Oxidative Stress in Hypertension: Mechanisms and Therapeutic Opportunities

R. Brito; G. Castillo; J. González; N. Valls; R. Rodrigo

doi:10.1055/s-0035-1548765

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2015; 123(06): 325-335
DOI: 10.1055/s-0035-1548765

Review

Oxidative Stress in Hypertension: Mechanisms and Therapeutic Opportunities

R. Brito

¹Laboratory of Oxidative Stress and Nephrotoxicity, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile

,

G. Castillo

¹Laboratory of Oxidative Stress and Nephrotoxicity, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile

,

J. González

¹Laboratory of Oxidative Stress and Nephrotoxicity, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile

,

N. Valls

¹Laboratory of Oxidative Stress and Nephrotoxicity, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile

,

R. Rodrigo

¹Laboratory of Oxidative Stress and Nephrotoxicity, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile

› Author Affiliations

Abstract

Hypertension is a highly prevalent disease worldwide. It is known for being one of the most important risk factors for developing cardiovascular disease, including acute myocardial infarction and stroke. Therefore, during the last decades there have been multiple efforts to fully understand the mechanisms underlying hypertension, and then develop effective therapeutic interventions to attenuate the morbidity and mortality associated with this condition. In this regard, oxidative stress has been proposed as a key mechanistic mediator of hypertension, which is an imbalance between oxidant species and the antioxidant defense systems. A large amount of evidence supports the role of vascular wall as a major source of reactive oxygen species. These include the activation of enzymes, such as NADPH oxidase and xanthine oxidase, the uncoupling eNOS and mitochondrial dysfunction, having as a major product the superoxide anion. Among the stimuli that increase the production of oxidative species can be found the action of some vasoactive peptides, such as angiotensin II, endothelin-1 and urotensin II. The oxidative stress state generated leads to a decrease in the biodisponibility of nitric oxide and prostacyclin, key factors in maintaining the vascular tone. The knowledge of the mechanisms mentioned above has allowed generating some therapeutic strategies using antioxidants as antihypertensives with different results. Further studies are required to position antioxidants as key agents in the treatment of hypertension. The current review summarize evidence of the role of oxidative stress in hypertension, emphasizing in therapeutic targets that can be consider in antioxidant therapy.

