Antihypertensive Drugs and Vascular Health

  • Alan C. Cameron
  • Giacomo Rossitto
  • Ninian N. Lang
  • Rhian M. TouyzEmail author
Part of the Updates in Hypertension and Cardiovascular Protection book series (UHCP)


Hypertension is a growing health burden and contributes to serious cardiovascular complications from target organ damage. The vascular system is particularly important in patients with elevated blood pressure, because vascular dysfunction is both a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, vascular inflammation, arterial remodelling and increased stiffness. Of the many classes of antihypertensive drugs, those that influence vascular health have the greatest efficacy for reducing cardiovascular risk. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and calcium channel blockers ameliorate vascular remodelling and improve endothelial function. Mineralocorticoid receptor antagonists reduce arterial stiffness, improve endothelial function and are established antihypertensive drugs, particularly in patients with resistant hypertension. Patients prone to salt-sensitivity benefit from diuretics, which influence salt physiology and balance and reduce arterial stiffness. Not all antihypertensive drugs are vasoprotective. Beta blockers, like atenolol, reduce blood pressure, but do not regress remodelling and fail to improve endothelial function. Selecting and refining the optimum drug therapy for the treatment of hypertension remains the key challenge and should prompt thought about the diverse pathophysiological mechanisms involved. This should always be in association with lifestyle modifications, which remains a cornerstone in preventing and improving vascular changes associated with high blood pressure.


Hypertension Antihypertensive drugs Endothelial function Vascular health Vascular remodelling 


  1. 1.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Touyz RM, Dominiczak AF. Hypertension guidelines: is it time to reappraise blood pressure thresholds and targets? Hypertension. 2016;67(4):688–9.CrossRefPubMedGoogle Scholar
  3. 3.
    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.CrossRefPubMedGoogle Scholar
  4. 4.
    Harvey A, Montezano AC, Touyz RM. Vascular biology of ageing—implications in hypertension. J Mol Cell Cardiol. 2015;83(C):112–21.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefPubMedGoogle Scholar
  6. 6.
    AlGhatrif M, Strait JB, Morrell CH, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    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.CrossRefPubMedGoogle Scholar
  8. 8.
    Lakatta EG. The reality of aging viewed from the arterial wall. Artery Res. 2013;7(2):73–80.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wind S, Beuerlein K, Armitage ME, 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.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Lee MY, Griendling KK. Redox signaling, vascular function, and hypertension. Antioxid Redox Signal. 2008;10(6):1045–59.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8(6 Pt 2):II127–34.PubMedGoogle Scholar
  15. 15.
    Dahl LK, Heine M, Tassinari L. Role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt ingestion. Nature. 1962;194:480–2.CrossRefPubMedGoogle Scholar
  16. 16.
    Elijovich F, Weinberger MH, Anderson CAM, et al. Salt sensitivity of blood pressure: a scientific statement from the American Heart Association. Hypertension. 2016;68(3):e7–e46.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen PY, Sanders PW. L-arginine abrogates salt-sensitive hypertension in dahl/Rapp rats. J Clin Investig. 1991;88(5):1559–67.CrossRefPubMedGoogle Scholar
  18. 18.
    Feng W, Ying W-Z, Aaron KJ, Sanders PW. Transforming growth factor-β mediates endothelial dysfunction in rats during high salt intake. Am J Physiol Renal Physiol. 2015;309(12):F1018–25.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Greaney JL, DuPont JJ, Lennon-Edwards SL, Sanders PW, Edwards DG, Farquhar WB. Dietary sodium loading impairs microvascular function independent of blood pressure in humans: role of oxidative stress. J Physiol Lond. 2012;590(21):5519–28.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nurkiewicz TR, Boegehold MA. High salt intake reduces endothelium-dependent dilation of mouse arterioles via superoxide anion generated from nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):R1550–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Raffai G, Durand MJ, Lombard JH. Acute and chronic angiotensin-(1-7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats. Am J Physiol Heart Circ Physiol. 2011;301(4):H1341–52.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gu JW, Anand V, Shek EW, et al. Sodium induces hypertrophy of cultured myocardial myoblasts and vascular smooth muscle cells. Hypertension. 1998;31(5):1083–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Machnik A, Neuhofer W, Jantsch J, et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009;15(5):545–52.CrossRefPubMedGoogle Scholar
  24. 24.
