dinoprost 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

The actions of prostanoids in various physiological and pathophysiological conditions have been being examined using mice lacking different prostanoid receptors. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic agent. PGF2alpha was found to be an essential inducer of labor. Several important actions of PGE2 are exerted via each of the four PGE2 receptor subtypes: EP1, EP2, EP3 and EP4. PGE2 participated in colon carcinogenesis via the EP1. PGE2 also participates in ovulation and fertilization and contributes to the control of blood pressure under high-salt intake via the EP2. PGE2 worked as a mediator of febrile responses to both endogenous and exogenous pyrogens and as a regulator of bicarbonate secretion induced by acid-stimulation in the duodenum via the EP3. It regulated the closure of ductus arteriosus and showed bone resorbing action via the EP4. PGD2 was found to be a mediator of allergic asthma. These studies have revealed important roles of prostanoids, some of which had not previously been known.

Topics: Animals; Asthma; Bicarbonates; Colonic Neoplasms; Dinoprost; Dinoprostone; Female; Fever; Hypertension; Inflammation; Labor, Obstetric; Mice; Mice, Knockout; Pregnancy; Prostaglandins; Receptors, Prostaglandin; Reproduction; Thrombosis; Thromboxane A2

In this review, we examine the possibility that small increments in angiotensin II are responsible for an increase in blood pressure and maintenance of hypertension through the stimulation of oxidative stress. A low dose of angiotensin II (2 to 10 ng x kg(-1) x min(-1), which does not elicit an immediate pressor response), when given for 7 to 30 days by continuous intravenous infusion, can increase mean arterial pressure by 30 to 40 mm Hg. This slow pressor response to angiotensin is accompanied by the stimulation of oxidative stress, as measured by a significant increase in levels of 8-iso-prostaglandin F(2alpha) (F(2)-isoprostane). Superoxide radicals and nitric oxide can combine chemically to form peroxynitrite, which can then oxidize arachidonic acid to form F(2)-isoprostanes. F(2)-isoprostanes exert potent vasoconstrictor and antinatriuretic effects. Furthermore, angiotensin II can stimulate endothelin production, which also has been shown to stimulate oxidative stress. In this way, a reduction in the concentration of nitric oxide (which is quenched by superoxide) along with the formation of F(2)-isoprostanes and endothelin could potentiate the vasoconstrictor effects of angiotensin II. We hypothesize that these mechanisms, which underlie the development of the slow pressor response to angiotensin II, also participate in the production of hypertension when circulating angiotensin II levels appear normal, as occurs in many cases of essential and renovascular hypertension.

Topics: Angiotensin II; Animals; Dinoprost; Humans; Hypertension; Nitric Oxide; Oxidative Stress

Topics: Animals; Antihypertensive Agents; Dinoprost; Dinoprostone; Epoprostenol; Humans; Hypertension; Natriuresis; Prostaglandins; Prostaglandins E; Prostaglandins F; Renin-Angiotensin System; Vasomotor System

Topics: Adolescent; Alprostadil; Animals; Arachidonic Acids; Blood Pressure; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Hemodynamics; Humans; Hypertension; Leukotriene B4; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Prostaglandins F; Rats; Renal Circulation; SRS-A; Stress, Psychological; Thromboxanes

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Water; Dinoprost; Female; Furosemide; Humans; Hyperaldosteronism; Hypertension; Indomethacin; Kallikreins; Kidney; Kinins; Male; Natriuresis; Prostaglandins; Prostaglandins E; Prostaglandins F; Renin; Renin-Angiotensin System; Spironolactone

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

Our purpose was to determine urinary 9 alpha,11 beta-prostaglandin F2, the primary metabolite of prostaglandin D2, in pregnancies at high risk for hypertensive disorders and the effect of acetylsalicylic acid on 9 alpha,11 beta-prostaglandin F2. Ninety high risk women were randomised to acetylsalicylic acid and placebo groups at 12-14 weeks of gestation, with 43 women in both groups followed up successfully. 9 alpha,11 beta-prostaglandin F2 was determined at baseline, at 24-26, and at 32-34 weeks of gestation. Fifteen normotensive non-pregnant women, 17 normotensive pregnant women at 12-14, and 15 at 30-34 weeks of gestation served as controls. Urinary 9 alpha,11 beta-prostaglandin F2 was significantly higher in pregnant women at 12-14 weeks of gestation as compared to non-pregnant women. High risk pregnancies had higher 9 alpha,11 beta-prostaglandin F2 as compared to normotensive pregnancies at 12-14, and at 30-34 weeks of gestation. Urinary 9 alpha,11 beta-prostaglandin F2 increased throughout pregnancy unrelated to the outcome of the pregnancy or to the treatment.

Topics: Aspirin; Dinoprost; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Prognosis; Time Factors

The present study was designed to test the hypothesis that blockade of angiotensin II type-1 receptors reduces oxidative stress and inflammation in patients with essential hypertension. The study population comprised 132 hypertensive patients, some receiving and others not receiving medical treatment. At enrollment their systolic and/or diastolic blood pressures were > or = 140 and/or > or = 90 mmHg, respectively. The serum concentration of C-reactive protein, and the urine concentrations of 8-epi-prostaglandin F2alpha and 8-hydroxydeoxyguanosine were measured at baseline and after 12 weeks of treatment either with an angiotensin II type-1 receptor blocker, candesartan (8 mg daily) (age 64 +/- 12 years; male/female 28/39; n = 67), or other antihypertensive agents that do not block the renin-angiotensin system (age 65 +/- 10 years, male/female 25/40, n = 65). Candesartan reduced the levels of C-reactive protein (from 0.07 +/- 0.04 [median value +/- median absolute deviation] to 0.06 +/- 0.03 mg/dl, p < 0.0001), 8-epi-prostaglandin F2alpha (from 210 +/- 92 to 148 +/- 59 pg/mg creatinine, p < 0.0001), and 8-hydroxydeoxyguanosine (from 5.7 +/- 1.9 to 4.0 +/- 1.3 ng/mg creatinine, p < 0.0001), while the levels of these markers were not altered after the treatment with other antihypertensive agents. Blood pressure decreased by a similar amount in both groups, and the reductions in the levels of the markers did not correlate with that of blood pressure. These results suggest that candesartan reduces oxidative stress and inflammation in hypertensive patients independently of its effects on blood pressure. This may provide useful information for determining therapeutic strategies to minimize tissue injury by inflammation and oxidative stress in hypertensive patients.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; C-Reactive Protein; Dinoprost; Female; Humans; Hypertension; Immunoenzyme Techniques; Inflammation; Male; Middle Aged; Oxidative Stress; Tetrazoles; Treatment Outcome

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

Angiotensin II (Ang II) type 1 receptor (AT(1)) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (GC-MS) [corrected] from serum samples revealed a maximum of 10(-7) mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35+/-4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450-dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10(-7) mol/L). LPS- and Ang II-induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II- and LPS-induced formation of prostaglandin F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Arachidonic Acid; Biotransformation; Cells, Cultured; Cyclooxygenase 2; Dinoprost; Drug Design; Endothelium, Vascular; Enzyme Activation; Female; Humans; Hypertension; Imidazoles; Inflammation; Intercellular Adhesion Molecule-1; Isoenzymes; Lipopolysaccharides; Losartan; Male; Membrane Proteins; Middle Aged; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; RNA, Messenger; Tetrazoles; Thromboxane A2; Up-Regulation; Vasoconstrictor Agents

The isoflavonoids genistein and daidzein have been shown to have antioxidant activity in vitro, but their effects on in vivo oxidation have not been assessed. The newly described F2-isoprostanes are believed to currently represent the best available marker of in vivo lipid peroxidation. Therefore we have assessed the effects of a 55 mg daily isoflavonoid supplement on urinary F2-isoprostane concentrations in subjects with high-normal blood pressure (BP). A total of 59 subjects completed an 8-week parallel design, randomized, double blind, and placebo-controlled study. F2-isoprostanes, isoflavonoids and creatinine were measured in 24-h urine samples taken at baseline and at the end of the intervention. There were significant increases in urinary excretion of genistein (5.22+/-0.75 mg/day, P < 0.0001) and daidzein (2.53+/-0.43 mg/day, P < 0.0001) in the group taking the isoflavonoid supplement. Creatinine excretion was significantly correlated with F2-isoprostanes at baseline (r = 0.45, P < 0.01). After adjustment for baseline values, there was no significant difference between groups in creatinine adjusted post-intervention F2-isoprostane concentrations (P = 0.74). In addition, changes in genistein and daidzein excretion were not significantly correlated with changes in F2-isoprostanes in the isoflavonoid treatment group. These results are not consistent with the suggestion that the two soy derived isoflavonoids have in vivo antioxidant activity at a level of intake achievable by dietary means and in subjects with high-normal BP.

Topics: Adult; Aged; Antioxidants; Blood Pressure; Creatinine; Dinoprost; Double-Blind Method; Female; Genistein; Humans; Hypertension; Isoflavones; Lipid Peroxidation; Male; Middle Aged

Significant disturbances of immune regulation of prostaglandine metabolism were found in patients with hypertension and obesity. Use of antisclerotic diet with low sodium contents promoted positive changes of clinical symptoms of diseases, in particular normalizations of process of immune regulation of prostaglandine metabolism connected with formation of natural antibodies.

Topics: Adult; Aged; Antibodies; Arteriosclerosis; Biomarkers; Diet, Sodium-Restricted; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Treatment Outcome

Cromakalim, a novel potassium channel-activating drug, was administered for a 3-day period in eight untreated hospitalized patients with established hypertension. The fixed and single dose of 1.5 mg/day produced a significant reduction in systolic and diastolic blood pressure with a small increase in heart rate. Glomerular filtration rate was unchanged and effective renal plasma flow was slightly increased with a concomitant small decrease in filtration fraction and in renal vascular resistance. No significant change was observed in urinary prostaglandin (PG)E2, PGF2 alpha, and thromboxane B2, while 6-keto-PGF1 alpha (the stable metabolite of prostacyclin) rose from 189 +/- 6 to 368 +/- 115 ng/day. The renal excretion of 6-keto-PGF1 alpha correlates with the modification observed in renal plasma flow, suggesting a compensatory role for prostacylin in preserving renal hemodynamics during antihypertensive therapy with cromakalim.

Topics: Adult; Antihypertensive Agents; Atrial Natriuretic Factor; Benzopyrans; Blood Pressure; Chlorides; Cromakalim; Dinoprost; Dinoprostone; Eicosanoids; Female; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Potassium; Prostaglandins; Pyrroles; Regional Blood Flow; Renin-Angiotensin System; Sodium; Thromboxane B2; Time Factors; Vascular Resistance

The antihypertensive effect of 200 mg metoprolol per day was compared to 25 mg hydrochlorothiazide over a period of four weeks. Metoprolol reduced mean arterial blood pressure from 120 +/- 13 mm Hg after placebo to 109 +/- 8 at the end of the study (n = 18; 38 +/- 12 years) (p less than 0.01). The corresponding values in the hydrochlorothiazide group were 119 +/- 13 mm Hg and 107 +/- 13 (n = 20; 33 +/- 12 years) (p less than 0.01). No significant difference between the groups was found for blood pressure at the end of the study. When blood pressure responders or non-responders of the metoprolol group were compared with the respective subgroup of the hydrochlorothiazide treated patients, no difference could be found for plasma renin activity as well as for aldosterone and PGE2- and PGF2a-excretion rates. However, when blood pressure responders were compared with non-responders within the same treatment group, plasma renin activity and PGE2-excretion rates were higher in the responder group corresponding with younger age in both treatments. Therefore high PGE2-excretion rate and high plasma renin activity might reflect a favorable vascular response to antihypertensive therapy. However, the hormonal analyses do not seem to help in the selection between a beta-blocker or a diuretic as a drug of first choice.

Topics: Adolescent; Adult; Aldosterone; Clinical Trials as Topic; Dinoprost; Dinoprostone; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Metoprolol; Middle Aged; Random Allocation; Renin

Topics: Adult; Blood Pressure; Canrenoic Acid; Clinical Trials as Topic; Dinoprost; Dinoprostone; Double-Blind Method; Female; Humans; Hypertension; Kidney; Middle Aged; Natriuresis; Pregnadienes; Random Allocation

1. In a double-blind, randomized, cross-over study the effects of potassium canrenoate administration (100 mg twice daily for 10 days orally) on renal prostaglandin synthesis (prostaglandin E2 and prostaglandin F2 alpha) were evaluated in 10 normotensive females and in 10 females with essential hypertension. 2. When compared with normotensive subjects, hypertensive patients in baseline conditions showed a reduced excretion of urinary prostaglandin E2 associated with an excessive prostaglandin F2 alpha production. 3. Potassium canrenoate significantly reduced mean blood pressure in hypertensive patients [from 118.9 +/- 8.7 mmHg (1.62 +/- 0.12 kPa) to a peak minimum value of 104.7 +/- 9.8 mmHg (1.42 +/- 0.13 kPa) on the seventh day of treatment; P less than 0.01 for the whole period] but not in control subjects [from 88 +/- 9.4 mmHg (1.20 +/- 0.13 kPa) to 84.3 +/- 8.3 mmHg (1.15 +/- 0.11 kPa) on the eighth day, NS] even though potassium canrenoate significantly increased sodium excretion in both groups. Renal prostaglandin excretion was affected differently in the two groups: in control subjects excretion of both prostaglandin E2 and prostaglandin F2 alpha was increased after drug administration, whereas in hypertensive patients only prostaglandin E2 excretion was enhanced.

Topics: Adult; Canrenoic Acid; Dinoprost; Dinoprostone; Double-Blind Method; Female; Humans; Hypertension; Kidney; Middle Aged; Pregnadienes; Random Allocation

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Pressure; Clinical Trials as Topic; Dinoprost; Dinoprostone; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Random Allocation; Renin

In a double-blind cross-over trial 15 captopril (daily dose 600 mg) treated patients, received in addition to the converting-enzyme inhibitor, placebo or bendrofluazide (7.5 mg). Bendrofluazide lowered blood pressure, while body weight decreased slightly. During captopril-bendrofluazide treatment, the plasma renin-angiotensin-aldosterone system was stimulated, while no effect on the urinary excretion of prostaglandin E2 and F2 alpha was found.

Topics: Bendroflumethiazide; Captopril; Clinical Trials as Topic; Dinoprost; Dinoprostone; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Proline; Prostaglandins E; Prostaglandins F; Random Allocation; Renin-Angiotensin System

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

The role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular contraction in hypertensive mice is poorly established. We tested the hypothesis that TRPV4 regulates endothelium-dependent contractions in aortas from hypertensive mice through the activation of cytosolic cPLA

Topics: Acetylcholine; Animals; Aorta; Cyclooxygenase 2; Dinoprost; Disease Models, Animal; Endothelium, Vascular; Hypertension; Leucine; Mice; Myography; Osmotic Pressure; Phospholipase A2 Inhibitors; Phospholipases A2; Sulfonamides; TRPV Cation Channels; Vasoconstriction

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

Topical prostaglandin F2α (PGF2α) analogs are widely used as the first line of therapy for glaucoma. Systemic PGF2α is suggested to increase blood pressure. Some ophthalmic formulations with β-receptor blocking or α-receptor stimulating actions are reported to cause systemic adverse events such as a decrease in heart rate and blood pressure. The objective of this study was to evaluate the association between topical PGF2α analogs and blood pressure elevation. We analyzed the reports obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2004 until the end of 2015 and the Japanese Adverse Drug Event Report (JADER) database from April 2004 to January 2016 for signal detection using reporting odds ratio (ROR), a method of disproportionality analyses. Signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. Preferred terms in the Medical Dictionary for Regulatory Activities were utilized to define blood pressure elevation. A total of 6156081 reports from the FAERS and 351226 reports from the JADER were analyzed. The significant RORs with 95% CI were calculated to be 1.82 (95% CI: 1.55-2.13) for bimatoprost, 1.69 (95% CI: 1.53-1.85) for latanoprost, and 2.17 (95% CI: 1.82-2.59) for travoprost from the FAERS. From the JADER, 5.01 (95% CI: 1.59-15.8) was calculated for bimatoprost and 8.02 (95% CI: 2.94-21.9) for tafluprost. The resulting data suggest the necessity for further clinical research on blood pressure elevation associated with topical PGF2α analogs and close monitoring.

Topics: Administration, Topical; Adverse Drug Reaction Reporting Systems; Blood Pressure; Databases, Factual; Dinoprost; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension; Incidence; Japan; Odds Ratio; United States; United States Food and Drug Administration

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

Activation of G protein-coupled receptors (GPCRs) can induce vasoconstriction via calcium signal-mediated and Rho-dependent pathways. Earlier reports have shown that diacylglycerol produced during calcium signal generation can be converted to an endocannabinoid, 2-arachidonoylglycerol (2-AG). Our aim was to provide evidence that GPCR signaling-induced 2-AG production and activation of vascular type1 cannabinoid receptors (CB1R) is capable of reducing agonist-induced vasoconstriction and hypertension. Rat and mouse aortic rings were examined by myography. Vascular expression of CB1R was demonstrated with immunohistochemistry. Rat aortic vascular smooth muscle cells (VSMCs) were cultured for calcium measurements and 2-AG-determination. Inhibition or genetic loss of CB1Rs enhanced vasoconstriction induced by angiotensin II (AngII) or phenylephrine (Phe), but not by prostaglandin(PG)F2α. AngII-induced vasoconstriction was augmented by inhibition of diacylglycerol lipase (tetrahydrolipstatin) and was attenuated by inhibition of monoacylglycerol lipase (JZL184) suggesting a functionally relevant role for endogenously produced 2-AG. In Gαq/11-deficient mice vasoconstriction was absent to AngII or Phe, which activate Gq/11-coupled receptors, but was maintained in response to PGF2α. In VSMCs, AngII-stimulated 2-AG-formation was inhibited by tetrahydrolipstatin and potentiated by JZL184. CB1R inhibition increased the sustained phase of AngII-induced calcium signal. Pharmacological or genetic loss of CB1R function augmented AngII-induced blood pressure rise in mice. These data demonstrate that vasoconstrictor effect of GPCR agonists is attenuated via Gq/11-mediated vascular endocannabinoid formation. Agonist-induced endocannabinoid-mediated CB1R activation is a significant physiological modulator of vascular tone. Thus, the selective modulation of GPCR signaling-induced endocannabinoid release has a therapeutic potential in case of increased vascular tone and hypertension.

