or matching polyphenol-free white chocolate.. Primary outcome measure was the change in BP after 18 weeks. Secondary outcome measures were changes in plasma markers of vasodilative nitric oxide (S-nitrosoglutathione) and oxidative stress (8-isoprostane), and bioavailability of cocoa polyphenols.. From baseline to 18 weeks, dark chocolate intake reduced mean (SD) systolic BP by -2.9 (1.6) mm Hg (P < .001) and diastolic BP by -1.9 (1.0) mm Hg (P < .001) without changes in body weight, plasma levels of lipids, glucose, and 8-isoprostane. Hypertension prevalence declined from 86% to 68%. The BP decrease was accompanied by a sustained increase of S-nitrosoglutathione by 0.23 (0.12) nmol/L (P < .001), and a dark chocolate dose resulted in the appearance of cocoa phenols in plasma. White chocolate intake caused no changes in BP or plasma biomarkers.. Data in this relatively small sample of otherwise healthy individuals with above-optimal BP indicate that inclusion of small amounts of polyphenol-rich dark chocolate as part of a usual diet efficiently reduced BP and improved formation of vasodilative nitric oxide.. clinicaltrials.gov Identifier: NCT00421499.

Topics: Aged; Beverages; Blood Pressure; Cacao; Candy; Diet; Dinoprost; Female; Flavonoids; Humans; Hypertension; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Phenols; Polyphenols; S-Nitrosoglutathione

We have reported that repeated sauna therapy improves impaired vascular endothelial function in a patient with coronary risk factors. We hypothesized that sauna therapy decreases urinary 8-epi-prostaglandin F(2alpha) (PGF(2alpha)) levels as a marker of oxidative stress and conducted a randomized, controlled study. Twenty-eight patients with at least one coronary risk factor were divided into a sauna group (n = 14) and non-sauna group (n = 14). Sauna therapy was performed with a 60 degrees C far infrared-ray dry sauna for 15 minutes and then bed rest with a blanket for 30 minutes once a day for two weeks. Systolic blood pressure and increased urinary 8-epi-PGF(2alpha) levels in the sauna group were significantly lower than those in the non-sauna group at two weeks after admission (110 +/- 15 mmHg vs 122 +/- 13 mmHg, P < 0.05, 230 +/- 67 pg/mg x creatinine vs 380 +/- 101 pg/mg x creatinine, P < 0.0001, respectively). These results suggest that repeated sauna therapy may protect against oxidative stress, which leads to the prevention of atherosclerosis.

Topics: Adult; Body Mass Index; Coronary Disease; Diabetes Mellitus; Dinoprost; Endothelium, Vascular; Female; Heart Rate; Hematocrit; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Nitric Oxide Synthase; Oxidative Stress; Risk Factors; Steam Bath

Cigarette smoking, a key risk factor for the development of vascular disease, is associated with an increased 8-epi-prostaglandin (PG) F(2alpha). Elevated 8-epi-PGF(2alpha) has been found in vascular tissue, blood and urine as well. We examined the influence of quitting cigarette smoking in 71 patients (38 males, 33 females; aged 32-67 a) with clinically manifested atherosclerosis and various risk factors. In addition, in eight patients with hypercholesterolemia without clinical manifestation of atherosclerosis quitting smoking was monitored as well. Twenty-six of the patients with manifested atherosclerosis and five with hypercholesterolemia restarted and the isoprostanes in plasma, serum and urine were monitored in these patients as well. Quitting cigarette smoking induces an immediate decline becoming significant after 1 or 2 weeks. Restarting smoking results in an increase in 8-epi-PGF(2alpha) reaching prevalues within almost 1 week. These findings indicate that the in vivo oxidation injury associated with cigarette smoking quickly decreases after quitting but increases soon after restarting immediately.

Topics: Adult; Aged; Arteriosclerosis; Biomarkers; Diabetes Complications; Diabetes Mellitus; Dinoprost; F2-Isoprostanes; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Risk Factors; Smoking; Smoking Cessation; Time Factors

Hypertensive patients with renovascular disease (RVD) may be exposed to increased oxidative stress, possibly related to activation of the renin-angiotensin system.. We measured the urinary excretion of 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane (TX) B2 as indexes of in vivo lipid peroxidation and platelet activation, respectively, in 25 patients with RVD, 25 patients with essential hypertension, and 25 healthy subjects. Plasma renin activity in peripheral and renal veins, angiotensin II in renal veins, cholesterol, glucose, triglycerides, homocysteine, and antioxidant vitamins A, C, and E were also determined. Patients were also studied 6 months after a technically successful angioplasty of the stenotic renal arteries. Urinary 8-iso-PGF2alpha was significantly higher in patients with RVD (median, 305 pg/mg creatinine; range, 124 to 1224 pg/mg creatinine) than in patients with essential hypertension (median, 176 pg/mg creatinine; range, 48 to 384 pg/mg creatinine) or in healthy subjects (median, 123 pg/mg creatinine; range, 58 to 385 pg/mg creatinine). Urinary 11-dehydro-TXB2 was also significantly higher in RVD patients compared with healthy subjects. In RVD patients, urinary 8-iso-PGF2alpha correlated with 11-dehydro-TXB2 (r(s)=0.48; P<0.05) and renal vein renin (r(s)=0.67; P<0.005) and angiotensin II (r(s)=0.65; P=0.005) ratios. A reduction in 8-iso-PGF2alpha after angioplasty was observed in RVD patients with high baseline levels of lipid peroxidation. Changes in 8-iso-PGF2alpha were related to baseline lipid peroxidation (r(s)=-0.73; P<0.001), renal vein angiotensin II (r(s)=-0.70; P<0.01) and renin (r(s)=-0.63; P<0.05) ratios.. Lipid peroxidation is markedly enhanced in hypertensive patients with RVD and is related to activation of the renin-angiotensin system. Moreover, persistent platelet activation triggered or amplified by bioactive isoprostanes may contribute to the progression of cardiovascular and renal damage in this setting.

Topics: Adolescent; Adult; Aged; Angioplasty; Angiotensin II; Antioxidants; Biomarkers; Blood Glucose; Cholesterol; Cross-Sectional Studies; Dinoprost; F2-Isoprostanes; Female; Homocysteine; Humans; Hypertension; Hypertension, Renovascular; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Platelet Activation; Reference Values; Renal Artery Obstruction; Renin; Renin-Angiotensin System; Thromboxane B2; Triglycerides; Vitamins

Topics: Aged; Antioxidants; Biomarkers; Catalase; Dinoprost; Female; Glutathione Peroxidase; Homocysteine; Humans; Hyperhomocysteinemia; Hypertension; Male; Malondialdehyde; Middle Aged; Nitric Oxide; Oxidative Stress; Peroxides; Risk Factors; Superoxide Dismutase

Tempol, a superoxide dismutase-mimetic drug, has been shown to attenuate radical-induced damage, exerting beneficial effects in the animal models of oxidative stress and hypertension. This study evaluated the effect of Tempol on renal structural and functional alterations in two-Kidney, one-Clip hypertensive rats. In this study, young male Wistar rats had the left kidney clipped (2K1C), and sham-operated animals (Sham) were used as controls. Animals received Tempol (1mmol/L in drinking water) or vehicle for 5 weeks. Systolic blood pressure was evaluated once a week. At the end of the experimental protocol, the animals were placed in metabolic cages to collect urine (24h) and then anesthetized with thiopental (70mg/kg i.p.) to collect blood by puncturing the descending aorta for biochemical analysis, and the clipped kidney for morphological and immunohistochemical analyses. The vasodilator effect of Tempol was evaluated in mesenteric arterial bed (MAB) isolated from adult Wistar rats. The chronic treatment with Tempol prevented the development of hypertension and the increased plasma levels of urea, creatinine, and 8-isoprostane in 2K1C animals. Tempol also improved both glomeruli number and kidney volume to normal levels in the 2K1C+Tempol group. In addition, the treatment prevented the increased collagen deposition and immunostaining for renin, caspase-3, and 8-isoprostane in the stenotic kidney of 2K1C animals. Moreover, Tempol induced a dose-dependent vasodilator response in MAB from Wistar rats. These results suggest that Tempol protects the stenotic kidney against chronic ischemic renal injury and prevents renal dysfunction in the 2K1C model, probably through its antioxidant, vasodilator and antihypertensive actions.

Topics: Animals; Antioxidants; Biomimetic Materials; Blood Pressure; Caspase 3; Chronic Disease; Creatinine; Cyclic N-Oxides; Dinoprost; Hypertension; Ischemia; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Oxidative Stress; Rats; Rats, Wistar; Renin; Spin Labels; Superoxide Dismutase; Urea; Vasodilation

Subcortical white matter hyperintensities (WMH), presumed to indicate small vessel ischemic vascular disease, are found commonly in elderly individuals with and without Alzheimer's disease (AD). Oxidative stress may instigate or accelerate the development of vascular disease, and oxidative stress markers are elevated in AD. Here, we assess independent relationships between three serum lipid peroxidation markers (lipid hydroperoxides [LPH], 8-isoprostane, and 4-hydroxynonenal) and the presence of extensive subcortical WMH and/or AD. Patients were recruited from memory and stroke prevention clinics into four groups: minimal WMH, extensive WMH, AD with minimal WMH, and AD with extensive WMH. Extensive WMH, but not AD, was associated with higher serum concentrations of 8-isoprostane and LPH. Peripheral LPH concentrations mediated the effect of hypertension on deep, but not periventricular, WMH volumes. 4-hydroxynonenal was associated with hyperlipidemia and cerebral microbleeds, but not with extensive WMH or AD. We conclude that lipid peroxidation mediates hypertensive injury to the deep subcortical white matter and that peripheral blood lipid peroxidation markers indicate subcortical small vessel disease regardless of an AD diagnosis.

Topics: Aged; Aged, 80 and over; Aldehydes; Alzheimer Disease; Biomarkers; Cerebral Small Vessel Diseases; Cohort Studies; Cross-Sectional Studies; Dinoprost; Female; Humans; Hypertension; Lipid Peroxidation; Lipid Peroxides; Magnetic Resonance Imaging; Male; Middle Aged; Oxidative Stress; Risk Factors; White Matter

We aimed to determine changes in oxidative stress, lipoprotein-associated phospholipase A. We divided 254 subjects with prehypertension according to their blood pressure (BP) status at 3.5 years of follow-up into three groups: reversed normotensive, persistent prehypertensive and developed hypertensive group. BP, serum lipid profile, oxidized LDL (ox-LDL), Lp-PLA. The reversed normotensive group showed a significant reduction in average BP (14.7/10.1 mmHg), whereas the developed hypertensive group showed a significant increase in average BP (15.2/11.5 mmHg). The persistent prehypertensive group showed increases in serum lipid profiles, circulating levels of Lp-PLA. This study indicates that in persistent prehypertension, increased ox-LDL hydrolysis by Lp-PLA

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Ankle Brachial Index; Biomarkers; Blood Pressure; Case-Control Studies; Dinoprost; Female; Follow-Up Studies; Humans; Hydrolysis; Hypertension; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Prehypertension; Prognosis; Risk Factors; Time Factors; Up-Regulation; Vascular Stiffness

The aim of this clinical study was to evaluate the influence of aging on the levels of lipid peroxidation (quantified as thiobarbituric acid-reactive substances (TBARS) content), lipid hydroperoxide (LOOH), hexanoyl lysine (HEL), 8-iso-prostaglandin F2α (8-iso-PGF2α) and total antioxidant capacity (TAC), and determine their relationships to the demographic and cardiovascular risk factors in elderly hypertensive (HT) patients. This study consisted of four groups: two elderly groups with 30 HT patients (11 males, 19 females) and 30 normotensive healthy volunteers (15 males, 15 females), and two young groups with 30 HT patients (13 males, 17 females) and 30 normotensive healthy volunteers (12 males, 18 females). In the elderly control group, the TBARS, LOOH, HEL and 8-iso-PGF2α levels, and the carotid intima media thickness (CIMT) were significantly higher than in the young control group. The TBARS, LOOH, HEL and 8-iso-PGF2α levels and the CIMT measurements were significantly higher in the elderly HT group than in the young HT group. In addition, the TAC levels were significantly lower in the elderly and young HT groups than in the elderly and young control groups. The CIMT was significantly positively correlated with TBARS (r=0.40, P<0.001), HEL (r= 0.30, P=0.001), LOOH (r= 0.44, P<0.001) and 8-iso-PGF2α (r= 0.32, P<0.001) in all of the HT groups. It seems that in elderly patients, the LOOH and TBARS are better biomarkers of lipid peroxidation in hypertension in terms of sensitivity. In all of the HT groups, 8-iso-PGF2α had the highest sensitivity. Hypertension is associated with lipid peroxidation due to an impaired oxidant/antioxidant status. Increased lipid peroxidation and decreased antioxidants with aging indicate that peroxidative damage further increases with higher blood pressure and the aging process.

Topics: Adult; Aged; Aged, 80 and over; Aging; Biomarkers; Carotid Intima-Media Thickness; Dinoprost; Female; Healthy Volunteers; Humans; Hypertension; Lipid Peroxidation; Lipid Peroxides; Male; Middle Aged; Risk Assessment; Risk Factors; Sensitivity and Specificity; Thiobarbituric Acid Reactive Substances

We investigated the effects of circulating factors in serum obtained from patients in the acute phase of different subtypes of ischemic stroke on non-ischemic cerebral and mesenteric arteries, as a potential mechanism involved in influencing regional perfusion and thus clinical evolution. Posterior cerebral arteries (PCAs) and mesentery arteries (MAs) isolated from Wistar Kyoto rats were perfused with serum from acute stroke patients with large vessel disease without (LVD) or with hypertension (LVD + HTN), cardioembolism with hypertension (CE + HTN), or physiologic saline as controls. Myogenic activity and nitric oxide-dependent vasorelaxation were assessed after 2 h of intraluminal exposure to serum. Vascular function was differentially affected by sera. Exposure to LVD serum increased myogenic tone and produced endothelial dysfunction in both PCAs and MAs. However, CE + HTN serum increased tone and decreased smooth muscle sensitivity to NO in vessels from both vascular beds. LVD + HTN serum was associated with reduced smooth muscle sensitivity to NO in vessels from both vascular beds but increased tone only in PCAs. Inflammation and oxidative stress, determined by measurement of high sensitivity C-reactive protein, uric acid, and free 8-isoprostane, were enhanced in all the serum groups. These results demonstrate vasoactive properties of acute stroke serum related to stroke subtypes that could potentially contribute to the pathogenesis of early hemodynamic-based clinical events.

Topics: Acetylcholine; Aged; Animals; C-Reactive Protein; Cerebral Arteries; Dinoprost; Disease Models, Animal; Female; Humans; Hypertension; Male; Middle Aged; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Rats; Rats, Inbred WKY; Serum; Splanchnic Circulation; Stroke; Uric Acid; Vasodilator Agents

Apelin is an adipokine directly associated with adiposity, insulin resistance, and decreased blood pressure. Urinary 8-isoprostane is a marker of chronic oxidative endothelial stress. Visfatin, an adipokine that acts by binding and activating the insulin receptor, has been associated with hypertension. As severe hypertension (SH) is highly prevalent among African Americans (AA), we aimed to assess the association of these biomarkers with SH status.. A sample of 250 AA participants (134 normotensive controls and 116 with SH (including 98 treatment controlled, SCH: severe controlled hypertension, and 18 treatment resistant, SRH: severe resistant hypertension)) from the Minority Health Genomics and Translational Research Bio-Repository Database (MH-GRID) in metro Atlanta had blood analyzed for apelin and visfatin and urine for 8-isoprostane. T-tests, sex-specific age-adjusted correlation coefficients, and multivariable logistic regression models were used to assess the association of biomarkers with hypertensive status.. Levels of apelin and 8-isoprostane were not statistically different between controls and SCH or SRH. Statistically significant differences were present in levels of visfatin between controls (1.03±0.84 pg/ml), SCH (1.34±1.14 pg/ml), and SRH (1.59±0.85 pg/ml). After multivariable adjustment, categorization in the middle 2 quartiles of urinary 8-isoprostane were associated with SH. In similar models, categorization into the highest quartile of visfatin was associated with SH (odds ratio = 2.80; 95% confidence interval: 1.02-7.02). A continuous association of visfatin with SH was present.. In our community sample of AA, there were increased odds of SH with increased levels of urinary 8-isoprostane and visfatin, but not with apelin.

Topics: Adult; Apelin; Biomarkers; Black or African American; Case-Control Studies; Dinoprost; Female; Humans; Hypertension; Logistic Models; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase

The renal autonomic nervous system may contribute to hypertension and vascular disease. Although the effects of renal artery denervation on blood pressure lowering are controversial, there may be other beneficial vascular effects independent of blood pressure lowering. Bilateral renal denervation (RDN) or sham operation (SO) was performed in 14-week-old male apolipoprotein E-deficient mice on a Western diet starting at 10 weeks of age. Efficacy of RDN was confirmed by reduction of renal norepinephrine levels (SO: 3.8±0.1 versus RDN: 1.7±0.3 ng/mL; P<0.01) at 6 weeks after procedure. Compared with SO, RDN had no effect on blood pressure (SO: 101.0±2.4 versus RDN: 97.5±1.6 mm Hg; P=0.25), total cholesterol (SO: 536.7±28.5 versus RDN: 535.7±62.9 mg/dL; P=0.99), or triglycerides (SO: 83.7±3.5 versus RDN: 86.9±10.2 mg/dL; P=0.78). Quantification of atherosclerosis at 20 weeks of age demonstrated reduced atherosclerosis in mice receiving RDN compared with SO (arterial tree oil-red-O surface staining RDN: 4.2±0.5% versus SO: 6.3±0.7%; P<0.05). Reduced atherosclerosis was associated with increased smooth muscle cell content in atherosclerotic plaques (RDN: 13.3±2.1 versus SO: 8.1±0.6%; P<0.05). Serum levels of aldosterone, monocyte chemoattractant protein-1, and 8-isoprostane were lower in mice that received RDN compared with sham-operated mice (aldosterone; RDN: 206.8±33.2 versus SO: 405.5±59.4 pg/mL, P<0.05; monocyte chemoattractant protein-1; RDN: 51.7±7.9 versus SO: 91.71±4.6 pg/mL, P<0.05; 8-isoprostane; RDN: 331.9±38.2 versus SO: 468.5±42.0 pg/mL, P<0.05). RDN reduces progression of atherosclerosis in apolipoprotein E-deficient mice. These changes are associated with reduced aldosterone levels, monocyte chemoattractant protein-1, and markers of oxidative stress.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Pressure Determination; Chemokine CCL2; Dinoprost; Disease Models, Animal; Disease Progression; Hypertension; Kidney; Male; Mice; Oxidative Stress; Sympathectomy

To determine whether 8-iso-prostaglandin F2α (8-iso-PGF2α) is a reliable biomarker of the accumulation of metabolic risks [e.g., overweight, hypertension, impaired glucose tolerance (IGT), and dyslipidemia].. This was a cross-sectional study of the baseline characteristics of a Japanese general population cohort study: Research on Osteoarthritis/Osteoporosis Against Disability (ROAD). Of 1,690 participants, 1,527 fulfilled all questionnaires and examinations. Free and conjugated urinary 8-iso-PGF2α levels and metabolic syndrome (MetS) components including blood pressure, HbA1c, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C were analyzed. The data were analyzed by ANCOVA, multiple regression analysis, and multinomial logistic analysis.. 8-iso-PGF2α was significantly associated with HbA1c and significantly inversely associated with total cholesterol and non-HDL-C. Notably, IGT with an HbA1c cut-off of 5.5% was significantly associated with 8-iso-PGF2α level in participants aged ≤50 years. Multinomial logistic regression analysis revealed 8-iso-PGF2α level was significantly associated with a greater number of MetS risks present; this association was stronger in younger participants. In participants aged ≥71 years, 8-iso-PGF2α was significantly associated with a greater number of MetS risks with higher IGT cut-offs.. Urinary 8-iso-PGF2α can be a reliable marker of IGT and the accumulation of MetS risks, especially in younger people.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Cohort Studies; Cross-Sectional Studies; Dinoprost; Female; Humans; Hypertension; Japan; Male; Metabolic Syndrome; Middle Aged; Oxidative Stress; Regression Analysis; Risk Factors; Waist Circumference

Hypertension is a common disease that includes oxidative stress as a major feature, and oxidative stress impairs physiological nitric oxide (NO) activity promoting cardiovascular pathophysiological mechanisms. While inorganic nitrite and nitrate are now recognized as relevant sources of NO after their bioactivation by enzymatic and non-enzymatic pathways, thus lowering blood pressure, mounting evidence suggests that sodium nitrite also exerts antioxidant effects. Here we show for the first time that sodium nitrite exerts consistent systemic and vascular antioxidant and antihypertensive effects in the deoxycorticosterone-salt (DOCA-salt) hypertension model. This is particularly important because increased oxidative stress plays a major role in the DOCA-salt hypertension model, which is less dependent on activation of the renin-angiotensin system than other hypertension models. Indeed, antihypertensive effects of oral nitrite were associated with increased plasma nitrite and nitrate concentrations, and completely blunted hypertension-induced increases in plasma 8-isoprostane and lipid peroxide levels, in vascular reactive oxygen species, in vascular NADPH oxidase activity, and in vascular xanthine oxidoreductase activity. Together, these findings provide evidence that the oral administration of sodium nitrite consistently decreases the blood pressure in association with major antioxidant effects in experimental hypertension.