Key words

hypertension - cardiovascular risk management - oxidative stress

Full Text

References

References
1 Alonso A, de la Fuente C, Martín-Arnau AM et al. Fruit and vegetable consumption is inversely associated with blood pressure in a Mediterranean population with a high vegetable-fat intake: the Seguimiento Universidad de Navarra (SUN) Study. Br J Nutr 2004; 92: 311-319
2 Appel LJ, Moore TJ, Obarzanek E et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997; 336: 1117-1124
3 Atarashi K, Ishiyama A, Takagi M et al. Vitamin E ameliorates the renal injury of Dahl Salt-sensitive rats. Am J Hypertens 1997; 10: 116-119
4 Azadbakht L, Fard NR, Karimi M et al. Effects of the Dietary Approaches to Stop Hypertension (DASH) eating plan on cardiovascular risks among type 2 diabetic patients: A Randomized Cross-Over Clinical Trial. Diabetes Care 2011; 34: 55-57
5 Barrios V, Calderón A, Navarro-Cid J et al. N-acetylcysteine potentiates the antihypertensive effect of ACE inhibitors in hypertensive patients. Blood Press 2002; 11: 235-239
6 Bengtsson SH, Gulluyan LM, Dusting GJ et al. Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology. Clin Exp Pharmacol Physiol 2003; 30: 849-854
7 Bilodeau JF, Hubel CA. Current concepts in the use of antioxidants for the treatment of preeclampsia. J Obstet Gynaecol Can 2003; 25: 742-750
8 Bitar MS, Wahid S, Mustafa S et al. Nitric oxide dynamics and endothelial dysfunction in type II model of genetic diabetes. Eur J Pharmacol 2005; 511: 53-64
9 Block G, Mangels AR, Norkus EP et al. Ascorbic acid status and subsequent diastolic and systolic blood pressure. Hypertension 2001; 37: 261-267
10 Blumenthal JA, Babyak MA, Hinderliter A et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med 2010; 170: 126-135
11 Brigelius-Flohé R, Banning A, Schnurr K. Selenium-dependent enzymes in endothelial cell function. Antioxid Redox Signal 2003; 5: 205-215
12 Briones AM, Touyz RM. Oxidative stress and hypertension: current concepts. Curr Hypertens Rep 2010; 12: 135-142
13 Campbell L, Howie F, Arthur JR et al. Selenium and sulforaphane modify the expression of selenoenzymes in the human endothelial cell line EAhy926 and protect cells from oxidative damage. Nutrition 2007; 23: 138-144
14 Campos RR, Oliveira-Sales EB, Nish EM et al. The role of oxidative stress in renovascular hypertension Special Series: Stress and Hypertension. Clin Exp Pharmacol Physiol 2011; 38: 144-152
15 Chen ST, Maruthur NM, Appel LJ. The effect of dietary patterns on estimated coronary heart disease risk: results from the Dietary Approaches to Stop Hypertension (DASH) trial. Circ Cardiovasc Qual Outcomes 2010; 3: 484-489
16 Chen X, Touyz RM, Park JB et al. Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension 2001; 38: 606-611
17 Chung S, Park CW, Shin SJ et al. Tempol or candesartan prevents high-fat diet-induced hypertension and renal damage in spontaneously hypertensive rats. Nephrol Dial Transplant 2010; 25: 389-399
18 Costa-Hong V, Bortolotto LA, Jorgetti V et al. Oxidative stress and endothelial dysfunction in chronic kidney disease. Arq Bras Cardiol 2009; 92: 381-386
19 De la Fuente M, Victor VM. Ascorbic acid and N-acetylcysteine improve in vitro the function of lymphocytes from mice with endotoxin-induced oxidative stress. Free Radic Res 2001; 35: 73-84
20 DeLano FA, Parks DA, Ruedi JM et al. Microvascular display of xanthine oxidase and NADPH oxidase in the spontaneously hypertensive rat. Microcirculation 2006; 13: 551-566
21 Djordjevic T, BelAiba RS, Bonello S et al. Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells. Arterioscler Thromb Vasc Biol 2005; 25: 519-525
22 Duarte J, Andriambeloson E, Diebolt M et al. Wine polyphenols stimulate superoxide anion production to promote calcium signaling and endothelial-dependent vasodilatation. Physiol Res 2004; 53: 595-602
23 Duffy SJ, Gokce N, Holbrook M et al. Treatment of hypertension with ascorbic acid. Lancet 1999; 354: 2048-2049
