, Volume 76, Issue 16, pp 1529–1550 | Cite as

Drug Treatment of Hypertension: Focus on Vascular Health

  • Alan C. Cameron
  • Ninian N. Lang
  • Rhian M. Touyz
Review Article


Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure (BP) elevation, the vascular system is particularly important because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high BP have greater efficacy for reducing cardiovascular risk than drugs that reduce BP, but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve endothelial function and prevent vascular remodelling. Calcium channel blockers also improve endothelial function, although to a lesser extent than ACEIs and ARBs. Mineralocorticoid receptor blockers improve endothelial function and reduce arterial stiffness, and have recently become more established as antihypertensive drugs. Lifestyle factors are essential in preventing the adverse vascular changes associated with high BP and reducing associated cardiovascular risk. Clinicians and scientists should incorporate these factors into treatment decisions for patients with high BP, as well as in the development of new antihypertensive drugs that promote vascular health.


Nitric Oxide Endothelial Dysfunction Endothelial Function Arterial Stiffness Pulse Wave Velocity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards


No external funding was used in the preparation of this manuscript.

Conflict of interest

Alan C. Cameron, Ninian N. Lang and Rhian M. Touyz declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.


  1. 1.
    Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep. 2010;12(6):448–55.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Harvey A, Montezano AC, Lopes RA, Rios F, Touyz RM. Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications. Can J Cardiol. 2016;32(5):659–68.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Touyz RM, Dominiczak AF. Hypertension guidelines: is it time to reappraise blood pressure thresholds and targets? Hypertension. 2016;67(4):688–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A. Effects of antihypertensive drugs on endothelial dysfunction: clinical implications. Drugs. 2002;62(2):265–84.PubMedCrossRefGoogle Scholar
  5. 5.
    The SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood pressure control. N Engl J Med. 2015;373:2103–16.PubMedCentralCrossRefGoogle Scholar
  6. 6.
    Harvey A, Montezano AC, Touyz RM. Vascular biology of ageing—implications in hypertension. J Mol Cell Cardiol. 2015;83(C):112–21.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Lopes RA, Neves KB, Tostes RC, Montezano AC, Touyz RM. Downregulation of nuclear factor erythroid 2-related factor and associated antioxidant genes contributes to redox-sensitive vascular dysfunction in hypertension. Hypertension. 2015;66(6):1240–50.PubMedGoogle Scholar
  8. 8.
    AlGhatrif M, Strait JB, Morrell CH, Canepa M, Wright J, Elango P, et al. Longitudinal trajectories of arterial stiffness and the role of blood pressure: the Baltimore Longitudinal Study of Aging. Hypertension. 2013;62(5):934–41.PubMedCrossRefGoogle Scholar
  9. 9.
    Huveneers S, Daemen MJAP, Hordijk PL. Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. Circ Res. 2015;116(5):895–908.PubMedCrossRefGoogle Scholar
  10. 10.
    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288(5789):373–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature. 1988;333(6174):664–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature. 1991;351(6329):714–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Yanagisawa M, Kurihara H, Kimura S, Goto K, Masaki T. A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. J Hypertens Suppl. 1988;6(4):S188–91.PubMedCrossRefGoogle Scholar
  15. 15.
    Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA. 1989;86(8):2863–7.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Xu D, Emoto N, Giaid A, Slaughter C, Kaw S, deWit D, et al. ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell. 1994;78(3):473–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990;348(6303):730–2.PubMedCrossRefGoogle Scholar
  18. 18.
    Seo B, Oemar BS, Siebenmann R, von Segesser L, Lüscher TF. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation. 1994;89(3):1203–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Haynes WG, Strachan FE, Webb DJ. Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation. 1995;92(3):357–63.PubMedCrossRefGoogle Scholar
  20. 20.
    de Nucci G, Thomas R, D’Orleans-Juste P, Antunes E, Walder C, Warner TD, et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA. 1988;85(24):9797–800.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Haynes WG, Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens. 1998;16(8):1081–98.PubMedCrossRefGoogle Scholar
  22. 22.
    Thuillez C, Richard V. Targeting endothelial dysfunction in hypertensive subjects. J Hum Hypertens. 2005;19:S21–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Hamburg NM, Benjamin EJ. Assessment of endothelial function using digital pulse amplitude tonometry. Trends Cardiovasc Med. 2009;19(1):6–11.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol. 2002;40(3):505–10.PubMedCrossRefGoogle Scholar
  25. 25.
    Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr, et al. Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation. 2004;109(5):613–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Linder L, Kiowski W, Bühler FR, Lüscher TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation. 1990;81(6):1762–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Panza JA, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990;323(1):22–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Taddei S, Virdis A, Mattei P, Salvetti A. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension. 1993;21(6 Pt 2):929–33.PubMedCrossRefGoogle Scholar
  29. 29.
    Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 1993;87(5):1468–74.PubMedCrossRefGoogle Scholar
  30. 30.
    Taddei S, Virdis A, Mattei P, Natali A, Ferrannini E, Salvetti A. Effect of insulin on acetylcholine-induced vasodilation in normotensive subjects and patients with essential hypertension. Circulation. 1995;92(10):2911–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Fasolo CB, et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation. 1995;91(7):1981–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Taddei S, Virdis A, Mattei P, Ghiadoni L, Fasolo CB, Sudano I, et al. Hypertension causes premature aging of endothelial function in humans. Hypertension. 1997;29(3):736–43.PubMedCrossRefGoogle Scholar
  33. 33.
    Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Cyclooxygenase inhibition restores nitric oxide activity in essential hypertension. Hypertension. 1997;29(1 Pt 2):274–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation. 1998;97(22):2222–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Antony I, Lerebours G, Nitenberg A. Angiotensin-converting enzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary arteries of hypertensive patients. Circulation. 1996;94(12):3115–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Taddei S, Virdis A, Ghiadoni L, Uleri S, Magagna A, Salvetti A. Lacidipine restores endothelium-dependent vasodilation in essential hypertensive patients. Hypertension. 1997;30(6):1606–12.PubMedCrossRefGoogle Scholar
  37. 37.
    Ghiadoni L, Virdis A, Magagna A, Taddei S, Salvetti A. Effect of the angiotensin II type 1 receptor blocker candesartan on endothelial function in patients with essential hypertension. Hypertension. 2000;35(1 Pt 2):501–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Widlansky ME, Gokce N, Keaney JF, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42(7):1149–60.PubMedCrossRefGoogle Scholar
  39. 39.
    Rubattu S, Pagliaro B, Pierelli G, Santolamazza C, Castro SD, Mennuni S, et al. Pathogenesis of target organ damage in hypertension: role of mitochondrial oxidative stress. Int J Mol Sci. 2015;16(1):823–39.CrossRefGoogle Scholar
  40. 40.
    Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.PubMedCrossRefGoogle Scholar
  41. 41.
    Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cochemé HM, et al. Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension. 2009;54(2):322–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Myung S-K, Ju W, Cho B, Oh SW, Park SM, Koo BK, et al. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2013;346:f10.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Schiffrin EL. Role of endothelin-1 in hypertension. Hypertension. 1999;34(4):876–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74(6):1141–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996;97(8):1916–23.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;2(8567):1057–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83(5):1774–7.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA. 1991;88(11):4651–5.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96(1):60–8.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ghiadoni L, Taddei S, Virdis A, Sudano I, Di Legge V, Meola M, et al. Endothelial function and common carotid artery wall thickening in patients with essential hypertension. Hypertension. 1998;32(1):25–32.PubMedCrossRefGoogle Scholar
  51. 51.
    Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000;101(9):948–54.PubMedCrossRefGoogle Scholar
  52. 52.
    Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101(16):1899–906.PubMedCrossRefGoogle Scholar
  53. 53.
    Neunteufl T, Heher S, Katzenschlager R, Wölfl G, Kostner K, Maurer G, et al. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol. 2000;86(2):207–10.PubMedCrossRefGoogle Scholar
  54. 54.
    Schiffrin EL. Vascular remodeling in hypertension: mechanisms and treatment. Hypertension. 2012;59(2):367–74.PubMedCrossRefGoogle Scholar
  55. 55.
    Renna NF, las Heras de N, Miatello RM. Pathophysiology of vascular remodeling in hypertension. Int J Hypertens. 2013;2013(22):1–7.Google Scholar
  56. 56.
    Savoia C, Sada L, Zezza L, Pucci L, Lauri FM, Befani A, et al. Vascular inflammation and endothelial dysfunction in experimental hypertension. Int J Hypertens. 2011;2011:281240.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001;89(9):763–71.PubMedCrossRefGoogle Scholar
  58. 58.
    Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA. 2003;290(22):2945–51.PubMedCrossRefGoogle Scholar
  59. 59.
    Preston RA, Ledford M, Materson BJ, Baltodano NM, Memon A, Alonso A. Effects of severe, uncontrolled hypertension on endothelial activation: soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and von Willebrand factor. J Hypertens. 2002;20(5):871–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Blake GJ, Rifai N, Buring JE, Ridker PM. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation. 2003;108(24):2993–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Thorand B, Löwel H, Schneider A, Kolb H, Meisinger C, Fröhlich M, et al. C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984–1998. Arch Intern Med. 2003;163(1):93–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Lee MY, Griendling KK. Redox signaling, vascular function, and hypertension. Antioxid Redox Signal. 2008;10(6):1045–59.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Wind S, Beuerlein K, Armitage ME, Taye A, Kumar AH, Janowitz D, et al. Oxidative stress and endothelial dysfunction in aortas of aged spontaneously hypertensive rats by NOX1/2 is reversed by NADPH oxidase inhibition. Hypertension. 2010;56(3):490–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Touyz RM, Briones AM, Sedeek M, Burger D, Montezano AC. NOX isoforms and reactive oxygen species in vascular health. Mol Interv. 2011;11(1):27–35.PubMedCrossRefGoogle Scholar
  65. 65.
    Montezano AC, Touyz RM. Molecular mechanisms of hypertension–reactive oxygen species and antioxidants: a basic science update for the clinician. Can J Cardiol. 2012;28(3):288–95.PubMedCrossRefGoogle Scholar
  66. 66.
    Montezano AC, Burger D, Ceravolo GS, Yusuf H, Montero M, Touyz RM. Novel Nox homologues in the vasculature: focusing on Nox4 and Nox5. Clin Sci. 2011;120(4):131–41.PubMedCrossRefGoogle Scholar
  67. 67.
    Nilsson PM, Khalili P, Franklin SS. Blood pressure and pulse wave velocity as metrics for evaluating pathologic ageing of the cardiovascular system. Blood Press. 2014;23(1):17–30.PubMedCrossRefGoogle Scholar
  68. 68.
    Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, Artery Society, European Society of Hypertension Working Group on Vascular Structure and Function, European Network for Noninvasive Investigation of Large Arteries, et al. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012;30(3):445–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Dudenbostel T, Glasser SP. Effects of antihypertensive drugs on arterial stiffness. Cardiol Rev. 2012;20(5):259–63.PubMedCrossRefGoogle Scholar
  70. 70.
    Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease. Circulation. 2003;107(1):139–46.PubMedCrossRefGoogle Scholar
  71. 71.
    Lakatta EG. The reality of aging viewed from the arterial wall. Artery Res. 2013;7(2):73–80.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T. Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem. 2003;253(1–2):269–85.PubMedCrossRefGoogle Scholar
  73. 73.
    Giannandrea M, Parks WC. Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech. 2014;7(2):193–203.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev. 2005;85(1):1–31.PubMedCrossRefGoogle Scholar
  75. 75.
    Wang M, Kim SH, Monticone RE, Lakatta EG. Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis. Hypertension. 2015;65(4):698–703.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Douillet CD, Velarde V, Christopher JT, Mayfield RK, Trojanowska ME, Jaffa AA. Mechanisms by which bradykinin promotes fibrosis in vascular smooth muscle cells: role of TGF-beta and MAPK. Am J Physiol Heart Circ Physiol. 2000;279(6):H2829–37.PubMedGoogle Scholar
  77. 77.
    O’Callaghan CJ, Williams B. Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-beta(1). Hypertension. 2000;36(3):319–24.PubMedCrossRefGoogle Scholar
  78. 78.
    Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, et al. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J. 1999;13(13):1774–86.PubMedGoogle Scholar
  79. 79.
    Li JH, Huang XR, Zhu H-J, Oldfield M, Cooper M, Truong LD, et al. Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. FASEB J. 2004;18(1):176–8.PubMedGoogle Scholar
  80. 80.
    Wang M, Zhao D, Spinetti G, Zhang J, Jiang LQ, Pintus G, et al. Matrix metalloproteinase 2 activation of transforming growth factor-beta1 (TGF-beta1) and TGF-beta1-type II receptor signaling within the aged arterial wall. Arterioscler Thromb Vasc Biol. 2006;26(7):1503–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest. 1992;90(2):456–61.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Itoh H, Mukoyama M, Pratt RE, Gibbons GH, Dzau VJ. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest. 1993;91(5):2268–74.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Sucosky P, Balachandran K, Elhammali A, Jo H, Yoganathan AP. Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway. Arterioscler Thromb Vasc Biol. 2009;29(2):254–60.PubMedCrossRefGoogle Scholar
  84. 84.
    Rodríguez-Vita J, Sanchez-Lopez E, Esteban V, Rupérez M, Egido J, Ruiz-Ortega M. Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanism. Circulation. 2005;111(19):2509–17.PubMedCrossRefGoogle Scholar
  85. 85.
    Rhyu DY, Yang Y, Ha H, Lee GT, Song JS, Uh ST, et al. Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells. J Am Soc Nephrol. 2005;16(3):667–75.PubMedCrossRefGoogle Scholar
  86. 86.
    Yamamoto K, Takeshita K, Saito H. Plasminogen activator inhibitor-1 in aging. Semin Thromb Hemost. 2014;40(6):652–9.PubMedCrossRefGoogle Scholar
  87. 87.
    de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold AC, van Gilst WH, Hillege HL, et al. The fibrosis marker galectin-3 and outcome in the general population. J Intern Med. 2012;272(1):55–64.PubMedCrossRefGoogle Scholar
  88. 88.
    Koopmans SM, Bot FJ, Schouten HC, Janssen J, van Marion AM. The involvement of Galectins in the modulation of the JAK/STAT pathway in myeloproliferative neoplasia. Am J Blood Res. 2012;2(2):119–27.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Song X, Qian X, Shen M, Jiang R, Wagner MB, Ding G, et al. Protein kinase C promotes cardiac fibrosis and heart failure by modulating galectin-3 expression. Biochim Biophys Acta. 2015;1853(2):513–21.PubMedCrossRefGoogle Scholar
  90. 90.
    Montezano AC, Nguyen Dinh Cat A, Rios FJ, Touyz RM. Angiotensin II and vascular injury. Curr Hypertens Rep. 2014;16(6):431.PubMedCrossRefGoogle Scholar
  91. 91.
    Martínez-Martínez E, Calvier L, Fernández-Celis A, Rousseau E, Jurado-López R, Rossoni LV, et al. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension. Hypertension. 2015;66(4):767–75.PubMedCrossRefGoogle Scholar
  92. 92.
    Messaoudi S, He Y, Gutsol A, Wight A, Hébert RL, Vilmundarson RO, et al. Endothelial Gata5 transcription factor regulates blood pressure. Nat Commun. 2015;6:8835.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Yu L, Ruifrok WPT, Meissner M, Bos EM, van Goor H, Sanjabi B, et al. Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis. Circ Heart Fail. 2013;6(1):107–17.PubMedCrossRefGoogle Scholar
  94. 94.
    Neves KB, Nguyen Dinh Cat A, Lopes RAM, Rios FJ, Anagnostopoulou A, Lobato NS, et al. Chemerin regulates crosstalk between adipocytes and vascular cells through Nox. Hypertension. 2015;66(3):657–66.PubMedCrossRefGoogle Scholar
  95. 95.
    Weigert C, Brodbeck K, Klopfer K, Häring HU, Schleicher ED. Angiotensin II induces human TGF-beta 1 promoter activation: similarity to hyperglycaemia. Diabetologia. 2002;45(6):890–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Montezano AC, Burger D, Paravicini TM, Chignalia AZ, Yusuf H, Almasri M, et al. Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (Nox5) regulation by angiotensin II and endothelin-1 is mediated via calcium/calmodulin-dependent, rac-1-independent pathways in human endothelial cells. Circ Res. 2010;106(8):1363–73.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Qi G, Jia L, Li Y, Bian Y, Cheng J, Li H, et al. Angiotensin II infusion-induced inflammation, monocytic fibroblast precursor infiltration, and cardiac fibrosis are pressure dependent. Cardiovasc Toxicol. 2011;11(2):157–67.PubMedCrossRefGoogle Scholar
  98. 98.