Topics: Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Desoxycorticosterone; Dinoprost; Disease Models, Animal; Hypertension; Lipid Peroxides; Male; NADPH Oxidases; Nitrites; Nitrogen Oxides; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Sodium Nitrite; Xanthine Oxidase

Impaired endothelial function and arterial stiffness are associated with hypertension and are important risk factors for cardiovascular events. Reactive oxygen species reduce nitric oxide bioavailability and have a pivotal role in endothelial function. Resistant hypertension (RHTN) is characterized by blood pressure (BP) above goal (140/90mmHg) in spite of the concurrent use of ≥3 antihypertensive drugs of different classes. This study evaluated the association between 8-isoprostane levels, an oxidative stress marker, endothelial function and arterial stiffness, in RHTN.. Ninety-four RHTN and 55 well-controlled hypertensive (HT) patients were included. Plasma 8-isoprostane levels were determined by ELISA. Also, flow-mediated dilation (FMD) and pulse wave velocity (PWV) were evaluated to determine endothelial function and arterial stiffness, respectively.. Levels of 8-isoprostane were markedly higher in RHTN compared to HT patients (22.5±11.2 vs. 17.3±9.8pg/ml, p<0.05, respectively). A significant inverse correlation was observed between FMD and 8-isoprostane (r=-0.35, p=0.001) in RHTN. Finally, multiple logistic regression revealed that 8-isoprostane was a significant predictor of endothelial dysfunction (FMD≤median) in RHTN group.. RHTN showed markedly higher oxidative stress measured by 8-isoprostane, compared to HT patients. Taken together, our findings suggest the involvement of oxidative stress in endothelial function in RHTN.

Topics: Antihypertensive Agents; Biomarkers; Dinoprost; Drug Resistance; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Vascular Stiffness

Heart failure and related cardiac complications remains a great health challenge. We investigated the effects of upregulating heme-oxygenase (HO) on myocardial histo-pathological lesions, proinflammatory cytokines/chemokines, oxidative mediators and important markers of heart failure such as osteopontin and osteoprotergerin in N(ω)-nitro-l-arginine methyl ester (L-NAME)-induced hypertension. Treatment with the HO-inducer, heme-arginate improved myocardial morphology in L-NAME hypertensive rats by attenuating subendocardial injury, interstitial fibrosis, mononuclear-cell infiltration and cardiomyocyte hypertrophy. These were associated with the reduction of several inflammatory/oxidative mediators including chemokines/cytokines such as macrophage inflammatory protein-1 alpha (MIP-1α), macrophage chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, endothelin-1, 8-isoprostane, nitrotyrosine, and aldosterone. Similarly, heme-arginate abated the elevated levels of extracellular matrix/remodeling proteins including transforming-growth factor beta (TGF-β1) and collagen-IV in the myocardium. These were accompanied by significant reduction of proteins of heart failure such as osteopontin and osteoprotegerin. Interestingly, the cardio-protective effects of heme-arginate were associated with the potentiation of adiponectin, atrial-natriuretic peptide (ANP), HO-1, HO-activity, cyclic gnanosine monophosphate (cGMP) and the total-anti-oxidant capacity, whereas the HO-inhibitor, chromium-mesoporphyrin nullified the effects of heme-arginate, exacerbating inflammatory injury and oxidative insults. We conclude that heme-arginate therapy protects myocardial damage by potentiating the HO-adiponectin-ANP axis, which in turn suppressed the elevated levels of aldosterone, pro-inflammatory chemokines/cytokines, mononuclear-cell infiltration and oxidative stress, with concomitant reduction of extracellular matrix/remodeling proteins and heart failure proteins. These data suggest a cardio-protective role of the HO system against L-NAME-induced hypertension that could be explored in the design of novel strategies against cardiomyopathy.

Topics: Adiponectin; Aldosterone; Animals; Antioxidants; Arginine; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiomyopathies; Cardiotonic Agents; Chemokine CCL2; Chemokine CCL3; Cyclic GMP; Dinoprost; Endothelin-1; Enzyme Induction; Extracellular Matrix Proteins; Heart Failure; Heme; Heme Oxygenase (Decyclizing); Hypertension; Interleukin-1beta; Interleukin-6; Male; NG-Nitroarginine Methyl Ester; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Tyrosine

Vitamin D increases renal expression of klotho in normotensive rats. Klotho reduces oxidative stress.. In this study, we aimed to determine if vitamin D would suppress oxidative stress using 4 groups of hypertensive rats: uninephrectomized, stroke-prone, spontaneously hypertensive rats fed a high-salt (6%) diet (controls; C); those treated with irbesartan (I); those treated with calcitriol (V); and those treated with both irbesartan and calcitriol (I+V).. Systolic blood pressure was higher in the C group than in the I and I+V groups. Albuminuria was attenuated in groups I, V, and I+V. Renal angiotensin II (AngII) concentration was lower in groups I and I+V than in group C, and plasma AngII levels of groups I and V were higher and lower than those in group C, respectively. Compared with group C, renal klotho expression, 8-epi-prostaglandin F2α excretion, and acetylcholine-induced decrease in blood pressure improved in the V and I+V groups.. The data indicate that irbesartan effectively decreases blood pressure and renal AngII levels, and improves albuminuria. Our findings indicate that vitamin D enhances klotho expression, suppressing oxidative stress and albuminuria without substantial changes in renal AngII levels. These results suggest that the amelioration of endothelium function by vitamin D involves free klotho.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Calcitriol; Dietary Supplements; Dinoprost; Disease Models, Animal; Endothelium, Vascular; Glucuronidase; Hypertension; Irbesartan; Kidney; Kidney Diseases; Klotho Proteins; Male; Oxidative Stress; Rats; Rats, Inbred SHR; Tetrazoles; Vasodilation; Vitamins

Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin [human recombinant relaxin-2 (RLX)] in male Sprague-Dawley rats given high-dose angiotensin (ANG) II (400 ng·kg(-1)·min(-1) sc) for 6 wk or shams. RLX was administered (4 μg/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid-reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 ± 5 vs. 135 ± 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 ± 6 vs. 41 ± 4 mg·day(-1)·100 g(-1), P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohydrolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Antioxidants; Arginine; Arterial Pressure; Dinoprost; Disease Models, Animal; Down-Regulation; Humans; Hypertension; Injections, Subcutaneous; Kidney; Liver; Male; NADPH Oxidases; Nitric Oxide; Oxidative Stress; Proteinuria; Rats, Sprague-Dawley; Recombinant Proteins; Relaxin; Thiobarbituric Acid Reactive Substances

Aging-associated declines in cognitive, emotional, and cardiovascular function are well known. Environmental stress triggers critical changes in the brain, further compromising cardiovascular and behavioral health during aging. Excessive dietary salt intake is one such stressor. Here, we tested the effect of high salt (HS) on anxiety, learning-memory function, and blood pressure (BP) in male Fischer brown Norway (FBN) rats. Adult (A; 2 mo) and old (O; 20 mo) male rats were fed normal-salt (NS; 0.4% NaCl) or HS (8% NaCl) diets for 4 wk after being implanted with telemeter probes for conscious BP measurement. Thereafter, tests to assess anxiety-like behavior and learning-memory were conducted. The rats were then killed, and samples of plasma, urine, and brain tissue were collected. We found that systolic BP was higher in O-NS (117 ± 1.2 mm Hg) than in A-NS (105 ± 0.8 mm Hg) rats (P < 0.05). Furthermore, BP was higher in O-HS (124 ± 1.4 mm Hg) than in O-NS (117 ± 1.2 mm Hg) rats (P < 0.05). Moreover, anxiety-like behavior (light-dark and open-field tests) was not different between A-NS and O-NS rats but was greater in O-HS rats than in A-NS, O-NS, or A-HS rats (P < 0.05). Short-term memory (radial arm water maze test) was similar in A-NS and O-NS rats but was significantly impaired in O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05). Furthermore, oxidative stress variables (in plasma, urine, and brain) as well as corticosterone (plasma) were greater in O-HS rats when compared with A-NS, O-NS, or A-HS rats (P < 0.05). The antioxidant enzyme glyoxalase-1 expression was selectively reduced in the hippocampus and amygdala of O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05), whereas other antioxidant enzymes, glutathione reductase 1, manganese superoxide dismutase (SOD), and Cu/Zn SOD remained unchanged. We suggest that salt-sensitive hypertension and behavioral derangement are associated with a redox imbalance in the brain of aged FBN rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aging; Animals; Anxiety; Blood Pressure; Corticosterone; Deoxyguanosine; Diet; Dinoprost; Disease Models, Animal; Gene Expression Regulation; Glutathione Reductase; Hypertension; Lactoylglutathione Lyase; Learning; Male; Memory, Short-Term; Oxidative Stress; Rats; Sodium Chloride, Dietary; Superoxide Dismutase

The intima-media thickness (IMT) is considered as a surrogate marker for atherosclerotic disease. The aim of this study was to analyze the relationship of carotid IMT with fetuin-A in patients with essential hypertension (EH) and normal renal function. The plasma levels of fetuin-A, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and the biomarker of oxidative stress 8-iso-PGF2alpha were assayed in samples from 105 untreated EH patients. Carotid IMT measurements were also performed. EH was studied overall and after dividing in EH with IMT ≥ and <0.9 mm. All of the biomarkers were significantly different between the two subgroups, in particular, the fetuin-A level was lower in the patients with an IMT ≥0.9 mm. In the overall group, the linear analysis of correlation demonstrated that the IMT was significantly inversely correlated with the fetuin-A level (r=-0.40, P<0.0001) and directly with TNF-α (r=0.39, P<0.0001), IL-6 (r=0.38, P<0.0001) and 8-iso-PGF2alpha (r=0.356, P<0.0003). The multiple regression analysis performed that assigned IMT as a dependent variable showed that fetuin-A (β=-0.268, P<0.0001) was independently correlated with the IMT. Receiver-operator curves demonstrated that fetuin-A levels have a predictive power of IMT>0.9 mm (AUC (area under the curve) 0.738, P<0.0001). Our results suggest that in EH, fetuin-A is associated with the IMT independently of oxidative stress and renal function, thus predicting increases in the IMT.

Topics: Adult; alpha-2-HS-Glycoprotein; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Case-Control Studies; Cross-Sectional Studies; Dinoprost; Essential Hypertension; Female; Humans; Hypertension; Interleukin-6; Kidney; Male; Middle Aged; Oxidative Stress; Predictive Value of Tests; Regression Analysis; Risk Factors; Tumor Necrosis Factor-alpha

The assessment of oxidative stress may aid in the identification of subsequent metabolic risk in obese children. The objective of this study was to determine whether the plasma level of advanced oxidation protein products, analyzed with a recently proposed modified assay that involves a delipidation step (mAOPPs), was related to metabolic risk factors (MRFs) in severely obese children.. The plasma levels of mAOPPs were determined by spectrophotometry in 54 severely obese and 44 healthy children. We also measured lipid peroxidation biomarkers (thiobarbituric acid-reactive substances, malondialdehyde, and 8-isoprotane F(2α)) and sulfhydryl groups, a marker of antioxidant defense. Protein oxidation and lipid peroxidation markers were higher and sulfhydryl levels were lower in obese children compared with controls. Taking metabolic risk into account, obese children were subdivided according to the cutoff point (53.2 μmol/L) obtained for their mAOPPs values from the ROC curve. Anthropometric measures and the existence of hypertension did not differ between groups. The presence of dyslipidemia and insulin resistance was significantly higher in the group with higher mAOPPs levels. The highest levels of mAOPPs were found in the children with ≥3 MRFs. The level of mAOPPs was positively correlated with triglycerides and negatively correlated with high-density lipoprotein cholesterol. There was no correlation of this marker of protein oxidation with biomarkers of lipid peroxidation.. The determination of mAOPPs in delipidated plasma is an easy way to evaluate protein oxidation. It may be useful in severely obese children for better cardiovascular risk assessment.

Topics: Adolescent; Age of Onset; Biomarkers; Chi-Square Distribution; Child; Dinoprost; Dyslipidemias; Female; Humans; Hypertension; Insulin Resistance; Linear Models; Lipid Peroxidation; Lipids; Male; Malondialdehyde; Metabolic Syndrome; Obesity; Oxidation-Reduction; Oxidative Stress; Proteins; Risk Assessment; Risk Factors; Severity of Illness Index; Spain; Spectrophotometry; Sulfhydryl Compounds; Thiobarbituric Acid Reactive Substances; Up-Regulation

Negatively charged low-density lipoprotein (LDL), generated via multiple processes such as oxidation, acetylation, or glycosylation, plays a key role in the initiation and progression of atherosclerosis and related diseases. Anion-exchange high-performance liquid chromatography (AE-HPLC) can subfractionate LDL into LDL-1, LDL-2, and LDL-3 based on LDL particle charge, but the clinical significance of LDL subfractions has not yet been elucidated. The aim of this study was to determine the clinical significance of these fractions with particular regard to atherogenic risk in hypertensive patients. Ninety-eight patients with essential hypertension (age 67.0 ± 10.7 years; 54 males) were enrolled in the present study. The relationships between LDL subfractions and atherogenic risk factors, including lipid profiles, blood pressure and plasma 8-isoprostane as a marker of oxidative stress, were examined. LDL-1 levels were significantly and negatively correlated with body mass index (r = -0.384, p < 0.001), systolic blood pressure (r = -0.457, p < 0.001), non-high-density lipoprotein cholesterol levels (r = -0.457, p < 0.001) and 8-isoprostane levels (r = -0.415, p < 0.001). LDL-3, which is the most negatively charged fraction of total LDL, was significantly and positively correlated with these parameters (r = 0.267, 0.481, 0.357, and 0.337, respectively). LDL-1 levels were significantly lower (p < 0.001), and LDL-2 and LDL-3 levels were significantly higher (each p < 0.001) in patients with poorly controlled hypertension than in patients with well-controlled hypertension. In addition, an increase in the total number of traditional risk factors at time of study participation, but not previous diagnosis, was associated with a decrease in LDL-1 levels and increases in LDL-2 and LDL-3 levels. These data suggest that LDL subfractions are associated with multiple atherogenic risk factors and that treatment to modify these risk factors could result in changes in LDL subfraction levels. In conclusion, LDL subfractions isolated by AE-HPLC may represent a marker of atherogenic risk in patients with hypertension.

Topics: Aged; Analysis of Variance; Anion Exchange Resins; Antihypertensive Agents; Atherosclerosis; Biomarkers; Blood Pressure; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Dinoprost; Female; Humans; Hypertension; Japan; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Risk Assessment; Risk Factors

Flavanol-rich diets have been reported to exert beneficial effects in preventing cardiovascular diseases, such as hypertension. We studied the effects of chronic treatment with epicatechin on blood pressure, endothelial function, and oxidative status in deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Rats were treated for 5 weeks with (-)-epicatechin at 2 or 10 mg kg(-1)day(-1). The high dose of epicatechin prevented both the increase in systolic blood pressure and the proteinuria induced by DOCA-salt. Plasma endothelin-1 and malondialdehyde levels and urinary iso-prostaglandin F(2α) excretion were increased in animals of the DOCA-salt group and reduced by the epicatechin 10 mg kg(-1) treatment. Aortic superoxide levels were enhanced in the DOCA-salt group and abolished by both doses of epicatechin. However, only epicatechin at 10 mg kg(-1) reduced the rise in aortic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and p47(phox) and p22(phox) gene overexpression found in DOCA-salt animals. Epicatechin increased the transcription of nuclear factor-E2-related factor-2 (Nrf2) and Nrf2 target genes in aortas from control rats. Epicatechin also improved the impaired endothelium-dependent relaxation response to acetylcholine and increased the phosphorylation of both Akt and eNOS in aortic rings. In conclusion, epicatechin prevents hypertension, proteinuria, and vascular dysfunction. Epicatechin also induced a reduction in ET-1 release, systemic and vascular oxidative stress, and inhibition of NADPH oxidase activity.

Topics: Animals; Aorta; Blood Pressure; Catechin; Desoxycorticosterone; Dinoprost; Endothelin-1; Endothelium, Vascular; Hypertension; Male; Malondialdehyde; NADPH Oxidases; NF-E2-Related Factor 2; Nitric Oxide Synthase Type III; Oxidative Stress; Proteinuria; Rats; Rats, Wistar; Sodium Chloride, Dietary; Superoxides

Most deaths in autosomal dominant polycystic kidney disease (ADPKD) are attributable to cardiovascular disease (CVD). We examined novel CVD biomarkers in different stages of ADPKD.. We recruited 50 hypertensive subjects with ADPKD with estimated GFR (eGFR) of >60 ml/min per 1.73 m(2); 52 hypertensive subjects with ADPKD with eGFR of 25 to 60 ml/min per 1.73 m(2); 42 normotensive subjects with ADPKD and eGFR of >60 ml/min per 1.73 m(2); and 50 healthy controls. We assayed serum C-reactive protein and IL-6 as markers of inflammation; plasma 8-epi-prostaglandin F(2α (8-epi-PGF2α)) and superoxide dismutase (SOD) as markers of oxidative stress; and homeostasis model assessment (HOMA) as a measure of insulin resistance.. The hypertensive ADPKD eGFR of 25 to 60 group had higher levels of C-reactive protein and IL-6 than controls, normotensive ADPKD with eGFR of >60, and hypertensive ADPKD with eGFR of >60. The normotensive ADPKD eGFR >60, hypertensive ADPKD eGFR >60, and hypertensive ADPKD eGFR 25 to 60 groups had higher 8-epi-PGF(2α) and lower SOD than controls, with no difference between the ADPKD groups. There was no difference in HOMA levels between any of the groups. Adjustment for age, race, gender, and body mass index did not alter these relationships.. Inflammation and oxidative stress are evident early in ADPKD even with preserved kidney function. Inflammation exhibits a graded relationship with levels of kidney function, whereas oxidative stress demonstrates a threshold effect. These pathways may be therapeutic targets for CVD risk mitigation.