Topics: Angiotensin II; Animals; Aorta; Arachidonic Acids; Benzodioxoles; Calcium; Calcium Signaling; Dinoprost; Endocannabinoids; Gene Expression Regulation; Glycerides; GTP-Binding Protein alpha Subunits, Gq-G11; Hypertension; Lactones; Lipoprotein Lipase; Male; Mice; Mice, Knockout; Monoacylglycerol Lipases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Orlistat; Phenylephrine; Piperidines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Tissue Culture Techniques; Vasoconstriction

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

This study investigated the effects of the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, Fenofibrate, on the secretion of vascular endothelial contraction factors in hypertensive rats to elucidate its possible mechanisms. The vascular ring contraction experiment was used to observe whether rat vascular tension of clean grade spontaneously hypertensive rats (SHR) changes after 1-h incubation of 0.1, 1.0, 10.0 μM Fenofibrate with 10.0 μM Fenofibrate, a PPAR-α antagonist (MK866), and a PPAR-γ antagonist (GW9662) in SHR. The results were compared with Wistar Kyoto rats. Enzyme-linked immunosorbent assay was used to detect the secretion of the serum vascular endothelial contraction factor prostacyclin-1α (PGF-1α), PGF-2α, and thromboxane B2 (TXB2). Western blot was used to detect COX-1 protein expression. A quantity of 10.0 μM Fenofibrate significantly reduced vasoconstriction in SHR compared to the control group (P = 0.013). The PPAR-α antagonist, MK866, significantly improved the vascular contractility of SHR when incubated with 10.0 μM Fenofibrate (P = 0.021). The PPAR-γ antagonist, GW9662, had no significant effect on the vascular contractility of SHR when incubated with 10.0 μM Fenofibrate (P = 0.071). The isolated aorta of SHR released significantly lower PGF- 1α (P = 0.014), PGF-2α (P = 0.023), and TXB2 (P = 0.017) levels in the 10.0 μM Fenofibrate group compared to the control group. COX-1 expression of SHR rat vascular endothelium was significantly depressed in the 10.0 μM Fenofibrate group compared to the control group (P = 0.027). In conclusion, Fenofibrate reduces the secretion of vascular endothelial contraction factors in hypertensive rats, which might arise through the endothelium influencing COX-1 expression.

Topics: Anilides; Animals; Aorta; Cyclooxygenase 1; Dinoprost; Dose-Response Relationship, Drug; Endothelium, Vascular; Fenofibrate; Gene Expression; Hypertension; Hypolipidemic Agents; Male; Membrane Proteins; PPAR alpha; PPAR gamma; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane B2; Tissue Culture Techniques; Vasoconstriction

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

A contributing factor to increased peripheral resistance seen during hypertension is an increased production of endothelium-derived contractile factors (EDCFs). The main EDCFs are vasoconstrictor prostanoids, metabolites of arachidonic acid (AA) produced by Ca(2+)-dependent cytosolic phospholipase A2 (cPLA2) following phosphorylation (at Ser(505)) mediated by extracellular signal-regulated kinase (ERK1/2) and cyclooxygenase (COX) activations. Although endoplasmic reticulum (ER) stress has been shown to contribute to pathophysiological alterations in cardiovascular diseases, the relationship between ER stress and EDCF-mediated responses remains unclear. We tested the hypothesis that ER stress plays a role in EDCF-mediated responses via activation of the cPLA2/COX pathway in the aorta of the spontaneously hypertensive rat (SHR). Male SHR and Wistar-Kyoto rats (WKY) were treated with ER stress inhibitor, tauroursodeoxycholic acid or 4-phenlybutyric acid (TUDCA or PBA, respectively, 100 mg·kg(-1)·day(-1) ip) or PBS (control, 300 μl/day ip) for 1 wk. There was a decrease in systolic blood pressure in SHR treated with TUDCA or PBA compared with control SHR (176 ± 3 or 181 ± 5, respectively vs. 200 ± 2 mmHg). In the SHR, treatment with TUDCA or PBA normalized aortic (vs. control SHR) 1) contractions to acetylcholine (ACh), AA, and tert-butyl hydroperoxide, 2) ACh-stimulated releases of prostanoids (thromboxane A2, PGF2α, and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA2 and ERK1/2, and 5) production of H2O2. Our findings demonstrate a novel interplay between ER stress and EDCF-mediated responses in the aorta of the SHR. Moreover, ER stress inhibition normalizes such responses by suppressing the cPLA2/COX pathway.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Aorta; Arachidonic Acid; bcl-2-Associated X Protein; Blood Pressure; Cells, Cultured; Cyclooxygenase 1; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Endothelium, Vascular; Epoprostenol; Hydrogen Peroxide; Hypertension; Male; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenylbutyrates; Phospholipases A2, Cytosolic; Phosphorylation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Taurochenodeoxycholic Acid; tert-Butylhydroperoxide; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

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

This study evaluates a possible relationship between reactive oxygen species (ROS) and cyclooxygenase (COX)-2-derived products in conductance and resistance arteries from hypertensive animals. Angiotensin II (Ang II)-infused mice or spontaneously hypertensive rats treated with the NAD(P)H Oxidase inhibitor apocynin, the mitochondrion-targeted SOD2 mimetic Mito-TEMPO, the superoxide dismutase analog tempol, or the COX-2 inhibitor Celecoxib were used.. Apocynin, Mito-TEMPO, and Celecoxib treatments prevented Ang II-induced hypertension, the increased vasoconstrictor responses to phenylephrine, and the reduced acetylcholine relaxation. The NOX-2 inhibitor gp91ds-tat, the NOX-1 inhibitor ML171, catalase, and the COX-2 inhibitor NS398 abolished the ex vivo effect of Ang II-enhancing phenylephrine responses. Antioxidant treatments diminished the increased vascular COX-2 expression, prostanoid production, and/or participation of COX-derived contractile prostanoids and thromboxane A(2) receptor (TP) in phenylephrine responses, observed in arteries from hypertensive models. The treatment with the COX-2 inhibitor normalized the increased ROS production (O(2)·(-) and H(2)O(2)), NAD(P)H Oxidase expression (NOX-1, NOX-4, and p22phox) and activity, MnSOD expression, and the participation of ROS in vascular responses in both hypertensive models. Apocynin and Mito-TEMPO also normalized these parameters of oxidative stress. Apocynin, Mito-TEMPO, and Celecoxib improved the diminished nitric oxide (NO) production and the modulation by NO of phenylephrine responses in the Ang II model.. This study provides mechanistic evidence of circuitous relationship between COX-2 products and ROS in hypertension.. The excess of ROS from NAD(P)H Oxidase and/or mitochondria and the increased vascular COX-2/TP receptor axis act in concert to induce vascular dysfunction and hypertension.

Topics: Acetophenones; Animals; Antioxidants; Aorta; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprost; Endothelium, Vascular; Hypertension; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Oxidative Stress; Phenylephrine; Pyrazoles; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Sulfonamides; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

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

African Americans develop hypertension earlier with more target manifestations than whites despite having a higher glomerular filtration rate (GFR) for any level of serum creatinine. STUDY DESIGN & PARTICIPANTS: This study tested the hypothesis that increased GFR and sodium reabsorption in African Americans is associated with increased metabolic work and medullary hypoxia in 49 nondiabetic patients with essential hypertension (29 whites and 20 African Americans) following a constant-sodium diet (150 mEq/d) and renin-angiotensin system blockade.. Ethnicity, age, measured GFR, sodium excretion, and body mass index.. We examined cortical and medullary volumes and blood flows using multidetector computed tomography and intrarenal deoxyhemoglobin (R2*) using blood oxygen level-dependent magnetic resonance.. Blood pressure and sodium excretion were similar, whereas African Americans were more obese and had higher iothalamate GFRs. Renal cortical volumes did not differ, but medullary volumes adjusted for body size and age were higher in African Americans (32.3 ± 11.2 vs 25.1 ± 7.4 cm(3)/m(2) body surface area; P < 0.001). Sodium reabsorption and blood flows were higher in African Americans. Basal cortical deoxyhemoglobin values were similar between ethnic groups, whereas medullary R2* was higher in African Americans (39.7 ± 5.1 vs 36.3 ± 6.5/s; P = 0.02), but decreased to levels similar to whites after furosemide treatment. Levels of the circulating isoprostane prostaglandin F(2α) were higher in African Americans and daily urinary prostaglandin F(2α) excretion in African Americans correlated directly with renal blood flow (R = 0.71; P < 0.01).. Studies were limited to treated volunteers with normal kidney function without knowledge of prior nutrient intake.. These data show for the first time that increased sodium reabsorption in obese African American patients with hypertension was associated with enlarged medullary volumes, functional hypoxia related to solute reabsorption, and a direct relationship between blood flows and urinary isoprostane levels. Our results support a model of increased oxygen consumption and oxidative stress in African Americans that may accelerate hypertension and target-organ injury compared with white patients with essential hypertension.

Topics: Adult; Aged; Aged, 80 and over; Black or African American; Blood Pressure; Comorbidity; Dinoprost; Diuretics; Furosemide; Glomerular Filtration Rate; Humans; Hypertension; Hypoxia; Kidney Medulla; Middle Aged; Obesity; Organ Size; Sodium; Sodium, Dietary; White People

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

FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC(50)) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF(2alpha) (1 microg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 microg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.

Topics: Administration, Topical; Animals; Cats; Dinoprost; Drug Discovery; Eye Diseases; Glaucoma; Haplorhini; Hypertension; Intraocular Pressure; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits; Structure-Activity Relationship

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

Little is known about prostaglandin F(2alpha) in cardiovascular homeostasis. Prostaglandin F(2alpha) dose-dependently elevates blood pressure in WT mice via activation of the F prostanoid (FP) receptor. The FP is expressed in preglomerular arterioles, renal collecting ducts, and the hypothalamus. Deletion of the FP reduces blood pressure, coincident with a reduction in plasma renin concentration, angiotensin, and aldosterone, despite a compensatory up-regulation of AT1 receptors and an augmented hypertensive response to infused angiotensin II. Plasma and urinary osmolality are decreased in FP KOs that exhibit mild polyuria and polydipsia. Atherogenesis is retarded by deletion of the FP, despite the absence of detectable receptor expression in aorta or in atherosclerotic lesions in Ldlr KOs. Although vascular TNF(alpha), inducible nitric oxide enzyme and TGF(beta) are reduced and lesional macrophages are depleted in the FP/Ldlr double KOs, this result reflects the reduction in lesion burden, as the FP is not expressed on macrophages and its deletion does not alter macrophage cytokine generation. Blockade of the FP offers an approach to the treatment of hypertension and its attendant systemic vascular disease.

Topics: Animals; Atherosclerosis; Blood Pressure; Dinoprost; Female; Hypertension; Macrophages; Male; Mice; Mice, Knockout; Nitric Oxide Synthase Type II; Receptors, Prostaglandin; Renin; Tumor Necrosis Factor-alpha

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

The transcription factor PPARgamma is expressed in endothelium and vascular muscle where it may exert antiinflammatory and antioxidant effects. We tested the hypothesis that PPARgamma plays a protective role in the vasculature by examining vascular structure and function in heterozygous knockin mice expressing the P465L dominant negative mutation in PPARgamma (L/+). In L/+ aorta, responses to the endothelium-dependent agonist acetylcholine (ACh) were not affected, but there was an increase in contraction to serotonin, PGF(2alpha), and endothelin-1. In cerebral blood vessels both in vitro and in vivo, ACh produced dilation that was markedly impaired in L/+ mice. Superoxide levels were elevated in cerebral arterioles from L/+ mice and responses to ACh were restored to normal with a scavenger of superoxide. Diameter of maximally dilated cerebral arterioles was less, whereas wall thickness and cross-sectional area was greater in L/+ mice, indicating cerebral arterioles underwent hypertrophy and remodeling. Thus, interference with PPARgamma signaling produces endothelial dysfunction via a mechanism involving oxidative stress and causes vascular hypertrophy and inward remodeling. These findings indicate that PPARgamma has vascular effects which are particularly profound in the cerebral circulation and provide genetic evidence that PPARgamma plays a critical role in protecting blood vessels.

Topics: Acetylcholine; Animals; Aorta; Arterioles; Cerebrovascular Circulation; Dinoprost; Endothelin-1; Female; Gene Expression Profiling; Genes, Dominant; Hypertension; Hypertrophy; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; PPAR gamma; Serotonin; Serotonin Agents; Signal Transduction; Vasodilator Agents

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

Cysteinyl leukotrienes (cysLT) are pro-inflammatory and vasoactive products suspected to be involved in the regulation of vascular tone and blood pressure in hypertension.. We investigated, in spontaneously hypertensive rats (SHR), the involvement of cysLT in the in-vivo regulation of blood pressure and the in-vitro endothelium-dependent contraction to acetylcholine in isolated aorta.. SHR and Wistar-Kyoto rats (WKY) were orally treated for 3 weeks with either the cysLT biosynthesis inhibitor MK-886 (0.1 mg/ml) or vehicle. After mean arterial blood pressure (MABP) measurement, aortic ring preparations were removed from all groups of animals, and contractions and relaxations were monitored subsequent to stimulation with acetylcholine.. MABP was higher in SHR. Chronic treatment with MK-886 did not alter MABP in either SHR or WKY. In the presence of the N-nitro-L-arginine (L-NA, 100 micromol/l), and on prostaglandin F2alpha (PGF2alpha)-induced tone, acetylcholine evoked concentration-dependent contractions in intact aortic rings from SHR only. Pretreatment with either MK-886 (10 micromol/l), the 5-lipoxygenase (5-LO) inhibitor AA861 (10 micromol/l), or the cysLT1 receptor antagonist MK571 (1 micromol/l) reduced (P < 0.05) acetylcholine-induced contractions in intact aortic rings from SHR only. Acetylcholine-induced contractions were weaker (P < 0.01) in SHR chronically treated with MK-886 than in SHR. In the presence of L-NA, leukotriene (LT) D4 induced greater (P < 0.05) concentration-dependent contractions in aortic rings from SHR than from WKY. MK571 abolished LTD4-evoked contractions.. These data suggested that 5-LO-derived products, through the activation of cysLT1 receptors, could be involved in the endothelium-dependent contraction to acetylcholine in aorta from SHR but not in the regulation of MABP in SHR.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Arachidonate 5-Lipoxygenase; Benzoquinones; Biopterins; Blood Pressure; Body Weight; Dinoprost; Endothelium, Vascular; Hypertension; Indoles; Leukotriene D4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Nitroarginine; Propionates; Quinolines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Leukotriene; Vasoconstriction

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

Although inward rectifier K+ channels contribute to the regulation of cerebral circulation, dilation of cerebral microvasculature mediated by these channels has not been demonstrated in chronic hypertension. We designed the present study to examine the roles of inward rectifier K+ channels in the vasodilation produced by increased levels of extracellular K+ in cerebral parenchymal arterioles from hypertensive and normotensive rats. During constriction to prostaglandin F2alpha (5 x 10(-7) M), the arterioles within brain slices were evaluated using computer-assisted microscopy. Potassium chloride (KCl) induced vasodilation in cerebral arterioles from normotensive (5-10 mM) and hypertensive (5-15 mM) rats, whereas an inward rectifier K+ channel antagonist barium chloride (BaCl2; 10(-5) M) completely abolished the vasodilation in both strains. In arterioles of hypertensive rats, vasodilator responses to KCl were augmented compared with those in normotensive rats. In contrast, the vasodilator responses induced by sodium nitroprusside (3 x 10(-8) to 3 x 10(-6) M) in these two strains were similar. These results suggest that in cerebral cortex parenchymal microvessels, inward rectifier K+ channels play a crucial role in vasodilation produced by extracellular K+ and that the dilation of cerebral arterioles via these channels is augmented in chronic hypertension.

Topics: Animals; Arterioles; Barium Compounds; Blood Pressure; Brain; Cerebrovascular Circulation; Chlorides; Dinoprost; Dose-Response Relationship, Drug; Hypertension; Male; Nitroprusside; Potassium Channels, Inwardly Rectifying; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

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

We hypothesized that GLUT4 is a predominant facilitative glucose transporter in vascular smooth muscle cells (VSMCs), and GLUT4 is necessary for agonist-induced VSMC contraction.. Glucose deprivation and indinavir, a GLUT4 antagonist, were used to assess the role of GLUT4 and non-GLUT4 transporters in vascular reactivity. In isolated endothelium-denuded mouse aorta, approximately 50% of basal glucose uptake was GLUT4-dependent. Norepinephrine-mediated contractions were dependent on both GLUT4 and non-GLUT4 transporters, serotonin (5-HT)-mediated contractions were mainly GLUT4-dependent, and prostaglandin (PG) F(2alpha)-mediated contractions were dependent on non-GLUT4 transporters, whereas indinavir had no effect in GLUT4 knockout vessels. We also observed a 46% decrease in GLUT4 expression in aortas from angiotensin II hypertensive mice. Indinavir caused a less profound attenuation of maximal 5-HT-mediated contraction in these vessels, corresponding to the lower GLUT4 levels in the hypertensive aortas. Finally, and somewhat surprisingly, chronic GLUT4 knockout was associated with increased vascular reactivity compared with that in wild-type animals, suggesting that chronic absence or reduction of GLUT4 expression in VSMCs leads to opposite effects observed with acute inhibition of GLUT4.. Thus, we conclude that GLUT4 is constitutively expressed in large arteries and likely participates in basal glucose uptake. In addition, GLUT4, as well as other non-GLUT4 facilitative glucose transporters, are necessary for agonist-induced contraction, but each transporter participates in VSMC contraction selectively, depending on the agonist, and changes in GLUT4 expression may account for some of the functional changes associated with vascular diseases like hypertension.