    Carver KA, Smith TL, Gallagher PE, Tallant EA. Angiotensin-(1-7) prevents angiotensin II-induced fibrosis in cremaster microvessels. Microcirculation. 2015;22(1):19–27.PubMedCrossRefGoogle Scholar
  99. 99.
    Attinà T, Camidge R, Newby DE, Webb DJ. Endothelin antagonism in pulmonary hypertension, heart failure, and beyond. Heart. 2005;91(6):825–31.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Lankhorst S, Kappers MHW, van Esch JHM, Danser AHJ, van den Meiracker AH. Hypertension during vascular endothelial growth factor inhibition: focus on nitric oxide, endothelin-1, and oxidative stress. Antioxid Redox Signal. 2014;20(1):135–45.PubMedCrossRefGoogle Scholar
  101. 101.
    Moorhouse RC, Webb DJ, Kluth DC, Dhaun N. Endothelin antagonism and its role in the treatment of hypertension. Curr Hypertens Rep. 2013;15(5):489–96.PubMedCrossRefGoogle Scholar
  102. 102.
    Remuzzi G, Perico N, Benigni A. New therapeutics that antagonize endothelin: promises and frustrations. Nat Rev Drug Discov. 2002;1(12):986–1001.PubMedCrossRefGoogle Scholar
  103. 103.
    Boffa JJ, Tharaux PL, Dussaule JC, Chatziantoniou C. Regression of renal vascular fibrosis by endothelin receptor antagonism. Hypertension. 2001;37(2 Pt 2):490–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Kitta Y, Obata J-E, Nakamura T, Hirano M, Kodama Y, Fujioka D, et al. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol. 2009;53(4):323–30.PubMedCrossRefGoogle Scholar
  105. 105.
    Ruilope LM, Redón J, Schmieder R. Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme. Vasc Health Risk Manag. 2007;3(1):1–9.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Schmieder RE, Delles C, Mimran A, Fauvel JP, Ruilope LM. Impact of telmisartan versus ramipril on renal endothelial function in patients with hypertension and type 2 diabetes. Diabetes Care. 2007;30(6):1351–6.PubMedCrossRefGoogle Scholar
  107. 107.
    Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359(9311):995–1003.PubMedCrossRefGoogle Scholar
  108. 108.
    Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, ACCOMPLISH Trial Investigators, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417–28.PubMedCrossRefGoogle Scholar
  109. 109.
    Hadi HAR, Carr CS, Suwaidi Al J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1(3):183–98.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Dagenais GR, Yusuf S, Bourassa MG, Yi Q, Bosch J, Lonn EM, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation. 2001;104(5):522–6.PubMedCrossRefGoogle Scholar
  111. 111.
    ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981–97.CrossRefGoogle Scholar
  112. 112.
    Clozel M, Kuhn H, Hefti F. Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats. Hypertension. 1990;16(5):532–40.PubMedCrossRefGoogle Scholar
  113. 113.
    Joannides R, Bellien J, Thurlure C, Iacob M, Abeel M, Thuillez C. Fixed combination of perindopril and indapamide at low dose improves endothelial function in essential hypertensive patients after acute administration. Am J Hypertens. 2008;21(6):679–84.PubMedCrossRefGoogle Scholar
  114. 114.
    Joannides R, Bellien J, Iacob M, Thurlure C, Abeel M, Thuillez C. Administration of low-dose combination of an angiotensin converting enzyme inhibitor and a diuretic improves conduit artery endothelial function in essential hypertension. J Hypertens. 2004;22(2):S123.CrossRefGoogle Scholar
  115. 115.
    Taddei S, Virdis A, Ghiadoni L, Mattei P, Salvetti A. Effects of angiotensin converting enzyme inhibition on endothelium-dependent vasodilatation in essential hypertensive patients. J Hypertens. 1998;16(4):447–56.PubMedCrossRefGoogle Scholar
  116. 116.
    Schiffrin EL. Correction of remodeling and function of small arteries in human hypertension by cilazapril, an angiotensin I-converting enzyme inhibitor. J Cardiovasc Pharmacol. 1996;27(Suppl 2):S13–8.PubMedCrossRefGoogle Scholar
  117. 117.
    Schiffrin EL, Deng LY. Comparison of effects of angiotensin I-converting enzyme inhibition and beta-blockade for 2 years on function of small arteries from hypertensive patients. Hypertension. 1995;25(4 Pt 2):699–703.PubMedCrossRefGoogle Scholar
  118. 118.
    Rizzoni D, Muiesan ML, Porteri E, Castellano M, Zulli R, Bettoni G, et al. Effects of long-term antihypertensive treatment with lisinopril on resistance arteries in hypertensive patients with left ventricular hypertrophy. J Hypertens. 1997;15(2):197–204.PubMedCrossRefGoogle Scholar
  119. 119.
    Mancini GB, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996;94(3):258–65.PubMedCrossRefGoogle Scholar
  120. 120.
    Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A, et al. Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation. 2001;103(6):799–805.PubMedCrossRefGoogle Scholar
  121. 121.
    Ghiadoni L, Magagna A, Versari D, Kardasz I, Huang Y, Taddei S, et al. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension. 2003;41(6):1281–6.PubMedCrossRefGoogle Scholar
  122. 122.