    Wiig H, Schröder A, Neuhofer W, et al. Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J Clin Invest. 2013;123(7):2803–15.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kopp C, Linz P, Dahlmann A, et al. 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension. 2013;61(3):635–40.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Titze J, Luft FC. Speculations on salt and the genesis of arterial hypertension. Kidney Int. 2017;91(6):1324–35.CrossRefPubMedGoogle Scholar
  27. 27.
    Laffer CL, Scott RC, Titze JM, Luft FC, Elijovich F. Hemodynamics and salt-and-water balance link sodium storage and vascular dysfunction in salt-sensitive subjects. Hypertension. 2016;68(1):195–203.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Oh YS, Appel LJ, Galis ZS, et al. National Heart, Lung, and Blood Institute working group report on salt in human health and sickness: building on the current scientific evidence. Hypertension. 2016;68(2):281–8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    McMaster WG, Kirabo A, Madhur MS, Harrison DG. Inflammation, immunity, and hypertensive end-organ damage. Circ Res. 2015;116(6):1022–33.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Schiffrin EL. Immune mechanisms in hypertension and vascular injury. Clin Sci. 2014;126(4):267–74.CrossRefPubMedGoogle Scholar
  31. 31.
    Foss JD, Kirabo A, Harrison DG. Do high-salt microenvironments drive hypertensive inflammation? Am J Physiol Regul Integr Comp Physiol. 2017;312(1):R1–4.CrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    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.CrossRefPubMedGoogle Scholar
  34. 34.
    Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333(6174):664–6.CrossRefPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    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.CrossRefPubMedGoogle Scholar
  37. 37.
    Inoue A, Yanagisawa M, Kimura S, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A. 1989;86(8):2863–7.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep. 2010;12(6):448–55. Scholar
  39. 39.
    Hamburg NM, Benjamin EJ. Assessment of endothelial function using digital pulse amplitude tonometry. Trends Cardiovasc Med. 2009;19(1):6–11.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Thuillez C, Richard V. Targeting endothelial dysfunction in hypertensive subjects. J Hum Hypertens. 2005;19:S21–5.CrossRefPubMedGoogle Scholar
  41. 41.
    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.CrossRefPubMedGoogle Scholar
  42. 42.
    Benjamin EJ, Larson MG, Keyes MJ, et al. Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham heart study. Circulation. 2004;109(5):613–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Widlansky ME, Gokce N, Keaney JF, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42(7):1149–60.CrossRefPubMedGoogle Scholar
  44. 44.
    Rakova N, Kitada K, Lerchl K, et al. Increased salt consumption induces body water conservation and decreases fluid intake. J Clin Invest. 2017;127(5):1932–43.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Haynes WG, Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens. 1998;16(8):1081–98.CrossRefPubMedGoogle Scholar
  46. 46.
    Schiffrin EL. Role of Endothelin-1 in hypertension. Hypertension. 1999;34(4):876–81.CrossRefPubMedGoogle Scholar
  47. 47.
    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.CrossRefPubMedGoogle Scholar
  48. 48.
    Rajagopalan S, Kurz S, Münzel T, 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 Investig. 1996;97(8):1916–23.CrossRefPubMedGoogle Scholar
  49. 49.
    Myung S-K, Ju W, Cho B, 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(jan18 1):f10.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;2(8567):1057–8.CrossRefPubMedGoogle Scholar
  51. 51.
    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 Investig. 1989;83(5):1774–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991;88(11):4651–5.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Investig. 1995;96(1):60–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Schiffrin EL. Vascular remodeling in hypertension: mechanisms and treatment. Hypertension. 2012;59(2):367–74.CrossRefPubMedGoogle Scholar
  55. 55.