Topics: Adult; C-Reactive Protein; Dinoprost; Female; Glomerular Filtration Rate; Humans; Hypertension; Inflammation; Insulin Resistance; Interleukin-6; Male; Middle Aged; Oxidative Stress; Polycystic Kidney, Autosomal Dominant; Superoxide Dismutase

To evaluate whether oxidative stress is correlated with adiposity, obesity-related metabolic abnormalities, and ambulatory blood pressure (ABP) in a multi-ethnic pediatric population.. We conducted a prospective study enrolling 42 obese children (age, 12.8 ± 2.4 years) and 34 non-obese children (age, 11.8 ± 3.4 years). We measured urine 8-isoprostane and hydrogen peroxide (markers of oxidative stress) in both obese and non-obese groups. In the obese group, we measured the 24-hour ABP and obtained an oral glucose tolerance test, lipid panel, interleukin-6, and tumor necrosis factor-α.. 8-isoprostane and hydrogen peroxide were correlated with body mass index standard deviation score and waist circumference. The mean 8-isoprostane and hydrogen peroxide levels of the obese group were higher than those of the non-obese group. In the subset of obese subjects who underwent ABP monitoring, 8-isoprostane was correlated with mean 24-hour systolic blood pressure: within the obese group, 8-isoprostane was higher in obese children with elevated mean 24-hour systolic blood pressure.. Our findings provide evidence of a significant correlation between oxidative stress, adiposity, and blood pressure in children. Longitudinal studies in a larger population sample are needed to validate the association between elevated urine 8-isoprostane level and cardiovascular risk factors in an obese pediatric population.

Topics: Adolescent; Child; Cross-Sectional Studies; Dinoprost; Dyslipidemias; Female; Humans; Hydrogen Peroxide; Hypertension; Interleukin-6; Male; Obesity; Oxidative Stress; Prospective Studies; Tumor Necrosis Factor-alpha

Renal prostacycline (PGI(2)) and oxidative stress are known to be important factors that effect the natriurezis and diuresis. 8-iso prostaglandin F(2)α± (8-isoprostane), a member of F(2)-isoprostanes, is formed from the nonenzymatic reaction of arachidonic acid and oxygen radicals in vivo and in vitro, and also it is a marker of oxidative stress in vivo. The aim of this study is to determine the role of renal PGI(2) and 8-isoprostane in a salt and nitric oxide (NO) inhibition-induced hypertension model. Rats were distributed equally among four groups (n = 6 per group). Control rats were given normal salt diet (0.32%); high-salt (HS) rats were given high salt diet (3.2%); NG-nitro-L-arginine (L-NNA) rats were given normal salt diet and 25 mg/kg L-NNA; HS+L-NNA rats were given high salt diet and 25 mg/kg L-NNA. Rats were placed in individual metabolic cages for 17 days. Systolic blood pressure (SBP) was measured at days initial, 7th and 14th .Urinary 8-isoprostane and PGI(2) levels were analyzed. Salt- loading alone did not change SBP values. The average SBP in L-NNA and HS+L-NNA groups were shown to significantly enhance compared to initial and day 7th in the same groups, respectively. The levels of 8-isoprostane in the HS+L-NNA group was significantly enhanced compared to the other groups. L-NNA or HS diet alone did not change the levels of 8-isoprostane compared to the control group. L-NNA alone did not change PGI(2) levels in urine compared to the control. PGI(2) levels in the HS, and the HS+L-NNA group was significantly higher compared to the control group. This study concluded that NOS inhibition plus salt-loading induced oxidative stress and increased renal PGI(2). Also, it is suggested that augmented oxidative stress may aggravate the hypertension. But the renal synthesis of PGI(2) is increased in order to augment the diuresis and natriuresis without the effect of blood pressure (BP).

Topics: Animals; Dinoprost; Disease Models, Animal; Enzyme Inhibitors; Epoprostenol; Hypertension; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary

We assessed the relative contribution of the mitochondrial respiratory chain and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to deoxycorticosterone acetate (DOCA)-salt hypertension in mice. The daily mean arterial pressure was monitored by radiotelemetry in DOCA-salt-treated mice given vehicle or the mitochondrial respiratory chain complex I inhibitor rotenone. This treatment produced remarkable attenuation of DOCA-salt hypertension. Similar results were obtained with other inhibitors of mitochondrial function, including 5-hydroxydecanoate (specific for mitochondrial potassium-ATP channels), benzylguanidine (complexes I and III), and the cell-permeable manganese tetrakis (4-benzoic acid) porphyrin (a mimic of mitochondrial superoxide dismutase). In parallel with the blood pressure-lowering effect of rotenone, the DOCA-salt-induced increases in urinary 8-isoprostane excretion and in reactive oxygen species production of isolated kidney mitochondria were both significantly attenuated. Conversely, the DOCA-salt-induced reduction of urinary nitrate/nitrite excretion was significantly elevated. Following DOCA-salt treatment, mice deficient in NADPH oxidase subunits gp91(phox) or p47(phox) exhibited a partial attenuation of the hypertensive response at early but not later time points. Thus, the mitochondrial respiratory chain is a major source of oxidative stress in DOCA-salt hypertension, whereas NADPH oxidase may have a relatively minor role during the early stage of hypertension.

Topics: Acetophenones; Albuminuria; Aldosterone; Animals; Blood Pressure; Cell Line; Desoxycorticosterone; Dinoprost; Electron Transport; Enzyme Inhibitors; Humans; Hypertension; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Myocytes, Smooth Muscle; NADPH Oxidase 2; NADPH Oxidases; Nitrogen Oxides; Oxidative Stress; Rotenone; Sodium Chloride

Dietary nitrite and nitrate are important sources of nitric oxide (NO). However, the use of nitrite as an antihypertensive drug may be limited by increased oxidative stress associated with hypertension. We evaluated the antihypertensive effects of sodium nitrite given in drinking water for 4 weeks in two-kidney one-clip (2K1C) hypertensive rats and the effects induced by nitrite on NO bioavailability and oxidative stress. We found that, even under the increased oxidative stress conditions present in 2K1C hypertension, nitrite reduced systolic blood pressure in a dose-dependent manner. Whereas treatment with nitrite did not significantly change plasma nitrite concentrations in 2K1C rats, it increased plasma nitrate levels significantly. Surprisingly, nitrite treatment exerted antioxidant effects in both hypertensive and sham-normotensive control rats. A series of in vitro experiments was carried out to show that the antioxidant effects induced by nitrite do not involve direct antioxidant effects or xanthine oxidase activity inhibition. Conversely, nitrite decreased vascular NADPH oxidase activity. Taken together, our results show for the first time that nitrite has antihypertensive effects in 2K1C hypertensive rats, which may be due to its antioxidant properties resulting from vascular NADPH oxidase activity inhibition.

Topics: Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Dinoprost; Down-Regulation; Hypertension; Lipid Peroxides; NADPH Oxidases; Nitric Oxide; Nitrites; Oxidative Stress; Rats; Reactive Oxygen Species; Sodium Nitrite; Xanthine Oxidase

This study aimed to determine if 25 days of canola oil intake in the absence of excess dietary salt or together with salt loading affects antioxidant and oxidative stress markers in the circulation. A further aim was to determine the mRNA expression of NADPH oxidase subunits and superoxide dismutase (SOD) isoforms in the aorta of stroke-prone spontaneously hypertensive (SHRSP) rats.. Male SHRSP rats, were fed a defatted control diet containing 10% wt/wt soybean oil or a defatted treatment diet containing 10% wt/wt canola oil, and given tap water or water containing 1% NaCl. Blood was collected at the end of study for analysis of red blood cell (RBC) antioxidant enzymes, RBC and plasma malondialdehyde (MDA), plasma 8-isoprostane and plasma lipids. The aorta was removed and the mRNA expression of NOX2, p22phox, CuZn-SOD, Mn-SOD and EC-SOD were determined.. In the absence of salt, canola oil reduced RBC SOD and glutathione peroxidase, and increased total cholesterol and LDL cholesterol compared with soybean oil. RBC glutathione peroxidase activity was significantly lower in both the salt loaded groups compared to the soybean oil only group. In addition, RBC MDA and plasma HDL cholesterol were significantly higher in both the salt loaded groups compared to the no salt groups. Plasma MDA concentration was higher and LDL cholesterol concentration lower in the canola oil group loaded with salt compared to the canola oil group without salt. The mRNA expression of NADPH oxidase subunits and SOD isoforms were significantly reduced in the canola oil group with salt compared to canola oil group without salt.. In conclusion, these results indicate that canola oil reduces antioxidant status and increases plasma lipids, which are risk factors for cardiovascular disease. However, canola oil in combination with salt intake increased MDA, a marker of lipid peroxidation and decreased NAPDH oxidase subunits and aortic SOD gene expression.

Topics: Animals; Aorta; Biomarkers; Diet, Sodium-Restricted; Dinoprost; Erythrocytes; Fatty Acids, Monounsaturated; Gene Expression Regulation, Enzymologic; Hypercholesterolemia; Hypertension; Isoenzymes; Lipid Peroxidation; Male; Oxidative Stress; Oxidoreductases; Random Allocation; Rapeseed Oil; Rats; Rats, Inbred SHR; Risk Factors; RNA, Messenger; Stroke

Induction of heme-oxygenase (HO) is an important cellular defense mechanism against oxidative and inflammatory insults. We analyzed the effects of the HO inducer, heme-arginate, on the phospholipase C (PLC)/inositol-triphosphate (IP(3)) pathway in the mesenteric arterioles of uninephrectomized (UnX) deoxycorticosterone acetate (DOCA)-salt hypertensive rats, which is a volume-overload model characterized by elevated endothelin (ET-1) and mineralocorticoid-induced oxidative/inflammatory insults. Our study included the following groups: (A) controls [(i) surgery-free Sprague-Dawley (SD) rats, (ii) UnX-Sham, (iii) UnX-Salt (0.9% NaCl+0.2% KCl) and (iv) UnX-DOCA)]; (B) UnX-DOCA-salt hypertensive rats; (C) UnX-DOCA-salt+heme-arginate; (D) UnX-DOCA-salt+heme-arginate+chromium mesoporphyrin (CrMP), the HO inhibitor; (E) UnX-DOCA-salt+CrMP (F); SD+heme-arginate, (G) UnX-DOCA-salt+vehicle dissolving heme-arginate and CrMP and (H) normal-SD+heme-arginate. Quantitative reverse transcriptase PCR, western blot, enzyme immunoassay and spectrophotometric analyses were used. Heme-arginate enhanced mesenteric arteriole HO-1, HO activity, cyclic guanosine monophosphate (cGMP) and anti-oxidants including bilirubin, ferritin, superoxide dismutase with potentiation of the total anti-oxidant capacity. Correspondingly, oxidative/inflammatory mediators such as 8-isoprostane, nuclear-factor kappaB (NF-kappaB) and ET-1 were markedly reduced. Furthermore, heme-arginate suppressed PLC activity, attenuated IP(3) and reduced resting intracellular calcium. The effects of heme-arginate were nullified by the HO inhibitor, with aggravation of oxidative/inflammatory insults. In heme-arginate-treated SD rats, the HO system was potentiated to a lesser magnitude and the suppression of ET-1, PLC, IP(3) and NF-kappaB were less accentuated, suggesting greater selectivity of HO against the ET-1-PLC-IP(3)-NF-kappaB destructive axis in the pathological condition of mineralocorticoid-induced hypertension. Given that ET-1 stimulates PLC and IP(3), which in turn activates NF-kappaB, the concomitant reduction of ET-1, PLC, IP(3) and NF-kappaB alongside the corresponding decline of resting intracellular calcium may account for the reduction of blood pressure and attenuation of oxidative/inflammatory injury by heme-arginate.

Topics: Animals; Arginine; Arterioles; Blood Pressure; Calcium; Cyclic GMP; Desoxycorticosterone; Dinoprost; Endothelin-1; Heme; Heme Oxygenase (Decyclizing); Hypertension; Inositol 1,4,5-Trisphosphate; Intracellular Fluid; Male; Mesenteric Arteries; Mineralocorticoids; NF-kappa B; Organometallic Compounds; Oxidative Stress; Rats; Rats, Sprague-Dawley; Second Messenger Systems; Sodium Chloride, Dietary; Type C Phospholipases; Up-Regulation

Recent evidence indicates that oxidative stress might actively participate in the pathophysiology of hypertension, atherosclerosis, and other cardiovascular diseases. The purpose of the present study was to assess the possible link between oxidative stress and membrane fluidity in hypertensive and normotensive men. We measured the membrane fluidity (a reciprocal value of membrane microviscosity) of red blood cells (RBCs) in hypertensive and normotensive men using an electron spin resonance (ESR) and spin-labeling method. Membrane fluidity of RBCs was decreased in hypertensive men compared with normotensive men. The levels of plasma 8-Iso-prostaglandin F2alpha (8-Iso-PG F2alpha : an index of oxidative stress) were significantly higher in hypertensive men than in normotensive men. In contrast, plasma nitric oxide (NO)-metabolite levels were significantly lower in hypertensive men than in normotensive men. In the overall analysis of hypertensive and normotensive men, plasma 8-Iso-PG F2alpha levels were inversely correlated with plasma NO-metabolites. Furthermore, the reduced membrane fluidity of RBCs was associated with increased plasma 8-Iso-PG F2alpha and decreased plasma NO-metabolite levels. In a multivariate regression analysis, plasma 8-Iso-PG F2alpha was found to be an independent determinant of membrane fluidity of RBCs. The results of the present study suggest that oxidative stress might have a close correlation with the rheologic behavior of RBCs and the microcirculation in hypertensive men.

Topics: Aged; Case-Control Studies; Cross-Sectional Studies; Dinoprost; Electron Spin Resonance Spectroscopy; Erythrocyte Membrane; Humans; Hypertension; Japan; Male; Membrane Fluidity; Middle Aged; Nitric Oxide; Oxidative Stress

A deficiency in nitric oxide (NO) generation leads to salt-sensitive hypertension, but the role of increased superoxide (O(2)(-)) in such salt sensitivity has not been delineated. We examined the hypothesis that an enhancement in O(2)(-) activity induced by high-salt (HS) intake under deficient NO production contributes to the development of salt-sensitive hypertension. Endothelial NO synthase knockout (eNOS KO; total n = 64) and wild-type (WT; total n = 58) mice were given diets containing either normal (NS; 0.4%) or high-salt (HS; 4%) for 2 wk. During this period, mice were chronically treated with a O(2)(-) scavenger, tempol (400 mg/l), or an inhibitor of NADPH oxidase, apocynin (1 g/l), in drinking water or left untreated (n = 6-8 per group). Blood pressure was measured by radiotelemetry and 24-h urine samples were collected in metabolic cages. Basal mean arterial pressure (MAP) in eNOS KO was higher (125 +/- 4 vs. 106 +/- 3 mmHg) compared with WT. Feeding HS diet did not alter MAP in WT but increased it in eNOS KO to 166 +/- 9 mmHg. Both tempol and apocynin treatment significantly attenuated the MAP response to HS in eNOS KO (134 +/- 3 and 139 +/- 4 mmHg, respectively). Basal urinary 8-isoprostane excretion rates (U(Iso)V), a marker for endogenous O(2)(-) activity, were similar (2.8 +/- 0.2 and 2.4 +/- 0.3 ng/day) in both eNOS KO and WT mice. However, HS increased U(Iso)V more in eNOS KO than in WT (4.6 +/- 0.3 vs. 3.8 +/- 0.2 ng/day); these were significantly attenuated by both tempol and apocynin treatment. These data indicate that an enhancement in O(2)(-) activity contributes substantially to the development of salt-sensitive hypertension under NO-deficient conditions.

Topics: Acetophenones; Animals; Antioxidants; Blood Pressure; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Sodium Chloride, Dietary; Spin Labels; Superoxides

Angiotensin II (ANG II) contributes to hypertension, cardiac hypertrophy, fibrosis, and dysfunction; however, it is difficult to separate the cardiac effect of ANG II from its hemodynamic action in vivo. To overcome the limitations, we used transgenic mice with cardiac-specific expression of a transgene fusion protein that releases ANG II from cardiomyocytes (Tg-ANG II) and treated them with deoxycorticosterone acetate (DOCA)-salt to suppress their systemic renin-angiotensin system. Using this unique model, we tested the hypothesis that cardiac ANG II, acting on the angiotensin type 1 receptor (AT(1)R), increases inflammation, oxidative stress, and apoptosis, accelerating cardiac hypertrophy and fibrosis. Male Tg-ANG II mice and their nontransgenic littermates (n-Tg) were uninephrectomized and divided into the following three groups: 1) vehicle-treated normotensive controls; 2) DOCA-salt; and 3) DOCA-salt + valsartan (AT(1)R blocker).Under basal conditions, systolic blood pressure (SBP) and cardiac phenotypes were similar between strains. In DOCA-salt hypertension, SBP increased similarly in both n-Tg and Tg-ANG II, and cardiac function did not differ between strains; however, Tg-ANG II had 1) greater ventricular hypertrophy as well as interstitial and perivascular fibrosis; 2) a higher number of deoxynucleotidyl-transferase-mediated dUTP nick end labeling-positive cells and infiltrating macrophages; 3) increased protein expression of NADPH oxidase 2 and transforming growth factor-β(1); and 4) downregulation of phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (Akt) phosphorylation. Valsartan partially reversed these effects in Tg-ANG II but not in n-Tg. We conclude that, when hemodynamic loading conditions remain unchanged, cardiac ANG II does not alter heart size or cardiac functions. However, in animals with hypertension, cardiac ANG II, acting via AT(1)R, enhances inflammation, oxidative stress, and cell death (most likely via downregulation of PI 3-kinase and Akt), contributing to cardiac hypertrophy and fibrosis.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Apoptosis; Collagen; Desoxycorticosterone; Dinoprost; Disease Models, Animal; Heart Rate; Hypertension; Male; Membrane Glycoproteins; Mice; Mice, Transgenic; Myocardium; Myocytes, Cardiac; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta1; Valine; Valsartan

Hypertension and additional non-traditional risk factors can damage the kidney directly and by promoting atherogenesis. Evidence indicates that increased oxidative stress and inflammation may mediate a large part of the effects of risk factors on the kidney. We hypothesized that in hypertensive patients (HT), oxidative stress, measured as 8-ISO-prostaglandin F2alpha (8-ISO-PGF2alpha), should raise paralleling decreasing renal function and should correlate with estimated glomerular filtration rate (eGFR).. In 626 HT with renal function ranging from stages 1 to 5 and 100 healthy controls, plasma levels of 8-ISO-PGF2alpha, high-sensitivity C-reactive protein (CRP), transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1) were measured. GFR was estimated by the Modification of Diet in Renal Disease study equation.. When HT were stratified according to renal function stages, 8-ISO-PGF2alpha, CRP, TGF-beta and ET-1 increased progressively and significantly with decreasing eGFR. The multiple regression analysis, considering eGFR as a dependent variable, showed that 8-ISO-PGF2alpha (beta = -0.361, P < 0.000001), ET-1 (beta = -0.197, P < 0.0001) and TGF-beta (beta = -0.170, P < 0.0004) correlated independently with eGFR. All biomarkers were good predictors of eGFR <60 ml/min/1.73 m(2) [receiver-operator-curve (ROC) areas]. ET-1 was shown to be the best predictor with a ROC area = 0.938; with a threshold of 4 pg/ml, 91% sensitivity and 85% specificity were observed, whereas 8-ISO had a ROC area = 0.931, and for a threshold of 329 pg/ml, sensitivity and specificity were 89%, respectively. In contrast, CRP showed the lower predictive value with a ROC area = 0.917; with a threshold of 2.52 mg/l, an 87% sensitivity and an 83% specificity were obtained.. Our findings are a clear-cut demonstration of a strong and negative correlation of both oxidative stress and ET-1 with renal function stages in HT. ET-1 and 8-isoprostane are predictive of eGFR.