    Protogerou AD, Stergiou GS, Vlachopoulos C, Blacher J, Achimastos A. The effect of antihypertensive drugs on central blood pressure beyond peripheral blood pressure. Part II: evidence for specific class-effects of antihypertensive drugs on pressure amplification. Curr Pharm Des. 2009;15(3):272–89.PubMedCrossRefGoogle Scholar
  123. 123.
    Hirata K, Vlachopoulos C, Adji A, O’Rourke MF. Benefits from angiotensin-converting enzyme inhibitor “beyond blood pressure lowering”: beyond blood pressure or beyond the brachial artery? J Hypertens. 2005;23(3):551–6.PubMedCrossRefGoogle Scholar
  124. 124.
    Morgan T, Lauri J, Bertram D, Anderson A. Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens. 2004;17(2):118–23.PubMedCrossRefGoogle Scholar
  125. 125.
    Jiang X-J, O’Rourke MF, Zhang Y-Q, He X-Y, Liu L-S. Superior effect of an angiotensin-converting enzyme inhibitor over a diuretic for reducing aortic systolic pressure. J Hypertens. 2007;25(5):1095–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Hahn AW, Resink TJ, Scott-Burden T, Powell J, Dohi Y, Bühler FR. Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell Regul. 1990;1(9):649–59.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Harrison DG, Venema RC, Arnal JF, Inoue N, Ohara Y, Sayegh H, et al. The endothelial cell nitric oxide synthase: is it really constitutively expressed? Agents Actions Suppl. 1995;45:107–17.PubMedGoogle Scholar
  128. 128.
    Wiemer G, Schölkens BA, Wagner A, Heitsch H, Linz W. The possible role of angiotensin II subtype AT2 receptors in endothelial cells and isolated ischemic rat hearts. J Hypertens Suppl. 1993;11(5):S234–5.PubMedCrossRefGoogle Scholar
  129. 129.
    Maeso R, Navarro-Cid J, Muñoz-García R, Rodrigo E, Ruilope LM, Lahera V, et al. Losartan reduces phenylephrine constrictor response in aortic rings from spontaneously hypertensive rats. Role of nitric oxide and angiotensin II type 2 receptors. Hypertension. 1996;28(6):967–72.PubMedCrossRefGoogle Scholar
  130. 130.
    Seyedi N, Xu X, Nasjletti A, Hintze TH. Coronary kinin generation mediates nitric oxide release after angiotensin receptor stimulation. Hypertension. 1995;26(1):164–70.PubMedCrossRefGoogle Scholar
  131. 131.
    Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation. 2000;101(14):1653–9.PubMedCrossRefGoogle Scholar
  132. 132.
    Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin–angiotensin system. J Hypertens. 2007;25(5):951–8.CrossRefGoogle Scholar
  133. 133.
    Imai E, Chan JCN, Ito S, ORIENT Study Investigators, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia. 2011;54(12):2978–86.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Savarese G, Costanzo P, Cleland JGF, Vassallo E, Ruggiero D, Rosano G, et al. A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure. J Am Coll Cardiol. 2013;61(2):131–42.PubMedCrossRefGoogle Scholar
  135. 135.
    Schiffrin EL, Deng LY. Structure and function of resistance arteries of hypertensive patients treated with a p-blocker or a calcium channel antagonist. J Hypertens. 1996;14(10):1247–55.PubMedCrossRefGoogle Scholar
  136. 136.
    Frielingsdorf J, Seiler C, Kaufmann P, Vassalli G, Suter T, Hess OM. Normalization of abnormal coronary vasomotion by calcium antagonists in patients with hypertension. Circulation. 1996;93(7):1380–7.PubMedCrossRefGoogle Scholar
  137. 137.
    Sudano I, Virdis A, Taddei S, Spieker L, Corti R, Noll G, et al. Chronic treatment with long-acting nifedipine reduces vasoconstriction to endothelin-1 in essential hypertension. Hypertension. 2007;49(2):285–90.PubMedCrossRefGoogle Scholar
  138. 138.
    Lyons D, Webster J, Benjamin N. The effect of antihypertensive therapy on responsiveness to local intra-arterial NG-monomethyl-l-arginine in patients with essential hypertension. J Hypertens. 1994;12(9):1047–52.PubMedCrossRefGoogle Scholar
  139. 139.
    Himmel HM, Whorton AR, Strauss HC. Intracellular calcium, currents, and stimulus-response coupling in endothelial cells. Hypertension. 1993;21(1):112–27.PubMedCrossRefGoogle Scholar
  140. 140.
    Lupo E, Locher R, Weisser B, Vetter W. In vitro antioxidant activity of calcium antagonists against LDL oxidation compared with alpha-tocopherol. Biochem Biophys Res Commun. 1994;203(3):1803–8.PubMedCrossRefGoogle Scholar
  141. 141.
    Mak IT, Boehme P, Weglicki WB. Antioxidant effects of calcium channel blockers against free radical injury in endothelial cells. Correlation of protection with preservation of glutathione levels. Circ Res. 1992;70(6):1099–103.PubMedCrossRefGoogle Scholar
  142. 142.
    Taddei S, Virdis A, Ghiadoni L, Magagna A, Favilla S, Pompella A, et al. Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. Hypertension. 2001;37(3):943–8.PubMedCrossRefGoogle Scholar
  143. 143.
    London GM, Pannier B, Guerin AP, Marchais SJ, Safar ME, Cuche JL. Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease. Comparative effects of ACE inhibition and calcium channel blockade. Circulation. 1994;90(6):2786–96.PubMedCrossRefGoogle Scholar
  144. 144.
    Savoia C, Touyz RM, Amiri F, Schiffrin EL. Selective mineralocorticoid receptor blocker eplerenone reduces resistance artery stiffness in hypertensive patients. Hypertension. 2008;51(2):432–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006;47(3):312–8.PubMedCrossRefGoogle Scholar
  146. 146.