Topics: Angiotensin II; Animals; Aorta; Cattle; Cells, Cultured; Dinoprost; Endothelial Cells; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 4; HIV Protease Inhibitors; Hypertension; Indinavir; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Norepinephrine; Serotonin; Vasoconstriction; Vasoconstrictor Agents

The extent of involvement of cyclooxygenase (COX)-mediated inflammation in type 1 diabetes is unknown, and the association between the COX- and cytokine-mediated inflammatory responses in type 1 diabetes is not fully understood.. Plasma high-sensitivity C-reactive protein (CRP), 24-h urinary and plasma 15-keto-dihydro-prostaglandin F(2alpha) (a metabolite of prostaglandin F(2alpha) [PGF(2alpha)] and an indicator of COX-mediated inflammation), serum amyloid protein A (SAA), and interleukin (IL)-6 (indicators of inflammation) were measured in 38 subjects with type 1 diabetes and 41 healthy age- and sex-matched control subjects.. The inflammatory indicators (urinary 15-keto-dihydro-PGF(2alpha), P < 0.01; IL-6, P < 0.04) were increased in men with diabetes. CRP and SAA did not show any significant difference between the diabetic and the control subjects. Urinary levels of 15-keto-dihydro-PGF(2alpha) correlated with the degree of glycemic control, HbA(1c) (r = 0.42, P < 0.0005). No correlation was found between the duration of diabetes and the inflammatory biomarkers or metabolic measurements.. These results suggest that an early low-grade inflammatory process reflected by elevated levels of PGF(2alpha) and IL-6 is involved in type 1 diabetes. Thus, both COX- and cytokine-mediated inflammatory pathways are significantly related to type 1 diabetes.

Topics: Adult; Albuminuria; C-Reactive Protein; Cytokines; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dinoprost; Female; Humans; Hypertension; Inflammation; Lipids; Male; Reference Values; Regression Analysis

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

Prostaglandin F(2alpha) (PGF(2alpha)) plays an important role in pathologic cardiac growth. After testing several immune cytokines, we found that interferon-gamma (IFN-gamma) inhibited responsiveness of adult myocytes to PGF(2alpha). The present study was designed to test the hypothesis that IFN-gamma inhibits cardiac hypertrophy induced by PGF(2alpha). Incubation of cultured adult rat cardiac myocytes with PGF(2alpha) caused cell spreading, which was inhibited by IFN-gamma. The inhibitory effect was not affected by nitric oxide (NO) synthase inhibitors. In addition, administration of fluprostenol, a more selective agonist at the PGF(2alpha) receptor, induced cardiac hypertrophy in rats. Chronic treatment with IFN-gamma inhibited this myocardial growth, and the inhibitory effect of IFN-gamma was not accompanied by an increase in myocardial NO synthase gene expression. Further, abdominal aortic constriction resulted in a substantial increase in heart, ventricular and left ventricular weights to BW ratio that was significantly attenuated by treatment with IFN-gamma. The results demonstrate that IFN-gamma inhibits the in vitro and in vivo effects of PGF(2alpha) on cardiac hypertrophy, and that the mechanism of action is likely independent of NO production. IFN-gamma also attenuated cardiac hypertrophy induced by pressure overload, suggesting that PGF(2alpha) plays a role in the pathogeneses of this severe type of cardiac hypertrophy.

Topics: Animals; Blotting, Northern; Cardiomegaly; Dinoprost; Dose-Response Relationship, Drug; Gene Expression; Hemodynamics; Hypertension; Interferon-gamma; Male; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; RNA, Messenger

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

Dietary saturated fat (SF) has adverse effects on cardiac and vascular smooth muscle (VSM) contractility. Furthermore, VSM of spontaneously hypertensive rats (SHR) is overreactive to various biological stimuli. The aim of this study was to investigate the effects of increasing dietary fat as lard on gut contractility in SHR. Control Wistar-Kyoto (WKY) rats and SHR (13 wk old) were fed for 12 wk a diet containing 3% sunflower oil [low fat (LF), 3% total fat] or diets supplemented with 7% lard [medium fat (MF), 10% total fat] or 27% lard [high fat (HF), 30% total fat]. For ileal and colonic tissues (WKY and SHR), there was a lower total phospholipid PUFA (n-6)/(n-3) ratio with increased dietary SF (P < 0.003). For WKY, increasing SF led to lower levels of the major SCFA and lower total SCFA levels in cecal digesta (P < 0.01). This trend was evident in SHR but significant only for butyrate (P < 0.01). Contractility responses were unaltered in ileum. In colon, there was a change of sensitivity (50% effective concentration) to angiotensin II in WKY (P < 0.05) due to increased SF and a change of sensitivity to prostaglandin (PG)E(2) and carbachol in SHR (P < 0.05). When the 3 dietary groups were combined, there was lower sensitivity (P < 0.01) and lower maximal contraction (P < 0.05) in ileum and lower maximal contraction in colon of SHR in response to PGF(2alpha) (P < 0.05) and PGE(2) (P < 0.01) compared with WKY. Unlike (n-3) PUFA, dietary SF had little overall effect on gut contractility. However, this is the first report of a defect in PG responsiveness from gut tissue from hypertensive rats.

Topics: Animals; Cecum; Colon; Dietary Fats; Dinoprost; Dinoprostone; Fatty Acids; Hydrogen-Ion Concentration; Hypertension; Ileum; Intestines; Muscle Contraction; Muscle, Smooth; Phospholipids; Prostaglandins; Rats; Rats, Inbred SHR; Rats, Inbred WKY

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

It is still unknown whether mechanisms of the hypertensinogenic effect of lead include changes in synthesis or release of vasoactive agents. This question is essential with regard to lead dissemination in the human environment as well as to frequent occurrence of arterial hypertension.. The aim of the study was to evaluate the effect of chronic exposure to lead on the vasoactive agents in blood in relation to redox system activity in vessel walls and to disturbances in homeostasis of essential metals. Using lead in double small, hypertensive doses we tried to estimate whether this effect dependents on the degree of lead exposure.. The study was performed on the male Buffalo rats which were given lead in drinking water, 50 or 100 ppm (lead acetate dissolved in distillate water) for 12 weeks. Control rats were given distillate water. Rats were fasted starting the night before the experiment, and the next day were anesthetized intramuscularly with ketaminum at a dose of 300 mg/kg body weight. The abdomen was opened and the aorta was isolated. Blood samples were drawn from heart, abdominal and thoracic aorta and then kidneys were excised. Serum nitric oxide and prostaglandin PGF(2alpha) concentrations were measured using R&D systems, and the plasma endothelin-1 level with enzymoimmunoassay; 5% homogenates of aorta were prepared from thoracic fragment in saccharose buffer. Lipid peroxides in homogenates were determined colorimetrically and glutathione was measured using colorimetric assay BIOXYTECH GSH-400. The concentration of metals (lead, copper and zinc) in blood and aorta were determined with a plasma spectrometer.. The study shows different changes in toxicological and biochemical status, depending on the dose of metal. Mean serum nitric oxide concentration was higher in rats treated with lead in a dose of 50 ppm (p < 0.01) or 100 ppm (p < 0.001) than in the control group. The plasma endothelin-1 level was lower in rats given lead in a dose of 50 ppm (p < 0.05) than in controls, whereas serum prostaglandin PGF(2alpha) concentration was similar in all animals. Glutathione concentration in aorta was higher in both groups of rats treated with lead (p < 0.001) in comparison to controls. There were positive linear dependencies between: (a) blood lead and serum nitric oxide; (b) aorta glutathione and serum nitric oxide; (c) copper in aorta and glutathione in aorta; (d) serum zinc and plasma endothelin-1 concentrations.. It was concluded, that lead in small doses increases synthesis and/or releases nitric oxide and its concentration in serum. This effect of lead is probably connected with the augmented production of glutathione in vessel walls. Additionally, lead in a dose of 50 ppm provokes the decrease in the level of plasma endothelin-1, probably through the decreased level of serum zinc. We suppose that the mechanisms responsible for the vascular effect of lead differ even within the range of hypertensive doses.

Topics: Animals; Copper; Dinoprost; Endothelin-1; Hypertension; Lead; Lead Poisoning; Nitric Oxide; Rats; Rats, Inbred BUF; Vasodilator Agents; Zinc

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

To explore the binding point of Syndrome Differentiation of TCM and disease differentiation by western medicine.. Selected laboratory diagnostic indexes were tested in 59 cases of Liver-Fire Ascending Syndrome (LFAS). Referring to clinical typing and staging, the data obtained were analysed by same syndrome with different diseases and same disease with different syndrome as well as the values determined in related syndrome-types were compared.. The levels of prostaglandin F2 alpha (PGF2 alpha) and arginine vasopressin (AVP) in patients of LFAS were higher than those in patients with Liver-Kidney Yin-Deficiency Syndrome and Liver-Yang Hyperactivity Syndrome. As for linking between Syndrome-type and stage of disease, most cases (70%) of herpes simplex viral keratitis of LFAS were deep matrix layer type; and 100% hypertension patients with LFAS belonged to stage II.. PGF2 alpha and AVP could be used as the reference laboratory diagnostic indexes of LFAS.

Topics: Adult; Aged; Arginine Vasopressin; Diagnosis, Differential; Dinoprost; Female; Humans; Hypertension; Keratitis, Herpetic; Male; Medicine, Chinese Traditional; Middle Aged; Norepinephrine; Yin Deficiency

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

1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. 2. Quercetin induced a significant reduction in systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha) excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. 6. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.

Topics: Acetylcholine; Animals; Antioxidants; Aorta; Blood Pressure; Body Weight; Dinoprost; Endothelium, Vascular; Heart Rate; Heart Ventricles; Hypertension; In Vitro Techniques; Kidney; Male; Malondialdehyde; Nitroprusside; Norepinephrine; Organ Size; Oxidants; Potassium Chloride; Quercetin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

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

1. The substrate of nitric oxide synthase (NOS), L-arginine (L-Arg, 0.01 microM - 1 mM), induced endothelium-independent relaxations in segments of middle cerebral arteries (MCAs) from normotensive Wistar-Kyoto (WKY) and hypertensive rats (SHR) precontracted with prostaglandin F2alpha (PGF2alpha). These relaxations were higher in SHR than WKY arteries. 2. L-N(G)-nitroarginine methyl ester (L-NAME) and 2-amine-5,6-dihydro-6-methyl-4H-1,3-tiazine (AMT), unspecific and inducible NOS (iNOS) inhibitors, respectively, reduced those relaxations, specially in SHR. 3. Four- and seven-hours incubation with dexamethasone reduced the relaxations in MCAs from WKY and SHR, respectively. 4. Polymyxin B and calphostin C, protein kinase C (PKC) inhibitors, reduced the L-Arg-induced relaxation. 5. Lipopolysaccharide (LPS, 7 h incubation) unaltered and inhibited these relaxations in WKY and SHR segments, respectively. LPS antagonized the effect polymyxin B in WKY and potentiated L-Arg-induced relaxations in SHR in the presence of polymyxin B. 6. The contraction induced by PGF2alpha was greater in SHR than WKY arteries. This contraction was potentiated by dexamethasone and polymyxin B although the effect of polymyxin B was higher in SHR segments. LPS reduced that contraction and antagonized dexamethasone- and polymyxin B-induced potentiation, these effects being greater in arteries from SHR. 7. These results suggest that in MCAs: (1) the induction of iNOS participates in the L-Arg relaxation and modulates the contraction to PGF2alpha; (2) that induction is partially mediated by a PKC-dependent mechanism; and (3) the involvement of iNOS in such responses is greater in the hypertensive strain.

Topics: Animals; Anti-Bacterial Agents; Arginine; Cerebral Arteries; Cyclooxygenase Inhibitors; Dexamethasone; Dinoprost; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Glucocorticoids; Hypertension; In Vitro Techniques; Indomethacin; Lipopolysaccharides; Male; Naphthalenes; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Polymyxin B; Protein Kinase C; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Superoxide Dismutase; Vasodilation

To measure in-vitro responses to the thromboxane A2 (TxA2) mimetic U46619 in the fetal placental vasculature of human placentae from normotensive women and those with pre-eclampsia. Furthermore, to compare fetal vascular responses to endothelin-1,5-hydroxytryptamine, potassium chloride (KCl) and prostacyclin (PGI2) in placentae from normal or pre-eclamptic pregnancies.. Single placental lobules of intact placentae were bilaterally perfused in situ (fetal and maternal) with constant flows of Krebs' solution. Changes in fetal arterial perfusion pressure during intra-arterial infusion of vasoactive agents were recorded. Fetal placental vasoconstrictor concentration response curves were obtained to U46619 (0.01-300 nmol/l), endothelin-1 (0.4-160 nmol/l), KCl (3-300 mmol/l) and 5-hydroxytryptamine (0.03-30 mumol/l). In addition, vasodilator concentration response curves were obtained for PGI2 (1.2-350 nmol/l) in the fetal placental circulation during submaximal increases in perfusion pressure with prostaglandin F2 alpha (PGF2 alpha; 0.7-2.0 mumol/l).. The maximum increase in perfusion pressure caused by U46619 in placentae from normotensive women was 194 +/- 25 mmHg. The maximum response to U46619 was significantly reduced in the placentae from women with pre-eclampsia (104 +/- 21 mmHg). In contrast, there were no differences in constrictor responses to endothelin-1,5-hydroxytryptamine and KCl, or in dilator responses to PGI2 in placentae obtained from either normotensive women or those with pre-eclampsia.. TxA2 receptor-mediated vasoconstriction is reduced in the fetal vasculature of placentae from women with pre-eclampsia, possibly to compensate for the increased levels of TxA2 seen in these conditions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Antihypertensive Agents; Dinoprost; Endothelin-1; Epoprostenol; Female; Fetus; Free Radical Scavengers; Humans; Hypertension; In Vitro Techniques; Oxytocics; Placenta; Potassium Chloride; Pregnancy; Pregnancy Complications, Cardiovascular; Serotonin; Vasoconstriction; Vasoconstrictor Agents

Methylripariochromene A (MRC) was isolated from the leaves of Orthosiphon aristatus (Lamiaceae) and subjected to the examination of several pharmacological actions related to antihypertensive activity. The following four findings were revealed from the present study: 1) MRC caused a continuous decrease in systolic blood pressure and a decrease in heart rate after subcutaneous administration in conscious male SHRSP, 2) MRC exhibited the concentration-dependent suppression of contractions induced by high K+, l-phenylephrine or prostaglandin F2alpha in endothelium-denuded rat thoracic aorta, 3) MRC showed a marked suppression of contractile force without a significant reduction in the beating rate in isolated bilateral guinea pig atria, and 4) MRC increased urinary volume and the excretion of Na+, K+ and Cl- for 3 h after oral administration with a load of saline in fasted rats. These findings indicate that MRC possesses some actions related to a decrease in blood pressure, i.e. vasodilating action, a decrease in cardiac output and diuretic action. Furthermore, it is presumed that the traditional use of this plant in the therapy of hypertension may be partially supported by these actions with MRC.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Atrial Function; Benzopyrans; Blood Pressure; Calcium; Dinoprost; Electrolytes; Guinea Pigs; Heart Rate; Hypertension; Indonesia; Male; Phenylephrine; Plants, Medicinal; Potassium; Rats; Rats, Inbred SHR; Rats, Wistar; Vasoconstriction

Prostacyclin (PGI2), thromboxane A2 (TXA2) and F2-isoprostanes, prostaglandin F2-like compounds, have wide and contrasting spectrum of biological activities and may influence blood pressure and atherogenesis. To investigate the dynamics of PGI2, TXA2 and F2-isoprostanes in patients with hypertension and hyperlipidemia (HH group), we measured the major urinary metabolites of PGI2: 6-keto PGF1alpha (Keto) and 2,3-dinor-6-keto PGF1alpha, (Dinor), those of TXA2:TXB2 and 11-dehydro TXB2 (Dehydro), and urinary 8-isoprostane (Iso) in 34 patients. Urinary excretion of Dinor was significantly lower in patients than in controls and that of Dehydro was significantly higher in patients than in controls. Keto, TXB2 and Iso were not significantly different between them. Antiplatelet agents decreased not only TXA2 metabolites but also PGI2 metabolites. Urinary C-peptide immunoreactivity was correlated with Dinor and Dehydro. After administration of eicosapentaenoic acid (EPA), total cholesterol (T-cho) and triglycerides (TG) significantly decreased. Although prostanoids did not show significant change, changes in T-cho were correlated with changes in Dinor and changes in Iso. These results suggest that PGI2 and TXA2 of systemic origin might be related to the pathophysiology of hypertension and hyperlipidemia and that the dynamics of PGI2, TXA2 and F2-isoprostanes might be related to not only blood pressure regulation but also lipid and glucose metabolism.

Topics: Aspirin; Dinoprost; Dipyridamole; Eicosapentaenoic Acid; Epoprostenol; Humans; Hyperlipidemias; Hypertension; Platelet Aggregation Inhibitors; Thromboxane A2; Ticlopidine

In human and experimental hypertension, flow (shear stress)-induced dilation in large arteries is attenuated and resistant to nitric oxide blockade. We tested the hypothesis that a defect in nitric oxide-and/or prostaglandin-dependent flow-induced dilation might occur in mesenteric resistance arteries from spontaneously hypertensive rats (SHR). We measured resistance mesenteric artery diameter in situ by intravital microscopy and simultaneously measured mesenteric arterial pressure in a collateral artery. The flow-diameter-pressure relationship was established in normotensive Wistar-Kyoto rats (WKY) and in SHR under control conditions and after endothelium removal, inhibition of nitric oxide synthesis with N omega-nitro-L-arginine methyl ester (10 micromol/L), or inhibition of prostaglandin synthesis with indomethacin (10 micromol/L). Production of prostaglandins was determined in the perfusate. Endothelium removal decreased artery diameter by 14 +/- 1.6% in WKY and 5 +/- 0.5% (P<.01 versus WKY) in SHR at a flow rate of 400 microL/min. In WKY, N omega-nitro-L-arginine methyl ester and indomethacin decreased resistance artery diameter by 12 +/- 3% (P<.001) and 5 +/- 2% (P<.01), respectively, at a flow rate of 400 microL/min; neither substance had any significant effect in SHR. In both strains, flow induced the production of 6-keto-prostaglandin F1alpha, the metabolite of prostacyclin; prostaglandin F2alpha; and thromboxane B2, the stable metabolite of thromboxane A2. Production of 6-keto-prostaglandin F1alpha and prostaglandin F2alpha was significantly lower in SHR than WKY, and TxB2 production was significantly higher in SHR than WKY. The present findings suggest that in SHR mesenteric resistance arteries, dilation in response to increases in flow was resistant to nitric oxide and prostaglandin synthesis blockade. A modification of the ratio of vasodilator to vasoconstrictor prostaglandins might be at least partly responsible for the decreased dilator response to flow in SHR.