Topics: Adult; Aged; Atherosclerosis; C-Reactive Protein; Case-Control Studies; Dinoprost; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Oxidative Stress; Renal Insufficiency, Chronic; Risk Factors; Transforming Growth Factor beta

Insulin resistance is associated with hypertension by mechanisms likely involving the kidney. To determine how the major apical sodium transporter of the thick ascending limb, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) is regulated by high-fat feeding, we treated young male, Fischer 344 X Brown Norway (F344BN) rats for 8 wk with diets containing either normal (NF, 4%) or high (HF, 36%) fat, by weight, primarily as lard. HF-fed rats had impaired glucose tolerance, increased urine excretion of 8-isoprostane (a marker of oxidative stress), increased protein levels for NKCC2 (50-125%) and the renal outer medullary potassium channel (106%), as well as increased natriuretic response to furosemide (20-40%). To test the role of oxidative stress in this response, in study 2, rats were fed the NF or HF diet plus plain drinking water, or water containing N(G)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor (100 mg/l), or tempol, a superoxide dismutase mimetic (1 mmol/l). The combination of tempol with HF nullified the increase in medullary NKCC2, while l-NAME with HF led to the highest expression of medullary NKCC2 (to 498% of NF mean). However, neither of these drugs dramatically affected the elevated natriuretic response to furosemide with HF. Finally, l-NAME led to a marked increase in blood pressure (measured by radiotelemetry), which was significantly enhanced with HF. Mean arterial blood pressure at 7 wk was as follows (mmHg): NF, 100 +/- 2; NF plus l-NAME, 122 +/- 3; and HF plus l-NAME, 131 +/- 2. Overall, HF feeding increased the abundance of NKCC2. Inappropriately high sodium reabsorption in the thick ascending limb via NKCC2 may contribute to hypertension with insulin resistance.

Topics: Animals; Antioxidants; Biomarkers; Blood Pressure; Blotting, Western; Crosses, Genetic; Cyclic N-Oxides; Dietary Fats; Dinoprost; Enzyme Inhibitors; Furosemide; Glucose Intolerance; Hypertension; Insulin Resistance; Kidney Medulla; Male; Natriuresis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Potassium Channels, Inwardly Rectifying; Rats; Rats, Inbred BN; Rats, Inbred F344; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Potassium-Chloride Symporters; Sodium-Potassium-Exchanging ATPase; Solute Carrier Family 12, Member 1; Spin Labels; Telemetry; Time Factors; Up-Regulation

Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with nitric oxide deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt sensitivity and for hypertension in hydronephrosis. Hydronephrosis was induced in superoxide dismutase 1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko), and wild-type mice and in rats. In mice, telemetric measurements were performed during normal (0.7% NaCl) and high-sodium (4% NaCl) diets and with chronic tempol supplementation. The 8-iso-prostaglandin-F(2alpha) (F2-IsoPs) and protein excretion profiles and renal histology were investigated. The acute effects of tempol on blood pressure and TGF were studied in rats. In hydronephrosis, wild-type mice developed salt-sensitive hypertension (114 +/- 1 to 120 +/- 2 mmHg), which was augmented in SOD1-ko (125 +/- 3 to 135 +/- 4 mmHg) but abolished in SOD1-tg (109 +/- 3 to 108 +/- 3 mmHg). SOD1-ko controls displayed salt-sensitive blood pressure (108 +/- 1 to 115 +/- 2 mmHg), which was not found in wild types or SOD1-tg. Chronic tempol treatment reduced blood pressure in SOD1-ko controls (-7 mmHg) and in hydronephrotic wild-type (-8 mmHg) and SOD1-ko mice (-16 mmHg), but had no effect on blood pressure in wild-type or SOD1-tg controls. SOD1-ko controls and hydronephrotic wild-type and SOD1-ko mice exhibited increased fluid excretion associated with increased F2-IsoPs and protein excretion. The renal histopathological changes found in hydronephrotic wild-type were augmented in SOD1-ko and diminished in SOD-tg mice. Tempol attenuated blood pressure and normalized TGF response in hydronephrosis [DeltaP(SF): 15.2 +/- 1.2 to 9.1 +/- 0.6 mmHg, turning point: 14.3 +/- 0.8 to 19.7 +/- 1.4 nl/min]. Oxidative stress due to SOD1 deficiency causes salt sensitivity and plays a pivotal role for the development of hypertension in hydronephrosis. Increased superoxide formation may enhance TGF response and thereby contribute to hypertension.

Topics: Animals; Antioxidants; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Feedback, Physiological; Female; Hydronephrosis; Hypertension; Infusions, Intravenous; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Spin Labels; Superoxide Dismutase; Superoxide Dismutase-1; Telemetry; Urodynamics

Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives.. Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% VO2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC).. Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2alpha levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in VO2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2alpha (P = 0.002) and plasma TAC (P=0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables.. We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2alpha but not the aerobic exercise-induced responses.

Topics: Adult; Aged; Analysis of Variance; Antioxidants; Dinoprost; Exercise; Exercise Therapy; Female; Humans; Hypertension; Male; Middle Aged; Multienzyme Complexes; NADH, NADPH Oxidoreductases; NADPH Oxidases; Nitric Oxide; Oxidative Stress; Oxygen Consumption; Physical Fitness; Polymorphism, Genetic

Although it has been reported that angiotensin II receptor blockers inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether they can do so clinically is not clear. We investigated the effects of 12-month valsartan therapy on various markers of inflammation, glycation, and oxidation in type 2 diabetic subjects with hypertension. We started 40 mg/day valsartan treatment in 15 type 2 diabetic patients with hypertension. In 6 patients, the dose of valsartan was increased to 80 mg/day after 6 months and maintained until 12 months. Metabolic parameters including BMI and serum high molecular weight (HMW)-adiponectin, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, AGEs, paraoxonase activity, platelet-activating factor (PAF)- acetylhydrolase activity, and urine 8-isoprostane levels were measured at baseline and after 6 and 12 months of treatment. Urine microalbumin level and carotid artery intima-media thickness (IMT) were also measured. Even after valsartan therapy, the blood pressure levels of the patients were not decreased significantly. Serum AGEs and urine 8-isoprostane levels decreased at both 6 and 12 months (P < 0.05 for both), although other metabolic and oxidative markers were unchanged. Though urine microalbumin levels tended to be decreased after 6 and 12 months of valsartan treatment, the changes were not significant. Mean IMT at 12 months was not changed from the baseline value. In conclusion, the findings suggest that treatment with valsartan, even at a low dose, may ameliorate some glycation and oxidative stress markers independently of an effect on blood pressure in hypertensive type 2 diabetic subjects.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adiponectin; Aged; Albuminuria; Antihypertensive Agents; Aryldialkylphosphatase; Biomarkers; C-Reactive Protein; Carotid Arteries; Diabetes Mellitus, Type 2; Dinoprost; Female; Glycation End Products, Advanced; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Tetrazoles; Valine; Valsartan

Obesity is independently associated with increased cardiovascular risk. However, since established obesity clusters with various cardiovascular risk factors, configuring the metabolic syndrome, the early effects of obesity on vascular function are still poorly understood. The current study was designed to evaluate the effect of early obesity on coronary endothelial function in a new animal model of swine obesity. As to method, juvenile domestic crossbred pigs were randomized to either high-fat/high-calorie diet (HF) or normal chow diet for 12 wk. Coronary microvascular permeability and abdominal wall fat were determined by using electron beam computerized tomography. Epicardial endothelial function and oxidative stress were measured in vitro. Systemic oxidative stress, renin-angiotensin activity, leptin levels, and parameters of insulin sensitivity were evaluated. As a result, HF pigs were characterized by abdominal obesity, hypertension, and elevated plasma lysophosphatidylcholine and leptin in the presence of increased insulin sensitivity. Coronary endothelium-dependent vasorelaxation was reduced in HF pigs and myocardial microvascular permeability increased compared with those values in normal pigs. Systemic redox status in HF pigs was similar to that in normal pigs, whereas the coronary endothelium demonstrated higher content of superoxide anions, nitrotyrosine, and NADPH-oxidase subunits, indicating increased tissue oxidative stress. In conclusion, the current study shows that early obesity is characterized by increased vascular oxidative stress and endothelial dysfunction in association with increased levels of leptin and before the development of insulin resistance and systemic oxidative stress. Vascular dysfunction is therefore an early manifestation of obesity and might contribute to the increased cardiovascular risk, independently of insulin resistance.

Topics: Animals; Blood Pressure; Capillary Permeability; Coronary Vessels; Dietary Fats; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Hypertension; Intra-Abdominal Fat; Leptin; Lipids; Microcirculation; Nitric Oxide; Obesity; Oxidative Stress; Random Allocation; Superoxides; Swine; Tomography, X-Ray Computed; Vasoconstrictor Agents; Vasodilator Agents

Experiments were designed to test the hypothesis that antioxidant treatment would increase the anti-hypertensive actions of endogenous kinins during angiotensin converting enzyme (ACE) inhibition. Four groups of rats, all given angiotensin II (Ang II) for 2 weeks, were studied: 1) control, 2) enalapril, 3) tempol or 4) both tempol and enalapril. Ang II significantly increased systolic blood pressure (BP) when compared with the baseline (170+/-8 vs. 128+/-4 mm Hg, P<0.05). Neither enalapril nor tempol alone was able to attenuate the elevation in BP (165+/-7 and 164+/-6 mm Hg, respectively). In contrast, combined administration of tempol and enalapril prevented the increase in BP (137+/-5 mm Hg). Plasma 8-isoprostane increased in Ang II-infused rats when compared with control untreated rats (69+/-14 vs. 23+/-0.5 pg/ml, P<0.05). Tempol alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane (29+/-6 and 34+/-7 pg/ml, respectively). In additional experiments, we used the bradykinin B(2) antagonist, icatibant to determine if increased B(2) receptor contributes to the anti-hypertensive effect of combined tempol and enalapril in Ang II-infused rats. Icatibant decreased the ability of this combination to lower arterial pressure. Additionally, a significant increase in B(1) receptor protein expression in renal cortex of Ang II-infused rats was observed compared to control suggesting that bradykinin receptor activation could account for the effect of enalapril to enhance the actions of tempol. These data support the hypothesis that combined reduction of superoxide along with enhanced endogenous kinins may facilitate blood pressure lowering in Ang II hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Bradykinin; Chronic Disease; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enalapril; Hydrogen Peroxide; Hypertension; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Spin Labels; Superoxides; Time Factors

Oxidant stress is implicated in the pathogenesis of atherosclerosis in cardiovascular diseases. Our aim was to test oxidative stress, as 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), and its relationship with inflammation markers C-reactive protein (CRP) and tumour necrosis factor-alpha (TNFalpha), and endothelial activation assayed as soluble intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in essential hypertension.. In 216 essential hypertensive patients and 55 healthy control individuals, plasma levels of high-sensitivity CRP and TNFalpha, 8-iso-PGF2alpha, ICAM-1 and VCAM-1 were measured in basal conditions. Moreover, basal and 24-h ambulatory blood pressure monitoring measurements were obtained.. Essential hypertensive patients showed higher levels of 8-iso-PGF2alpha (P < 0.0001), high-sensitivity CRP, TNFalpha, ICAM-1 and VCAM-1 (P < 0.001, respectively) than control individuals. In control individuals, 8-iso-PGF2alpha correlated only with high-sensitivity CRP (P < 0.001). In essential hypertensive patients, 8-iso-PGF2alpha correlated with high-sensitivity CRP (P < 0.000001), TNFalpha (P < 0.0001), ICAM-1 (P < 0.000001), VCAM-1 (P < 0.0001) and blood pressure. The multiple regression analysis considering 8-iso-PGF2alpha as the dependent variable showed that in essential hypertensive patients the independent predictors of 8-iso-PGF2alpha were ICAM-1, high-sensitivity CRP (P < 0.00001, respectively), and TNFalpha (P = 0.028).. Our findings demonstrate that oxidant stress is increased in essential hypertension, and relates to inflammation and endothelial activation. Factors other than blood pressure are stronger predictors of oxidant stress.

Topics: Adult; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; C-Reactive Protein; Case-Control Studies; Dinoprost; Humans; Hypertension; Inflammation; Intercellular Adhesion Molecule-1; Middle Aged; Oxidative Stress; Predictive Value of Tests; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

This study analyzes the role of angiotensin II (Ang II), via AT1) receptors, in the involvement of cyclooxygenase (COX)-2-derived prostanoids in phenylephrine responses in normotensive rats (Wistar Kyoto; WKY) and spontaneously hypertensive rats (SHR). Aorta from rats untreated or treated for 12 weeks with losartan (15 mg/kg . day) or hydralazine plus hydrochlorothiazide (44 and 9.4 mg/kg . day, respectively) and vascular smooth muscle cells (VSMC) from SHR were used. Vascular reactivity was analyzed by isometric recording; COX-2 expression by Western blot and reverse transcription-polymerase chain reaction; prostaglandin (PG)I2, PGF(2alpha), 8-isoprostane, and total antioxidant status (TAS) by commercial kits; superoxide anion (O2*-) by lucigenin chemiluminescence; and plasmatic malondialdehyde (MDA) by thiobarbituric acid assay. The COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) at 1 microM reduced phenylephrine responses more in SHR than in WKY rats. COX-2 protein and mRNA expressions, PGF(2alpha), PGI2, 8-isoprostane, and O2*- production, and MDA levels were higher in SHR, but TAS was similar in both strains. Losartan, but not hydralazine-hydrochlorothiazide treatment, reduced COX-2 expression and the effect of NS-398 on phenylephrine responses in SHR. Losartan also increased TAS and reduced PGF(2alpha), PGI2, 8-isoprostane, and O2*- production and MDA levels in SHR. Ang II (0.1 microM) induced COX-2 expression in VSMC from SHR that was reduced by 30 microM apocynin and 100 microM allopurinol, NADPH oxidase, and xanthine oxidase inhibitors, respectively. In conclusion, AT1 receptor activation by Ang II could be involved in the increased participation of COX-2-derived contractile prostanoids in vasoconstriction to phenylephrine with hypertension, probably through COX-2 expression regulation. The increased oxidative stress seems to be one of the mechanisms involved.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Antioxidants; Blotting, Western; Cyclooxygenase 2; Desoxycorticosterone; Dinoprost; Hypertension; In Vitro Techniques; Isometric Contraction; Losartan; Male; Malondialdehyde; Muscle Contraction; Muscle, Smooth, Vascular; Prostaglandins I; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

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.

Topics: Adult; Aldosterone; Ascorbic Acid; Blood Pressure; Cross-Sectional Studies; Dinoprost; Endothelin-1; Glutathione; Homocysteine; Humans; Hypertension; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Renin; Vitamin E

An enhancement of superoxide (O2-) activity was shown to contribute to the development of hypertension induced by NO deficiency. To better understand the mechanistic role of O2- in this NO-deficient hypertension, we evaluated the renal responses to acute intraarterial administration of an O2- scavenger, tempol (50 microg/min per 100 g of body weight) in anesthetized male Sprague-Dawley rats treated with NO synthase inhibitor nitro-L-arginine methyl ester (15 mg/kg per day in drinking water, n=7) for 4 weeks, which caused increases in mean arterial pressure (146+/-3 versus 124+/-2 mm Hg) compared with normotensive control rats (n=6). Hypertensive rats had higher renal vascular resistance (29+/-2 versus 20+/-1 mm Hg/mL per minute per gram), as well as lower renal blood flow (5.2+/-0.3 versus 6.3+/-0.2 mL/min per gram; cortical blood flow, 153+/-13 versus 191+/-8 perfusion units; medullary blood flow, 43+/-2 versus 51+/-3 perfusion units) and glomerular filtration rate (0.69+/-0.04 versus 0.90+/-0.05 mL/min per gram) without a significant difference in urinary sodium excretion (0.81+/-0.07 versus 0.86+/-0.12 micromol/min per gram) compared with normotensive rats. Urinary 8-isoprostane excretion rate (6.8+/-0.7 versus 4.5+/-0.3 pg/min per gram) was higher in hypertensive than normotensive rats. Intraarterial infusion of tempol did not alter renal function in normotensive rats. However, tempol significantly decreased renal vascular resistance by 12+/-2% and urinary 8-isoprostane excretion rate by 24+/-4% and increased renal blood flow by 10+/-2%, cortical blood flow by 9+/-2%, medullary blood flow by 15+/-6%, glomerular filtration rate by 11+/-3%, and urinary sodium excretion by 19+/-5% in hypertensive rats. These data indicate that enhanced O2- activity modulates renal hemodynamics and excretory function during reduced NO production and, thus, contributes to the pathophysiology of the NO-deficient form of hypertension.

Topics: Animals; Antioxidants; Cyclic N-Oxides; Dinoprost; Enzyme Inhibitors; Glomerular Filtration Rate; Hemodynamics; Hypertension; Injections, Intra-Arterial; Kidney; Male; Natriuresis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renal Artery; Renal Circulation; Spin Labels; Superoxides; Vascular Resistance

The controversy over beneficial versus harmful effects of salt on cardiovascular outcomes may be caused by different effects of salt on intermediate phenotypes of hypertension not characterized in epidemiological studies. Hence, we investigated acute effects of salt on oxidative stress in hypertensive subjects classified as salt sensitive (SS, n=14) or salt resistant (SR, n=13) by an inpatient protocol of salt loading (460 mmol NaCl) and salt depletion (10 mmol NaCl and furosemide). Oxidative stress was assessed by measuring the plasma isoprostane 8-iso-PGF2alpha. SS had lower plasma renin activity, higher aldosterone/renin ratios, and exaggerated endothelin and catecholamine responses to salt depletion compared with SR. Baseline lipid-bound isoprostanes (749+/-70 pmol/L) were 83% of the total and were slightly but not significantly higher in SS than SR. Baseline free isoprostanes did not differ between groups. After salt loading, lipid-bound isoprostanes were higher in SS (945+/-106) than SR (579+/-57; P<0.01). Salt depletion significantly decreased them in SS (-174+/-84) and increased them in SR (+129+/-58), equalizing their levels (771+/-61 versus 708+/-91; P value not significant). Free isoprostanes were decreased by salt depletion only if data in all of the patients were analyzed together. Total isoprostanes followed the pattern of the lipid-bound fraction. Correlations between salt depletion-induced changes in lipid-bound isoprostanes, plasma renin activity (r=0.45; P<0.02), and aldosterone/renin ratios (r=-0.41; P<0.04) suggested that the more SS the patient, the greater the reduction of oxidative stress by salt depletion. Our research is the first to show that salt affects oxidative stress acutely in humans, particularly in SS hypertension, which may explain the controversial results of epidemiological studies on salt and morbidity and may have implications for therapy.

Topics: Adult; Biomarkers; Blood Pressure; Dinoprost; Diuretics; Drug Resistance; Female; Furosemide; Humans; Hypertension; Isoprostanes; Male; Middle Aged; Oxidative Stress; Sodium Chloride

To examine the hypothesis that NAD(P)H oxidase (Nox)-derived superoxide generation is involved in the development of angiotensin II (ANG II)-induced hypertension, we evaluated the responses to ANG II infusion (65 ng/min; osmotic mini-pump) for 2 weeks in rats treated with or without apocynin (APO) (inhibitor of Nox subunits assembly) in drinking water (12 mmol/L). Rats were grouped according to their diets with varying salt content (normal salt [NS], 0.4%; high salt [HS], 8%; low salt [LS], 0.03%) given during the 2-week experimental period. The variation in salt intake did not alter mean arterial pressure (MAP, recorded via pre-implanted arterial catheter) but showed proportionate levels in urinary excretion rate of Isoprostaglandin(2alpha) (U(ISO)V; NS, 179 +/- 26; HS, 294 +/- 38; LS, 125 +/- 7 ng/kg/24 h). Treatment with ANG II increased MAP proportional to salt intake (NS, 126 +/- 3 to 160 +/- 5; HS, 116 +/- 4 to 184 +/- 5; LS, 125 +/- 1 to 154 +/- 5 mm Hg). However, ANG II increased U(ISO)V only in NS rats (250 +/- 19 ng/kg/24 h) but not in HS or LS rats. In response to ANG II, Nox subunits protein expression increased in HS but not in the NS or LS rats. Apocynin treatment partially ameliorated these changes in Nox proteins in HS rats but did not alter ANG II-induced increases in MAP or U(ISO)V. These data suggest that Nox activation may not be the sole factor or alternatively, that a constitutively active isoform of Nox is involved in oxidative stress mechanism that is associated with dietary salt or ANG II-induced hypertension.