    Williams GH. Cardiovascular benefits of aldosterone receptor antagonists: what about potassium? Hypertension. 2005;46(2):265–6.PubMedCrossRefGoogle Scholar
  147. 147.
    de Souza F, Muxfeldt E, Fiszman R, Salles G. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension. 2010;55(1):147–52.PubMedCrossRefGoogle Scholar
  148. 148.
    Mohandas A, Suboc TB, Wang J, Ying R, Tarima S, Dharmashankar K, et al. Mineralocorticoid exposure and receptor activity modulate microvascular endothelial function in African Americans with and without hypertension. Vasc Med. 2015;20(5):401–8.PubMedCrossRefGoogle Scholar
  149. 149.
    Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Van Nueten L, et al. Nebivolol vasodilates human forearm vasculature: evidence for an l-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995;274(3):1067–71.PubMedGoogle Scholar
  150. 150.
    Kubli S, Feihl F, Waeber B. Beta-blockade with nebivolol enhances the acetylcholine-induced cutaneous vasodilation. Clin Pharmacol Ther. 2001;69(4):238–44.PubMedCrossRefGoogle Scholar
  151. 151.
    Dhakam Z, Yasmin, McEniery CM, Burton T, Brown MJ, Wilkinson IB. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens. 2008;26(2):351–6.PubMedCrossRefGoogle Scholar
  152. 152.
    Mahmud A. Reducing arterial stiffness and wave reflection—quest for the Holy Grail? Artery Res. 2007;1(1):13–9.CrossRefGoogle Scholar
  153. 153.
    Kampus P, Serg M, Kals J, Zagura M, Muda P, Karu K, et al. Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. Hypertension. 2011;57(6):1122–8.PubMedCrossRefGoogle Scholar
  154. 154.
    Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, BHS guidelines working party, for the British Hypertension Society, et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ. 2004;328(7440):634–40.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    NICE. Hypertension in adults: diagnosis and management. NICE guidelines [CG127]. London: NICE; 2011 Aug.Google Scholar
  156. 156.
    McCall DO, McGartland CP, McKinley MC, Patterson CC, Sharpe P, McCance DR, et al. Dietary intake of fruits and vegetables improves microvascular function in hypertensive subjects in a dose-dependent manner. Circulation. 2009;119(16):2153–60.PubMedCrossRefGoogle Scholar
  157. 157.
    Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks FM, American Heart Association. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension. 2006;47(2):296–308.PubMedCrossRefGoogle Scholar
  158. 158.
    Stamler R. Implications of the INTERSALT study. Hypertension. 1991;17(1 Suppl):I16–20.PubMedCrossRefGoogle Scholar
  159. 159.
    He FJ, MacGregor GA. Effect of modest salt reduction on blood pressure: a meta-analysis of randomized trials. Implications for public health. J Hum Hypertens. 2002;16(11):761–70.PubMedCrossRefGoogle Scholar
  160. 160.
    The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure. The Trials of Hypertension Prevention, phase II. Arch Intern Med. 1997;157(6):657–67.Google Scholar
  161. 161.
    Langford HG, Blaufox MD, Oberman A, Hawkins CM, Curb JD, Cutter GR, et al. Dietary therapy slows the return of hypertension after stopping prolonged medication. JAMA. 1985;253(5):657–64.PubMedCrossRefGoogle Scholar
  162. 162.
    Whelton PK, Appel LJ, Espeland MA, Applegate WB, Ettinger WH Jr, Kostis JB, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled Trial of Nonpharmacologic Interventions in the Elderly (TONE). TONE Collaborative Research Group. JAMA. 1998;279(11):839–46.PubMedCrossRefGoogle Scholar
  163. 163.
    Weir MR, Hall PS, Behrens MT, Flack JM. Salt and blood pressure responses to calcium antagonism in hypertensive patients. Hypertension. 1997;30(3 Pt 1):422–7.PubMedCrossRefGoogle Scholar
  164. 164.
    Appel LJ, Espeland MA, Easter L, Wilson AC, Folmar S, Lacy CR. Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE). Arch Intern Med. 2001;161(5):685–93.PubMedCrossRefGoogle Scholar
  165. 165.
    Kopkan L, Majid DSA. Superoxide contributes to development of salt sensitivity and hypertension induced by nitric oxide deficiency. Hypertension. 2005;46(4):1026–31.PubMedCrossRefGoogle Scholar
  166. 166.
    Majid DSA, Kopkan L. Nitric oxide and superoxide interactions in the kidney and their implication in the development of salt-sensitive hypertension. Clin Exp Pharmacol Physiol. 2007;34(9):946–52.PubMedCrossRefGoogle Scholar
  167. 167.
    Kopkan L, Castillo A, Navar LG, Majid DSA. Enhanced superoxide generation modulates renal function in ANG II-induced hypertensive rats. Am J Physiol Renal Physiol. 2006;290(1):F80–6.PubMedCrossRefGoogle Scholar
  168. 168.
    Jablonski KL, Gates PE, Pierce GL, Seals DR. Low dietary sodium intake is associated with enhanced vascular endothelial function in middle-aged and older adults with elevated systolic blood pressure. Ther Adv Cardiovasc Dis. 2009;3(5):347–56.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206–52.PubMedCrossRefGoogle Scholar
  170. 170.
    Whelton PK, He J, Appel LJ, Cutler JA, Havas S, Kotchen TA, National High Blood Pressure Education Program Coordinating Committee, et al. Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. JAMA. 2002;288(15):1882–8.PubMedCrossRefGoogle Scholar
  171. 171.