Topics: Animals; Dinoprost; Hypertension; Mesenteric Arteries; Nitric Oxide; Prostaglandins; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regional Blood Flow; Thromboxane B2; Vascular Resistance

To compare renin-sodium profile and renal prostaglandins (PGs) of Black normotensive and hypertensive patients, with the same parameters of Caucasian normotensives and hypertensives, e.g. to reveal some of the ethnic differences in the pathogenesis of systemic (essential) hypertension.. 27 Black Zimbabwean normotensive and 27 hypertensive patients were matched by age, sex and number to Caucasian normotensives and hypertensives (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 95 mm Hg, or both). All were examined during two protocols producing sodium depletion (less than 40 mmol sodium diet/day) for five days, followed by sodium loading (300 mmol sodium diet/day) for another five days. Changes in plasma renin activity (PRA), urinary aldosterone (Aldo), prostaglandin E2(PGE2) and prostaglandin F2 alpha (PGF2 alpha) excretions were simultaneously assessed by radioimmunoassay.. Compared to caucasians the Blacks showed similar basal aldosterone and Na+ excretion but significant Na+ retention (30pc) during Na+ loading. Their basal PRA was lower (32pc) and poorly responding to sodium depletion/loading. They had suppressed PG synthesis, the PGE2/PGF2 ratio being significantly decreased 11pc. Renin profiles, obtained by plotting PRA against urinary Na+ excretion showed prevalence of low renin hypertension (62pc) in Black patients. All Caucasian patients had normal renin hypertension. At basal level the Black hypertensives had suppressed synthesis of vasodilator PGF2/PGF2 alpha ratio by 32pc. This finding was in accordance with their low renin hypertension. During sodium depletion the PGs excretion was increased in both hypertensive groups. The opposite effect was found during sodium loading.. This study shows ethnic differences in renin-sodium profile and renal PG synthesis, during changes in dietary sodium. It addresses an old medical controversy about the usefulness of renin profiling in identifying hypertensive patients who are at increased risk for heart attack (Whites with normal/high renin hypertension) or increased risk of stroke (Blacks with low renin, sodium mediated hypertension).

Topics: Adult; Aldosterone; Black People; Case-Control Studies; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Male; Renin; Sodium; White People

Decreased response to vasopressor agents characterizes pregnancy. Endothelium-derived relaxing factors and vasodilating prostaglandins play an important role in the vascular tone during pregnancy. Since inhibition of nitric oxide (NO) biosynthesis induced by NO2-arginine enriched diet produced hypertension we measured in vivo cardiovascular responses to PGF2 alpha, L-arginine (L-arg) and cicletanine (Cic, IPSEN, France) which enhances PGI2 production. From day 13 to day 20 of gestation 4 groups of female Wistar rats were fed NO2-arg (31 mg/kg/d), NO2-arg+Cic (10 mg/kg/d), Cic enriched or control diet (C). Mean arterial pressure (MAP) was measured via a carotid catheter in anesthetized rats. Injection of PGF2 alpha (50 micrograms/kg) in jugular vein significantly increased MAP in the NO2-arg group versus, NO2-arg+Cic, Cic and C group (+23.5 +/- 3.3 vs +15.7 +/- 2.2, +15.8 +/- 2.2 and +17 +/- 1.85 mmHg; p < 0.01). Injection of L-arg (100 mg/kg) or Cic (1 mg/kg) 5 min before PGF2 alpha produced no modification in MAP in C and Cic group. Likewise in NO2-arg group injection of L-arg or Cic produced a diminished pressor response to PGF2 alpha (+23.5 +/- 3.3 vs -17.5 +/- 1.7 mmHg; p < 0.05 and +15.2 +/- 2.4 mmHg; p < 0.01 respectively). In NO2-arg+Cic group, only injection of Cic induced a diminished pressor response to PGF2 alpha which is more important without L-arg (+15.7 +/- 2.2 vs +9.1 +/- 1.3 mmHg; p < 0.001) or with L-arg (+13.6 +/- 1.5 vs +9.1 +/- 1.3 mmHg; p < 0.01). Cicletanine also significantly diminished the proteinuria in the NO2-arg+Cic group versus NO2-arg group (13.9 +/- 4.36 vs 63.4 +/- 21.6 mmHg; p < 0.01). IN CONCLUSION, chronic NO synthesis inhibition enhanced blood pressure and pressor responses to PGF2 alpha during pregnancy in rats. Chronic administration of cicletanine in Wistar pregnant rats decreases the response to vasopressor agents like PGF2 alpha. Moreover acute and chronic administration of cicletanine blunted the pressor effect, which was lower than in normal gestation.

Topics: Animals; Antihypertensive Agents; Arginine; Blood Pressure; Dinoprost; Enzyme Inhibitors; Female; Hypertension; Nitric Oxide; Nitroarginine; Oxytocics; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy, Animal; Prostaglandins F; Proteinuria; Pyridines; Rats; Rats, Wistar; Vasoconstriction

This study examined the activity of sodium nitroprusside (SNP) in the human fetal-placental circulation in vitro in pathological and experimental conditions in which vascular function may be impaired. SNP (13-3400 nM) caused a concentration-dependent reduction in fetal arterial perfusion pressure (FAP) in Krebs' perfused placental cotyledons, at basal tone and following pre-constriction with prostaglandin F2 alpha (PGF2 alpha). SNP-induced reduction in FAP in the PGF2 alpha pre-constricted fetal-placental circulation was enhanced approximately six-fold (5.85) in those placentae pre-treated with the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (100 microM). Reductions in FAP in the preconstricted fetal-placental vasculature caused by SNP were not altered by prior infusion of ouabain (100 nM) into the fetal circulation or during low oxygen perfusion (O2 tension < 50 mmHg). No differences were observed in the responses obtained to SNP in placentae obtained from women with normotensive pregnancies or those associated with (i) pregnancy-induced hypertension, (ii) intra-uterine growth retardation, or (iii) an elevated umbilical-artery Doppler-ultrasound systolic/diastolic ratio, in either preconstricted placentae or those at basal tone. These findings are consistent with an up-regulation of guanylate cyclase/cGMP-mediated vasodilatation in the fetal-placental vasculature following complete blockade of endogenous NO production.

Topics: Adolescent; Adult; Arginine; Blood Pressure; Dinoprost; Enzyme Inhibitors; Female; Fetal Growth Retardation; Fetus; Humans; Hypertension; In Vitro Techniques; Nitric Oxide Synthase; Nitroarginine; Nitroprusside; Ouabain; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Vasoconstriction; Vasodilation

The hypolipidemic, antiatherogenic and thrombolytic effects and decrease of prostaglandin F2 alpha (PG) excretion were observed in 55 patients suffering from Ischemic heart disease, hyperlipidemia and hypertension fed the antiatherosclerotic diet containing 20 g of eiconol during 55 days. The low initial level of natural antibodies to PGF2 alpha was increased significantly in blood serum. Authors consider that decrease of PGF2 alpha level under diet influence is connected not only with the change of fatty acid composition of cell membranes but also with increasing of natural antibody production.

Topics: Adult; Aged; Diet, Atherogenic; Dietary Fats, Unsaturated; Dinoprost; Fatty Acids, Omega-3; Female; Fish Oils; Humans; Hyperlipidemias; Hypertension; Hypolipidemic Agents; Immunity, Innate; Male; Middle Aged; Myocardial Ischemia

To study the changes of endothelium-dependent and -independent relaxation in structurally remodeled pulmonary arteries with hypoxic pulmonary hypertension and their reversibility during recovery in room air, rats were exposed to hypobaric hypoxia (air at 380 mmHg) for 10 days and then allowed to recover in room air for 3, 14, 28, or 56 days. Relaxation by acetylcholine, sodium nitroprusside (SNP), and isoproterenol was depressed in large- and small-conduit pulmonary arterial rings from rats exposed to 10 days of hypoxia. The relaxant response to isoproterenol and SNP was normalized completely after 3 and 28 days of recovery, respectively. The relaxation by acetylcholine was still impaired at high concentrations after 56 days. A cyclooxygenase inhibitor, indomethacin, enhanced relaxation by acetylcholine of rings from experimental rats but not from control rats. Endothelium-denuded rings showed no difference in the response to acetylcholine between control and experimental rats. In conclusion, the impaired response to acetylcholine may be related to acetylcholine-induced, cyclooxygenase-dependent production of a vasoconstrictor by endothelial cells and to depressed smooth muscle response to nitric oxide (NO). During recovery, the NO-induced guanosine 3',5'-cyclic monophosphate-dependent dilation returned to normal. However, the release of cyclooxygenase-dependent production of a vasoconstrictor may persist even after 56 days of recovery.

Topics: Animals; Body Weight; Dinoprost; Endothelium, Vascular; Hypertension; Hypertrophy, Right Ventricular; Hypoxia; Male; Nitric Oxide; Potassium Chloride; Pulmonary Artery; Rats; Rats, Wistar; Vasodilator Agents

Chronic hypertension is associated with impaired endothelial function [i.e., reduced synthesis/release of endothelium-derived relaxing factor (EDRF) and increased synthesis/release of endothelium-derived contracting factor (EDCF)] in both animals and humans. Although it is not known whether endothelial dysfunction is the consequence and/or an important pathogenetic cause of hypertension, the goal of effective antihypertensive therapy should include restoration of normal endothelial function as well. Because angiotensin I-converting enzyme (ACE) inhibitors are effectively used in the treatment of hypertension, the aim of the present study was to test whether in vivo treatment of spontaneously hypertensive rats (SHRs) with the ACE inhibitor cilazapril improves endothelial function in the isolated thoracic aorta of SHRs. Treatment of SHRs with cilazapril (10 mg/kg/day orally for 2 weeks) resulted in a significant decrease in blood pressure and normalization of endothelium-dependent relaxation evoked by acetylcholine (ACh) and adenosine diphosphate (ADP). However, cilazapril treatment had no significant effect on endothelium-dependent contractions evoked by 5-hydroxytryptamine (5-HT; serotonin) and prostaglandin F2 alpha (PGF2 alpha). In contrast, in vitro treatment of isolated thoracic aortas with indomethacin (10(-5) M) normalized endothelium-dependent relaxations to ACh and ADP as well as inhibited endothelium-dependent contractions to 5-HT and PGF2 alpha. These results suggest that the ACE inhibitor cilazapril increases the synthesis/release of EDRFs whereas indomethacin prevents the synthesis/release of cyclo-oxygenase-derived EDCFs in the endothelium of rat aorta. The exact mechanism of action of ACE inhibitors on endothelial dysfunction remains to be determined.

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Aorta, Thoracic; Blood Pressure; Cilazapril; Dinoprost; Endothelium, Vascular; Hypertension; In Vitro Techniques; Indomethacin; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Phenylephrine; Rats; Rats, Inbred SHR; Rats, Wistar; Serotonin

In blood pressure (BP) reduction induced by gallopamil, hydralazine and prazosin in patients with essential hypertension a common trend was found in renal prostanoid production which included increased TxB2 excretion and/or augmented TxB2/6-keto-PGF1alfa ratio and, with the exception of response to prazosin, enhanced PGF2alfa excretion. Role of direct biochemical actions by the drugs in these responses was excluded by in vitro experiments with kidney slices from rats. The clinical and in vitro experimental findings suggested a mediator role of sympathetic activation but not that of the increased renin release in the urinary eicosanoid responses. Significant correlation was observed between the changes in reabsorbed amounts of sodium and excreted amounts of TxB2 and PGF2alfa. The results suggest that the reactivity of pressure type prostanoids in the kidney could be considered as part of a more complex renal counteraction to BP decrease.

Topics: Adolescent; Adult; Blood Pressure; Dinoprost; Epoprostenol; Female; Gallopamil; Glomerular Filtration Rate; Humans; Hydralazine; Hypertension; Kidney; Male; Middle Aged; Prazosin; Prostaglandins; Sodium; Thromboxane A2; Vasodilator Agents; Venous Pressure

The contractile potencies of the alpha-adrenoceptor agonist phenylephrine (PhE) and two nonadrenergic vasoconstrictors, prostaglandin F2 alpha (PGF2 alpha) and endothelin, were evaluated in renal arterial muscle strips isolated from obese hypertensive (OH) dogs. Responses were compared with those obtained from renal arteries isolated from lean normotensive (LN) dogs. Identical dose-response curves were produced by PGF2 alpha in arteries from OH and LN dogs. This was also true for endothelin. However, the vasoconstrictor potency of PhE for arteries from OH dogs was approximately 2.5-fold less than that for arteries from LN dogs. This difference was not dependent on endothelial integrity. Although they were less potent to PhE, arteries from OH dogs did not produce weaker maximum contractile responses than arteries from LN dogs; responses produced by maximum K+ depolarization (S(o)) were approximately 2 x 10(5) N/m2, and responses to the maximally effective concentrations of PhE, PGF2 alpha, and endothelin were approximately 0.97-, 0.50-, and 0.87-fold S(o), respectively. In addition to the rightward shift in contractile potency to PhE, arteries from OH dogs precontracted with a maximum PhE concentration relaxed more to a high nitroglycerin concentration than did arteries from LN dogs. At a PhE concentration that produced equivalent maximum force responses, arteries from OH dogs had a lower rate of muscle shortening than did arteries from LN dogs, suggesting reduced cross-bridge activation in the arteries from OH dogs. These data suggest that alpha-adrenoceptor-induced activation was selectively downregulated in renal arteries from OH dogs.

Topics: Animals; Dinoprost; Dogs; Endothelins; Female; Hypertension; In Vitro Techniques; Nitroglycerin; Obesity; Phenylephrine; Receptors, Adrenergic, alpha; Renal Artery; Vasoconstriction; Vasodilation

The influence of indapamide on the prostaglandin system was studied in spontaneously hypertensive rats (SHR) and compared with SHR control and normal WKY rats. The results show that the synthesis of vasoconstrictive prostaglandins (PGE2 and PGF2 alpha) in the renal medullary tissues of SHR is higher than that of normal rats, and this may have something to do with the development and maintenance of high blood pressure in SHR. After indapamide administration, the synthesis of prostacyclin in SHR aorta increased significantly as compared with the SHR control group, whereas PGE2 and PGF2 alpha production in renal medullary tissues decreased markedly. The results support the idea that the prostaglandin system, especially PGE2 and PGF2 alpha, plays an important role in the antihypertensive mechanism of indapamide.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Dinoprost; Dinoprostone; Female; Hypertension; Indapamide; Kidney Medulla; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane B2

Chronic subcutaneous administration of heparin consistently lowers blood pressure in hypertensive rats. This antihypertensive effect is related at least in part to a concomitant decrease in hematocrit. Groups of spontaneously hypertensive (SHR) and normotensive Wistar (NWR) rats were treated with subcutaneous heparin (700 U/d) for 6 weeks. Weekly determinations of systolic blood pressure (tail-cuff) and hematocrit were done. Peripheral plasma renin activity, plasma aldosterone, plasma prostaglandins (PGs) (PGF2 alpha, PGI2), thromboxane A2, and urinary kallikrein were measured. Blood pressure responses of acute and chronic heparin treatment to vasoconstrictor substances, including angiotensin I, angiotensin II, and norepinephrine, were determined. As before, heparin produced a significant (P < .01) decrease in hematocrit in both SHRs and NWRs, but a parallel decrease in blood pressure was noted only in SHRs. A significant (P < .001) increase in plasma renin activity was found in heparin-treated SHRs and NWRs; however, a corresponding elevation of plasma aldosterone level was noted only in heparin-treated NWR. Plasma aldosterone level significantly (P < .01) decreased in heparin-treated SHRs. Plasma PGs and urinary kallikrein levels were not different among the groups. The blood pressure responses to vasoconstrictor substances were essentially similar among the heparin-treated and control groups. These findings suggest that PGs or kallikrein have a slight or no role in determining the antihypertensive effect of heparin. Conversely, the results suggest that a reduced aldosterone level contributes to the antihypertensive mechanism of heparin.

Topics: Aldosterone; Animals; Blood Pressure; Dinoprost; Epoprostenol; Hematocrit; Heparin; Hypertension; Injections, Subcutaneous; Kallikreins; Prostaglandins; Rats; Rats, Inbred SHR; Rats, Wistar; Renin-Angiotensin System; Thromboxane A2

The isolated and perfused kidney of the spontaneously hypertensive rat (SHR) exhibits an increased vascular reactivity and a delayed tachyphylaxis to serotonin (5-hydroxytryptamine) when compared with normotensive Wistar-Kyoto (WKY) rats. Experiments were designed to determine the involvement of products of cyclooxygenase in the augmented response and delayed tachyphylaxis to serotonin in the SHR kidney. Kidneys taken from male, 4-month-old SHR and WKY rats were studied in parallel and perfused with Tyrode's solution at constant, optimal flow rates. Vasoconstrictor responses were recorded as increases in perfusion pressure. The vasoconstrictor responses to serotonin, norepinephrine and angiotensin II were exaggerated in the SHR kidney compared with that of the WKY rat. Indomethacin did not affect the responsiveness to serotonin in the kidney of the SHR but increased the responses to the higher doses of the monoamine in the kidney of the WKY rats. Indomethacin accelerated the tachyphylaxis to serotonin in the SHR but delayed it in the WKY rats. Dazoxiben did not alter the responses to serotonin in the SHR. Responses to norepinephrine in the kidneys from both strains were not affected by indomethacin. The inhibitor of cyclooxygenase reduced the responses to angiotensin II in the kidneys from both hypertensive and normotensive animals. The basal and stimulated (serotonin, norepinephrine and angiotensin II) release of prostaglandins were measured by radioimmunoassay. The basal release of prostacyclin was lower, but that of thromboxane A2 higher, in the kidneys of SHR compared with those of WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Arachidonic Acids; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Hypertension; In Vitro Techniques; Indomethacin; Kidney; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serotonin; Tachyphylaxis; Thromboxane A2; Vasoconstriction

To study the modulatory role of renal eicosanoids on renal hemodynamics and electrolyte excretion, pressor doses of norepinephrine (NE) were infused in 10 control subjects (mean age, 26 y) and 13 patients (mean age, 25 y) with borderline hypertension. The highest NE dose used (150 ng/kg/min) produced comparable increases in mean blood pressure in control subjects (20 +/- 2 mmHg) and in patients (23 +/- 3 mmHg). NE induced a significant increase in renal vascular resistance (p less than 0.01, both groups), with a smaller decrease in glomerular filtration rate resulting in a concomitant increase in filtration fraction (p less than 0.01, both groups). The renal hemodynamic changes tended to be more pronounced in borderline hypertension. NE infusion led to similar decreases in electrolyte clearances in the two groups. Urinary prostaglandin (PG)E2, PGF2 alpha (p less than 0.01), and 6-keto-PGF1 alpha increased with NE infusion. Urinary thromboxane (TX)B2 increased slightly in control subjects and decreased in borderline hypertension (p less than 0.05). The 6-keto-PGF1 alpha/TXB2 ratio, an index of vasodilation, was significantly increased (p less than 0.05) in borderline hypertension. These results demonstrate that in both groups pressor infusion of NE induced significant modifications in renal hemodynamics and in urinary electrolyte and eicosanoid excretion. The vasodilatory component of the renal eicosanoid system appears hyperresponsive in borderline hypertension, which may represent an early antihypertensive defense mechanism.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprost; Dinoprostone; Eicosanoids; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Norepinephrine; Thromboxane B2; Vascular Resistance

The important role played by prostaglandins in the pathogenesis of coronary disease and essential hypertension is well known. The authors have attempted to reveal a relationship between blood levels of natural autoantibodies to PGF2 alpha and PGE2 and specific features of coronary disease and essential hypertension course and complications. A total of 87 subjects were examined, 23 of these--normal controls, 25 patients with myocardial infarction, 22 with angina pectoris, and 17 with essential hypertension. Solid-phase enzyme immunoassay was employed to detect anti-PGF2 alpha and anti-PGE2 antibodies. These antibodies were found in normal subjects, coronary patients and hypertensives. Blood levels of these antibodies correlated with some complications of coronary disease and essential hypertension. These results permit a hypothesis that the pathogenetic physiologic role of the detected natural antibodies to prostaglandins consists in their defense homeostatic function.