Topics: Acetophenones; Angiotensin II; Animals; Blood Pressure; Blotting, Western; Diet, Sodium-Restricted; Dinoprost; Disease Models, Animal; Enzyme Inhibitors; Hypertension; Infusions, Intravenous; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances; Vasoconstrictor Agents

The major aim of this study was to determine whether the angiotensin converting enzyme (ACE) inhibitors, captopril or enalapril, restore the diminished vasodilator potency of the endothelium-dependent agonist, acetylcholine (ACh), and the endothelium-derived relaxing factor (EDRF), L-S-nitrosocysteine (L-SNC), in conscious Spontaneously Hypertensive (SH) rats.. The hemodynamic responses elicited by i.v. injections of ACh, L-SNC, and nitric oxide donors such as MAHMA NONOate, were determined in SH rats treated for 7 days with captopril, enalapril, or the direct vasodilator hydralazine. The effects of captopril, enalapril or hydralazine on oxidant stress levels in blood serum and aorta of WKY and SH rats were also determined.. Captopril, enalapril and hydralazine elicited equivalent falls in mean arterial pressure and systemic vascular resistances in SH rats. ACh- and L-SNC-induced vasodilation were increased in captopril- or enalapril-treated SH rats such that the responses were equal to those in normotensive Wistar Kyoto rats. The attenuated responses of ACh and L-SNC in SH rats were not improved by hydralazine. The vasodilator effects of MAHMA NONOate, which were substantially augmented in SH rats, were not affected by captopril, enalapril or hydralazine. The levels of oxidant stress were markedly reduced in captopril- or enalapril-treated but not hydralazine-treated SH rats.. The finding that the ACE inhibitors improved the vasodilator potencies of L-SNC and the EDRF released by ACh in SH rats, suggests that the diminished vasodilator potency of these compounds was due to augmented ACE activity, which increased oxidant stress levels. This study provides the first evidence to support the concept that ACE inhibition lowers arterial pressure in SH rats, at least in part, by restoring the vasodilator potency of endothelium-derived L-SNC.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Captopril; Cysteine; Dinoprost; Dose-Response Relationship, Drug; Enalapril; Femoral Artery; Glutathione Disulfide; Hydralazine; Hypertension; Male; Nitric Oxide Donors; Oxidative Stress; Rats; Rats, Inbred SHR; S-Nitrosothiols; Splanchnic Circulation; Vascular Resistance; Vasodilation; Vasodilator Agents

Several studies have shown that chronic renal failure (CRF) is characterized by "accelerated atherosclerosis". More recent studies emphasize that inflammation and oxidative stress play a central role in atherosclerosis, and it is well-established that C-reactive protein (CRP) is a cardiovascular risk marker in the general population, in end-stage renal disease (ESRD) patients and in allograft recipients.. We measured the serum concentration of high sensitivity CRP, TNFalpha, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha, an in vivo oxidative stress marker) in 15 CRF patients and in 15 transplant recipients. Exclusion criteria were age < 30 and > 65 years, smoking, diabetes mellitus and history of cardiovascular diseases. Immunosuppressive therapy was not withdrawn, and antihypertensive treatment was the same for both groups. Systolic (SBP) and diastolic blood pressure (DBP), serum creatinine (sCr) and estimated glomerular filtration rate (GFR) were also evaluated. 15 healthy subjects were enrolled as controls.. The transplanted group showed significantly higher values than controls of CRP (p < 0.05), TNFalpha (p < 0.05), 8-iso-PGF2alpha (p < 0.05). The CRF group as well exhibited, in comparison with controls significantly higher concentrations of CRP (p < 0.05), TNFalpha (p < 0.05), and 8-iso-PGF2alpha (p < 0.05). SBP, DBP and sCr were not different between transplanted and CRF patients. CRP was higher in transplant recipients than in CRF patients (p < 0.05). No difference in TNFalpha levels between the 2 groups was found. 8-iso-PGF2alpha was significantly higher in CRF than in the transplanted group (p < 0.05). In this latter, 8-iso-PGF2alpha showed a positive correlation with TNFalpha (p < 0.001), sCr (p < 0.001), SBP (p < 0.05) and DBP (p < 0.05). In the same group both 8-iso-PGF2alpha and TNFalpha were negatively correlated with GFR (r = -0.873 and -0.912, respectively, p < 0.001 for both).. Our data have shown the coexistence of an increased oxidative stress and an inflammatory state in long-term renal graft recipients.

Topics: Adult; C-Reactive Protein; Case-Control Studies; Dinoprost; Humans; Hypertension; Inflammation Mediators; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Oxidative Stress; Time Factors; Tumor Necrosis Factor-alpha

To determine the mechanism(s) underlying enhanced oxidative stress in kidneys of salt-sensitive hypertension, neonatal Wistar rats were given vehicle or capsaicin (CAP, 50 mg/kg sc) on the first and second days of life. After being weaned, male rats were assigned into four groups and treated for 2 wk with the following: vehicle + a normal sodium diet (NS, 0.4%, CON-NS), vehicle + a high-sodium diet (HS, 4%, CON-HS), CAP + NS (CAP-NS), and CAP + HS (CAP-HS). Systolic blood pressure was significantly increased in CAP-HS but not CAP-NS or CON-HS rats. Plasma and urinary 8-iso-prostaglandin F(2alpha) levels increased by approximately 40% in CON-HS and CAP-HS rats compared with their respective controls fed a NS diet (P < 0.05), and these parameters were higher in CAP-HS compared with CON-HS rats. Superoxide (O(2)(-)*) levels in the renal cortex and medulla increased by approximately 45% in CAP-HS compared with CON-HS, CON-NS, and CAP-NS rats (P < 0.05). Enhanced O(2)(-)* levels in the cortex and medulla in CAP-HS rats were prevented by preincubation of renal tissues with apocynin, a selective NAD(P)H oxidase inhibitor. Protein expression of NAD(P)H oxidase subunits, including p47(phox) and gp91(phox) in the renal cortex and medulla, was significantly increased in CAP-HS compared with CON-HS, CON-NS, and CAP-NS rats. In contrast, protein expression and activities of Cu/Zn SOD and Mn SOD were significantly increased in the renal medulla in both CAP-HS and CON-HS but in the cortex in CAP-HS rats only. Creatinine clearance decreased by approximately 45% in CAP-HS rats compared with CON-HS, CON-NS, and CAP-NS rats (P < 0.05). O(2)(-)* levels in the renal cortex of CAP-HS rats negatively correlated with creatinine clearance (r = -0.76; P < 0.001). Therefore, regardless of enhanced SOD activity to suppress oxidative stress, increased oxidative stress in the kidney of CAP-treated rats fed a HS diet is likely the result of increased expression and activities of NAD(P)H oxidase, which may contribute to decreased renal function and increased blood pressure in these rats. Our results suggest that sensory nerves may play a compensatory role in attenuating renal oxidative stress during HS intake.

Topics: Analgesics, Non-Narcotic; Animals; Animals, Newborn; Blood Pressure; Capsaicin; Dinoprost; Hypertension; Kidney; Kidney Cortex; Kidney Medulla; Male; NADP; Neurons, Afferent; Oxidative Stress; Rats; Rats, Wistar; Sodium, Dietary; Superoxide Dismutase; Superoxides

Superoxide anions react with nitric oxide to form peroxynitrite and hence reduce the bioavailability of nitric oxide in the arteries. Extracellular superoxide dismutase (EC-SOD) is a major superoxide scavenger in human plasma and vascular tissues. The objective of this study is to assess whether essential hypertension is associated with an alteration in EC-SOD activity. In this report, blood samples were obtained from hypertensive (n=39) and normotensive (n=37) African-Americans. Plasma EC-SOD activity was measured using in-gel activity staining and spectrophotometric assays, EC-SOD protein level was measured using Western blotting, nitrotyrosine was measured using slot blotting, 8-isoprostane was measured with an enzyme immunoassay, and plasma copper and zinc concentrations were measured using an atomic absorption assay. Our data demonstrate that the copper, zinc, and plasma EC-SOD protein concentrations in the hypertensive and normotensive subjects are indistinguishable. Compared to normotensive controls, hypertensive patients have significantly reduced plasma EC-SOD activity. Plasma nitrotyrosine and 8-isoprostane levels are significantly higher in the hypertensive patients than in normotensive controls. Results from this study suggest that a reduction in EC-SOD activity in hypertensive patients is not due to a down-regulation of the SOD3 gene (encoding EC-SOD) or deficiency in mineral cofactors. Furthermore, the reduced EC-SOD activity might be at least partially responsible for the increased oxidative stress, as reflected by increased plasma nitrotyrosine and 8-isoprostane, in hypertensive subjects.

Topics: Adult; Black or African American; Blood Glucose; Cholesterol; Copper; Dinoprost; Female; Humans; Hypertension; Male; Middle Aged; Superoxide Dismutase; Triglycerides; Zinc

Several lines of evidence suggest that both advanced glycation end products (AGEs) and oxidation processes play key roles in the physiology of aging and age-related pathologies, leading to irreversible proteins modifications in both tissues and the extracellular matrix. Such an accelerated accumulation of these modifications has been reported to be present in several age-related chronic diseases, such as atherosclerosis, diabetes, arthritis, and neurodegenerative diseases. The current literature reveals that the specific inhibition of AGEs may constitute an innovative therapeutic goal. In experimental animals, the use of sartans significantly reduces blood pressure and kidney pentosidine content, improving both histologic renal damage and proteinuria. In this study, 12 subjects who were affected by diabetes mellitus and hypertension were subjected to oral antihypertensive therapy with valsartan (class of sartans) with timed sampling of plasma and urine pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), malondialdehyde, and isoprostanes levels, respectively, at baseline and after both 3 and 6 months, with parallel ongoing evaluation of glycemic control and blood pressure levels. Valsartan elicited a good antihypertensive effect with a 30% decrease in plasma pentosidine levels (P < .05) after 3 months of therapy, followed by a slight increase after 6 months. Urinary pentosidine concentrations exhibited a 40% decrease after 3 months (215 +/- 19 vs 129 +/- 23 nmol/24 h) and a further significant reduction after 6 months of therapy (105 +/- 24 nmol/24 h). Plasma CML levels showed a progressive decrease after 3 months (23.15 +/- 3.215 vs 19.88 +/- 1.684 micromol/mL) and achieved a further slight reduction after 6 months of therapy (19.48 +/- 1.339 micromol/mL); for urinary CML, a statistically significant reduction was gained after the sixth month of therapy (48.51 +/- 5.70 vs 30.30 +/- 2.77 micromol/24 h after 3 months and 27.02 +/- 4.13 micromol/24 h after 6 months; F = 7.62, P < .005). Plasma and urinary concentrations of malondialdehyde were slightly modified by valsartan treatment; the mean levels after both 3 and 6 months did not significantly differ from baseline. Urinary 15-F2t-isoprostanes (2.96 +/- 0.45 ng/24 h) levels displayed a progressive decrease after both 3 (2.27 +/- 0.31 ng/24 h) and 6 months (1.70 +/- 0.23 ng/24 h) with statistical significance achieved only at the end of the study (P < .05). The present data suggest interesting in vivo ant

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Arginine; Dinoprost; Female; Glycation End Products, Advanced; Glycosylation; Humans; Hypertension; Lysine; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Proteins; Tetrazoles; Valine; Valsartan

The roles of nitric oxide (NO) and plasma renin activity (PRA) in the depressor response to chronic administration of Tempol in spontaneously hypertensive rats (SHR) are not clear. The present study was done to determine the effect of 2 wk of Tempol treatment on blood pressure [mean arterial pressure (MAP)], oxidative stress, and PRA in the presence or absence of chronic NO synthase inhibition. SHR were divided into four groups: control, Tempol (1 mmol/l) alone, nitro-L-arginine methyl ester (L-NAME, 4.5 mg x g(-1).day(-1)) alone, and Tempol + L-NAME or 2 wk. With Tempol, MAP decreased by 22%: 191 +/- 3 and 162 +/- 21 mmHg for control and Tempol, respectively (P < 0.05). L-NAME increased MAP by 16% (222 +/- 2 mmHg, P < 0.01), and L-NAME + Tempol abolished the depressor response to Tempol (215 +/- 3 mmHg, P < 0.01). PRA was not affected by Tempol but was increased slightly with L-NAME alone and 4.4-fold with L-NAME + Tempol. Urinary nitrate/nitrite increased with Tempol and decreased with L-NAME and L-NAME + Tempol. Tempol significantly reduced oxidative stress in the presence and absence of L-NAME. In conclusion, in SHR, Tempol administration for 2 wk reduces oxidative stress in the presence or absence of NO, but in the absence of NO, Tempol is unable to reduce MAP. Therefore, NO, but not changes in PRA, plays a major role in the blood pressure-lowering effects of Tempol. These data suggest that, in hypertensive individuals with endothelial damage and chronic NO deficiency, antioxidants may be able to reduce oxidative stress but not blood pressure.

Topics: Acridines; Animals; Antihypertensive Agents; Blood Pressure; Cyclic N-Oxides; Dinoprost; Enzyme Inhibitors; Hypertension; Luminescent Measurements; Male; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Oxidative Stress; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; Spin Labels; Superoxides

We examined if administration of an antioxidant compound protects against the development of insulin resistance and hypertension. Male rats were assigned randomly into four groups, and treated for 12 weeks with normal chow, normal chow plus N-acetylcysteine (1.5 g/day/kg), fructose (60% of diet), and fructose plus N-acetylcysteine. After 10 weeks, plasma triglyceride and 15-F2t-isoprostane, and insulin sensitivity were measured, and after 12 weeks, pressor response to methoxamine (15-60 microg/kg min) was assessed. Relative to normal chow-fed controls, the fructose-fed rats had increased blood pressure, plasma insulin, triglyceride and 15-F2t-isoprostane, and decreased insulin sensitivity; these changes were inhibited by N-acetylcysteine. Maximal pressor response to methoxamine was attenuated in the fructose-fed rats given N-acetylcysteine relative to the other three groups. Therefore, chronic treatment with N-acetylcysteine increases insulin sensitivity and prevents the blood pressure increase associated with fructose feeding in rats, the mechanism may involve the decrease of oxidative stress and alpha-adrenoceptor-mediated vasoconstriction.

Topics: Acetylcysteine; Adrenergic alpha-Agonists; Animals; Blood Pressure; Dinoprost; Dose-Response Relationship, Drug; Fructose; Glucose Tolerance Test; Hypertension; Insulin Resistance; Male; Methoxamine; Random Allocation; Rats; Rats, Sprague-Dawley; Triglycerides

Oxidative stress has been proposed as important in the pathogenesis of hypertension. Measurement of 8-iso prostaglandin F2alpha (8-ISO) is introduced for evaluating oxidative stress in vivo. 8-ISO is the major urinary metabolite of F2-isoprostanes and is formed nonenzymatically from the attack of superoxide radicals on arachidonic acid. We examined the oxidative stress level in the Dahl salt-sensitive (Dahl-S) rats and the Dahl salt-resistant (Dahl-R) rats. Dahl-S and Dahl-R rats were fed either a high salt diet (8% NaCl; HS) or low salt diet (0.3% NaCl; LS) for 3 weeks, and systolic blood pressure (SBP) and 24-hr urinary excretion of 8-ISO (U-8-ISO) were measured. In Dahl-S rats, the high salt diet induced hypertension (139 +/- 3 mmHg in LS versus 186 +/- 2 mmHg in HS, p < .05) and significantly increased the U-8-ISO (24.9 +/- 3.6 ng/24 hr in LS versus 63.2 +/- 14.6 ng/24 hr in HS, p < .05). No significant difference in blood pressure or U-8-ISO was observed between high-salt and low-salt treated Dahl-R rats. U-8-ISO concentration was correlated with SBP in all four experimental groups (r = 0.866). Moreover, urinary 8-hydroxy-2'-deoxyguanosine (U-8-OHdG), which is one of the most commonly used markers for evaluation of oxidative stress, was higher in Dahl-S-8% rats than in Dahl-S-0.3% rats (136.1 +/- 48.4 ng/24 hr in LS versus 322.8 +/- 46.7 ng/24 hr in HS, p < .05), and U-8-OHdG was correlated with SBP (r = 0.681) in Dahl-S rats. These results suggest oxygen radicals are involved in the pathogenesis of hypertension.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Blood Pressure; Body Weight; Deoxyguanosine; Dinoprost; Heart Rate; Hypertension; Male; Oxidative Stress; Rats; Rats, Inbred Dahl

The present study was designed to analyse whether hypertension alters the involvement of cyclooxygenase-2-derived mediators in phenylephrine-induced vasoconstrictor responses.. Vascular reactivity experiments were performed in aortic segments from normotensive, Wistar-Kyoto, and spontaneously hypertensive rats (SHR); protein expression was measured by western blot and/or immunohistochemistry, and prostaglandin F2alpha (PGF2alpha), 8-isoprostane and prostacyclin release were determined by enzyme immunoassay commercial kits.. The protein synthesis inhibitor dexamethasone (1 micromol/l), the non-selective cyclooxygenase inhibitor indomethacin (10 micromol/l), the selective cyclooxygenase-2 inhibitor NS 398 (1 micromol/l), and the thromboxane A2/prostaglandin H2 (TP) receptor antagonist SQ 29,548 (1 micromol/l), reduced the concentration-response curves to phenylephrine more in segments from hypertensive than from normotensive rats; however, the thromboxane A2 (TxA2) synthase inhibitors furegrelate (10 micromol/l) and OKY 046 (1 and 10 micromol/l) had no effect in either strain. Removing endothelium or adding dexamethasone almost abolished the NS 398 effect. Cyclooxygenase-2 protein expression, which was reduced by dexamethasone, was higher in aorta from hypertensive animals. In both strains cyclooxygenase-2 was localized mainly in endothelial cells and adventitial fibroblasts. 13,14-Dihydro-15-keto-PGF2alpha, 6-keto-PGF1alpha and 8-isoprostane levels were greater in the medium from hypertensive than from normotensive rats; NS 398 decreased levels of the three metabolites studied only in the medium from SHR.. PGF2alpha and 8-isoprostane seem to be involved in the response to phenylephrine in rat aorta; this involvement is greater in hypertensive rats, probably due to a higher endothelial induction of cyclooxygenase-2.

Topics: Animals; Aorta; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Endothelium, Vascular; Hypertension; Male; Nitrobenzenes; Phenylephrine; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sulfonamides; Vasoconstriction; Vasoconstrictor Agents

This study evaluated the activity of cardiac and renal antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR)] and whether chronic treatment with tempol, a cell membrane-permeable SOD mimetic, ameliorates the hypertension of hyperthyroidism. Two experiments were performed. In experiment I, the following four groups of male Wistar rats were used: control group and three groups that received thyroxine (T4) at 10, 50, or 75 microg x rat(-1) x day(-1). In experiment II, tempol was orally administered (18 mg x kg(-1) x day(-1)) to control and T4-treated (75 microg x rat(-1) x day(-1)) rats. All treatments were maintained for 6 wk. Body weight, tail systolic blood pressure (BP), and heart rate were measured one time a week, and direct BP and morphological, metabolic, plasma, and renal variables were measured at the end of the experiment. Enzymatic activities were measured in renal cortex and medulla and right and left ventricles. In renal cortex, SOD activity was decreased in the T4-75 group, and there was a dose-related increase in CAT activity and decrease in GPX and GR activities in T4-treated groups. Activity of all antioxidant enzymes was reduced in left ventricle in T4-50 and T4-75 groups and in right ventricle in the T4-75 group. Tempol reduced BP, plasma malondialdehyde, and total urinary excretion of F2 isoprostanes in hypertensive hyperthyroid rats but not in controls. Tempol did not improve cardiac hypertrophy, proteinuria, or creatinine clearance in hyperthyroid rats. In conclusion, the results obtained indicate that the activity of SOD, GPX, and GR in renal and cardiac tissues is decreased in hyperthyroidism and that antioxidant treatment with tempol ameliorates T4-induced hypertension.