    Mattes RD, Donnelly D. Relative contributions of dietary sodium sources. J Am Coll Nutr. 1991;10(4):383–93.PubMedCrossRefGoogle Scholar
  172. 172.
    Havas S, Roccella EJ, Lenfant C. Reducing the public health burden from elevated blood pressure levels in the United States by lowering intake of dietary sodium. Am J Public Health. 2004;94(1):19–22.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336(16):1117–24.PubMedCrossRefGoogle Scholar
  174. 174.
    de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343(8911):1454–9.PubMedCrossRefGoogle Scholar
  175. 175.
    de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99(6):779–85.PubMedCrossRefGoogle Scholar
  176. 176.
    Anter E, Thomas SR, Schulz E, Shapira OM, Vita JA, Keaney JF. Activation of endothelial nitric-oxide synthase by the p38 MAPK in response to black tea polyphenols. J Biol Chem. 2004;279(45):46637–43.PubMedCrossRefGoogle Scholar
  177. 177.
    Widlansky ME, Duffy SJ, Hamburg NM, Gokce N, Warden BA, Wiseman S, et al. Effects of black tea consumption on plasma catechins and markers of oxidative stress and inflammation in patients with coronary artery disease. Free Radic Biol Med. 2005;38(4):499–506.PubMedCrossRefGoogle Scholar
  178. 178.
    Duffy SJ, Gokce N, Holbrook M, Hunter LM, Biegelsen ES, Huang A, et al. Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension. Am J Physiol Heart Circ Physiol. 2001;280(2):H528–34.PubMedGoogle Scholar
  179. 179.
    Darko D, Dornhorst A, Kelly FJ, Ritter JM, Chowienczyk PJ. Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in type II diabetes. Clin Sci. 2002;103(4):339–44.PubMedCrossRefGoogle Scholar
  180. 180.
    Chen H, Karne RJ, Hall G, Campia U, Panza JA, Cannon RO 3rd, et al. High-dose oral vitamin C partially replenishes vitamin C levels in patients with type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Am J Physiol Heart Circ Physiol. 2006;290(1):H137–45.PubMedCrossRefGoogle Scholar
  181. 181.
    Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2003;42(5):878–84.PubMedCrossRefGoogle Scholar
  182. 182.
    Klatsky AL, Friedman GD, Siegelaub AB, Gérard MJ. Alcohol consumption and blood pressure Kaiser-Permanente Multiphasic Health Examination data. N Engl J Med. 1977;296(21):1194–200.PubMedCrossRefGoogle Scholar
  183. 183.
    Xin X, He J, Frontini MG, Ogden LG, Motsamai OI, Whelton PK. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2001;38(5):1112–7.PubMedCrossRefGoogle Scholar
  184. 184.
    Santos-Parker JR, LaRocca TJ, Seals DR. Aerobic exercise and other healthy lifestyle factors that influence vascular aging. Adv Physiol Educ. 2014;38(4):296–307.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Suboc TB, Strath SJ, Dharmashankar K, Coulliard A, Miller N, Wang J, et al. Relative importance of step count, intensity, and duration on physical activity’s impact on vascular structure and function in previously sedentary older adults. J Am Heart Assoc. 2013;3(1):e000702.CrossRefGoogle Scholar
  186. 186.
    Fleenor BS, Marshall KD, Durrant JR, Lesniewski LA, Seals DR. Arterial stiffening with ageing is associated with transforming growth factor-β1-related changes in adventitial collagen: reversal by aerobic exercise. J Physiol (Lond). 2010;588(Pt 20):3971–82.PubMedCentralCrossRefGoogle Scholar
  187. 187.
    Moreau KL, Stauffer BL, Kohrt WM, Seals DR. Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women. J Clin Endocrinol Metab. 2013;98(11):4507–15.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Pierce GL, Eskurza I, Walker AE, Fay TN, Seals DR. Sex-specific effects of habitual aerobic exercise on brachial artery flow-mediated dilation in middle-aged and older adults. Clin Sci. 2011;120(1):13–23.PubMedCrossRefGoogle Scholar
  189. 189.
    DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan KD, Tanaka H, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation. 2000;102(12):1351–7.PubMedCrossRefGoogle Scholar
  190. 190.
    Taddei S, Galetta F, Virdis A, Ghiadoni L, Salvetti G, Franzoni F, et al. Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation. 2000;101(25):2896–901.PubMedCrossRefGoogle Scholar
  191. 191.
    Durrant JR, Seals DR, Connell ML, Russell MJ, Lawson BR, Folian BJ, et al. Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase. J Physiol (Lond). 2009;587(Pt 13):3271–85.PubMedCentralCrossRefGoogle Scholar
  192. 192.
    Pierce GL, Donato AJ, LaRocca TJ, Eskurza I, Silver AE, Seals DR. Habitually exercising older men do not demonstrate age-associated vascular endothelial oxidative stress. Aging Cell. 2011;10(6):1032–7.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Lesniewski LA, Durrant JR, Connell ML, Henson GD, Black AD, Donato AJ, et al. Aerobic exercise reverses arterial inflammation with aging in mice. Am J Physiol Heart Circ Physiol. 2011;301(3):H1025–32.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Eskurza I, Monahan KD, Robinson JA, Seals DR. Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men. Am J Physiol Heart Circ Physiol. 2004;286(4):H1528–34.PubMedCrossRefGoogle Scholar
  195. 195.