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases; Coronary Disease; Dinoprost; Dinoprostone; Humans; Hypertension; Middle Aged

The plasma levels of prostaglandins A, E, and F2 alpha were measured by the radioimmunoassay in 146 hypertensive and 62 healthy pregnant females. It was ascertained that beginning in the second trimester, the ratio of various prostaglandins is impaired in the direction of increasing values of substances from the pressor group as the hypertensive disease evolves. This is due to lower levels of prostaglandins A and E and/or higher levels of prostaglandins F2 alpha. In associated late gestosis, prostaglandin levels are related to the clinical manifestations of this disease. There are increased prostaglandin F2 alpha concentrations with severe nephropathy. The studies indicate that prostaglandins affect the course of hypertensive disease in pregnant women and the development of associated late gestosis.

Topics: Dinoprost; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Prostaglandins; Prostaglandins A; Prostaglandins E

Pathological, muscular arteries (common and superficial femoral [FC, FS], anterior and posterior tibial [TA, TP] arteries) of patients suffering from arteriosclerosis obliterans (ASO), thromboangiitis obliterans (TAO), and diabetes mellitus (DIA), removed during amputation of the lower limb were studied as isolated organs. The vessels were cut into transverse rings and contractile force was measured isometrically. The total number of used rings was 828. The following agonists were applied: KCl (80 mM), serotonin (5-HT) (10 microM), prostaglandin F2 alpha (PGF2 alpha) (0.1 mM) or phenylephrine (PE) (10 microM). It was established that applying KCl, 5-HT or PGF2 alpha, the majority of arterial rings display a contraction, but most of the preparations (66%) give no response against PE. The measure of contraction depends on the diagnosis (TAO greater than ASO greater than DIA), on the age of patient and also the anatomical location of the artery in the case of TAO (TP greater than greater than TA), on the associated hypertension in the case of ASO (normotensive greater than hypertensive) and finally on the time elapsed between the operation and usage of preparation if the agonist is KCl. As a conclusion, despite the terminal clinical stage the majority of studied human arteries retained at least a part of their functional integrity.

Topics: Adult; Aged; Arteries; Arteriosclerosis Obliterans; Diabetic Angiopathies; Dinoprost; Female; Femoral Artery; Humans; Hypertension; In Vitro Techniques; Male; Middle Aged; Muscle Contraction; Muscle, Smooth, Vascular; Phenylephrine; Potassium Chloride; Reference Values; Serotonin; Thromboangiitis Obliterans

Prostacyclin (PGI2) synthase is one of the key enzymes for vasodepressor PGI2 biosynthesis in the vascular wall. In this study, we attempted to define the alterations in PGI2 synthase and its role in the PGI2 generation in the vascular wall of deoxycorticosterone acetate (DOCA)-salt rats. The PGI2-generating capacity was enhanced significantly when DOCA-salt rats established hypertension, whereas the generation of other arachidonate metabolites, eg, PGE2, PGF2 alpha, and thromboxane, was unaltered. Moreover, the increase in PGI2 generation was associated with an increase in PGI2 synthase activity in the vascular wall. Indeed, the averaged PGI2 generating capacity was closely correlated to the averaged PGI2 synthase activity in DOCA-salt hypertensive rats and three lines of control rats. Incontrast, phospholipase C and phospholipase A2, both of which liberate arachidonate for PGI2 synthesis, were rather lowered in DOCA-salt hypertensive rats. These data clearly indicate that vascular PGI2 generation is increased in the development of DOCA-salt hypertension and that PGI2 synthase is mainly responsible for this enhancement. The increased PGI2 synthase may be relevant to the blood pressure elevation and is expected to have beneficial effects on the vascular protection in hypertension.

Topics: Animals; Cytochrome P-450 Enzyme System; Desoxycorticosterone; Dinoprost; Dinoprostone; Epoprostenol; Hypertension; Intramolecular Oxidoreductases; Isomerases; Phospholipases A; Phospholipases A2; Rats; Rats, Inbred Strains; Thromboxanes; Type C Phospholipases

Eighteen patients with senile pyelonephritis and nephrogenic arterial hypertension were examined for the effect of trental monotherapy (600 mg/day) on intrarenal hemodynamics, the rate of glomerular filtration (effective renal blood flow, the intensity of blood flow in the medullary layer of the kidney), activity of the renin-angiotensin-aldosterone system (plasma renin activity, plasma and urine aldosterone), prostaglandin synthetic capacity of the kidneys (PGE and PGF2 alpha), water-electrolyte balance (circulating blood volume, sodium content in the serum and its excretion with urine), and on arterial pressure and general vascular peripheral resistance. Prolonged administration of the drug (from 3 weeks to 6 months) led to a significant improvement of the medullary blood flow, increase (p less than or equal to 0.05) of excretion of natriuretic PGE [correction of RGE] and lowering (p less than or equal to 0.05) of diurnal excretion of PGF2 alpha, which was accompanied by a rise of natriuresis (p less than or equal to 0.05) and diuresis.

Topics: Dinoprost; Drug Evaluation; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Pentoxifylline; Prostaglandins E; Pyelonephritis; Renin-Angiotensin System; Time Factors; Water-Electrolyte Balance

1. In Gordon's syndrome (GS; a syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate), excessive proximal sodium reabsorption leads to suppression of renin and aldosterone, hyperkalaemia and hyperchloraemic acidosis. 2. Low urinary levels of vasodilator prostaglandins (PG) have been reported in GS, suggesting renal hypoprostaglandinism as a pathophysiological mechanism. 3. In four cases of GS, levels of vasodilator prostaglandins PGE2 and 6-keto-PGF1 alpha were low. 4. In one case of GS, low PGE2 levels were normalized by dietary salt restriction or diuretic therapy.

Topics: Adult; Child; Dinoprost; Dinoprostone; Family Health; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Hypertension; Male; Prostaglandins; Sodium, Dietary; Syndrome

Authors assessed correlation between venous blood catecholamines and prostaglandins concentrations before and after inhibition of sympathetic activity by clonidine in patients with primary hypertension or pheochromocytoma. 30 patients with essential uncomplicated hypertension and 11 with pheochromocytoma underwent the study. The control group consisted of 6 healthy volunteers. Serum norepinephrine (NA), epinephrine (A), prostaglandins: PGE2 PGF2 alpha and prostacyclin metabolite -6-keto-PGF1 alpha were determined before and 3 hours after oral administration of 0.3 mg clonidine. Negative correlation was stated between basic serum norepinephrine and 6-keto-PGF1 alpha concentrations in patients with pheochromocytoma, which could indicate prostacyclin metabolism disorders during persistent hypercatecholaminemia . There was no correlation between catecholamines and prostaglandins during the inhibition of sympathetic activity in patients with pheochromocytoma as well as essential hypertension. The positive correlation was observed between changes in serum NA and PGF2 alpha levels in patients with borderline hypertension. Thus, one may suppose, that correlation between na excretion and vasoconstrictive PGF2 proved in acute experiments, becomes evident within the early stage of hypertension also during sympathetic activity inhibition.

Topics: Adrenal Gland Neoplasms; Adult; Clonidine; Dinoprost; Dinoprostone; Epinephrine; Humans; Hypertension; Middle Aged; Norepinephrine; Pheochromocytoma

We investigated the vascular responsiveness to vasoactive agents and the inhibition by H-7 (1-(5-isoquinoline-sulfonyl)-2-methylpiperazine), which inhibits cyclic nucleotide-dependent protein kinases and protein kinase C(PKC) equally potently in helically cut strips of thoracic aortas from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The susceptibility of norepinephrine (NE)- and angiotensin II (Ang II)-induced contractions to H-7 was significantly higher in the aortas from SHR than in those from WKY. H-7 decreased the contractile responses to KCl to a similar extent in both strains without affecting the high K(+)-stimulated Ca2+ influx. H-7 produced a shift to the right of the dose-response curve for the PKC activator, 12-o-tetradecanoylphorbol-13-acetate (TPA) in the case of SHR aortas, while no such shift was noted in tissues from WKY. Functional alterations in the PKC branch of the Ca2+ messenger system in vascular smooth muscle may play an important role in SHR during the sustained contraction.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Angiotensin II; Animals; Aorta, Thoracic; Calcimycin; Calcium; Dinoprost; Hypertension; In Vitro Techniques; Isoquinolines; Lanthanum; Male; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Phorbol Esters; Piperazines; Potassium Chloride; Protein Kinase Inhibitors; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Urinary excretion of sodium, potassium and some hormones influencing their transport was investigated before and after i.v. furosemide administration in 10 offsprings of normotensive subjects who had a normal Na(+)-K+ cotransport activity and in 26 normotensive men with a positive family history of essential hypertension. The latter group was divided into two subgroups with regard to the activity of red cell Na(+)-K+ cotransport. The Co[-] subjects with a decreased Na(+)-K+ cotransport activity had lower urinary excretion of sodium and vasodilators (kallikrein, dopamine, PGE2 and prostacyclin) after furosemide administration. The urinary excretion of vasopressor factors (PGF2 alpha, thromboxane) was unchanged as compared with that in the control group. There was a significant correlation between Na(+)-K+ cotransport activity and kallikrein excretion. These results suggest a deficit in the secretion of renal substances with vasodilating or natriuretic effects in Co[-] subjects. This could negatively affect their sodium excretion.

Topics: Adult; Aldosterone; Biological Transport; Dinoprost; Erythrocytes; Furosemide; Humans; Hypertension; Kallikreins; Male; Natriuresis; Potassium; Renin; Sodium; Thromboxanes

After ineffective combined drug therapy patients with the resistant patterns of arterial hypertension were given 3 to 5 intravenous injections of prostenon (prostaglandin E2) in the total dose 3-5 mg. Prostenon was noted to produce a lasting hypotensive effect in patients with resistant essential hypertension and parenchymatous renal hypertension. The patients manifested favourable changes in the general clinical symptomatology. The antihypertensive effect of prostenon was related to appreciable activation of depressor humoral factors, with activation of pressor humoral factors being less remarkable.

Topics: Adult; Aged; Alprostadil; Blood Pressure; Dinoprost; Dinoprostone; Drug Evaluation; Female; Humans; Hypertension; Infusions, Intravenous; Kallikrein-Kinin System; Male; Middle Aged; Renin-Angiotensin System; Time Factors

With radioimmunoassay, daily urinary levels of prostaglandins E2 and F2 alpha (PGE2, FGF2 alpha were measured in 45 patients with hypertensive disease, 13 patients with chronic diffuse glomerulonephritis and 14 healthy persons. A progressive reduction in urinary PGE2 excretion was found to accompany the occurrence of labile arterial hypertension (AH), its stabilization, and development of malignant AH in patients with hypertensive disease or chronic diffuse glomerulonephritis. When labile AH developed, urinary PGF2 alpha excretion was increased, but when AH stabilized, its excretion became increased up to the baseline level. The specific features of malignant AH are significantly higher urinary PGF2 alpha and sharply greater PGF2 alpha/PGE2 coefficient. The identified abnormal metabolism of renal prostaglandins may contribute to the stabilization of blood pressure at a high level and to the development of malignant AH.

Topics: Circadian Rhythm; Dinoprost; Dinoprostone; Glomerulonephritis; Humans; Hypertension; Hypertension, Malignant; Reference Values

In young patients with borderline arterial hypertension the system of pressor and depressor prostaglandins (PG) is activated with maintenance of their physiological proportion. In patients with I stage essential hypertension a considerable rise in the level of PGF2 alpha and thromboxane determines the system imbalance in the direction of the predominance of pressor components. The platelet hemostatic link in I stage essential hypertension is characterized by an increase in platelet aggregation activity which is mediated by the imbalance of the prostacyclin-thromboxane system in the direction to thromboxane.

Topics: Adult; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Male; Platelet Aggregation; Thromboxane A2; Time Factors

The results of the study of depressor (PGE+A) and pressor (PGF2 alpha) prostaglandins in the blood plasma and of PGE2 and PGF2 alpha excretion in the urine of 52 patients with an acute stage of Itsenko-Cushing disease are presented. It has been established that the different components of the PG system have dissimilar changes: the absence of differences in the content of depressor and significant increase in pressor PG, which may be the cause of hypertension in Itsenko-Cushing disease. Stress due to insulin hypoglycemia and furosemide load brought about disturbances in the reaction of the PG system, which were more pronounced in the system pressor component. Disturbances of the PG system which were more pronounced in the presence of stable hypertension were established in all patients.

Topics: Adolescent; Adult; Blood Pressure; Cushing Syndrome; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Male; Middle Aged; Prostaglandins E

The patients suffering from hypertonic nephritis were examined for renal hemodynamics, the activity of the renin-angiotensin-aldosterone system (RAAS), excretion of PGE2 and PGF2 alpha, and for a number of the parameters of water-electrolyte homeostasis. In A series, the patients suffering from latent and hypertonic nephritis (n = 11 in each group) were compared. In B series, two groups of the patients (n = 13 in each group) suffering from hypertonic nephritis associated with moderate or grave arterial hypertension were compared. The patients under comparison belonging to A and B series did not differ as regards the sex, age, nephritis standing, serum creatinine or proteinuria. As compared with the patients suffering from latent nephritis (A series), the patients with hypertonic nephritis showed a lower effective renal plasma flow, a greater resistance of the renal vessels, lesser PGE2 secretion, and a higher serum sodium concentration. As compared with the patients suffering from moderate hypertension (B series), the patients with associated hypertonic nephritis and grave hypertension demonstrated a higher resistance of the renal vessels, a higher activity of plasma renin, a larger concentration of plasma aldosterone and its excretion with urine, as well as a greater volume of the circulating blood. It is assumed that the development of arterial hypertension associated with hypertonic nephritis may be caused by renal hemodynamics deterioration, by relative activation of the renin-angiotensin system, inhibition of the depressor prostaglandin system and sodium retention. The progression of hypertension may be related to further deterioration of renal hemodynamics attended by RAAS activation and hypervolemia.

Topics: Creatinine; Dinoprost; Dinoprostone; Female; Hemodynamics; Humans; Hypertension; Hypertension, Renal; Male; Nephritis; Proteinuria; Renin-Angiotensin System; Water-Electrolyte Balance

Differential-diagnosis tests for low-renin hypertension viz essential hypertension and arterial hypertension due to Conn's syndrome (adrenocortical adenoma or hyperplasia) have been assessed. The examined patients showed considerable humoral and metabolic differences, as compared to patients with high and normal plasma renin activity (PRA). For example, patients with essential hypertension and low PRA showed depressed noradrenalin and PGE2 secretion, increased PGF2 alpha secretion, low triglyceride level, and elevated erythrocyte sodium content. Patients with adrenocortical adenoma exhibited increased secretion of adrenalin, dopamine and PGF2 alpha, and a higher erythrocyte sodium level. Enhanced dopamine synthesis in patients with Conn's syndrome may be an adaptive response to a high aldosterone level.

Topics: Adrenal Gland Diseases; Adrenal Glands; Adult; Catecholamines; Dinoprost; Dinoprostone; Erythrocytes; Female; Humans; Hypertension; Male; Middle Aged; Potassium; Prostaglandins; Renin; Sodium; Sympathetic Nervous System

The purpose of the study was to characterize the renal TxA2, PGI2 and PGF2 alpha release in response to arterial blood pressure (BP) fall induced by systemic and intrarenal vasorelaxation in subjects with essential hypertension. Significantly enhanced TxB2- and PGF2 alpha excretion and no change in ratio TxB2/6-keto-PGF1 alpha were found in urine in hypertensive patients after administration of the Ca++ entry blocker gallopamil, used to induce BP fall. This response was associated with significant PRA elevation in peripheral venous samples. In in vitro experiments, direct and indirect effects of gallopamil on renal tissue could be distinguished. Gallopamil resulted in significant diminution of TxA2 production and a decrease in TxB2/6-keto PGF1 alpha ratio in incubated rat kidney slices. This model was also used to test biochemically the effect of reflex sympathetic activation on prostanoid generation in kidney. It was concluded that this mechanism was only one among the indirect mechanisms by which gallopamil could induce that renal prostanoid response in hypertensive subjects. The response in urinary TxB2- and PGF2 alpha excretion was found to be significantly related to the changes in sodium reabsorption. These results suggested, that the increase in renal TxA2 and PGF2 alpha production in response to systemic and intrarenal "vasodilation" induced by gallopamil in hypertensive subjects can be interpreted as part of counteraction of the kidneys to BP fall.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Blood Pressure; Dinoprost; Female; Gallopamil; Glomerular Filtration Rate; Humans; Hypertension; In Vitro Techniques; Kidney; Male; Middle Aged; Norepinephrine; Rats; Renin; Sodium; Thromboxane B2

This study was designed to assess the contribution of thromboxane A2 to high blood pressure in rats with angiotensin II (Ang II)-salt hypertension. Hypertension was induced in rats drinking 0.15 M NaCl by infusion of Ang II (125 ng/min i.p.) for 12 days. Relative to values in water-drinking rats without Ang II infusion, Ang II-salt hypertensive rats exhibited augmentation (p less than 0.05) of blood pressure (from 129 +/- 3 to 217 +/- 12 mm Hg), urinary thromboxane B2 excretion (from 5.4 +/- 0.9 to 25.4 +/- 2.1 ng/day), and thromboxane B2 release from renal cortex slices (from 71.3 +/- 6.7 to 121.1 +/- 14.4 pg/mg) and aortic rings (from 28.8 +/- 2.9 to 115.8 +/- 12.8 pg/mg). Treatment with an inhibitor of thromboxane A2 synthetase, UK 38485, had no effect on blood pressure in normotensive and Ang II-salt hypertensive rats. Treatment with a thromboxane A2 receptor blocker, SQ 29548, decreased blood pressure in Ang II-salt hypertensive rats from 191 +/- 9 to 152 +/- 9 mm Hg after 3 hours, but it had no effect on blood pressure in normotensive rats. Since SQ 29548 interfered with the pressor effects of the prostaglandin endoperoxide analogue U-46619, prostaglandin F2 alpha, and 9 alpha,11 beta-prostaglandin F2, we suggest that the SQ 29548-induced blood pressure reduction in Ang II-salt hypertensive rats is the manifestation of blockade of the vascular actions of one or more endogenous prostanoids including thromboxane A2 and prostaglandin endoperoxides. If so, pressor prostanoids may be contributory factors in the pathogenesis of severe Ang II-salt hypertension in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Arteries; Bridged Bicyclo Compounds, Heterocyclic; Dinoprost; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Kidney Cortex; Male; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Rats; Rats, Inbred Strains; Sodium Chloride; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The ELISA test was performed on sera of normal donors and patients with myocardial infarction (MI) and essential hypertension (EH) to detect autoantibodies against prostaglandin F2 alpha (a-PGF2 alpha). The a-PGF2 alpha level was much higher after immune complexes dissociation. Baseline a-PGF2 alpha was elevated in EH patients with a sudden rise in blood pressure, and in MI patients without hypertension and unstable angina. MI patients with bradyarrhythmias also had elevated a-PGF2 alpha levels. Baseline a-PGF2 alpha was rather low in the sera of donors, chronic EH patients with hypertension and unstable angina, suggesting that a-PGF2 alpha has a physiological role to play.