Topics: Animals; Antioxidants; Blood Pressure; Catalase; Cyclic N-Oxides; Dinoprost; Glutathione Peroxidase; Glutathione Reductase; Heart Rate; Hypertension; Hyperthyroidism; Kidney; Male; Malondialdehyde; Myocardium; Rats; Rats, Wistar; Spin Labels; Superoxide Dismutase; Thyroxine

Tempol is a permeant nitroxide superoxide dismutase (SOD) mimetic that lowers mean arterial pressure (MAP) in spontaneously hypertensive rats (SHRs). We investigated the hypothesis that the antihypertensive response entails a negative salt balance, blunting of plasma renin activity (PRA), endothelin-1 (ET-1), or catecholamines or correction of oxidative stress as indexed by 8-isoprostane prostaglandin F(2alpha) (PGF(2alpha)) (8-Iso).. Groups (N= 6 to 8) of SHRs were infused for 2 weeks with vehicle or tempol (200 nmol/kg/min) or given tempol (2 mmol/L) in drinking water.. Tempol infusion reduced the MAP of anesthetized SHRs (150 +/- 5 vs. 126 +/- 6 mm Hg) (P < 0.005). Oral tempol did not change the heart rate but reduced the MAP of conscious SHRs (-23 +/- 6 mm Hg) (P < 0.01) but not Wistar-Kyoto (WKY) rats. Tempol infusion increased the PRA (2.2 +/- 0.2 vs. 5.0 +/- 0.9 ng/mL/hour) (P < 0.005), did not change excretion of nitric oxide (NO) [NO(2)+ NO(3) (NOx)], ET-1, or catecholamines but reduced excretion of 8-Iso (13.2 +/- 1.4 vs. 9.6 +/- 0.9 ng/24 hours; P < 0.01). Cumulative Na(+) balance and gain in body weight were unaltered by tempol infusion. Tempol prevented a rise in MAP with high salt intake.. Tempol corrects hypertension without a compensatory sympathoadrenal activation or salt retention. The response is independent of nitric oxide, endothelin, or catecholamines and occurs despite increased PRA. It is accompanied by a reduction in oxidative stress and is maintained during increased salt intake.

Topics: Animals; Antioxidants; Blood Pressure; Catecholamines; Cyclic N-Oxides; Dinoprost; Endothelin-1; Hypertension; Male; Oxidative Stress; Rats; Rats, Inbred SHR; Renin; Sodium Chloride; Spin Labels

F2-isoprostanes are a family of compounds derived from arachidonic acid by free radical-catalyzed peroxidation. Among F2-isoprostanes, 15-F2t-IsoP is a vasoconstrictor in animal and human vascular beds. Several recent studies found increased 15-F2t-IsoP levels in animal models of hypertension. However, no data is available on the vascular effect of 15-F2t-IsoP in such models. The contractile responses of 15-F2t-IsoP (10(-9) to 3 x 10(-5) mol/L) were tested on rat thoracic aortic rings in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats. The contraction induced by 15-F2t-IsoP was not significantly different in aortic rings from WKY rats and SHR (Emax 139% +/- 5% vs. 134% +/- 6%, respectively) and was mediated through thromboxane A2-prostaglandin H2 receptor activation as shown by the rightward shift of the concentration-contraction curves in presence of GR 32191, a specific thromboxane A2-prostaglandin H2 receptor antagonist. Endothelial denudation increased the maximal contraction compared to intact rings induced by 15-F2t-IsoP in both WKY rats (170% +/- 20% vs. 139% +/- 5%, p < 0.05) and SHR (194% +/- 11% vs. 134% +/- 6%, p < 0.01), whereas pretreatment with Nomega-nitro-L-arginine (10(-4) mol/L) or with indomethacin (10(-5) mol/L) increased the maximal contraction to 15-F2t-IsoP in WKY rats but not in SHR. SHRs treated with an angiotensin-converting enzyme inhibitor, enalapril, for four weeks showed decreased maximal contraction to 15-F2t-IsoP in vessels with and without endothelium compared with untreated SHR. In conclusion, 15-F2t-IsoP-induced vasoconstriction is similar in SHR compared with WKY rats. Endothelium modulates 15-F2t-IsoP contraction in both strains. However, whereas this effect is mediated through nitric oxide- and cyclooxygenase-dependent pathways in WKY rats, other mediators are implicated in SHR.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Cyclooxygenase Inhibitors; Dinoprost; Dose-Response Relationship, Drug; Enalapril; Endothelium, Vascular; Hypertension; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Thromboxane A2, Prostaglandin H2; Vasoconstrictor Agents

This study was performed to examine the role of superoxide (O2-) in the development of salt sensitivity and hypertension induced by inhibition of nitric oxide (NO) generation. Male Sprague-Dawley rats were fed with diet containing either normal salt (NS) (0.4% NaCl) or high salt (HS) (4% NaCl). These rats were treated with or without an NO synthase inhibitor, nitro-L-arginine methylester (L-NAME) (15 mg/kg/d) and O2- scavenger, tempol (30 mg/kg per day) in the drinking water for 4 weeks. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and urine collection was performed during the course of experimental periods. At the end of 4 weeks, L-NAME treatment resulted in greater increases in SBP in HS rats (127+/-2 to 172+/-3 mm Hg; n=8) than in NS rats (130+/-2 to 156+/-2 mm Hg; n=9). Co-administration of tempol with L-NAME markedly attenuated these SBP responses to a similar level in both HS (128+/-3 to 147+/-2 mm Hg; n=8) and NS rats (126+/-2 to 142+/-3 mm Hg; n=8). Urinary 8-isoprostane excretion (UIsoV) increased in response to L-NAME treatment that was higher in HS (10.6+/-0.5 to 21.5+/-0.8 ng/d) than in NS rats (10.8+/-0.7 to 16.9+/-0.6 ng/d). Co-treatment with tempol completely abolished these UIsoV responses to L-NAME in both HS and NS rats but did not alter urinary H2O2 excretion rate. The decreases in urinary nitrate/nitrite excretion in response to L-NAME treatment were not altered by co-administration of tempol in both HS and NS rats. These data suggest that enhancement of O2- activity during NO inhibition contributes to the development of salt sensitivity that is associated with NO-deficient hypertension.

Topics: Animals; Blood Pressure; Cyclic N-Oxides; Dinoprost; Diuresis; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Hydrogen Peroxide; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Spin Labels; Superoxides

The renin angiotensin system has been shown to be involved in the pathogenesis of vascular and renal sequelae of diabetes mellitus. In type 2 diabetes mellitus, angiotensin receptor blockers have been shown to exert clinical benefit by reducing the progression of diabetic nephropathy. They also improve endothelium-mediated vascular function. The latter effect is partly due to the reduction of angiotensin II-associated oxidative stress. Moreover, small clinical studies have shown that treatment with angiotensin receptor blockers also reduces the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. In the VIVALDI trial, the ability of the angiotensin receptor blocker telmisartan to reduce the progression of diabetic nephropathy (associated with proteinuria) in comparison with valsartan in more than 800 patients with type 2 diabetes during 1 year of treatment is being studied. In order to gain more detailed insight into the potential pathomechanisms associated with this effect, further end-points have been defined. Among these are the circulating levels of ADMA and the urinary excretion rate of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). The former is an endogenous inhibitor of NO-mediated vascular function(s) and a prospectively determined marker of major cardiovascular events and mortality; the latter is a lipid peroxidation product resulting from the nonenzymatic peroxidation of arachidonic acid, which exerts detrimental vascular effects similar to those of thromboxane A2. Urinary 8-iso-PGF2alpha has been shown in clinical studies to be an independent marker of cardiovascular disease. Highlighting the effects of telmisartan on ADMA and 8-iso-PGF levels in such a large cohort of diabetic patients will enhance our understanding of the roles of dysfunctional NO metabolism and redox mechanisms in the pathogenesis of end-organ damage and its prevention by pharmacotherapy with angiotensin receptor blockers.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Arginine; Benzimidazoles; Benzoates; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Endothelium, Vascular; Humans; Hypertension; Middle Aged; Multicenter Studies as Topic; Oxidative Stress; Randomized Controlled Trials as Topic; Renal Insufficiency; Telmisartan; Tetrazoles; Valine; Valsartan

Experimental data suggest that oxidative stress might be enhanced in hypertension and contribute to platelet activation. We hypothesized that both oxidative stress and platelet activation could be related to the clinical characteristics of hypertensive patients. The urinary excretion of 11-dehydrothromboxane (TX) B2, reflecting in vivo platelet activation, was measured in 75 patients with mild to severe essential hypertension and 75 pair-matched, healthy controls. The urinary excretion of 8-iso-prostaglandin (PG) F2alpha was determined as an index of in vivo lipid peroxidation. Urinary 11-dehydro-TXB2 was significantly higher in essential hypertensives compared with controls. Although no statistically significant difference in urinary 8-iso-PGF2alpha was observed between patients and controls, plasma vitamin C was lower and plasma homocysteine higher in hypertensive patients than in controls. Both urinary 11-dehydro-TXB2 and 8-iso-PGF2alpha were higher in patients with advanced hypertensive retinopathy compared with patients without retinopathy. Multivariate linear regression analysis identified urinary 8-iso-PGF2alpha, plasma fibrinogen, homocysteine, and vitamin E as the only variables independently correlated with urinary 11-dehydro-TXB2. Logistic regression analysis showed that high urinary 8-iso-PGF2alpha, plasma fibrinogen, and homocysteine, as well as low plasma vitamin E, advanced retinopathy, elevated diastolic blood pressure, and the absence of antihypertensive treatment, were predictors of high urinary 11-dehydro-TXB2. We demonstrated increased oxidative stress and persistent platelet activation in essential hypertensives with advanced vascular lesions. These findings might help identify hypertensive patients who are at increased risk of cardiovascular events and who might benefit from long-term antiplatelet therapy.

Topics: Adolescent; Adult; Aged; Dinoprost; F2-Isoprostanes; Female; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Platelet Activation; Thromboxane B2

Oxidative stress is involved in the pathophysiology of atherosclerosis, diabetes mellitus, hypertension, obesity, and cigarette smoking, all of these being risk factors for coronary heart disease (CHD). We tested the hypothesis that risk factors of CHD are associated with abundant systemic oxidative stress.. We conducted a case-control study with 93 CHD patients and 93 control subjects frequency-matched by age and sex. Urinary excretion of the F2-isoprostane 8-iso-prostaglandin (PG) F2alpha and its major urinary metabolite, 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha, were measured by gas chromatography-tandem mass spectrometry. Body mass index, systolic blood pressure, and C-reactive protein were elevated in CHD patients (P<0.01). Urinary 8-iso-PGF2alpha and 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha also differed, from 77 (interquartile range, 61-101) to 139 (93-231) pmol/mmol creatinine and from 120 (91-151) to 193 (140-275) pmol/mmol in control subjects and case subjects, respectively (P<0.001). 8-iso-PGF2alpha and its metabolite were highly correlated (Spearman's rho=0.664, P<0.001). HDL cholesterol was diminished in CHD patients (P<0.001). All of these characteristics predicted CHD in univariate analysis. In a multivariate model, the odds ratios were increased only for 8-iso-PGF2alpha (> or =131 pmol/mmol, P<0.001) and C-reactive protein (>3 mg/L, P<0.01), ie, by 30.8 (95% CI, 7.7-124) and 7.2 (1.9-27.6), respectively. 8-iso-PGF2alpha was found to be a novel marker in addition to known risk factors of CHD, ie, diabetes mellitus, hypercholesterolemia, hypertension, and smoking. Urinary excretion of 8-iso-PGF2alpha correlated with the number of risk factors for all subjects (P<0.001 for trend).. 8-iso-PGF2alpha is a sensitive and independent risk marker of CHD.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Case-Control Studies; Comorbidity; Coronary Disease; Diabetes Mellitus; Dinoprost; Female; Gas Chromatography-Mass Spectrometry; Germany; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Obesity; Oxidative Stress; Risk Factors; Sensitivity and Specificity; Smoking

Decreased baroreflex sensitivity (BRS) is a prognostic marker in essential hypertension. Animal experiments suggest that decreased BRS is related to increased oxidative stress. Our study was aimed at testing whether oxidative stress, estimated by isoprostane 15-F(2t)-IsoP urinary levels, is correlated to BRS variation in healthy subjects as well as in patients suffering from essential hypertension. Urinary 15-F(2t)-IsoP levels and BRS were evaluated in two groups of subjects: healthy volunteers (n=64) and patients with untreated mild-to-moderate hypertension (n=33). Data were analysed in 61 and 31 subjects, respectively, BRS analysis being impossible in three and two subjects, respectively. 15-F(2t)-IsoP levels were measured using gas chromatography/mass spectrometry. BRS was measured using the sequence method [PS+/RR+ and PS-/RR-] and crossspectral analysis (CSP) (MF gain) at rest, lying down. No significant correlation was found between basal urinary 15-F(2t)-IsoP levels and BRS (sequence method and CSP) in either healthy controls or hypertensive patients. Our study shows that oxidative stress is not involved in interindividual variations of BRS in healthy subjects and patients suffering from mild-to-moderate hypertensionJournal of Human Hypertension (2004) 18, 517-521. doi:10.1038/sj.jhh.1001684 Published online 12 February 2004

Topics: Adult; Baroreflex; Case-Control Studies; Dinoprost; Female; Gas Chromatography-Mass Spectrometry; Humans; Hypertension; Male; Middle Aged; Oxidative Stress; Rest; Severity of Illness Index; Supine Position; Vasoconstrictor Agents

Oxidative stress and NO are thought to play important roles in arteriosclerosis pathogenesis, a major cause of white matter lesions in the brain. Therefore, we examined whether NO metabolites (NOx) and 8-iso-prostaglandin F(2alpha) (IsoP) levels in vivo correlated with the severity of periventricular hyperintensity (PVH) to evaluate potential roles of oxidative stress and NO in white matter lesions.. Participants (687 males and 528 females) of a health-screening examination were recruited into the study. The plasma NOx and urinary IsoP levels were measured using the Griess method and ELISA, respectively. PVH was diagnosed on the basis of MRIs. In nonparametric univariate trend analyses, plasma NOx as well as aging, presence of hypertension and of lacunes, mean blood pressure, and high-density lipoprotein cholesterol showed highly significant monotone correlation with PVH severity (P

Topics: Age Factors; Aged; Brain; Brain Diseases; Brain Infarction; Cholesterol, HDL; Dinoprost; Disease Progression; Female; Humans; Hypertension; Magnetic Resonance Imaging; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Risk Factors; Triglycerides

Dihydropyridine Ca2+-blockers, frequently used as antihypertensive and antianginal agents, have been found to exert potent antioxidant and cytoprotective activities against free radical-mediated vascular injury.. In the current study we examined the effect of amlodipine (AMLOD) on oxidative stress-induced hypertension in Sprague-Dawley rats administered buthionine-sulfoximine (BSO), a glutathione (GSH) synthase inhibitor, in the drinking water. The control animals received drug-free water. Blood pressure (BP) was measured by tail-cuff plethysmography. Plasma levels of total 8-isoprostane, thromboxane A2, prostacyclin, nitric oxide, and aortic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were determined by enzyme immunoassay. Plasma, kidney, and heart GSH were analyzed by high-performance liquid chromatography.. Administration of BSO significantly increased BP, isoprostane, and thromboxane A2, whereas GSH, PGI2, and cAMP were reduced. When given alone, AMLOD alone reduced BP and the plasma levels of isoprostane and thromboxane A2, and elevated prostacyclin, nitric oxide, cGMP, and cAMP. When administered with BSO, AMLOD reversed the BSO-induced elevation of BP, isoprostane, and thromboxane A2 as well as the reduction in prostacyclin, cAMP, and cardiac GSH levels.. The antihypertensive effect of amlodipine involves a reduction in oxidative stress, which appears to be mediated in part by the prostanoid endothelium-derived factors and nitric oxide.

Topics: Amlodipine; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Cyclic AMP; Cyclic GMP; Dinoprost; Epoprostenol; Glutathione; Heart Rate; Hypertension; Male; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Second Messenger Systems; Thromboxane B2

To examine the relationship between 8-isoprostane and blood pressure, we measured plasma 8-isoprostane concentration and home blood pressure levels in an elderly Japanese population. Our study population comprised 569 subjects aged 70 years and over who were not receiving antihypertensive medication. On the basis of their blood pressure values, the participants were classified into three groups: normotensive (home blood pressure <135/85 mmHg), hypertensive (home blood pressure 135/85-160/90 mmHg), and severely hypertensive (home blood pressure > or =160/90 mmHg). The mean plasma 8-isoprostane level in the severely hypertensive group (21.1+/-5.2 pg/ml) was significantly higher than that in the normotensive (20.2+/-4.9 pg/ml) or hypertensive (19.7+/-5.1 pg/ml) group, and this result was unchanged when we adjusted for possible confounding factors such as age, sex, use of vitamin A, C or E supplements, smoking status, drinking status, body mass index, use of non-steroidal anti-inflammatory drugs, history of diabetes, hypercholesterolemia, home heart rate and serum creatinine level. Thus, the level of plasma 8-isoprostane appears to be elevated in older subjects with severe hypertension.

Topics: Aged; Aged, 80 and over; Blood Pressure; Dinoprost; Female; Humans; Hypertension; Japan; Male; Oxidative Stress; Severity of Illness Index; Urban Population

Recent studies implicate of reactive oxygen species (ROS) in hypertension; however, whether reactive oxygen species promote hypertensive derangements is not fully clear. We thus investigated the effects of an antioxidant, N-acetyl-L-cysteine, on hypertensive Dahl salt-sensitive rats. High-salt intake for 4 weeks markedly elevated systolic arterial pressure, urinary excretion of protein, 8-isoprostane, and H(2)O(2), and the enzyme activity of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase along with the elevated expression of its subunits gp91phox and p47phox at the levels of mRNA and protein. Supplement with N-acetyl-L-cysteine reduced the increase in systolic arterial pressure and counteracted the elevation of urinary excretion of protein, 8-isoprostane, and H(2)O(2), and the increases in NADPH oxidase activity/expression in high-salt-loaded Dahl salt-sensitive rats. N-acetyl-L-cysteine supplement ameliorated plasma and urinary levels of thromboxane B(2) (an end metabolite of thromboxane A(2)), associated with improvement of both the abnormal contraction and the impaired nitric oxide-dependent relaxation in renal arteries. These results revealed that oxidative stress mediates hypertensive changes in Dahl salt-sensitive rats, because thiol antioxidant N-acetyl-L-cysteine attenuated the augmentation of local ROS production by diminishing the elevation of NADPH oxidase expression and ameliorated renal/vascular hypertensive changes.

Topics: Acetylcholine; Acetylcysteine; Animals; Antioxidants; Blood Pressure; Dinoprost; Endothelium, Vascular; Hydrogen Peroxide; Hypertension; Kidney Glomerulus; Male; NADPH Oxidases; Oxidative Stress; Proteinuria; Rats; Rats, Inbred Dahl; Sodium Chloride; Superoxides; Thromboxane B2; Up-Regulation

We hypothesize that endothelin-A receptor stimulation contributes to the elevated blood pressure and superoxide production in endothelin-B receptor-deficient rats on a high salt diet. Experiments were conducted on homozygous endothelin-B-deficient (sl/sl) and wild-type rats (wt) fed a high salt diet (8% NaCl) for 3 weeks. Separate groups were given normal drinking water or water containing the endothelin-A receptor antagonist, ABT-627 (5 mg/kg per day; n = 8-9 in all groups). On a normal salt diet, (sl/sl) rats had a significantly elevated systolic blood pressure compared with wt (138 +/- 3 vs 117 +/- 4 mmHg, respectively; P < 0.05). High salt diet caused a significant increase in systolic blood pressure in (sl/sl) rats compared with wt (158 +/- 2 vs 138 +/- 3 mmHg, respectively; P < 0.05). Endothelin-A receptor blockade decreased systolic blood pressure in (sl/sl) rats on high salt (125 +/- 5 mmHg; P < 0.05 vs without antagonist) without affecting the systolic blood pressure in wt (119 +/- 4 mmHg). Aortic superoxide production (lucigenin chemiluminescence) and plasma 8-isoprostane were elevated in sl/sl rats and were significantly reduced by endothelin-A receptor blockade in sl/sl, but not in wt rats. These findings suggest that endothelin-1, through the endothelin-A receptor, contributes to salt-induced hypertension and vascular superoxide production in endothelin-B-deficient rats.