24 Duffy SJ, Gokce N, Holbrook M et al. Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension. Am J Physiol Heart Circ Physiol 2001; 280: 528-534
25 Ettarh RR, Odigie IP, Adigun SA. Vitamin C lowers blood pressure and alters vascular responsiveness in salt-induced hypertension. Can J Physiol Pharmacol 2002; 80: 1199-1202
26 Eto Y, Kang D, Hasegawa E et al. Succinate-dependent lipid peroxidation and its prevention by reduced ubiquinone in beef heart submitochondrial particles. Arch Biochem Biophys 1992; 295: 101-106
27 Faure P. Protective effects of antioxidant micronutrients (vitamin E, zinc and selenium) in type 2 diabetes mellitus. Clin Chem Lab Med 2003; 41: 995-998
28 Faure P, Ramon O, Favier A et al. Selenium supplementation decreases nuclear factor-kappa B activity in peripheral blood mononuclear cells from type 2 diabetic patients. Eur J Clin Invest 2004; 34: 475-481
29 Feairheller DL, Brown MD, Park JY et al. Exercise training, NADPH oxidase p22phox gene polymorphisms, and hypertension. Med Sci Sports Exerc 2009; 41: 1421-1428
30 Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 2008; 300: 924-932
31 Feldman EB, Gold S, Greene J et al. Ascorbic acid supplements and blood pressure:a four-week pilot study. Ann N Y Acad Sci 1992; 669: 342-344
32 Fotherby MD, Williams JC, Forster LA et al. Effect of vitamin C on ambulatory blood pressure and plasma lipids in older persons. J Hypertens 2000; 18: 411-415
33 Galley HF, Thornton J, Howdle PD et al. Combination oral antioxidant supplementation reduces blood pressure. Clin Sci (Lond) 1997; 92: 361-365
34 Gavazzi G, Banfi B, Deffert C et al. Decreased blood pressure in NOX1-deficient mice. FEBS Lett 2006; 580: 497-504
35 George J, Struthers A. The role of urate and xanthine oxidase in vascular oxidative stress: future directions. Ther Clin Risk Manag 2009; 5: 799-803
36 Ghiadoni L, Magagna A, Versari D et al. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension 2003; 41: 1281-1286
37 Ghosh SK, Ekpo EB, Shah IU et al. A double-blind, placebo-controlled parallel trial of vitamin C treatment in elderly patients with hypertension. Gerontology 1994; 40: 268-272
38 Goicoechea M, Vinuesa SG, Verdalles U et al. Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk. Clin J Am Soc Nephrol 2010; 5: 1388-1393
39 Gomez-Alamillo C, Juncos LA, Cases A et al. Interactions between vasoconstrictors and vasodilators in regulating hemodynamics of distinct vascular beds. Hypertension 2003; 42: 831-836
40 Grande MT, Pérez-Barriocanal F, López-Novoa JM. Role of inflammation in túbulo-interstitial damage associated to obstructive nephropathy. J Inflamm (Lond) 2010; 7: 19-32
41 Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: Achievements and perspectives. Hypertension 2009; 54: 690-697
42 Guarnieri G, Zanetti M, Vinci P et al. Metabolic syndrome and chronic kidney disease. J Ren Nutr 2010; 20: 19-23
43 Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci 2006; 7: 335-346
44 Hajjar IM, George V, Sasse EA et al. A randomized, double-blind, controlled trial of vitamin C in the management of hypertension and lipids. Am J Ther 2002; 9: 289-293
45 Han D, Antunes F, Canali R et al. Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 2003; 278: 5557-5563
46 Harrison DG, Gongora MC. Oxidative stress and hypertension. Med Clin North Am 2009; 93: 621-635
47 Heller R, Werner-Felmayer G, Werner ER. Alpha-tocopherol and endothelial nitric oxide synthesis. Ann N Y Acad Sci 2004; 1031: 74-85
48 Heller R, Werner-Felmayer G, Werner ER. Antioxidants and endothelial nitric oxide synthesis. Eur J Clin Pharmacol 2006; 62: 21-28
49 Hirooka Y, Sagara Y, Kishi T et al. Oxidative stress and central cardiovascular regulation. Pathogenesis of hypertension and therapeutic aspects. Circ J 2010; 74: 827-835
50 Hitomi H, Kiyomoto H, Nishiyama A. Angiotensin II and oxidative stress. Curr Opin Cardiol 2007; 22: 311-315