Topics: Adult; Aged; Autoantibodies; Dinoprost; Enzyme-Linked Immunosorbent Assay; Humans; Hypertension; Middle Aged; Myocardial Infarction; Prostaglandins F; Reference Values

The roles of intracellular mechanisms of contraction were compared in aortas from genetically hypertensive and normotensive rats by investigating the contractile activities of prostaglandin F2 alpha (PGF2 alpha) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in the absence of extracellular calcium. PGF2 alpha induced a greater amount of tension in aortic strips from hypertensive than normotensive rats. Furthermore, in hypertensive but not normotensive rat aortas, PGF2 alpha- and TPA-induced contractions were additive and were capable of sustaining a near maximum degree of muscle activation. Therefore, the intracellular contractile mechanisms in hypertensive vascular tissue may differ from those in normotensive tissue.

Topics: Animals; Aorta; Dinoprost; Hypertension; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetradecanoylphorbol Acetate

Topics: Acupuncture Therapy; Adult; Alprostadil; Dinoprost; Evaluation Studies as Topic; Female; Humans; Hypertension; Male; Middle Aged; Prostaglandins F; Reflexotherapy; Time Factors

A case of inadvertent intravascular injection of PGF2alpha during induction of labor by intraamniotic injection for fetal demise, involving alternating extreme hypotension and hypertension, is described. The woman was a 29-year old in late 2nd trimester with oligohydramnios, but no other related history. She was given epidural anesthesia, 7.5 mg midazolam and 5 mg morphine S04 for anxiety. Because of oligohydramnios, 300 ml Ringers lactate was instilled to dilute the PG. A test dose of 1 mg PGF2alpha was tolerated well. 80 g urea and 20 mg PGF2alpha were injected over 10 minutes. A few minutes later contractions began, followed by complaints of burning on face and chest and dyspnea. Oxygen was given by mask. Systolic pressure fell to 70 mm by cuff; peripheral pulses could not be palpated, but the patient remained alert and oriented. She was given 35 mg ephedrine and increased iv fluids. She remained dyspneic, her extremities became mottled, and she complained of chest pressure, severe headache and severe breast tenderness. Blood pressure rose to 220/135 mm Hg; pulse to 95, and respiratory rate to 44. Pulse oximetry, detectable at the earlobe only, was 94% saturation. After 50 mg labetalol, blood pressure fell to 134/77, but symptoms remained. For 2 hours blood pressure swung between 76/50 and 225/125, until delivery of the fetus. An arterial line could not be started because of extreme vasoconstriction. Central venous pressure was 13 cm H20. After artificial rupture of the membranes and removal of remaining PG, blood pressure stabilized. Delivery was accomplished without incident. The symptoms and labile blood pressure were considered to be due to intravascular injection of PGF2alpha, caused by repeated bolus injection at each uterine contraction. In case of PG induction for fetal demise, it is recommended that anesthesiologists be prepared to treat intravascular collapse, hypertension and bronchoconstriction.

Topics: Abortion, Induced; Absorption; Adult; Anesthesia, Epidural; Bronchial Spasm; Dinoprost; Ephedrine; Female; Humans; Hypertension; Hypotension; Infusions, Intravenous; Pregnancy

Topics: Dinoprost; Hemodynamics; Humans; Hypertension; Prostaglandins E; Renin-Angiotensin System; Water-Electrolyte Balance

beta-Adrenoceptor agonists and other drugs were studied for their relaxant effects on femoral and mesenteric arterial strips from spontaneously hypertensive rats (SHR). The potency and efficacy of isoproterenol (ISO) in these arteries were decreased in SHR before and during the development of hypertension as compared with age-matched Wistar Kyoto rats (WKY). Reserpine and 6-hydroxydopamine inhibited the development of hypertension but did not alter the reduced ISO-induced relaxation of the arteries. These arteries from prehypertensive SHR (PHSHR) were less sensitive to salbutamol and cyclic AMP and cyclic GMP derivatives than arteries from age-matched WKY. The relaxation response to nitroprusside was less in the femoral but not in the mesenteric arteries from PHSHR than in arteries from age-matched WKY. The relaxation response to papaverine was not diminished in the PHSHR arteries. It was found that the SHR arteries had a reduced responsiveness to the beta-adrenoceptor agonists before the initiation of hypertension and that the diminished relaxation was not specific to the beta-agonists, although there was no generalized defect in vasorelaxation in PHSHR.

Topics: Albuterol; Animals; Arteries; Dinoprost; Hydroxydopamines; Hypertension; Isoproterenol; Male; Nitroprusside; Nucleotides, Cyclic; Oxidopamine; Papaverine; Potassium Chloride; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, beta; Reserpine; Vasodilation

Topics: Adult; Catecholamines; Dinoprost; Dinoprostone; Erythrocytes; Female; Humans; Hypertension; Male; Middle Aged; Potassium; Prostaglandins E; Prostaglandins F; Renin; Sodium

As an experimental model, we used 6-week-old genetically obese-hypertensive rats (SHR-fa/fa) which were obtained by transferring the fatty/fa gene of hyperlipaemic obese rats into the genome of the SHR strain: the SHR-fa/fa were bigger and more hypertensive than their SHR littermates. Studying the capacity of the hearts, kidneys, spleens, brains and lungs to synthesize PGE2, PGF2 alpha and TXA2, enabled us to show that the hearts and lungs of SHR-fa/fa synthesized more PG than those of SHR; SHR-fa/fa brains generated less icosanoids than those of SHR; the amounts of PGE2 and TXA2 produced by the kidneys are similar in SHR and in SHR-fa/fa. From the experimental data we can infer that the introduction of the fatty/fa gene into the genome of SHR does not significantly alter the capacity of the kidneys to synthesize icosanoids; the more severe hypertension in the SHR-fa/fa would result from an increase in TXA2 biosynthesis by cardiac tissue which, at the same time, synthesized more PGE2, which could be a means of defence against hypertension. Moreover this genetical manipulation inhibited the icosanoid-synthesizing capacity of the brain which thus attenuated the central nervous system activity of the animals.

Topics: Animals; Brain; Dinoprost; Dinoprostone; Female; Hypertension; Kidney; Lung; Microsomes; Myocardium; Obesity; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred SHR; Spleen; Thromboxane A2

Parenteral administration of prostaglandins in the F2 alpha family, agents with known vasoconstrictive properties, is useful in the control of postpartum hemorrhage. Hemodynamic responses in this setting are usually modest. We treated a patient for a transient but very severe hypertensive response during the administration of general anesthesia.

Topics: Acute Disease; Adult; Anesthesia, General; Anesthesia, Obstetrical; Cesarean Section; Dinoprost; Female; Humans; Hypertension; Pregnancy; Prostaglandins F

The effects of angiotensin I (AI) and angiotensin II (AII) on ring segments of femoral arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were studied. AI and AII elicited significantly greater direct contractile response in arteries from SHR than those from WKY. These peptides also potentiated the contractile response to transmural adrenergic nerve stimulation (TNS) in both preparations, but to a greater extent in those of WKY than SHR, without potentiating the contractile response to exogenous norepinephrine (NE). The potentiation of the TNS response and direct contraction caused by AI were markedly attenuated by captopril, an AI-converting enzyme inhibitor. Destruction of endothelium failed to alter the contractile response to AI in both WKY and SHR but augmented that to AII in WKY. Isoproterenol and salbutamol produced significant potentiation of TNS response only in arteries of SHR. Yohimbine and prostaglandin F2 alpha potentiated TNS response to a similar extent in arteries of WKY and SHR. These results suggest that AII locally generated from AI can act postsynaptically to cause contraction and presynaptically to promote adrenergic neurotransmission in the isolated rat femoral artery. The AI to AII conversion appears to take place mainly at sites other than endothelial cells. The postsynaptic effect of AII is greater in SHR than WKY, but its presynaptic effect is diminished in SHR unlike some other agents which facilitate adrenergic neurotransmission, and unlike that in mesenteric arteries of SHR.

Topics: Adrenergic Fibers; Angiotensin I; Angiotensin II; Animals; Captopril; Dinoprost; Endothelium; Hypertension; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Yohimbine

Renin activity, aldosterone, prostaglandin (PGF2 alpha and PGB) and cyclic nucleotide levels and catecholamine excretion were measured in 165 essentially hypertensive patients exposed to therapeutic effects of "running" impulse magnetic field (RIMF). The correction of arterial blood pressure in RIMF-treated patients is shown to be mediated by BP-controlling humoral factors, the magnitude and direction of changes in levels and activity of biologically-active substances and hormones being determined by their respective baselines. A decrease of hyperfunction, as reflected in elevated hormonal production, and an increase of hypofunction were the most common therapeutic effect of RIMF exposure.

Topics: Adult; Aldosterone; Blood Pressure; Cyclic AMP; Cyclic GMP; Dinoprost; Female; Homeostasis; Humans; Hypertension; Magnetic Field Therapy; Male; Middle Aged; Prostaglandins F; Renin

The relaxation effects of endothelium-dependent (acetylcholine, histamine) and endothelium-independent (nitroprusside, nitrite) relaxing substances were comparatively examined on contracted thoracic aortic rings from normotensive and experimental renal and desoxycorticosterone acetate (DOCA)-salt hypertensive Wistar rats. On the aorta preparations from hypertensive animals a highly significant depression of the maximal relaxation effect of histamine and acetylcholine was observed. This was not seen with nitroprusside and nitrite. By use of a bioassay technique it was demonstrated that the depression of the endothelium-mediated response is not due to a diminished release of endothelium-derived relaxing factor. Impaired coupling between the endothelium and the smooth muscle cells is suggested to be responsible for that depression.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Desoxycorticosterone; Dinoprost; Endothelium; Histamine; Hypertension; In Vitro Techniques; Ligation; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Prostaglandins F; Rats; Rats, Inbred Strains; Renal Artery; Sodium Chloride; Sodium Nitrite

An estimation of renal secretion rates of PGE2 and PGF2 alpha, in parallel with renin-angiotensin-aldosterone system and catecholamines was performed on control subjects, essential hypertensive, and renovascular hypertensive patients. In essential hypertensive patients with normal plasma renin activity (PRA) and normal catecholamines level. We did not find any changes in the renal prostaglandin (PG) secretion rate as compared to the control subjects. Our results do not support the hypothesis that a reduction of PGE2 production is a specific feature of patients with essential hypertension. In renovascular hypertensive patients with unilateral renal artery stenosis we found: 1. High PRA in the renal plasma of the abnormal (with renal artery stenosis) kidney, and in peripheral plasma; 2. Decreased renal release of PGE2 from both kidneys, more distinct in abnormal kidney; 3. No changes of renal production of PGF2 alpha. The positive and negative correlation between renin-angiotensin system and renal PGs in physiological and pathological conditions was discussed.

Topics: Aldosterone; Dinoprost; Dinoprostone; Epinephrine; Humans; Hypertension; Hypertension, Renal; Kidney; Norepinephrine; Prostaglandins; Prostaglandins A; Prostaglandins E; Prostaglandins F; Renal Circulation; Renin-Angiotensin System; Water-Electrolyte Balance

The production rate of four prostanoids (PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2) in human umbilical cords from normal pregnancies (control) and cases with pregnancy-induced hypertension (PIH) were compared. The cords in the PIH-group produced significantly less 6-keto-PGF1 alpha and more TXB2 than did those in the control-group. Production rates of PGE2 and PGF2 alpha were almost equal in the two groups. After stimulation with angiotensin II the PIH-cords displayed a far smaller increase in 6-keto-PGF1 alpha production compared to the control cords. The responses in PGE2 and PGF2 alpha production were again equal in the two groups. The present results indicate that the angiotensin-prostanoid interactions are disturbed in fetal as well as in maternal vessels. Such a disturbance may explain the observed relative hypersensitivity to angiotensin II observed in gravidae prone to develop pregnancy-induced hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Dinoprost; Dinoprostone; Female; Humans; Hypertension; In Vitro Techniques; Perfusion; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane B2; Umbilical Arteries

We studied endothelium-dependent responses to substances released from aggregating platelets in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Rings of thoracic aorta with and without endothelium were taken from adult rats and suspended for isometric tension recording in organ chambers containing modified Krebs-Ringer bicarbonate solution. Aggregating platelets caused statistically similar contractions in rings without endothelium in both strains. In rings with endothelium from SHR the contractions were significantly more pronounced than in rings with endothelium from WKY. In contracted rings with endothelium, serotonin caused a slight relaxation at lower concentrations but contraction at higher concentrations; only contractions were seen in rings without endothelium. The higher concentrations of the monoamine caused contractions, which in the SHR but not in the WKY were larger in the presence than in the absence of endothelium. In both strains adenosine diphosphate induced concentration-dependent relaxation in rings with endothelium but not in those without it; at high concentrations of adenosine diphosphate, the relaxation responses were significantly smaller in the SHR than in the WKY. Endothelium-dependent relaxation in response to thrombin did not differ in the two strains. The increased contraction in response to aggregating platelets and serotonin and the decreased relaxation in response to adenosine diphosphate in the SHR suggest that functional changes occur in the endothelium in this model of hypertension, possibly because of the release of one or more endothelium-derived contracting factors.

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Blood Platelets; Dinoprost; Endothelium; Hypertension; In Vitro Techniques; Male; Nitric Oxide; Platelet Aggregation; Prostaglandins F; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serotonin; Thrombin; Vasoconstriction; Vasodilator Agents

The circadian rhythms of sodium (Na+), potassium (K+), aldosterone (ALDO), 11-deoxycorticosterone (DOC), 18-hydroxy-DOC (18-OH-DOC), cortisol (F), corticosterone (B), adrenaline (A), noradrenaline (NA), dopamine (DA), metanephrine (MN), normetanephrine (NMN), homovanillic acid (HVA), kallikrein (KE) and prostaglandins E (PGE) and F2 alpha (PGF2 alpha) excretion were studied in eight young borderline hypertensive men (BHT) and in six healthy age-matched normotensive subjects (NT) during hospitalization, after adaptation to the hospital regimen and a diet containing 135 mmol Na+ and 90 nmol K+. Urine samples were collected in 4 h periods for 24 h: 1. at normal daily activity, 2. during a 24 h bed rest. The results were evaluated by means of cosinor analysis. The circadian rhythms of ALDO, F, B, 18-OH-DOC and PGF2 alpha excretion were similar in both groups, with the exception of higher mesors of urinary ACTH-dependent corticosteroids in BHT at normal daily activity. Differences were observed in the rhythms of Na+, A, NA, DA, HVA and PGE excretion, this, however, above all during the normal daily regimen. The curve of urinary Na+ was flat in BHT due to a higher portion of Na+ excreted during the night. In the rhythms of A, NA and PGE excretion, the acrophases were shifted to the later hours in BHT, and the mesors of A and NA were also significantly higher. In contrast, DA and HVA excretion curves were flat with a lower mesor. These changes normalized, or at least mitigated, during a 24 h bed rest. The results of the study show that the circadian rhythm of Na+ excretion are disturbed already in the initial stage of hypertension. The likely cause is the exaggerated rise in adrenergic activity in the kidney during the day, induced by orthostasis and the concomitant physical (and mental?) activity, which is inadequately compensated for by the activation of natriuretic mechanisms.

Topics: Adolescent; Adult; Aldosterone; Circadian Rhythm; Corticosterone; Desoxycorticosterone; Dinoprost; Dopamine; Epinephrine; Homovanillic Acid; Humans; Hydrocortisone; Hypertension; Kallikreins; Male; Metanephrine; Norepinephrine; Normetanephrine; Potassium; Prostaglandins E; Prostaglandins F; Sodium

Different levels of water-salt metabolism control were studied in patients with stable essential hypertension (SEH). The sample was found to be highly heterogeneous in terms of the magnitude of the body's water-filled spaces in relation to plasma renin activity (PRA) and the cooking salt gustatory sensitivity threshold, examined in the presence of various salt diets and diuretic treatments. Three patterns of response to salt loads were identified in SEH patients with respect to sodium and water elimination by the kidneys: the first was identical to that of normal subjects, while the second one featured increased, and the third one, decreased, diuresis and natriuresis. Prostaglandin E2 and kallikrein were shown to be involved in the formation of the second- and third-type renal response to excessive salt. Differential treatment of EH patients with diuretics alone or, where necessary, in combinations with small-dose beta-blockers or vasodilators provides effective BP control for some 1.5 to 2 years in 65% of patients.