Topics: Animals; Animals, Genetically Modified; Antihypertensive Agents; Aorta; Atrasentan; Blood Pressure; Dinoprost; Disease Models, Animal; Down-Regulation; Endothelin A Receptor Antagonists; Endothelins; Hypertension; Male; Pyrrolidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Sodium Chloride, Dietary; Superoxides; Time Factors

In contrast with the huge amount of experimental data available, only few and somewhat unconvincing clinical studies support the hypothesis that oxidative stress is involved in the early stages of essential hypertension in humans. Isoprostanes are chemically stable lipid peroxidation products of arachidonic acid, the quantification of which provides a novel approach to the assessment of oxidative stress in vivo. The main objective of this study was to quantify the urinary levels of 15-F(2t)-IsoP in the early stages of essential hypertension, using gas chromatography/mass spectrometry, by comparing 30 patients with never-treated mild-to-moderate hypertension with 30 gender- and age-paired healthy controls. Urinary 15-F(2t)-IsoP levels were not significantly different in hypertensive patients (69+/-36 pmol/mmol creatinine) compared with controls (75+/-34 pmol/mmol creatinine, 95% confidence intervals on differences: -23 to 13). No significant correlation was found between basal urinary 15-F(2t)-IsoP levels and age, low-density lipoprotein cholesterol, glucose, clinical pulse pressure, carotid intima-media thickness, left ventricular mass index, or aortic pulse wave velocity. In conclusion, this study shows that lipid peroxidation is not increased in never-treated mild-to-moderate hypertension. This suggests that oxidative stress is not implicated in the pathogenesis of human essential hypertension, at least in the early stages.

Topics: Blood Pressure; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dinoprost; F2-Isoprostanes; Female; Humans; Hypertension; Lipid Peroxidation; Male; Middle Aged; Single-Blind Method

The present study evaluated whether reactive oxygen species-induced alterations in bioavailability of 20-HETE in the kidney contribute to the antihypertensive and renoprotective actions of antioxidant therapy with Tempol in the Dahl salt-sensitive (DS) rat. Superoxide inhibited the synthesis of 20-HETE by renal cortical microsomes and enhanced breakdown of 20-HETE to a more polar product. Addition of Tempol (1 mmol/L) to the drinking water reduced mean arterial pressure from 187+/-9 to 160+/-3 mm Hg in DS rats fed an 8%-NaCl diet for 2 weeks. 20-HETE excretion rose from 117+/-11 to 430+/-45 ng/day, and 8-isoprostane excretion fell from 14+/-1 to 8+/-1 ng/day. Tempol also increased creatinine clearance and reduced the severity of renal damage in DS rats fed a high-salt diet. Blockade of NO synthase with NG-nitro-L-arginine methyl ester (25 mg/kg per day) did not attenuate the antihypertensive or renoprotective actions of Tempol in DS rats. However, chronic blockade of the formation of 20-HETE with N-hydroxy-N'-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) blunted the antihypertensive and renoprotective effects of Tempol. These findings indicate that the antihypertensive and renoprotective effects of reducing oxidative stress with Tempol depends in part on increasing the bioavailability of 20-HETE in the kidney.

Topics: Animals; Antihypertensive Agents; Antioxidants; Cyclic N-Oxides; Dinoprost; F2-Isoprostanes; Hydroxyeicosatetraenoic Acids; Hypertension; Kidney; Male; Nitric Oxide; Rats; Rats, Inbred Dahl; Spin Labels; Superoxides

The inhibition of nitric oxide (NO) exerts injurious effects on the cardiovascular system by several mechanisms, such as the activation of the renin-angiotensin system, oxidative stress, and inflammatory cytokines. We examined whether COX-2, an inducible isoform of cyclooxygenase, is associated with the pathogenesis observed in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats.. Three groups of 8-week-old male Sprague-Dawley rats were studied (n = 6 in each group): group 1, untreated controls; group 2, treated with L-NAME (1 g/l for 3 weeks, p.o.); and group 3, L-NAME co-treated with COX-2 inhibitor NS-398 (5 mg/kg per day, i.p.). The L-NAME-induced expression of COX-2 mRNA and protein was semi-quantified in the kidneys and the thoracic aorta. Urinary excretion of the prostaglandin 6-keto PGF(1alpha), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2) was measured in the three groups. Moreover, urinary excretion of 8-iso-PGF(2alpha), a potent vasoconstricting arachidonic acid metabolite acting through thromboxane A (TXA) receptor activation, proposed recently as a marker of oxidative stress, was also measured.. L-NAME induced significant increases in systolic blood pressure (P< 0.01), urinary protein (P< 0.05), and renal excretion of 8-iso-PGF(2alpha)(P< 0.01), compared with the control. In L-NAME-treated rats, the levels of COX-2 mRNA and protein were more than 50% higher in the kidneys (P< 0.05), and six-fold higher in the thoracic aorta (P< 0.01) than in control rats. NS-398 significantly ameliorated an increase in systolic blood pressure (P< 0.01) and urinary protein (P< 0.05) induced by L-NAME.. These data indicate that an increase in COX-2 expression might have a hypertensive effect, partly associated with 8-iso-PGF(2alpha) formation in l-NAME-treated rats.

Topics: Animals; Base Sequence; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; DNA, Complementary; F2-Isoprostanes; Hemodynamics; Hypertension; Isoenzymes; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides

It is well known that free radicals contribute to endothelial dysfunction and are involved in ageing and in the pathogenesis and development of many cardiovascular diseases, such as atherosclerosis. Measurement of F(2)-isoprostanes has emerged as probably the most reliable approach to assess oxidative stress status in vivo. In particular, 8-isoprostane (8-epiPGF(2alpha)) has been indicated as a marker of antioxidant deficiency and oxidative stress of potential relevance to assess human vascular diseases.. To provide evidence for enhanced oxidative stress in coronary artery disease (CAD).. Plasma levels of 8-epiPGF(2alpha) (EIA, Cayman Chemicals, Ann Arbor, Michigan, USA) were measured in 51 patients (19 females, 32 males, age: 58.7+/-1.6 years, mean+/-SEM). Subjects included 13 healthy control subjects (group I), and 38 patients underwent coronary angiography; 11 patients without coronary artery atherosclerotic lesions (group II), and 27 with angiographically proven CAD (group III).. Plasma levels of 8-epiPGF(2alpha) were 123.2+/-9.5, 314.6+/-40 and 389.6+/-36.2 pg/ml in groups I, II and III respectively (P<0.05 and P<0.001 groups II and III versus group I, respectively). In group III, 8-epiPGF(2alpha) levels increased with the number of affected vessels (324.4+/-47.2 and 408.3+/-44.1 pg/ml for one- and multi-vessel disease, P=0.07 and P<0.001 versus control subjects, respectively). A significant difference in 8-epiPGF(2alpha) levels was observed between patients with and without hypertension (394.2+/-42.7 and 232.7+/-25.1 pg/ml, P<0.01, respectively). In addition, patients with dyslipidaemia presented higher 8-epiPGF(2alpha) levels with respect to non-dyslipidaemic patients (359.1+/-35.6 and 240.3+/-34.3 pg/ml, P<0.05, respectively). A positive relationship was found between age and 8-epiPGF(2alpha) levels (r=0.42, P<0.01) in the whole population.. These findings indicate that elevated levels of plasma 8-epiPGF(2alpha) levels are associated with the extent and the severity of coronary artery disease and with the occurrence of different atherogenic risk factors, supporting the hypothesis that the evaluation of oxidative stress may represent an additional prognostic predictor in such events and a potential target of future therapeutic interventions.

Topics: Aged; Biomarkers; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Dinoprost; Evidence-Based Medicine; F2-Isoprostanes; Female; Humans; Hyperlipidemias; Hypertension; Italy; Male; Middle Aged; Oxidative Stress; Regression Analysis; Risk Factors; Smoking; Statistics as Topic

Hypertension induced by oxidative stress has been demonstrated in normal rats. In the current study, we investigated the effect of the oral AT(1) receptor blocker losartan (10 mmol/kg/day) on oxidative stress, induced by glutathione (GSH) depletion (using buthionine-sulfoximine, BSO, 30 mmol/L/day in the drinking water), in Sprague-Dawley rats.. Mean arterial pressure (MAP) was measured by tail-cuff plethysmography and the plasma levels of total 8-isoprostane, nitric oxide, prostacyclin, thromboxane A(2), angiotensin II, aldosterone, and aortic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were determined by enzyme immunoassay. Plasma, heart, and kidney GSH were analyzed by high-performance liquid chromatography. Aortic and renal superoxide production was determined by fluorescence spectrometry.. In the BSO-treated group, MAP, angiotensin II, isoprostane, thromboxane A(2), and superoxide were elevated; whereas prostacyclin, GSH, cAMP, and cGMP were reduced, compared to control. Losartan alone reduced MAP, and increased renal GSH, plasma nitric oxide, angiotensin II, aldosterone, and aortic cGMP. When administered concurrently with BSO, losartan reversed the BSO-induced elevation of MAP, superoxide, and thromboxane A(2) as well as the reduction in prostacyclin and aortic cAMP levels, but did not significantly alter the reduction in GSH or the elevation in angiotensin II and aldosterone.. Losartan attenuates BSO-induced hypertension, which appears to be mediated, in part, by angiotensin II and the prostanoid endothelium-derived factors.

Topics: Aldosterone; Angiotensin II; Animals; Antihypertensive Agents; Aorta; Biomarkers; Blood Pressure; Buthionine Sulfoximine; Cyclic AMP; Cyclic GMP; Dinoprost; Disease Models, Animal; Enzyme Inhibitors; Epoprostenol; F2-Isoprostanes; Glutathione; Heart Rate; Hypertension; Kidney; Losartan; Male; Models, Cardiovascular; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxides; Thromboxane A2; Treatment Outcome

We have recently reported that exaggerated oxidative stress in the renal medulla due to superoxide dismutase inhibition resulted in a reduction of renal medullary blood flow and sustained hypertension. The present study tested the hypothesis that selective scavenging of O2*- in the renal medulla would prevent hypertension associated with this exaggerated oxidative stress. An indwelling, aortic catheter was implanted in nonnephrectomized Sprague-Dawley rats for daily measurement of arterial blood pressure, and a renal medullary interstitial catheter was implanted for continuous delivery of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETC, 7.5 mg x kg(-1) x d(-1)) and a chemical superoxide dismutase mimetic, 4-hydroxytetramethyl piperidine-1-oxyl (TEMPOL, 10 mg. kg-1. d-1). Renal medullary interstitial infusion of TEMPOL completely blocked DETC-induced accumulation of O2*- in the renal medulla, as measured by the conversion rate of dihydroethidium to ethidium in the dialysate and by urinary excretion of 8-isoprostanes. However, TEMPOL infusion failed to prevent DETC-induced hypertension, unless catalase (5 mg x kg(-1) d(-1)) was coinfused. Direct infusion of H2O2 into the renal medulla resulted in increases of mean arterial pressure from 115+/-2.5 to 131+/-2.1 mm Hg, which was similar to that observed in rats receiving the medullary infusion of both TEMPOL and DETC. The results indicate that sufficient catalase activity in the renal medulla is a prerequisite for the antihypertensive action of TEMPOL and that accumulated H2O2 in the renal medulla associated with exaggerated oxidative stress might have a hypertensive consequence.

Topics: Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Catalase; Catheters, Indwelling; Cyclic N-Oxides; Dinoprost; Ditiocarb; Enzyme Inhibitors; F2-Isoprostanes; Free Radical Scavengers; Hydrogen Peroxide; Hypertension; Kidney Medulla; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Spin Labels; Superoxide Dismutase; Superoxides; Vasoconstriction

Topics: Biomarkers; Dinoprost; F2-Isoprostanes; Humans; Hypertension; Isoprostanes; Lipid Peroxidation; Oxidative Stress; Platelet Activation; Vasomotor System

The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2). Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2). Lewis at 4 to 5 weeks resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 weeks, the ovariectomized mRen(2). Lewis (OVX) systolic blood pressure averaged 195+/-3.7 mm Hg versus 141+/-4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concentration, as well as urinary excretion of Ang II, 8-isoprostane F2alpha, and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 weeks (125+/-2.9 mm Hg, n=7, P<0.01 versus OVX and sham). Moreover, the AT1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113+/-5.4 mm Hg (n=6, P<0.01 versus OVX and sham). The attenuation of the hypertension was still evident 7 weeks after complete withdrawal of treatment (124+/-4.1 mm Hg at week 23). In summary, the OVX mRen.2. Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2. Lewis strain, possibly by limiting activation of the renin-angiotensin system.

Topics: Angiotensin Receptor Antagonists; Animals; Animals, Congenic; Blood Pressure; Dinoprost; Disease Progression; Endothelin-1; Estradiol; F2-Isoprostanes; Female; Hypertension; Imidazoles; Male; Mice; Olmesartan Medoxomil; Ovariectomy; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Tetrazoles

Recent reports have indicated that endothelin-induced vasoconstriction in isolated aortic vascular rings may be mediated by the production of superoxide anion. The purpose of this study was to determine the role of superoxide anion in mediating the chronic renal and hypertensive actions of endothelin. Endothelin-1 (5 pmol/kg per minute) was chronically infused into the jugular vein by use of mini-osmotic pump for 9 days in male Sprague-Dawley rats and in rats treated with the superoxide anion scavenger tempol (30 mg/kg per day). Mean arterial pressure in the endothelin-1-treated rats was 141+/-3 mm Hg, compared with 125+/-2 mm Hg in control rats. Endothelin-1 increased renal vascular resistance (15.3+/-2.5 versus 10+/-1.3 mm Hg/mL per minute) and decreased renal plasma flow (6.5+/-0.9 versus 8.7+/-0.7 mL/min) in control rats. Endothelin-1 also significantly increased TBARS in the kidney and urinary 8-isoprostaglandin F2alpha excretion. The increase in arterial pressure in response to endothelin-1 was completely abolished by tempol (127+/-4 versus 127+/-4 mm Hg). Tempol also markedly attenuated the renal plasma flow and renal vascular resistance response to endothelin-1. Tempol also significantly decreased the level of 8-isoprostaglandin F2alpha in the endothelin-1-treated rats. Tempol had no effect on arterial pressure or renal hemodynamics in control rats. These data indicate that formation of reactive oxygen species may play an important role in mediating hypertension induced by chronic elevations in endothelin.

Topics: Animals; Cells, Cultured; Chronic Disease; Cyclic N-Oxides; Dinoprost; Endothelin-1; F2-Isoprostanes; Free Radical Scavengers; Hemodynamics; Hypertension; Kidney; Male; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Spin Labels; Superoxides; Thiobarbituric Acid Reactive Substances; Vasoconstrictor Agents

Free radical-catalysed oxidation of arachidonic acid esterified to lipids leads to the formation of the F(2)-isoprostane family which may theoretically comprise up to 64 isomers. We have previously shown that the combination of TLC and GC-tandem MS (referred to as method A) allows for the accurate and highly specific quantification of 8-iso-PGF(2alpha) (iPF(2alpha)-III, 15-F(2t)-IsoP) in human urine. Immunoaffinity column chromatography (IAC) with immobilized antibodies raised against 8-iso-PGF(2alpha) (i.e. 15(S)-8-iso-PGF(2alpha)) has been shown by others to be highly selective and specific for this 8-iso-PGF(2alpha) isomer when quantified by GC-MS. In the present study we established IAC for urinary 8-iso-PGF(2alpha) for subsequent quantification by GC-tandem MS (referred to as method B). This method was fully validated and found to be highly accurate and precise for urinary 15(S)-8-iso-PGF(2alpha). 8-iso-PGF(2alpha) was measured in urine of 10 young healthy humans by both methods. 8-iso-PGF(2alpha) was determined to be 291+/-102 pg/mg creatinine by method A and 141+/-41 pg/mg creatinine by method B. Analysis of the combined through and wash phases of the IAC step, i.e. of the unretained compounds, by method A showed the presence of non-immunoreactive 8-iso-PGF(2alpha) at 128+/-55 pg/mg creatinine. This finding suggests that urinary 8-iso-PGF(2alpha) is heterogenous, with 15(S)-8-iso-PGF(2alpha) contributing by approximately 50%. PGF(2alpha) and other 8-iso-PGF(2alpha) isomers including 15(R)-8-iso-PGF(2alpha) are not IAC-immunoreactive and are chromatographically separated from 15(S)-8-iso-PGF(2alpha). We assume that ent-15(S)-8-iso-PGF(2alpha) is also contributing by approximately 50% to urinary 8-iso-PGF(2alpha). This finding may have methodological, mechanistic and clinical implications.

Topics: Adult; Case-Control Studies; Chromatography, Affinity; Chromatography, Thin Layer; Dinoprost; F2-Isoprostanes; Female; Gas Chromatography-Mass Spectrometry; Humans; Hypertension; Lipids; Male; Middle Aged; Reproducibility of Results; Smoking

Derangements in the production and degradation of reactive oxygen species (ROS) as well as nitric oxide (NO) have been implicated in cardiovascular diseases. We explored how supplementation with l-arginine, an NO synthase substrate, restores such derangements of ROS/NO systems in Dahl salt-sensitive, hypertensive (DS) rats. We detected an increase of NADPH oxidase activity, a key enzyme that produces superoxide, in the membrane fraction of the renal cortex derived from DS rats loaded with high salt for 4 weeks; high salt loading also remarkably increased urinary H2O2, 8-isoprostane, and thromboxane B2 excretion and decreased plasma NO end products. These changes from high salt loading were counteracted by oral l-arginine supplementation. We further examined expression patterns of NADPH oxidase subunits in renal cortex derived from these animals. High salt loading increased gp91phox and p47phox but not p22phox or Rac1 or mRNA abundance, which were counteracted with L-arginine supplementation. Western blot analyses after subcellular fractionation revealed that l-arginine supplementation distinctly decreases membrane localization of p47phox protein, as it decreases total expression of Rac1 protein in DS rats with high salt loading. These results disclose that high salt loading causes a deficiency in available L-arginine amounts for NO synthases and induces NADPH oxidase activation in the renal cortex of DS rats, which l-arginine supplementation markedly restores. Since superoxide rapidly eliminates NO, which inhibits sodium reabsorption in the cortical collecting duct, superoxide production caused by upregulated NADPH oxidase activity in the renal cortex of high salt-loaded DS rats may accelerate sodium reabsorption and hypertension.