51 AWJH Hoitink. Research on the influence of vitamin C administration on the human organism, in particular in connection with the working capacity. Verh Nederlands Inst Praevent 1946; 4: 62-63
52 Hool LC, Corry B. Redox control of calcium channels: from mechanisms to therapeutic opportunities. Antioxid Redox Signal 2007; 9: 409-435
53 Houston MC. Nutraceuticals, vitamins, antioxidants, and minerals in the prevention and treatment of hypertension. Prog Cardiovasc Dis 2005; 47: 396-449
54 Ito Y, Fujita T. Trace elements and blood pressure regulation. Nippon Rinsho 1996; 54: 106-110
55 Jackson TS, Xu A, Vita JA et al. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 1998; 83: 916-922
56 Jegou S, Cartier D, Dubessy C et al. Localization of the urotensin II receptor in the rat central nervous system. J Comp Neurol 2006; 495: 21-36
57 Juraschek SP, Guallar E, Appel LJ et al. Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2012; 95: 1079-1088
58 Kim MK, Sasaki S, Sasazuki S et al. Lack of long-term effect of vitamin C supplementation on blood pressure. Hypertension 2002; 40: 797-803
59 Kim IY, Stadtman TC. Inhibition of NF-kappaB DNA binding and nitric oxide induction in human T cells and lung adenocarcinoma cells by selenite treatment. Proc Natl Acad Sci 1997; 94: 12904-12907
60 Kimura S, Zhang GX, Nishiyama A et al. Mitochondria-derived reactive oxygen species and vascular MAP kinases: comparison of angiotensin II and diazoxide. Hypertension 2005; 45: 438-444
61 Kishi T, Hirooka Y, Kimura Y et al. Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation 2004; 109: 2357-2362
62 Klahr S. Urinary tract obstruction. Semin Nephrol 2001; 21: 133-145
63 Koh ET. Effect of vitamin C on blood parameters of hypertensive subjects. J Okla State Med Assoc 1984; 77: 177-182
64 Kuzkaya N, Weissmann N, Harrison DG et al. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem 2003; 278: 22546-22554
65 Laakso JT, Teräväinen TL, Martelin E et al. Renal xanthine oxidoreductase activity during development of hypertension in spontaneously hypertensive rats. J Hypertens 2004; 22: 1333-1340
66 Lacy F, Kailasam MT, O’Connor DT et al. Plasma hydrogen peroxide production in human essential hypertension: role of heredity, gender, and ethnicity. Hypertension 2000; 36: 878-884
67 Landmesser U, Cai H, Dikalov S et al. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension 2002; 40: 511-515
68 Landmesser U, Dikalov S, Price SR et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 2003; 111: 1201-1209
69 Lassègue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 2003; 285: 277-297
70 Lassègue B, Griendling K. Reactive Oxygen Species in Hypertension, An Update. Am J Hypertens 2004; 17: 852-860
71 Laursen JB, Somers M, Kurz S et al. Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 2001; 103: 1282-1288
72 Lee IM, Cook NR, Gaziano JM et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005; 294: 56-65
73 Levitan EB, Wolk A, Mittleman MA. Relation of consistency with the dietary approaches to stop hypertension diet and incidence of heart failure in men aged 45 to 79 years. Am J Cardiol 2009; 104: 1416-1420
74 Lonn E, Bosch J, Yusuf S et al. HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005; 293: 1338-1347
75 Lymbury RS, Marino MJ, Perkins AV. Effect of dietary selenium on the progression of heart failure in the ageing spontaneously hypertensive rat. Mol Nutr Food Res 2010; 54: 1436-1444
76 Malyszko J. Mechanism of endothelial dysfunction in chronic kidney disease. Clin Chim Acta 2010; 411: 1412-1420
77 Matsushita M, Shichiri M, Imai T et al. Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues. J Hypertens 2001; 19: 2185-2190
78 Mazzali M, Hughes J, Kim Y et al. Elevated Uric Acid Increases Blood Pressure in the Rat by a Novel Crystal-Independent Mechanism. Hypertension 2001; 38: 1101-1106
79 Michel JB, Feron O, Sase K et al. Caveolin versus calmodulin. Counterbalancing allosteric modulators of endothelial nitric oxide synthase. J Biol Chem 1997; 272: 25907-25912