    Savoia C, Sada L, Zezza L, et al. Vascular inflammation and endothelial dysfunction in experimental hypertension. Int J Hypertens. 2011;2011(2 Suppl):1–8.CrossRefGoogle Scholar
  56. 56.
    Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001;89(9):763–71.CrossRefPubMedGoogle Scholar
  57. 57.
    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.CrossRefPubMedGoogle Scholar
  58. 58.
    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.CrossRefPubMedGoogle Scholar
  59. 59.
    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.CrossRefPubMedGoogle Scholar
  60. 60.
    Thorand B, Löwel H, Schneider A, 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.CrossRefPubMedGoogle Scholar
  61. 61.
    Van Bortel LM, Laurent S, Boutouyrie P, 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.CrossRefPubMedGoogle Scholar
  62. 62.
    Agnoletti D, Zhang Y, Borghi C, Blacher J, Safar ME. Effects of antihypertensive drugs on central blood pressure in humans: a preliminary observation. Am J Hypertens. 2013;26(8):1045–52.CrossRefPubMedGoogle Scholar
  63. 63.
    Mackenzie IS, McEniery CM, Dhakam Z, Brown MJ, Cockcroft JR, Wilkinson IB. Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension. 2009;54(2):409–13.CrossRefPubMedGoogle Scholar
  64. 64.
    Alem M, Milia P, Muir S, Lees K, Walters M. Comparison of the effects of diuretics on blood pressure and arterial stiffness in patients with stroke. J Stroke Cerebrovasc Dis. 2008;17(6):373–7.CrossRefPubMedGoogle Scholar
  65. 65.
    Safar M, Laurent S, Safavian A, Pannier B, Asmar R. Sodium and large arteries in hypertension. Effects of indapamide. Am J Med. 1988;84(1B):15–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Roush GC, Sica DA. Diuretics for hypertension: a review and update. Am J Hypertens. 2016;29(10):1130–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association professional education Committee of the Council for high blood pressure research. Hypertension. 2008;51(6):1403–19.CrossRefPubMedGoogle Scholar
  68. 68.
    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.CrossRefPubMedGoogle Scholar
  69. 69.
    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
  70. 70.
    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.CrossRefPubMedGoogle Scholar
  71. 71.
    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.CrossRefPubMedGoogle Scholar
  72. 72.
    Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417–28.CrossRefPubMedGoogle Scholar
  73. 73.
    Hadi HAR, Carr CS, Suwaidi AJ. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1(3):183–98.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Dagenais GR, Yusuf S, Bourassa MG, 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.CrossRefPubMedGoogle Scholar
  75. 75.
    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
  76. 76.
    Fretheim A, Odgaard-Jensen J, Brørs O, et al. Comparative effectiveness of antihypertensive medication for primary prevention of cardiovascular disease: systematic review and multiple treatments meta-analysis. BMC Med. 2012;10:33.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    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.CrossRefPubMedGoogle Scholar
  78. 78.
    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.CrossRefPubMedGoogle Scholar
  79. 79.
    Rizzoni D, Muiesan ML, Porteri E, 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.CrossRefPubMedGoogle Scholar
  80. 80.
    Mancini GB, Henry GC, Macaya C, 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.CrossRefPubMedGoogle Scholar
  81. 81.
    Hornig B, Landmesser U, Kohler C, 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.CrossRefPubMedGoogle Scholar
  82. 82.
    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.CrossRefPubMedGoogle Scholar
  83. 83.
    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.CrossRefPubMedGoogle Scholar
  84. 84.
    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.CrossRefPubMedGoogle Scholar
  85. 85.
    Ghiadoni L, Magagna A, Versari D, et al. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension. 2003;41(6):1281–6.CrossRefPubMedGoogle Scholar
  86. 86.
    Dudenbostel T, Glasser SP. Effects of antihypertensive drugs on arterial stiffness. Cardiol Rev. 2012;20(5):259–63.CrossRefPubMedGoogle Scholar
  87. 87.