Topics: Animals; Arginine; Blood Pressure; Dinoprost; F2-Isoprostanes; Gene Expression Regulation; Hypertension; Kidney Cortex; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Nitric Oxide; Phosphoproteins; Rats; Rats, Inbred Dahl; RNA, Messenger; Sodium Chloride; Thromboxane B2

In view of the ongoing controversy about potential differences in cardiovascular safety of selective cyclooxygenase (COX)-2 inhibitors (coxibs), we compared the effects of 2 different coxibs and a traditional NSAID on endothelial dysfunction, a well-established surrogate of cardiovascular disease, in salt-induced hypertension.. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed a high-sodium diet (4% NaCl) for 56 days. From days 35 to 56, diclofenac (6 mg x kg(-1) x d(-1); DS-diclofenac), rofecoxib (2 mg x kg(-1) x d(-1); DS-rofecoxib), celecoxib (25 mg x kg(-1) x d(-1); DS-celecoxib) or placebo (DS-placebo) was added to the chow. Blood pressure increased with sodium diet in the DS groups, which was more pronounced after diclofenac and rofecoxib treatment (P<0.005 versus DS-placebo) but was slightly decreased by celecoxib (P<0.001 versus DS-placebo). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (10-10-10-5 mol/L) in aortic rings of untreated hypertensive rats (P<0.005 versus DR-placebo). Relaxation to acetylcholine improved after celecoxib (P<0.005 versus DS-placebo and DS-rofecoxib) but remained unchanged after rofecoxib and diclofenac treatment. Vasoconstriction after nitric oxide synthase inhibition, indicating basal NO release, with N(omega)-nitro-L-arginine methyl ester (10-4 mol/L) was blunted in DS rats (P<0.05 versus DR-placebo), normalized by celecoxib, but not affected by rofecoxib or diclofenac. Indicators of oxidative stress, 8-isoprostane levels, were elevated in untreated DS rats on 4% NaCl (6.55+/-0.58 versus 3.65+/-1.05 ng/mL, P<0.05) and normalized by celecoxib only (4.29+/-0.58 ng/mL).. These data show that celecoxib but not rofecoxib or diclofenac improves endothelial dysfunction and reduces oxidative stress, thus pointing to differential effects of coxibs in salt-induced hypertension.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprost; Endothelium, Vascular; Enzyme Inhibitors; F2-Isoprostanes; Hypertension; Interleukin-1; Isoenzymes; Lactones; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Dahl; Safety; Sodium Chloride, Dietary; Sulfonamides; Sulfones; Vasodilation

Acetylcholine releases a non-prostanoid endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide from physiological salt solution perfused rat mesenteric arteries. This study reports an impairment in EDHF-mediated vasodilation in deoxycorticosterone acetate (DOCA)-salt hypertensive versus control normotensive rats. Nitric oxide-mediated vasodilation to acetylcholine was not altered in the animals. We hypothesize that free radical species generated as by-products of arachidonic acid metabolism contribute to impaired EDHF-mediated dilation in DOCA-salt hypertension. With or without reduced nicotinamide adenine dinucleotide phosphate (NADPH) as co-factor, arterial microsomes generate free radical species upon incubation with arachidonic acid. The production of free radicals was significantly higher in DOCA-salt versus control rat microsomes, and was totally eliminated by addition of cyclooxygenase-2 inhibitors NS-398 or celecoxib at 30 microM. Treatment of DOCA-salt rats with tempol (an antioxidant; 15 mg/kg, i.p., 21 days) alleviates hypertension; improves acetylcholine-induced EDHF-mediated vasodilation in DOCA-salt rats, and decreases arachidonic acid-driven microsomal free radical production. Serum level of 8-isoprostanes is elevated in DOCA-salt hypertension versus control or sham-salt rats, and the increase was reversed by tempol treatment. These results show that EDHF-mediated dilation of rat mesenteric arteries is impaired in DOCA-salt induced hypertension. Our data also suggest that cyclooxygenase-2 mediates free radical production, and that free radicals modulate the EDHF-mediated vascular response in DOCA-salt induced hypertension.

Topics: Acetylcholine; Animals; Antioxidants; Benzimidazoles; Biological Factors; Blood Pressure; Calcium Channel Agonists; Cyclic N-Oxides; Cyclooxygenase Inhibitors; Desoxycorticosterone; Dinoprost; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radicals; Hypertension; Imidazoles; In Vitro Techniques; Indomethacin; Male; Mesenteric Arteries; Microsomes; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Spin Labels; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Coupling factor 6 is an endogenous inhibitor of prostacyclin synthesis and might function as an endogenous vasoconstrictor in the fashion of a circulating hormone in rats. We investigated the role of coupling factor 6 in human hypertension.. The patients with essential hypertension (EH) (n = 30) received a series of normal salt diet (12 g salt/day) for 3 days, low salt diet (2 g salt/day) for 7 days, and high salt diet (20-23 g salt/day) for 7 days. Normotensive control subjects (n = 27) received normal and low salt diets. The plasma level of coupling factor 6, measured by radioimmunoassay, during normal salt diet was higher in patients with EH than in normotensive subjects (17.6 +/- 1.7 versus 12.8 +/- 0.5 ng/ml, P < 0.01). Whereas the plasma level of coupling factor 6 was unchanged after salt restriction in normotensive subjects, it was decreased after salt restriction (from 12 g/day to 2 g/day) and was increased after salt loading (from 2 g/day to 20-23 g/day) in patients with EH. This increase in plasma level of coupling factor 6 was abolished by oral administration of ascorbic acid, but the level of blood pressure was unaffected. The percentage changes in plasma coupling factor 6 level after salt restriction and loading were positively correlated with those in mean blood pressure (r = 0.57, P < 0.01), and negatively correlated with those in plasma nitric oxide level (r = -0.51, P < 0.05).. These indicate that circulating coupling factor 6 is elevated in human hypertension and modulated by salt intake presumably via reactive oxygen species.

Topics: Antioxidants; Ascorbic Acid; Biomarkers; Blood Pressure; Diet, Sodium-Restricted; Dinoprost; Endothelial Cells; Female; Humans; Hypertension; Male; Middle Aged; Mitochondrial Proton-Translocating ATPases; Nitrates; Nitrites; Norepinephrine; Oxidative Phosphorylation Coupling Factors; Reactive Oxygen Species; Renin; Sodium, Dietary; Statistics as Topic

Angiotensin II (Ang II)-induced renal damage is associated with perivascular inflammation and increased oxidative stress. We tested the hypothesis whether entacapone, a catechol-O-methyltransferase (COMT) inhibitor exerting antioxidative and anti-inflammatory properties, protects against the Ang II-induced inflammatory response and end-organ damage.. Samples from double-transgenic rats harbouring human renin and human angiotensinogen genes (dTGR) and normotensive Sprague-Dawley rats (SD) were assessed by light microscopy, immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and high pressure liquid chromatography. The effects of entacapone treatment for 3 weeks were examined in dTGR and SD.. Entacapone completely prevented cardiovascular mortality and decreased albuminuria by 85% in dTGR. Entacapone ameliorated Ang II-induced vascular and glomerular damage, leucocyte infiltration, and intercellular adhesion molecule-1 (ICAM-1) overexpression in the kidneys. Serum 8-isoprostane concentration, as well as renal nitrotyrosine and 8-hydroxydeoxyguanosine expressions, all markers of oxidative stress, were markedly increased in dTGR and normalized by entacapone. Entacapone also decreased p22phox mRNA expression in the kidney. COMT expression was increased by 500% locally in the renal vascular wall in dTGR; however, COMT activity in the whole kidney remained unchanged. Urinary dopamine excretion, a marker of renal dopaminergic tone, was decreased by 50% in untreated dTGR. Even though entacapone decreased renal COMT activity by 40%, the renal dopaminergic tone remained unchanged in entacapone-treated dTGR.. Our findings suggest that entacapone provides protection against Ang II-induced renal damage through antioxidative and anti-inflammatory mechanisms, rather than by COMT inhibition-induced changes in renal dopaminergic tone.

Topics: Angiotensin II; Animals; Animals, Genetically Modified; Biomarkers; Blood Pressure; Cardiomegaly; Catechol O-Methyltransferase; Catechols; Creatinine; Dinoprost; Disease Models, Animal; Dopamine; Enzyme Inhibitors; Hypertension; Inflammation; Intercellular Adhesion Molecule-1; Kidney; Kidney Diseases; Leukocytes; Male; Models, Cardiovascular; Nitriles; Norepinephrine; Rats; Rats, Sprague-Dawley; RNA, Messenger

Diet and exercise can affect blood pressure and atherosclerotic risk.. The present study was designed to examine the effects of a short-term, rigorous diet and exercise intervention on blood pressure, hyperinsulinemia, and nitric oxide (NO) availability. Men (n=11) were placed on a low-fat, high-fiber diet combined with daily exercise for 45 to 60 minutes for 3 weeks. Pre- and post fasting blood was drawn for serum lipid, insulin, 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)), and glucose measurements. Anthropometric parameters, blood pressure (BP), and 24-hour urinary NO metabolite excretion (NO(X)), a marker of NO bioavailability, were measured. Systolic (P<0.01) and diastolic BP (P<0.01) and 8-iso-PGF(2alpha) decreased (P<0.05), whereas urinary NO(X) increased (P<0.05). There was a significant reduction in fasting insulin (P<0.01) and a significant correlation between the decrease in serum insulin and the increase in urinary NO(X) (r2=0.68, P<0.05). All fasting lipids decreased significantly, and the total cholesterol to high-density lipoprotein cholesterol ratio improved. Although body weight and body mass index (P<0.01) decreased, obesity was still present and there were no correlations between the change in body mass index and the change in insulin, BP, or urinary NO(X).. This intervention resulted in dramatic improvements in BP, oxidative stress, NO availability, and the metabolic profile within 3 weeks, mitigating the risk for atherosclerosis progression and its clinical sequelae.

Topics: Adult; Aged; Arteriosclerosis; Blood Pressure; Body Mass Index; Body Weight; Combined Modality Therapy; Dinoprost; Exercise; F2-Isoprostanes; Humans; Hypertension; Insulin; Male; Middle Aged; Nitric Oxide; Oxidative Stress

We investigated the extent of oxidative stress evoked in the hypertensive rat by measuring plasma levels of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), a marker of in vivo oxidative stress. Administration of angiotensin (Ang) II and norepinephrine at doses of 0.7 and 2.8 mg. kg(-1). d(-1), respectively, resulted in similar significant elevations in plasma levels of 8-epi-PGF(2alpha). A 7-day infusion of Ang II at a nonpressor dose, but not norepinephrine at a nonpressor dose, also increased plasma levels of 8-epi-PGF(2alpha). The norepinephrine-induced increase in 8-epi-PGF(2alpha) levels could be completely normalized by 3 different classes of antihypertensive drugs: prazosin, an alpha-adrenergic receptor blocker; hydralazine, a nonspecific vasodilator; and losartan, a specific angiotensin type 1 (AT(1)) receptor antagonist. This finding suggests that the norepinephrine-induced increase is a pressor-dependent event. In contrast, among these antihypertensive drugs, only losartan was effective in inhibiting the Ang II-induced increase in plasma 8-epi-PGF(2alpha), suggesting that Ang II increases plasma levels of 8-epi-PGF(2alpha) in both a pressor-independent and an AT(1) receptor-dependent manner. In summary, continuous infusion of both Ang II and norepinephrine potently increases plasma levels of 8-epi-PGF(2alpha) and thus in vivo oxidative stress. Ang II and norepinephrine seem to induce this increase in 8-epi-PGF(2alpha) via mechanisms with different pressor dependencies.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Cyclooxygenase Inhibitors; Dinoprost; Dose-Response Relationship, Drug; Hypertension; Ibuprofen; Male; Norepinephrine; Oxidative Stress; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents

We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II-induced vascular dysfunction in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes. In 7-week-old hypertensive dTGR, the endothelium-mediated relaxation of noradrenaline (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro was markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular relaxation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation. Preincubation with the XOR inhibitor oxypurinol also improved endothelium-dependent vascular relaxation. The endothelium-independent relaxation to sodium nitroprusside was similar in both strains. In dTGR, serum 8-isoprostaglandin F(2alpha), a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased by 100%, and the activity of XOR in the kidney was increased by 40%. Urinary nitrate plus nitrite (NO(x)) excretion, a marker of total body NO generation, was decreased by 85%. Contractile responses of renal arteries to Ang II, endothelin-1 (ET-1), and NA were decreased in dTGR, suggesting hypertension-associated generalized changes in the vascular function rather than a receptor-specific desensitization. Valsartan (30 mg/kg PO for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. Valsartan also normalized serum 8-isoprostaglandin F(2alpha) levels, renal XOR activity, and, to a degree, NO(x) excretion. Thus, overproduction of Ang II in dTGR induces pronounced endothelial dysfunction, whereas the sensitivity of vascular smooth muscle cells to nitric oxide is unaltered. Ang II-induced endothelial dysfunction is associated with increased oxidative stress and vascular xanthine oxidase activity.

Topics: Acetylcholine; Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Antihypertensive Agents; Dinoprost; Disease Models, Animal; Endothelium, Vascular; F2-Isoprostanes; Humans; Hypertension; Ketone Oxidoreductases; Male; Nitrates; Nitrites; Nitroprusside; Norepinephrine; Rats; Rats, Sprague-Dawley; Renal Artery; Renin; Superoxide Dismutase; Tetrazoles; Valine; Valsartan; Vasoconstrictor Agents; Vasodilation

The mechanisms underlying the development of hypertension in obesity are not yet fully understood. We recently reported the development of hypertension in a rat model of diet-induced obesity. When Sprague-Dawley rats (n=60) are fed a moderately high fat diet (32 kcal% fat) for 10 to 16 weeks, approximately half of them develop obesity (obesity-prone [OP] group) and mild hypertension (158+/-3.4 mm Hg systolic pressure), whereas the other half (obesity-resistant [OR] group) maintains a body weight equivalent to that of a low fat control group and is normotensive (135.8+/-3.8 mm Hg). We examined the potential role of oxidative stress in the development of hypertension in this model. Lipid peroxides measured as thiobarbituric acid-reactive substances showed a significant increase in the LDL fraction of OP rats (2.8+/-0.32 nmol malondialdehyde/mg protein) compared with OR and control rats (0.9+/-0.3 nmol malondialdehyde/mg protein). Also, aortic and kidney thiobarbituric acid-reactive substances showed a significant (3- and 5- fold) increase in OP rats after 16 weeks of diet. In addition, superoxide generation by aortic rings, measured by lucigenin luminescence, showed a 2-fold increase in the OP group compared with both the OR and control groups. In addition, free isoprostane excretion and nitrotyrosine in the kidney showed an increase in OP rats only. The urine and plasma nitrate/nitrite measured by the LDH method showed a 1.8-fold decrease in OP rats compared with OR rats. However, endothelial NO synthase expression in the kidney cortex and medulla assessed by reverse transcriptase-polymerase chain reaction showed a strong increase in the OP rats versus OR and control rats (endothelial NO synthase/beta-actin ratio 1.3+/-0.04 in OP rats versus 0.44+/-0.02 in OR rats), suggesting a possible shift toward superoxide production by the enzyme. Collectively, the data show a decreased NO bioavailability in OP animals that is due in part to the increased oxidative stress.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Dietary Fats; Dinoprost; Disease Models, Animal; F2-Isoprostanes; Hyperlipidemias; Hypertension; Kidney Cortex; Kidney Medulla; Lipid Peroxides; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Obesity; Oxidative Stress; Rats; Rats, Sprague-Dawley; Renin; Thiobarbituric Acid Reactive Substances

Isoprostanes are known as reliable markers of in vivo oxidation injury. Cigarette smoking has been shown to be associated with a significant increase in 8-epi-PGF(2alpha), a major member of this family of compounds. Quitting smoking reduces 8-epi-PGF(2alpha) values to normal within a couple of weeks only. In this follow-up we checked the 8-epi-PGF(2alpha), values in plasma, serum and urine in 28 people who restarted smoking after a quitting attempt of various duration. 8-epi-PGF(2alpha)shows a certain increase after restarting smoking reaching a maximum after already 1 week. Continuation of smoking does not significantly further increase 8-epi-PGF(2alpha). These data indicate a fast response of restarting as on quitting smoking on in vivo oxidation injury. The oxidation injury reflected by 8-epi-PGF(2alpha)may be a key pathogenetic mechanism in smoking-induced vascular injury.

Topics: Adult; Aged; Arteriosclerosis; Biomarkers; Dinoprost; F2-Isoprostanes; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Oxidative Stress; Smoking; Smoking Cessation; Time Factors

Hypertension is a risk factor for the development of end-stage renal disease. The mechanisms underlying hypertensive nephropathy are poorly understood. There is evidence, however, that in hypertension there is an accumulation of partially reduced oxygen and its derivatives, known collectively as reactive oxygen species, which may contribute to progressive renal dysfunction. In the present study, we assess the contribution of oxidative stress in the development of salt-dependent hypertensive nephrosclerosis. Going beyond previous end point studies, which inferred renal function either indirectly or only qualitatively, we have determined oxidative stress concurrently with direct and quantitative measurements of renal function (via inulin and p-aminohippuric acid clearances). Moreover, in this time-dependent study, the measurements have been taken under low- as well as high-salt diets. As was expected from previous studies, in the Dahl salt-sensitive rat, a high-salt diet (8% NaCl) resulted in the development of hypertension, in a decreased glomerular filtration rate, and in a decreased renal plasma flow as compared with the normotensive control, the Dahl salt-resistant rat. In addition, however, we found clear evidence for the accumulation of reactive oxygen species in renal tissue homogenates of Dahl salt-sensitive rats on the high-salt diet. Our time-dependent protocol also indicated that renal oxidative stress follows, in time, the development of hypertension. We also found that after 2 weeks of increased salt loading, Dahl salt-sensitive rats excreted less cyclic guanosine monophosphate and NO(x) than Dahl salt-resistant rats on the same diet. It is known that urinary cyclic guanosine monophosphate and NO(x) represent the activity and stable derivatives of renal NO., respectively, and that they closely correlate with renal vascular resistance. Therefore, our results suggest that, in the Dahl salt-sensitive rat, increased oxidative stress is associated with salt-dependent hypertensive nephrosclerosis and that decreased NO. bioavailability may represent a common factor responsible for the vascular and glomerular dysfunction.

Topics: Animals; Cyclic GMP; Diet, Sodium-Restricted; Dinoprost; Dose-Response Relationship, Drug; F2-Isoprostanes; Genetic Predisposition to Disease; Humans; Hypertension; Inulin; Lipid Peroxidation; Male; Metabolic Clearance Rate; Nephrosclerosis; Nitrogen Oxides; Oxidation-Reduction; Oxidative Stress; p-Aminohippuric Acid; Rats; Rats, Mutant Strains; Reactive Oxygen Species; Sodium Chloride, Dietary; Superoxides

8-Iso prostaglandin F2alpha (8-ISO) is formed nonenzymatically from the attack of superoxide radical on arachidonic acid. Therefore, 8-ISO is a marker of oxidative stress in vivo. We have recently shown that short-term administration of the membrane-permeable, metal-independent superoxide dismutase mimetic tempol (4-hydroxy-2, 2, 6, 6-tetramethyl piperidinoxyl) normalizes blood pressure in spontaneously hypertensive rats (SHR). The present study was designed to test whether prolonged administration of tempol ameliorates oxidative stress and hypertension in SHR. In control SHR (n=8), mean arterial pressure and heart rate were increased and renal blood flow and glomerular filtration rate were reduced compared with control Wistar-Kyoto rats (WKY) (n=7). Twenty-four-hour renal excretion of 8-ISO was significantly increased in SHR compared with WKY. Two weeks of tempol administration in the drinking water (1 mmol/L) to SHR (n=8) decreased mean arterial pressure by 18% (162+/-8 to 134+/-6 mm Hg, P<0.05), increased glomerular filtration rate by 17% (1.6+/-0.2 to 1. 9+/-0.3 mL/min), and decreased renal excretion of 8-ISO by 39% (9. 8+/-0.7 to 6.0+/-0.7 ng/24 hours, P<0.05). In contrast, tempol administration to WKY (n=6) had no significant effect on mean arterial pressure (115+/-5 versus 118+/-8 mm Hg), glomerular filtration rate (3.0+/-0.4 versus 2.5+/-0.5 mL/min), or renal excretion of 8-ISO (7.9+/-0.4 versus 6.8+/-0.7 ng/24 hours). In conclusion, the SHR is a model of hypertension and renal vasoconstriction associated with oxidative stress. Because long-term administration of a superoxide scavenger reduces blood pressure and oxidative stress in vivo, this study suggests a role for oxygen radicals in the maintenance of hypertension in SHR.

Topics: Administration, Oral; Animals; Antioxidants; Blood Pressure; Cyclic N-Oxides; Dinoprost; F2-Isoprostanes; Glomerular Filtration Rate; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Regional Blood Flow; Renal Circulation; Spin Labels; Time Factors; Vascular Resistance