Topics: Adult; Body Fluid Compartments; Body Water; Dinoprost; Dinoprostone; Diuretics; Furosemide; Humans; Hypertension; Kallikreins; Male; Middle Aged; Plasma Volume; Prostaglandins E; Prostaglandins F; Renin; Sodium Chloride; Vasopressins; Water-Electrolyte Balance

Prostaglandin (PG) I2 (measured as 6-keto-PGF1 alpha) was the major PG synthesized by aortic homogenates from normotensive and hypertensive male rats, with lesser quantities of PGF2 alpha and PGE2. Homogenates of vena cava from the same rats synthesized PGI2 and PGE2 in similar quantities. PGF2 alpha synthesis by aortic homogenates was significantly higher in hypertensive than in normotensive male rats. A similar trend was seen in PGF2 alpha synthesis by homogenates of the vena cava. Separation of the aorta of normotensive and hypertensive, male rats showed that PGI2 was the major PG synthesized by endothelial cells and smooth muscle, and that PGF2 alpha was the major PG synthesized by adventitia. PGI2 synthesis by smooth muscle and PGE2 synthesis by endothelial cells were lower, and PGF2 alpha synthesis by endothelial cells and smooth muscle were higher in hypertensive than in normotensive, male rats. PGI2 was the major PG released from the aorta of normotensive and hypertensive male rats, together with lesser quantities of PGE2 and PGF2 alpha. Aortic PGF2 alpha output, but not PGI2 and PGE2 outputs, was significantly higher in hypertensive compared to normotensive, male rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Vessels; Dinoprost; Dinoprostone; Epoprostenol; Female; Hypertension; Male; Mesenteric Arteries; Norepinephrine; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Reference Values; Venae Cavae

Topics: Adult; Dinoprost; Female; Humans; Hypertension; Oxytocics; Prostaglandins F, Synthetic

Topics: Adult; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Kidney; Middle Aged; Natriuresis; Prostaglandins E; Prostaglandins F; Saline Solution, Hypertonic; Time Factors

Topics: Age Factors; Aged; Dinoprost; Dinoprostone; Humans; Hypertension; Middle Aged; Prostaglandins E; Prostaglandins F

Short-term (0 to 30 minutes) physiologic responses of neonatal lambs infused with a trichloroacetic extract of a type III (strain 878) group B streptococcus (878-TCA) were studied. Bolus injections of 878-TCA were associated with pulmonary hypertension, peripheral arterial hypoxemia, and reductions in circulating white blood cell and platelet counts. These events were associated with a rise in plasma levels of prostaglandins F2 alpha and E and could be prevented by proper treatment with ibuprofen. Continuous infusions of 878-TCA were associated with a dose-dependent rise in systemic and pulmonary arterial pressures and a fall in arterial PO2. During infusion, inhibition of prostaglandin synthesis resulted in a return toward preinfusion values. The authors conclude that venous infusions of extracts of 878-TCA induce significant pulmonary and systemic arterial vascular perturbations in the neonatal lamb and that some of these alterations are associated with the release of prostaglandins or other arachidonic acid metabolites.

Topics: Animals; Animals, Newborn; Cell Extracts; Dinoprost; Female; Hypertension; Ibuprofen; Infusions, Parenteral; Injections; Leukocyte Count; Lung; Male; Oxygen; Platelet Count; Prostaglandins; Prostaglandins E; Prostaglandins F; Pulmonary Artery; Sheep; Shock, Septic; Streptococcus agalactiae; Trichloroacetic Acid

The possible relation between prostaglandin production and the sensitivity of pregnant women with pregnancy-induced hypertension to the pressor effects of angiotensin II was investigated. Plasma prostaglandin levels were determined in four groups of women before, during, and after intravenous infusion of angiotensin II. Concentrations of the stable metabolites of prostaglandin E2, prostaglandin F2 alpha, and prostaglandin I2 (prostacyclin) were quantified by specific radioimmunoassays in the plasma of nonpregnant women, women pregnant in the late third trimester, and women pregnant in the late third trimester with either pregnancy-induced or chronic hypertension. Plasma prostaglandin concentrations did not change significantly during angiotensin II infusion in any of the four groups of women. Levels of the prostacyclin metabolite, however, were significantly higher in the hypertensive pregnant women than in the normotensive pregnant women.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Angiotensin II; Dinoprost; Dinoprostone; Epoprostenol; Female; Humans; Hypertension; Infusions, Parenteral; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Prostaglandins; Prostaglandins E; Prostaglandins F

In the present studies, spontaneously hypertensive rats (SHR) were used as the experimental model of hypertension in pregnancy. Systolic blood pressure of the NaCl loading group was maintained in a hypertensive state throughout pregnancy, probably because of NaCl retention, whereas that of the control group fell in the last stage of gestation. Urinary kallikrein levels, prostaglandin F2 alpha main urinary metabolite (PGF-MUM), plasma renin activity and plasma aldosterone concentration were determined both in the control group and the NaCl loading group. The results suggested that the NaCl loading group successfully preserved negative feed back in the kallikrein-kinin system, prostaglandin system and renin-angiotensin-aldosterone system as the blood pressure regulation mechanism. Fetal prognosis was poor in the NaCl loading group, because the incidence of SFD and fetal death rate were significantly higher than those of the control group. These findings, including histological observations, were similar to those of hypertensive pregnancy in human subjects reported in recent studies, and suggested that NaCl was closely related to hypertension in pregnancy.

Topics: Animals; Blood Pressure; Diet, Sodium-Restricted; Dinoprost; Electrolytes; Female; Hypertension; Kallikreins; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins F; Rats; Rats, Inbred SHR; Renin; Sodium Chloride

Topics: Adult; Dinoprost; Dinoprostone; Diuresis; Dose-Response Relationship, Drug; Furosemide; Humans; Hypertension; Male; Middle Aged; Natriuresis; Prostaglandins E; Prostaglandins F; Stimulation, Chemical; Time Factors

The state of the renal prostaglandins (PG) system was assessed in 54 patients with essential hypertension, stage IB-IIA, as compared to that of patients with symptomatic arterial hypertensions. A decrease in renal PGE2 production, noted in all hypertensive patients and determined on the basis of its diurnal excretion, was particularly pronounced in essential hypertension. Diurnal PGE2 excretion decreased as hypertension progressed in patients with essential hypertension, and renal PGF2 alpha production became prevalent. Renal function is dependent on the level of PG production by the kidney. As renal concentration capacity decreases and renographic findings become less satisfactory, PGE2 excretion decreases as well. Salt loads can bring out functional insufficiency of the renal PG system in essential hypertension, as reflected in a much smaller increase in PGE2 excretion, as compared to the control values, at early stages of salt loading and a considerable increase in PGF2 alpha excretion. In essential hypertension, inadequate renal prostaglandin response to salt loading is, to a certain degree, related to changed renal PGE-9-ketoreductase activity.

Topics: Dinoprost; Dinoprostone; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Kidney; Prostaglandins; Prostaglandins E; Prostaglandins F; Pyelonephritis; Sodium Chloride

Reduced PG formation in the renal vascular bed and urinary tract with increased PGF2 alpha/PGE2 ratio and altered PG response to acute and chronic salt loads were revealed in 100 patients with EH of different severity. The experiment on 70 rats has shown that the above changes in renal PG can be related to the increased Na concentration in the renal parenchyma resulting in decreased biosynthesis of both PGs in the kidneys and increased PGE2 transformation into PGF2 alpha. Renal PG changes are reversible after sodiumuresis and diuresis induced by various diuretics and other agents. The role of renal prostaglandins (PG) in the pathogenesis of essential hypertension (EH) and regulation of water-electrolyte metabolism has been studied for many years (B. Scherer et al., B. Lee et al., K. Abe et al., J.C. McGiff et al.). Reduced urinary PGE2 excretion was observed in patients with elevated blood pressure, while normotensive rats and healthy subjects on a low salt diet, treated by furosemide, showed PGE2 excretion increase. Salt loads, according to different authors, reduced, increased or caused no changes in urinary PGE2 excretion, with PGE2-9-ketoreductase activity increased. The aim of the present paper was the study of PGE2 and PGF2 alpha content in renal veins, their urinary excretion, biosynthesis and renal metabolism. The study was performed on patients with EH and on experimental rats at different salt loads.

Topics: Adult; Animals; Diet; Dinoprost; Dinoprostone; Humans; Hydroxyprostaglandin Dehydrogenases; Hypertension; Kallikreins; Kidney; Male; Microsomes; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Sodium Chloride

Sixty-four patients with stage IIB essential hypertension were examined for the urinary excretion of prostaglandins E2 and F2 alpha, natriuresis and diuresis in the control period and then on the 3rd, and the 12th-14th day of the treatment with diuretics (furosemid, hypotiazid, oxodolin, brinaldix). All diuretics were found to alter the urinary PG excretion, with the degree of their effect depending on the type of the drug, the route and duration of its administration. Furosemid, to a greater degree than other diuretics, increased the urinary excretion of PGE2 thus bringing down the PGF2 alpha/PGE2 ratio, brinaldix increased PGF2 alpha excretion whereas hypotiazid, in cases of its prolonged employment, reduced the excretion of both PGs, the PGF2 alpha decrease being more prominent. PGE2 contributed to a decrease in BP and to the development of natriuresis. The physiological effect of PGF2 alpha depended on the status of the water-electrolyte balance in the body: in patients with IIB stage essential hypertension it facilitated the development of natriuresis and BP decrease. When following the administration of the diuretics the balance of sodium and water in the body lowered, PGF2 alpha caused the retention of sodium and water in the body and did not affect the BP.

Topics: Adult; Dinoprost; Dinoprostone; Diuresis; Diuretics; Humans; Hypertension; Kidney; Male; Middle Aged; Natriuresis; Prostaglandins E; Prostaglandins F; Time Factors; Water-Electrolyte Balance

Topics: Adult; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Prostaglandins E; Prostaglandins F

Topics: 6-Ketoprostaglandin F1 alpha; Adrenal Glands; Adult; Dinoprost; Dinoprostone; Humans; Hypertension; Male; Middle Aged; Prostaglandins E; Prostaglandins F; Stress, Psychological; Sympathetic Nervous System

Levels of PGE2, PGF2 alpha and renin activity were measured in renal venous blood of 29 patients with essential hypertension (EH), 23 patients with renovascular hypertension (RVH) and 10 patients with unilateral pyelonephritis and high arterial hypertension. The pattern of change in renal venous PG content was found to be related to the type of renal lesion: the level of PGE2 was lowered and PGF2 alpha/PGF2 ratio increased in the blood outflow from the kidneys of EH patients and from ischemized kidneys of RVH patients as compared to similar parameters in the outflow from contralateral kidneys of patients with RVH and pyelonephritis. Venous levels of both PGs were the highest in pyelonephritis-affected kidneys. Renal venous PG levels go down in all cases as the disease grows older. An acute drop in arterial pressure is accompanied with increased withdrawal of PGF2 alpha from the kidneys and enhanced renin activity in renal veins, while PGE2 drops simultaneously. PGF2 and PGE2 showing different trends of change in response to falling arterial pressure suggests increased transition of PGE2 to PGF2 alpha under the effect of enhanced PG-9-ketodehydrogenase activity. In the abdominal aorta, the scope of drop in arterial pressure correlates to the change in PGF2 alpha level, that is an evidence of PG direct involvement in the autoregulation of renal blood flow.

Topics: Dinoprost; Dinoprostone; Humans; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Kidney; Prostaglandins E; Prostaglandins F; Pyelonephritis; Renal Artery; Renal Veins; Renin

A study was undertaken in 19 patients with benign to moderate essential hypertension to verify the effect of indapamide alone or combined with a beta-blocker on plasma renin activity, plasma aldosterone, serum potassium and urinary prostaglandins PGE2 and PGF2a. Blood pressure was normalized in 11 (58%) patients with 2.5 mg indapamide/day. In the remaining 8 patients, the addition of pindolol resulted in blood pressure control. Under indapamide, a 70% increase in plasma renin activity and 81% (p less than 0.01) in plasma aldosterone was observed, whereas there was an 18% (p less than 0.001) decrease in potassium. Simultaneously, an increase in urinary PGE2 and PGF2a was observed; these values were significant for PGE2 (p less than 0.025). The addition of pindolol did not produce significant change in the biochemical parameters measured. The increase in the excretion rate of primary prostaglandins could play a role in the mode of action of indapamide.

Topics: Adult; Aged; Antihypertensive Agents; Dinoprost; Dinoprostone; Diuretics; Drug Therapy, Combination; Female; Humans; Hypertension; Indapamide; Kidney; Male; Middle Aged; Pindolol; Potassium; Prostaglandins E; Prostaglandins F; Renin-Angiotensin System

Lasix effects on diuresis, natriuresis and pulmonary and renal prostaglandin biosynthesis and catabolism were examined in spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NTR). PGE2 and PGF2 biosynthesis from 14C-arachidonic acid, and 3H-PGF1 and PGE2 catabolism were measured in kidney and lung homogenates. Changes in PG metabolism were shown to be dependent on age, blood pressure and the time of lasix action. Decreased biosynthesis and increased catabolism were demonstrated for PGE2, and reverse changes were shown for the production and decay of PGF2 alpha. Reciprocal changes were demonstrated in renal and pulmonary PG metabolism, an evidence of inter-organ relationships between prostaglandin systems of the organs in question. SHRs and NTRs showed different response of renal and pulmonary PGs, natriuresis and diuresis to lasix administration.

Topics: Age Factors; Animals; Dinoprost; Dinoprostone; Furosemide; Hypertension; Kidney; Lung; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains

Topics: Abortion, Induced; Adolescent; Amnion; Dinoprost; Female; Humans; Hypertension; Injections; Pregnancy; Pregnancy in Adolescence; Prostaglandins F; Vasoconstriction

Topics: Adult; Dinoprost; Dinoprostone; Endocrine Glands; Humans; Hypertension; Kallikreins; Kidney; Male; Middle Aged; Natriuresis; Prostaglandins E; Prostaglandins F; Renin-Angiotensin System; Water-Electrolyte Balance

Topics: Chromatography, Ion Exchange; Dinoprost; Dinoprostone; Humans; Hydrogen-Ion Concentration; Hypertension; Polystyrenes; Prostaglandins E; Prostaglandins F; Reference Values

Experiments on anesthesized normotensive rats (NR), spontaneous-hypertensive rats (SHR) and rats with experimental renovascular hypertension (RVR) were made to study the effect of prostaglandins (PG) - PGI2, PGE1, PGF2, and indomethacin on systemic hemodynamics, pressor reaction and cardiac component of the baroreflex. PGI1 (0.015 microgram/kg) PGE1 (5 micrograms/kg) produced marked hypotension which was more remarkable in RVR and SHR than in NR. The hypotensive effect of both PG was determined by peripheral vasodilatation. After administration of PGI2 and PGE1 the baroreflex appreciably rises in hypertensive rats. PGE2 (10 micrograms/kg) elevates arterial blood pressure in NR to a greater degree than in RVR and SHR. Indomethacin (10 mg/kg) raises the pressure by 33% in NR, by 16% in SHR and by 5% in RVR. At the same time baroreflex sensitivity in NR declines by 208%.

Topics: Alprostadil; Animals; Dinoprost; Epoprostenol; Hemodynamics; Hypertension; Hypertension, Renovascular; Indomethacin; Prostaglandin Antagonists; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains

Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin (PRC), aldosterone (PAC), noradrenaline (PNA) and adrenaline (PA) were determined in the third trimester of pregnancy, 5 days and 3 months after delivery in preeclampsia and normotensive pregnant and non-pregnant control subjects. PGE2 was higher in pregnant control subjects than in non-pregnant subjects, but reduced to non-pregnant level in preeclampsia. PGF2 alpha was the same in preeclampsia and normotensive pregnancy but higher than in the non-pregnant group. PRC and PAC were increased during pregnancy, but considerably lesser in preeclampsia than during normotensive pregnancy. PNA and PA were the same in all three groups. All parameters were normal 3 months after delivery. There were no correlations between any of the hormones and blood pressure in any of the groups. PGE2 was positively correlated to PRC. The lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion, and the changes in PRC and PAC are supposed to be secondary to changes in PGE2. It is hypothesised that preeclampsia is a state of prostaglandin deficiency.

Topics: Aldosterone; Dinoprost; Dinoprostone; Epinephrine; Female; Humans; Hypertension; Norepinephrine; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins; Prostaglandins E; Prostaglandins F; Reference Values; Renin

The concentrations of 13,14-dihydro-15-oxo-prostaglandin F2 alpha (PGFM), 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (T X B2) were measured by radioimmunoassay in peripheral plasma from 183 pregnancy women attending routine antenatal clinics. A total of 141 patients (47 nulliparous, 94 parous) remained normotensive and had uncomplicated pregnancies. The results from this group showed that there was no significant difference in the concentration of any metabolite in relation to parity or gestational age. The concentrations (pmol/l; means +/- SD) were PGFM 373 +/- 105, 6-oxo-PGF1 alpha 391 +/- 104 and T X B2 373 +/- 121. Nineteen patients (12 nulliparous, 7 parous) who had pregnancy-induced hypertension (PIH) by the time of sampling (three) or who subsequently developed the symptom (mean time from sampling to diagnosis 11 weeks, range 1-24 weeks) had significantly higher levels of 6-oxo-PGF1 alpha (574 +/- 216; P less than 0.0005, Student's t-test) and T X B2 (603 +/- 268; P less than 0.0005). The concentrations in seven nulliparous patients with PIH and proteinuria were 656 +/- 276 for 6-oxo-PGF1 alpha and 754 +/- 228 pmol/l for T X B2.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprost; Female; Humans; Hypertension; Parity; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins F; Radioimmunoassay; Thromboxane B2; Thromboxanes

The 24-h urinary excretion of prostaglandins (PG) E2 and F2 alpha, which reflects the renal synthesis of these substances, was measured by radioimmunoassay in 10 patients with essential hypertension before and after treatment with propranolol. In addition, changes in the urinary excretion of PGE2 and PGF2 alpha after furosemide injection were also studied before and after propranolol treatment. The urinary excretion of PGE2 was significantly increased after propranolol treatment, whereas that of PGF2 alpha did not change. An enhanced response in PGE2 excretion after furosemide injection was observed after propranolol treatment. In contrast PGF2 alpha increased in response to furosemide before, but not after, propranolol treatment. Changes in renal hemodynamics induced by propranolol seem to be the main factor in PGE2 alpha increase. However, an indirect effect of beta-blockade or a direct effect on the enzymes governing renal PG synthesis cannot be ruled out.

