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Drug Treatment of Hypertension: Focus on Vascular Health

Abstract

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.

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References

  1. Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep. 2010;12(6):448–55.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  3. Touyz RM, Dominiczak AF. Hypertension guidelines: is it time to reappraise blood pressure thresholds and targets? Hypertension. 2016;67(4):688–9.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed Central  Article  CAS  Google Scholar 

  6. Harvey A, Montezano AC, Touyz RM. Vascular biology of ageing—implications in hypertension. J Mol Cell Cardiol. 2015;83(C):112–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  12. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature. 1988;333(6174):664–6.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  21. Haynes WG, Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens. 1998;16(8):1081–98.

    CAS  PubMed  Article  Google Scholar 

  22. Thuillez C, Richard V. Targeting endothelial dysfunction in hypertensive subjects. J Hum Hypertens. 2005;19:S21–5.

    CAS  PubMed  Article  Google Scholar 

  23. Hamburg NM, Benjamin EJ. Assessment of endothelial function using digital pulse amplitude tonometry. Trends Cardiovasc Med. 2009;19(1):6–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  38. Widlansky ME, Gokce N, Keaney JF, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42(7):1149–60.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  40. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Schiffrin EL. Role of endothelin-1 in hypertension. Hypertension. 1999;34(4):876–81.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;2(8567):1057–8.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  54. Schiffrin EL. Vascular remodeling in hypertension: mechanisms and treatment. Hypertension. 2012;59(2):367–74.

    CAS  PubMed  Article  Google Scholar 

  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. 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.

    PubMed  PubMed Central  Article  Google Scholar 

  57. Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001;89(9):763–71.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  62. Lee MY, Griendling KK. Redox signaling, vascular function, and hypertension. Antioxid Redox Signal. 2008;10(6):1045–59.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  69. Dudenbostel T, Glasser SP. Effects of antihypertensive drugs on arterial stiffness. Cardiol Rev. 2012;20(5):259–63.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  71. Lakatta EG. The reality of aging viewed from the arterial wall. Artery Res. 2013;7(2):73–80.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  73. Giannandrea M, Parks WC. Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech. 2014;7(2):193–203.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev. 2005;85(1):1–31.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  86. Yamamoto K, Takeshita K, Saito H. Plasminogen activator inhibitor-1 in aging. Semin Thromb Hemost. 2014;40(6):652–9.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  90. Montezano AC, Nguyen Dinh Cat A, Rios FJ, Touyz RM. Angiotensin II and vascular injury. Curr Hypertens Rep. 2014;16(6):431.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  99. Attinà T, Camidge R, Newby DE, Webb DJ. Endothelin antagonism in pulmonary hypertension, heart failure, and beyond. Heart. 2005;91(6):825–31.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  102. Remuzzi G, Perico N, Benigni A. New therapeutics that antagonize endothelin: promises and frustrations. Nat Rev Drug Discov. 2002;1(12):986–1001.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  139. Himmel HM, Whorton AR, Strauss HC. Intracellular calcium, currents, and stimulus-response coupling in endothelial cells. Hypertension. 1993;21(1):112–27.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  145. Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006;47(3):312–8.

    CAS  PubMed  Article  Google Scholar 

  146. Williams GH. Cardiovascular benefits of aldosterone receptor antagonists: what about potassium? Hypertension. 2005;46(2):265–6.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  152. Mahmud A. Reducing arterial stiffness and wave reflection—quest for the Holy Grail? Artery Res. 2007;1(1):13–9.

    Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  155. NICE. Hypertension in adults: diagnosis and management. NICE guidelines [CG127]. London: NICE; 2011 Aug.

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  158. Stamler R. Implications of the INTERSALT study. Hypertension. 1991;17(1 Suppl):I16–20.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  171. Mattes RD, Donnelly D. Relative contributions of dietary sodium sources. J Am Coll Nutr. 1991;10(4):383–93.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  198. Virdis A, Giannarelli C, Fritsch Neves M, Taddei S, Ghiadoni L. Cigarette smoking and hypertension. Curr Pharm Des. 2010;16(23):2518–25.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  200. World Health Organization. WHO Global Report. Mortality attributable to tobacco. 2012. http://www.who.int/tobacco/publications/surveillance/fact_sheet_mortality_report.pdf. Accessed May 2016.

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  208. Csordas A, Bernhard D. The biology behind the atherothrombotic effects of cigarette smoke. Nat Rev Cardiol. 2013;10(4):219–30.

    CAS  PubMed  Article  Google Scholar 

  209. Becker CG, Hajjar DP, Hefton JM. Tobacco constituents are mitogenic for arterial smooth-muscle cells. Am J Pathol. 1985;120(1):1–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  213. Tuomilehto J, Elo J, Nissinen A. Smoking among patients with malignant hypertension. Br Med J (Clin Res Ed). 1982;284(6322):1086.

    CAS  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  215. Seltzer CC. Effect of smoking on blood pressure. Am Heart J. 1974;87(5):558–64.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  217. Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 2015;116(6):1074–95.

    CAS  PubMed  Article  Google Scholar 

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Correspondence to Rhian M. Touyz.

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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.

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Cameron, A.C., Lang, N.N. & Touyz, R.M. Drug Treatment of Hypertension: Focus on Vascular Health. Drugs 76, 1529–1550 (2016). https://doi.org/10.1007/s40265-016-0642-8

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Keywords

  • Nitric Oxide
  • Endothelial Dysfunction
  • Endothelial Function
  • Arterial Stiffness
  • Pulse Wave Velocity