    DeVan AE, Eskurza I, Pierce GL, Walker AE, Jablonski KL, Kaplon RE, et al. Regular aerobic exercise protects against impaired fasting plasma glucose-associated vascular endothelial dysfunction with aging. Clin Sci (Lond). 2013;124(5):325–31.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Walker AE, Eskurza I, Pierce GL, Gates PE, Seals DR. Modulation of vascular endothelial function by low-density lipoprotein cholesterol with aging: influence of habitual exercise. Am J Hypertens. 2009;22(3):250–6.PubMedCrossRefGoogle Scholar
  197. 197.
    Lesniewski LA, Zigler ML, Durrant JR, Nowlan MJ, Folian BJ, Donato AJ, et al. Aging compounds western diet-associated large artery endothelial dysfunction in mice: prevention by voluntary aerobic exercise. Exp Gerontol. 2013;48(11):1218–25.PubMedCrossRefGoogle Scholar
  198. 198.
    Virdis A, Giannarelli C, Fritsch Neves M, Taddei S, Ghiadoni L. Cigarette smoking and hypertension. Curr Pharm Des. 2010;16(23):2518–25.PubMedCrossRefGoogle Scholar
  199. 199.
    Messner B, Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol. 2014;34(3):509–15.PubMedCrossRefGoogle Scholar
  200. 200.
    World Health Organization. WHO Global Report. Mortality attributable to tobacco. 2012. Accessed May 2016.
  201. 201.
    Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340(8828):1111–5.PubMedCrossRefGoogle Scholar
  202. 202.
    Garbin U, Fratta Pasini A, Stranieri C, Cominacini M, Pasini A, Manfro S, et al. Cigarette smoking blocks the protective expression of Nrf2/ARE pathway in peripheral mononuclear cells of young heavy smokers favouring inflammation. PLoS One. 2009;4(12):e8225.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Ishizaka N, Ishizaka Y, Toda E-I, Hashimoto H, Nagai R, Yamakado M. Association between white blood cell count and carotid arteriosclerosis in Japanese smokers. Atherosclerosis. 2004;175(1):95–100.PubMedCrossRefGoogle Scholar
  204. 204.
    Lavi S, Prasad A, Yang EH, Mathew V, Simari RD, Rihal CS, et al. Smoking is associated with epicardial coronary endothelial dysfunction and elevated white blood cell count in patients with chest pain and early coronary artery disease. Circulation. 2007;115(20):2621–7.PubMedCrossRefGoogle Scholar
  205. 205.
    Barbieri SS, Zacchi E, Amadio P, Gianellini S, Mussoni L, Weksler BB, et al. Cytokines present in smokers’ serum interact with smoke components to enhance endothelial dysfunction. Cardiovasc Res. 2011;90(3):475–83.PubMedCrossRefGoogle Scholar
  206. 206.
    Jefferis BJ, Lowe GDO, Welsh P, Rumley A, Lawlor DA, Ebrahim S, et al. Secondhand smoke (SHS) exposure is associated with circulating markers of inflammation and endothelial function in adult men and women. Atherosclerosis. 2010;208(2):550–6.PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Wannamethee SG, Lowe GDO, Shaper AG, Rumley A, Lennon L, Whincup PH. Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease. Eur Heart J. 2005;26(17):1765–73.PubMedCrossRefGoogle Scholar
  208. 208.
    Csordas A, Bernhard D. The biology behind the atherothrombotic effects of cigarette smoke. Nat Rev Cardiol. 2013;10(4):219–30.PubMedCrossRefGoogle Scholar
  209. 209.
    Becker CG, Hajjar DP, Hefton JM. Tobacco constituents are mitogenic for arterial smooth-muscle cells. Am J Pathol. 1985;120(1):1–5.PubMedPubMedCentralGoogle Scholar
  210. 210.
    Xing A-P, Du Y-C, Hu X-Y, Xu JY, Zhang HP, Li Y, et al. Cigarette smoke extract stimulates rat pulmonary artery smooth muscle cell proliferation via PKC-PDGFB signaling. J Biomed Biotechnol. 2012;2012(2):534384.PubMedPubMedCentralGoogle Scholar
  211. 211.
    Nordskog BK, Blixt AD, Morgan WT, Fields WR, Hellmann GM. Matrix-degrading and pro-inflammatory changes in human vascular endothelial cells exposed to cigarette smoke condensate. Cardiovasc Toxicol. 2003;3(2):101–17.PubMedCrossRefGoogle Scholar
  212. 212.
    Primatesta P, Falaschetti E, Gupta S, Marmot MG, Poulter NR. Association between smoking and blood pressure: evidence from the health survey for England. Hypertension. 2001;37(2):187–93.PubMedCrossRefGoogle Scholar
  213. 213.
    Tuomilehto J, Elo J, Nissinen A. Smoking among patients with malignant hypertension. Br Med J (Clin Res Ed). 1982;284(6322):1086.CrossRefGoogle Scholar
  214. 214.
    Berglund G, Wilhelmsen L. Factors related to blood pressure in a general population sample of Swedish men. Acta Med Scand. 1975;198(4):291–8.PubMedGoogle Scholar
  215. 215.
    Seltzer CC. Effect of smoking on blood pressure. Am Heart J. 1974;87(5):558–64.PubMedCrossRefGoogle Scholar
  216. 216.
    Mann SJ, James GD, Wang RS, Pickering TG. Elevation of ambulatory systolic blood pressure in hypertensive smokers. A case-control study. JAMA. 1991;265(17):2226–8.PubMedCrossRefGoogle Scholar
  217. 217.
    Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 2015;116(6):1074–95.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Alan C. Cameron
    • 1
  • Ninian N. Lang
    • 1
  • Rhian M. Touyz
    • 1
  1. 1.Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research CentreUniversity of GlasgowGlasgowUK

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