80 Miller S, Walker SW, Arthur JR et al. Selenite protects human endothelial cells from oxidative damage and induces thioredoxin reductase. Clin Sci (Lond) 2001; 100: 543-550
81 Mistry HD, Wilson V, Ramsay MM et al. Reduced selenium concentrations and glutathione peroxidase activity in preeclamptic pregnancies. Hypertension 2008; 52: 881-888
82 Moran JP, Cohen L, Greene JM et al. Plasma ascorbic acid concentrations relate inversely to blood pressure in human subjects. Am J Clin Nutr 1993; 57: 213-217
83 Mullan BA, Young IS, Fee H et al. Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes. Hypertension 2002; 40: 804-809
84 Münzel T, Keaney Jr JF. Are ACE inhibitors a “magic bullet” against oxidative stress?. Circulation 2001; 104: 1571-1574
85 Nanayakkara PW, Teerlink T, Stehouwer CD et al. Plasma asymmetric dimethylarginine (ADMA) concentration is independently associated with carotid intima-media thickness and plasma soluble vascular cell adhesión molecule-1 (sVCAM-1) concentration in patients with mild-to-moderate renal failure. Kidney Int 2005; 68: 2230-2236
86 Nawrot TS, Staessen JA, Roels HA et al. Blood pressure and blood selenium: a cross-sectional and longitudinal population study. Eur Heart J 2007; 28: 628-633
87 Nishikawa Y, Tatsumi K, Matsuura T et al. Effects of vitamin C on high blood pressure induced by salt in spontaneously hypertensive rats. J Nutr Sci Vitaminol (Tokyo) 2003; 49: 301-309
88 Nowson CA, Wattanapenpaiboon N, Pachett A. Low-sodium Dietary Approaches to Stop Hypertension-type diet including lean red meat lowers blood pressure in postmenopausal women. Nutr Res 2009; 29: 8-18
89 Oliveira-Sales EB, Nishi EE, Carillo BA et al. Oxidative stress in the sympathetic promotor neurons contributes to sympathetic activation in renovascular hypertension. Am J Hypertens 2009; 22: 484-492
90 On YK, Kim CH, Sohn DW et al. Improvement of endothelial function by amlodipine and vitamin C in essential hypertension. Korean J Intern Med 2002; 17: 131-137
91 Padayatty SJ, Katz A, Wang Y et al. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr 2003; 22: 18-35
92 Palumbo G, Avanzini F, Alli C et al. Effects of vitamin E on clinic and ambulatory blood pressure in treated hypertensive patients. Collaborative Group of the Primary Prevention Project (PPP) – Hypertension study. Am J Hypertens 2000; 13: 564-567
93 Paravicini TM, Touyz RM. Redox signalling in hypertension. Cardiovasc Res 2006; 71: 247-258
94 Pechánová O, Zicha J, Kojsová S et al. Effect of chronic N-acetylcysteine treatment on the development of spontaneous hypertension. Clin Sci (Lond) 2006; 110: 235-242
95 Pechánová O, Rezzani R, Babál P et al. Beneficial effects of Provinols: cardiovascular system and kidney. Physiol Res 2006; 55: 17-30
96 Pechánová O. Contribution of captopril thiol group to the prevention of spontaneous hypertension. Physiol Res 2007; 56: 41-48
97 Penugonda S, Mare S, Goldstein G et al. Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12. Brain Res 2005; 1056: 132-138
98 Plantinga Y, Ghiadoni L, Magagna A et al. Suplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients. Am J Hypertens 2007; 20: 392-397
99 Piccoli C, Quarato G, D'Aprile A et al. Native LDL-induced oxidative stress in human proximal 1 tubular cells: multiple players involved. J Cell Mol Med 2011; 15: 375-395
100 Pietta P, Simonetti P, Gardana C et al. Relationship between rate and extent of catechin absorption and plasma antioxidant status. Biochem Mol Biol Int 1998; 46: 895-903
101 Rapola JM, Virtamo J, Ripatti S et al. Randomised trial of a-tocopherol and b-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 1997; 349: 1715-1720
102 Reckelhoff JF, Kanji V, Racusen LC et al. Vitamin E ameliorates enhanced renal lipid peroxidation and accumulation of F2-isoprostanes in aging kidneys. Am J Physiol 1998; 274: 767-774
103 Redon J, Oliva MR, Tormos C et al. Antioxidant activities and oxidative stress byproducts in human hypertension. Hypertension 2003; 41: 1096-1101