Topics: Adult; Blood Pressure; Dinoprost; Dinoprostone; Drug Therapy, Combination; Female; Furosemide; Humans; Hypertension; Male; Middle Aged; Propranolol; Prostaglandins E; Prostaglandins F

Prostaglandin F2 alpha (PGF2 alpha) is one of the most common metabolites of arachidonic acid (AA) in rat brain. When administered intracerebroventricularly (i.c.v.) to rats, both AA and PGF2 alpha exert dose-related hypertensive, tachycardic and hyperthermic effects. Metabolic alterations in the endogenous formation of some prostaglandins in the brain-stem of spontaneously hypertensive rats (SHR) have been reported. Therefore the central effects of AA and PGF2 alpha on blood pressure, heart rate and body temperature were studied by in SHR and normotensive Wistar rats (NR) under urethane-anaesthesia. The hypertensive effect of AA i.c.v. (0.01-100 micrograms/rat) was larger in magnitude of SHR than in NR, but there was no significant difference in the AA-induced changes of heart rate and body temperature between the groups. Pretreatment of NR with sodium meclofenamate (1 mg/rat i.c.v.) antagonised the central effects of AA indicating that these effects are not due to AA itself but it its conversion to prostaglandins. Unlike the effects of AA, the central hypertensive, tachycardic and hyperthermic responses to PGF2 alpha (0.5-50 micrograms/rat i.c.v.) were significantly attenuated in SHR. The present results obtained with AA are compatible with the previous assumption that the synthesis of prostaglandins in the brain of SHR might differ from that in NR. The results also demonstrate that the central effect of PGF2 alpha are reduced in SHR.

Topics: Animals; Arachidonic Acids; Blood Pressure; Body Temperature; Dinoprost; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Male; Meclofenamic Acid; Prostaglandins F; Rats

3 patients with fetal death, 2 of whom had pregnancy-induced hypertension and a third with eclampsia had pregnancy termination before 22 weeks' gestation with vaginal prostaglandin E2 (PGE2) suppositories, without complication. PGE2 has a hypotensive action, decreasing blood pressure by arteriolar dilation and blocking the angiotensin-induced rise in blood pressure in the pregnant rhesus monkey and should be useful abortifacient in patients with hypertension including preeclampsia and eclampsia. One patient received magnesium sulfate and the other 2 received hydralazine and methyldopa during PGE2 administration which could alter mean arterial pressure (MAP). MAPs remained stable and dropped slightly after PGE2 administration in the 2nd and 3rd patients. These outcomes suggest that PGE2 suppositories can be used to terminate 2nd trimester pregnancy in cases of hypertension and eclampsia when routine medical management is ineffective or when fetal death occurs although caution is advised since severe hypotension can occur with PGE2 administration.

Topics: Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Adult; Dinoprost; Eclampsia; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Second; Prostaglandins F; Suppositories

The 24-hour urinary excretion of prostaglandins (PGs) E2 and F2 alpha, plasma renin activity (PRA), and aldosterone were measured in 7 normal subjects and 8 patients with essential hypertension before and after 5 days of a diet containing less than 20 mmol/day of sodium. Subsequently, sodium was infused intravenously for 4 h (77 mmol/h), and urinary PGs measured in hourly urine collections. Plasma renin activity and aldosterone were measured at hours 2 and 4. In the normal subjects, PGE2 increased significantly (p less than 0.0005), with the diet, while PGF2 alpha did not change. The E/F ratio was increased significantly (p less than 0.01). In contrast, in the hypertensive patients no changes were observed in PGs excretion or in the E/F ratio. PRA and aldosterone were in the normal range after the diet in 4 patients and low in the other 4. Apart from PRA and aldosterone levels, there were no differences between these two subgroups of patients, with regard to change in body weight, blood pressure or electrolyte excretion. PG excretions were also similar. With the Na infusion, PGs returned to control values in the normal subjects. In the hypertensive patients, PG excretion decreased to almost undetectable levels. This coincided with the phenomenon of exaggerated natriuresis. It is concluded that: (1) in hypertensive subjects PGs synthesis is not influenced by chronic changes in the volume status, and (2) renin secretion is relatively independent of PG production in the hypertensive subjects. We suggest that the changes in PG synthesis in hypertension are possibly related to altered sodium handling by the hypertensive kidney.

Topics: Adult; Diet, Sodium-Restricted; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Male; Postural Balance; Prostaglandins E; Prostaglandins F; Sodium; Sodium Chloride

Plasma prostaglandins PGE2 and PGF2 alpha, cardiac hemodynamics, total effective vascular compliance, plasma (PV), interstitial (IFV) and extracellular fluid volumes, and renal indices were determined in 13 men with either borderline or sustained essential hypertension. PGE2 measured in the central venous blood was increased in borderline and in sustained hypertensives (p less than 0.01), while PGF2 alpha remained within normal ranges. Pulmonary degradation of both prostaglandins was decreased. In the overall population, the PGE2/PGF2 alpha ratio was: (i) negatively correlated with central venous pressure (r = -0.68; p less than 0.01), and (ii) positively correlated with total effective vascular compliance (r = 0.76; p less than 0.001), the PV/IFV ratio (r = 0.63; p less than 0.02) and the renal plasma flow (r = 0.79; p less than 0.001). The study suggests that, in hypertensive patients, prostaglandins PGE2 and PGF2 alpha play an important role on the compliance of the venous system and on the control of renal blood flow, contributing to the autoregulatory mechanisms of the hypertensive vascular disease.

Topics: Adolescent; Adult; Blood Pressure; Central Venous Pressure; Dinoprost; Dinoprostone; Extracellular Space; Glomerular Filtration Rate; Humans; Hypertension; Middle Aged; Plasma Volume; Prostaglandins E; Prostaglandins F; Renal Circulation; Vascular Resistance

The 24-hour urinary excretion of prostaglandins (PGs) E2 and F2 alpha (which reflects the renal synthesis of these substances) was measured by radioimmunoassay in normal nonpregnant women (NW, n = 23), nonpregnant women suffering from essential hypertension (HW, n = 23), normal pregnant women (NP, n = 24) and women with hypertension in pregnancy (HP, n = 14). All pregnant women were in the third trimester of their pregnancy (week 24-40). The excretion of both PGE2 and PGF2 alpha was increased in NP as compared to NW. PGF2 alpha was relatively more elevated, leading to a decreased PGE2/PGF2 alpha ratio. In HP, PGE2 and PGF2 alpha excretions were even greater, and the PGE2/PGF2 alpha ratio was even lower than in NP. This contrasted with the lowered PGE2 excretion in HW. The increased renal PGs synthesis in normal pregnancy could be related to the effects on the kidney of several hormonal changes peculiar to pregnancy. In addition, the lowered PGE2/PGF2 alpha ratio suggests the possibility of an increased activity of the PGE2-9-ketoreductase, which could be related to the changes in renal sodium handling observed in pregnancy. The pattern of PGE2 excretion in HP is opposite to that observed in HW (i.e. increase rather than decrease). However, both groups share the lowered PGE2/PGF2 alpha ratio with respect to the normotensive counterparts. The causes of altered PG synthesis in pregnant women with hypertension are presently unclear.

Topics: Adult; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Kidney; Male; Potassium; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins E; Prostaglandins F; Sodium

Topics: Adult; Dinoprost; Dinoprostone; Humans; Hydroxyprostaglandin Dehydrogenases; Hypertension; Middle Aged; Prostaglandins E; Prostaglandins F; Radioimmunoassay

The effects of 15(S) 15-methyl-PGF2 alpha were studied on the cardiovascular system of dogs. Intravenous and intravertebral artery administration of 15(S)-methyl-PGF 2 alpha induced arterial hypertensive and respiratory effects more intense and longer lasting than those observed for PGF2 alpha. Intravenous administration of 15(S) 15-methyl-PGF2 alpha induced a decrease of vascular reactivity to 1-norepinephrine and 1-epinephrine and to carotidal occlusion. Infiltration of the carotid sinus walls with 15(S) 15-methyl-PGF2 alpha decreased the baroreceptor reactivity.

Topics: Animals; Blood Pressure; Bradycardia; Cardiovascular System; Carotid Sinus; Dinoprost; Dogs; Heart Rate; Hypertension; Injections, Intra-Arterial; Prostaglandins F; Respiration; Tachycardia; Venous Pressure; Vertebral Artery

To assess the implication of renal prostaglandins in the pathogenesis of essential hypertension, urinary PGE2 and PGF2 alpha were measured in 22 control subjects (11 males) and in 58 patients (33 males) with borderline and sustained essential hypertension under strictly control conditions. Although the mean PGs urinary excretion in essential hypertension was not significantly different from control subjects, 12% of the patients had very low PGE2 levels comparable to subjects receiving prostaglandin synthetase inhibitors. There was no difference in urinary PGE2 between borderline and sustained essential hypertension. Urinary PGF2 alpha values were also not significantly different in normal subjects and in hypertensive patients, although four patients (2 of each sex) had excessively elevated PGF2 alpha. There was no significant correlation between the two urinary prostaglandins and blood pressure levels, plasma renin activity, urinary volumes and sodium excretion. These results suggest that with the exception of a small percentage of patients, the renal production of PGE2 and PGF2 alpha are comparable in normal and in hypertensive patients; the production rates of these two compounds are also not influenced by the degree or stage of hypertension.

Topics: Adult; Creatinine; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Male; Prostaglandins E; Prostaglandins F; Renin

The effect of dietary sodium intake (5 days' low salt, 4 days' high salt) on 24-h urinary prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) excretion, blood pressure (BP), and plasma renin activity (PRA) was evaluated in 16 patients with essential hypertension. Sodium restriction significantly increased urinary PGE2 excretion (p less than 0.05) from 151 +/- 76 to 328 +/- 94 ng/24 h, while high salt intake reduced renal PGE2 production to 114 +/- 41 ng/24 h (p less than 0.05). There was a moderate but not significant increase in urinary PGF2 alpha excretion on the low salt regimen, which was reversed under high salt diet. Systolic and diastolic blood pressure fell from 162 +/- 11 to 145 +/- 10 mm Hg, i.e., 102 +/- 6 to 90 +/- 9 mm Hg on low sodium intake (35 mEq/day) and returned to levels close to control after 4 days on a high salt diet (250 mEq/day). Under low salt conditions, PRA increased significantly (p less than 0.001) from 0.83 +/- 0.33 to 2.82 +/- 1.12 ng AI/ml/h and fell to 0.45 +/- 0.31 ng AI/ml/h on high salt regimen (p less than 0.001). The results demonstrate that dietary sodium chloride intake modulates renal PGE2 production in patients with essential hypertension. The depressed PGE2 production under high salt conditions may play a role in regulation of renal vascular resistance and influence sustainment of chronic hypertension disease.

Topics: Adult; Dinoprost; Dinoprostone; Female; Humans; Hypertension; Male; Middle Aged; Prostaglandins E; Prostaglandins F; Renin; Sodium Chloride

Menhaden oil (MO), whose polyunsaturated fatty acids consist mainly of (n-3) fatty acids, was fed to spontaneously hypertensive rats to determine the effect of (n-3) fatty acid on the in vitro production of prostaglandins produced from arachidonic acid (20:4[n-6]). Capacity to form PGE2 and PGF2 alpha was impaired in homogenates of kidney medullae and cortices from rats fed the MO diet compared to rats fed the control diet. The lower amounts of diene prostaglandins produced corresponded to the decrease in the amount of 20:4 (n-6) in the tissue. Possibly changes produced in tissue lipids by dietary fatty acids affect prostaglandin production by reducing the availability of substrate in tissue lipids.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Dietary Fats; Dinoprost; Dinoprostone; Fatty Acids; Fish Oils; Hypertension; Kidney Cortex; Kidney Medulla; Male; Oils; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains

Topics: Adolescent; Adult; Creatinine; Dinoprost; Dinoprostone; Diuresis; Female; Humans; Hypertension; Middle Aged; Potassium; Pregnancy; Pregnancy Complications, Cardiovascular; Prostaglandins E; Prostaglandins F; Sodium

The serum of perinephritic hypertensive dogs causes waterlogging and increased sodium (Na) content of rabbit aorta explants in tissue culture. In the present study, we investigated the role of tissue glycosaminoglycans in the pathogenesis of these changes. The effect of ouabain and prostaglandin F2 alpha on the composition of rabbit aorta explants in tissue culture was studied to determine if they produced alterations that were similar to those produced by the serum of hypertensive dogs. Rabbit aortic media explants were cultured in tissue culture medium supplemented (15-20%) with serum obtained from 12 dogs during a pre-hypertension control period and after induction of one-kidney, one-wrapped hypertension. After 3 weeks of culture, the explants were harvested, and their Na, potassium (K) and hexosamine content was measured. Compared to the composition of explants cultured in pre-hypertension control serum, the water and Na content of explants cultured in the serum of hypertensive dogs was increased (p less than 0.02, and p less than 0.01). There were no differences in the K and hexosamine content of explants cultured in the two sera. There was a dose-dependent increase in the NA content and a reduction in the K content of explants cultured in the presence of ouabain (5 X 10-8 to 5 X 10-7 M) and PGF2 alpha (1 microgram/ml). The findings of this study provide further evidence for angiopathic serum factor(s) in perinephritic hypertensive dogs. The excess Na of explants cultured in the serum of hypertensive dogs does not appear to be bound to glycosaminoglycans, The accumulation of excess Na is not due to an ouabain-like mechanism.

Topics: Animals; Aorta; Blood Proteins; Creatinine; Culture Techniques; Dinoprost; Dogs; Dose-Response Relationship, Drug; Hexosamines; Hypertension; Male; Ouabain; Potassium; Prostaglandins F; Sodium; Water

A dynamic study is made of the content of PGE and PGF2 alpha in the kidneys of rats with experimental coarctation hypertension, as well as the PGF2 alpha-metabolite in the blood plasma of the same experimental model in rats and in patients with arterial hypertension. The level of the PGF2 alpha-metabolite tends to decrease both in the animals with experimental hypertension and in hypertonic patients. In rats with 30-day hypertension low values are established in 55 per cent, while in 45 per cent there are high values of the PGE level in the kidney homogenate compared with the control group. The concentration of PGF2 alpha in the left ("endocrine") kidney (whose artery originates distally from the place of aortic coarctation) is higher than the concentration of the same PG in the right kidney. Our findings give grounds for the following assumptions: 1. The PGF2 alpha-metabolite as hormone and partly PGE in the kidneys seem to be involved in the pathogenesis of arterial hypertension as compensatory factors. 2. PGF2 alpha in the kidneys probably participates directly as one of the elements of the complex pathogenesis of arterial hypertension.

Topics: Adolescent; Adult; Animals; Biotransformation; Dinoprost; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains

Severe intractable atonic postpartum hemorrhage can be treated by either uterine packing or surgical techniques. However, certain prostaglandins possess properties of potential value for the control of postpartum uterine atony. Two hundred fifty micrograms 15-methyl prostaglandin F2 alpha (15-methyl PGF2 alpha) was given intramuscularly to 16 subjects for whom a uterine pack of operative management was the only other alternative. Fifteen patients responded satisfactorily following a mean of 1.75 injections (437.5 microgram); only 1 patient required hysterectomy. The latter had a case of severe intrauterine infection. The incidence of side effects was very low. The use of intramuscularly administered 15-methyl PGF2 alpha in uncontrollable atonic postpartum hemorrhage appears to be a valuable lifesaving medical tool in critical cases.

Topics: Diarrhea; Dinoprost; Female; Humans; Hypertension; Injections, Intramuscular; Postpartum Hemorrhage; Pregnancy; Prostaglandins F, Synthetic; Uterine Contraction

The author studied the renin-angiotensin, and kallikrein-kinin systems and renal prostaglandins in patients with different stages of hypertension. The activity of plasma renin and the content to PG in the peripheral blood and the blood from the renal veins, PGE2 excretion, PGG2 and kallikrein in the urine have been studied. Overloads have been used, directed at the activation of the sympathetic nervous system. It is concluded that a functional rearrangement of the endocrine renal function exists in patients with the hypertensive disease, which is related to the development of defects in the control of one series of the humoral systems and to the compensatory changes in the others. The increase of extracellular volume is the reason of the functional endocrine changes in the kidney, which is shown by the results of studies after salt overloads.

Topics: Blood Pressure; Chronic Disease; Dinoprost; Dinoprostone; Humans; Hypertension; Juxtaglomerular Apparatus; Kallikreins; Kidney; Physical Exertion; Prostaglandins E; Prostaglandins F; Renin; Renin-Angiotensin System

The hemodynamic effects of a synthetic compound of PGF 2 alpha have been studied before and after vagosympathectomy. Synthetic PGF 2 alpha caused a marked hypertension in the pulmonary circulation linked with the vasoconstrictor action of this substance on the small lung vessels. A slight hypotension was observed in the denervated animal where the highest values of pulmonary pressure were reached. The authors conclude that this fact may be due to an inhibition of the vasoconstrictor systemic tone secondary to the pulmonary hypertensive state.

Topics: Animals; Dinoprost; Female; Hypertension; Male; Prostaglandins F, Synthetic; Pulmonary Circulation; Swine; Sympathectomy; Vagotomy

The introduction of dinoprost tromethamine (Prostin F2 Alpha) as an abortifacient in the second trimester of pregnancy represents the first clinical use of a prostaglandin. Various synthetic analogues of the naturally occurring derivatives are being employed investigationally in the treatment of peptic ulcer, hypertension, asthma, and hypercalcemia. In the United States, dinoprost tromethamine is primarily administered intra-amniotically. Despite the fact that a substantial number of patients experience allergic reactions, hypertension, bronchospasm, nausea, vomiting, cramps, and diarrhea, the efficacy and relative safety of dinoprost tromethamine establish it as superior to intra-amniotic instillation of hypertonic saline. Cervical laceration, laceration or rupture of the lower uterine segment, retention of the placenta, and hemorrhage in part reflect the intensity of uterine contraction induced by dinoprost. Experience in administration improves the therapeutic response and diminishes adverse reactions.

Topics: Abortifacient Agents; Bronchial Spasm; Diarrhea; Dinoprost; Dose-Response Relationship, Drug; Drug Evaluation; Drug Hypersensitivity; Female; Humans; Hypertension; Injections; Muscle Contraction; Myometrium; Nausea; Pregnancy; Pregnancy Trimester, Second; Prostaglandins F; Vomiting