104 Rodrigo R, Rivera G. Renal damage mediated by oxidative stress: a hypothesis of protective effects of red wine. Free Radic Biol Med 2002; 33: 409-422
105 Rodrigo R, Passalacqua W, Araya J et al. Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension. J Cardiovasc Pharmacol 2003; 42: 453-461
106 Rodrigo R, Passalacqua W, Araya J et al. Homocysteine and essential hypertension. J Clin Pharmacol 2003; 43: 1299-1306
107 Rodrigo R, Bosco C. Oxidative stress and protective effects of polyphenols: comparative studies in human and rodent kidney. A review. Comp Biochem Physiol C Toxicol Pharmacol 2006; 142: 317-327
108 Rodrigo R, Prat H, Passalacqua W et al. Relationship between oxidative stress and essential hypertension. Hypertens Res 2007; 30: 1159-1167
109 Rodrigo R, Guichard C, Charles R. Clinical pharmacology and therapeutic use of antioxidant vitamins. Fundam Clin Pharmacol 2007; 21: 111-127
110 Rodrigo R, Prat H, Passalacqua W et al. Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension. Clin Sci (Lond) 2008; 114: 625-634
111 Rodrigo R, Gil D, Miranda-Merchak A et al. Antihypertensive role of polyphenols. Adv Clin Chem 2012; 58: 225-254
112 Sachse A, Wolf G. Angiotensin II-induced reactive oxygen species and the kidney. J Am Soc Nephrol 2007; 18: 2439-2446
113 Sato K, Dohi Y, Kojima M et al. Effects of ascorbic acid on ambulatory blood pressure in elderly patients with refractory hypertension. Arzneimittelforschung 2006; 56: 535-540
114 Savica V, Bellinghieri G, Kopple JD. The effect of nutrition on blood pressure. Annu Rev Nutr 2010; 30: 365-401
115 Schneider MP, Delles C, Schmidt BM et al. Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension. Am J Hypertens 2005; 18: 1111-1117
116 Simko F, Luptak I, Matuskova J et al. L-arginine fails to protect against myocardial remodelling in L-NAME-induced hypertension. Eur J Clin Invest 2005; 35: 362-368
117 Sládková M, Kojsová S, Jendeková L et al. Chronic and acute effects of different antihypertensive drugs on femoral artery relaxation of L-NAME hypertensive rats. Physiol Res 2007; 56: 85-91
118 Smith PJ, Blumenthal JA, Babyak MA et al. Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure. Hypertension 2010; 55: 1331-1338
119 Steinbrenner H, Sies H. Protection against reactive oxygen species by selenoproteins. Biochim Biophys Acta 2009; 1790: 1478-1485
120 Stirrat A, Gallagher M, Douglas SA et al. Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries. Am J Physiol Heart Circ Physiol 2001; 280: 925-928
121 Stojiljkovic MP, Lopes HF, Zhang D et al. Increasing plasma fatty acids elevates F2-isoprostanes in humans: implications for the cardiovascular risk factor cluster. J Hypertens 2002; 20: 1215-1221
122 Suzuki H, DeLano FA, Parks DA et al. Xanthine oxidase activity associated with arterial blood pressure in spontaneously hypertensive rats. Proc Natl Acad Sci USA 1998; 95: 4754-4759
123 Sved AF, Ito S, Sved JC. Brainstem mechanisms of hypertension: Role of the rostral ventrolateral medulla. Curr Hypertens Rep 2003; 5: 262-268
124 Taddei S, Virdis A, Ghiadoni L et al. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 1998; 97: 2222-2229
125 Takizawa M, Komori K, Tampo Y et al. Paraquat-induced oxidative stress and dysfunction of cellular redox systems including antioxidative defense enzymes glutathione peroxidase and thioredoxin reductase. Toxicol In Vitro 2007; 21: 355-363
126 Tanito M, Nakamura H, Kwon YW et al. Enhanced oxidative stress and impaired thioredoxin expression in spontaneously hypertensive rats. Antioxid Redox Signal 2004; 6: 89-97
127 Taniyama Y, Griendling K. Reactive Oxygen Species in the Vasculature: Molecular and Cellular Mechanisms. Hypertension 2003; 42: 1075-1081
128 Tian N, Rose RA, Jordan S et al. N-Acetylcysteine improves renal dysfunction, ameliorates kidney damage and decreases blood pressure in salt-sensitive hypertension. J Hypertens 2006; 24: 2263-2270
129 Touyz RM, Schiffrin EL. Increased generation of superoxide by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients: role of phospholipase D-dependent NAD(P)H oxidase-sensitive pathways. J Hypertens 2001; 19: 1245-1254
130 Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance?. Hypertension 2004; 44: 248-252
131 Ulker S, McKeown PP, Bayraktutan U. Vitamins reverse endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities. Hypertension 2003; 41: 534-539
132 Viel EC, Benkirane K, Javeshghani D et al. Xanthine oxidase and mitochondria contribute to vascular superoxide anion generation in DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 2008; 295: 281-288
133 Vita JA, Frei B, Holbrook M et al. L-2-Oxothiazolidine-4-carboxylic acid reverses endothelial dysfunction in patients with coronary artery disease. J Clin Invest 1998; 101: 1408-1414
134 Ward NC, Hodgson JM, Croft KD et al. The combination of vitamin C and grape-seed polyphenols increases blood pressure: a randomized, double-blind, placebo-controlled trial. J Hypertens 2005; 23: 427-434
135 Ward NC, Wu JH, Clarke MW et al. The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. J Hypertens 2007; 25: 227-234
136 Wen H, Gwathmey JK, Xie LH. Oxidative stress-mediated effects of angiotensin II in the cardiovascular system. World J Hypertens 2012; 2: 34-44
137 Yoshida J, Yamamoto K, Mano T et al. AT1 receptor blocker added to ACE inhibitor provides benefits at advanced stage of hypertensive diastolic heart failure. Hypertension 2004; 43: 686-691
138 Yoshioka M, Aoyama K, Matsushita T. Effects of ascorbic acid on blood pressure and ascorbic acid metabolism in spontaneously hypertensive rats (SH rats). Int J Vitam Nutr Res 1985; 55: 301-307
139 Yoshioka J, Schreiter ER, Lee RT. Role of thioredoxin in cell growth through interactions with signaling molecules. Antioxid Redox Signal 2006; 8: 2143-2145
140 Young JM, Florkowski CM, Molyneux SL et al. A randomized, double-blind, placebo-controlled crossover study of coenzyme Q10 therapy in hypertensive patients with the metabolic syndrome. Am J Hypertens 2012; 25: 261-270
141 Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART Study): case control study. Lancet 2004; 364: 937-952
142 Zaslavskaia RM, Shcherban’ EA, Lilitsa GV et al. Melatonin in the combined treatment of cardiovascular diseases. Klin Med (Mosk) 2010; 88: 26-30
143 Zembowicz A, Hatchett RJ, Radziszewski W et al. Inhibition of endothelial nitric oxide synthase by ebselen. Prevention by thiols suggests the inactivation by ebselen of a critical thiol essential for the catalytic activity of nitric oxide synthase. J Pharmacol Exp Ther 1993; 267: 1112-1118
144 Zenebe W, Pechánová O, Andriantsitohaina R. Red wine polyphenols induce vasorelaxation by increased nitric oxide bioactivity. Physiol Res 2003; 52: 425-432
145 Zhang Y, Hogg N. S-Nitrosothiols: cellular formation and transport. Free Radic Biol Med 2005; 38: 831-838
146 Zhang C, Hu JJ, Xia M et al. Redox signaling via lipid raft clustering in homocysteine-induced injury of podocytes. Biochim Biophys Acta 2010; 1803: 482-491
147 Zhou L, Xiang W, Potts J et al. Reduction in extracellular superoxide dismutase activity in African-American patients with hypertension. Free Radic Biol Med 2006; 41: 1384-1391
148 Zhou X, Ji WJ, Zhu Y et al. Enhancement of endogenous defenses against ROS by supra-nutritional level of selenium is more safe and effective than antioxidant supplementation in reducing hypertensive target organ damage. Med Hypotheses 2007; 68: 952-956
149 Zimmerman MC, Lazartigues E, Sharma RV et al. Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circ Res 2004; 95: 210-216
150 Zoccali C, Bode-Böger S, Mallamaci F et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: aprospective study. Lancet 2001; 358: 2113-2117
151 Zou MH, Cohen RA, Ullrich V. Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus. Endothelium 2004; 11: 89-97