    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.CrossRefPubMedGoogle Scholar
  88. 88.
    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.CrossRefPubMedGoogle Scholar
  89. 89.
    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.CrossRefPubMedGoogle Scholar
  90. 90.
    Maeso R, Navarro-Cid J, Muñoz-García R, 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.CrossRefPubMedGoogle Scholar
  91. 91.
    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.CrossRefPubMedGoogle Scholar
  92. 92.
    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.CrossRefPubMedGoogle Scholar
  93. 93.
    Blood Pressure Lowering Treatment Trialists’ Collaboration, Turnbull F, Neal B, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25(5):951–8.CrossRefGoogle Scholar
  94. 94.
    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.CrossRefPubMedGoogle Scholar
  95. 95.
    Sudano I, Virdis A, Taddei S, et al. Chronic treatment with long-acting Nifedipine reduces vasoconstriction to Endothelin-1 in essential hypertension. Hypertension. 2007;49(2):285–90.CrossRefPubMedGoogle Scholar
  96. 96.
    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.CrossRefPubMedGoogle Scholar
  97. 97.
    Himmel HM, Whorton AR, Strauss HC. Intracellular calcium, currents, and stimulus-response coupling in endothelial cells. Hypertension. 1993;21(1):112–27.CrossRefPubMedGoogle Scholar
  98. 98.
    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.CrossRefPubMedGoogle Scholar
  99. 99.
    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.CrossRefPubMedGoogle Scholar
  100. 100.
    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.CrossRefPubMedGoogle Scholar
  101. 101.
    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.CrossRefPubMedGoogle Scholar
  102. 102.
    Ohta Y, Ishizuka A, Hayashi S, et al. Effects of a selective aldosterone blocker and thiazide-type diuretic on blood pressure and organ damage in hypertensive patients. Clin Exp Hypertens. 2015;37(7):569–73.CrossRefPubMedGoogle Scholar
  103. 103.
    Matsui Y, Eguchi K, O'Rourke MF, Ishikawa J, Shimada K, Kario K. Association between aldosterone induced by antihypertensive medication and arterial stiffness reduction: the J-CORE study. Atherosclerosis. 2011;215(1):184–8.CrossRefPubMedGoogle Scholar
  104. 104.
    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.CrossRefPubMedGoogle Scholar
  105. 105.
    Chrysant SG. Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/valsartan. J Am Soc Hypertens. 2017;11:461.CrossRefPubMedGoogle Scholar
  106. 106.
    Zhou M-S, Schulman IH, Jaimes EA, Raij L. Thiazide diuretics, endothelial function, and vascular oxidative stress. J Hypertens. 2008;26(3):494–500.CrossRefPubMedGoogle Scholar
  107. 107.
    Muiesan ML, Salvetti M, Monteduro C, et al. Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension. Hypertension. 1999;33(1 Pt 2):575–80.CrossRefPubMedGoogle Scholar
  108. 108.
    Muiesan ML, Salvetti M, Belotti E, et al. Effects of barnidipine in comparison with hydrochlorothiazide on endothelial function, as assessed by flow mediated vasodilatation in hypertensive patients. Blood Press. 2011;20(4):244–51.CrossRefPubMedGoogle Scholar
  109. 109.
    Vergely C, Walker MK, Zeller M, et al. Antioxidant properties of indapamide, 5-OH indapamide and hydrochlorothiazide evaluated by oxygen-radical absorbing capacity and electron paramagnetic resonance. Mol Cell Biochem. 1998;178(1–2):151–5.CrossRefPubMedGoogle Scholar
  110. 110.
    Calder JA, Schachter M, Sever PS. Vasorelaxant actions of 5-OH-indapamide, a major metabolite of indapamide: comparison with indapamide, hydrochlorothiazide and cicletanine. Eur J Pharmacol. 1994;256(2):185–91.CrossRefPubMedGoogle Scholar
  111. 111.
    Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887–98.CrossRefPubMedGoogle Scholar
  112. 112.
    Burnier M, Narkiewicz K, Kjeldsen SE. Prevention of heart failure mortality and hospitalizations in SPRINT, EMPA-REG, ALLHAT and HYVET: are diuretics the clue? Blood Press. 2017;26(4):193–4.CrossRefPubMedGoogle Scholar
  113. 113.
    Waddingham MT, Paulus WJ. Microvascular paradigm in heart failure with preserved ejection fraction: a quest for proof of concept. Circ Heart Fail. 2017;10(6):e004179.CrossRefPubMedGoogle Scholar
  114. 114.
    Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263–71.CrossRefPubMedGoogle Scholar
  115. 115.
    Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131(6):550–9.CrossRefPubMedGoogle Scholar
  116. 116.
    Hwang S-J, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63(25 Pt A):2817–27.CrossRefPubMedGoogle Scholar
  117. 117.
    Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006;47(3):312–8.CrossRefPubMedGoogle Scholar
  119. 119.
    Williams GH. Cardiovascular benefits of aldosterone receptor antagonists: what about potassium? Hypertension. 2005;46(2):265–6.CrossRefPubMedGoogle Scholar
  120. 120.
    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.CrossRefPubMedGoogle Scholar
  121. 121.
    Yamanari H, Nakamura K, Miura D, Yamanari S, Ohe T. Spironolactone and chlorthalidone in uncontrolled elderly hypertensive patients treated with calcium antagonists and angiotensin II receptor-blocker: effects on endothelial function, inflammation, and oxidative stress. Clin Exp Hypertens. 2009;31(7):585–94.CrossRefPubMedGoogle Scholar
  122. 122.
    Joffe HV, Kwong RY, Gerhard-Herman MD, Rice C, Feldman K, Adler GK. Beneficial effects of eplerenone versus hydrochlorothiazide on coronary circulatory function in patients with diabetes mellitus. J Clin Endocrinol Metab. 2007;92(7):2552–8.CrossRefPubMedGoogle Scholar
  123. 123.
    Bärfacker L, Kuhl A, Hillisch A, et al. Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem. 2012;7(8):1385–403.CrossRefPubMedGoogle Scholar
  124. 124.
    Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059–68.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Cockcroft JR, Chowienczyk PJ, Brett SE, 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
  126. 126.
    Kubli S, Feihl F, Waeber B. Beta-blockade with nebivolol enhances the acetylcholine-induced cutaneous vasodilation. Clin Pharmacol Ther. 2001;69(4):238–44.CrossRefPubMedGoogle Scholar
  127. 127.
    Dhakam Z, Yasmin MECM, et al. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens. 2008;26(2):351–6.CrossRefPubMedGoogle Scholar
  128. 128.
    Kampus P, Serg M, Kals J, et al. Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. Hypertension. 2011;57(6):1122–8.CrossRefPubMedGoogle Scholar
  129. 129.
    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.CrossRefPubMedGoogle Scholar
  130. 130.
    Tuomilehto J, Elo J, Nissinen A. Smoking among patients with malignant hypertension. Br Med J (Clin Res Ed). 1982;284(6322):1086.CrossRefGoogle Scholar
  131. 131.
    Virdis A, Giannarelli C, Fritsch Neves M, Taddei S, Ghiadoni L. Cigarette Smoking and Hypertension. Curr Pharm Des. 2010;16(23):2518–25.CrossRefPubMedGoogle Scholar
  132. 132.
    Messner B, Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol. 2014;34(3):509–15.CrossRefPubMedGoogle Scholar
  133. 133.
    Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340(8828):1111–5.CrossRefPubMedGoogle Scholar
  134. 134.
    Kannel WB. Importance of hypertension as a risk factor in cardiovascular disease. In: Hypertension: pathopsychology and treatment. New York, NY: McGraw-Hill; 1977. p. 888–910.Google Scholar
  135. 135.
    Williams B, Poulter NR, Brown MJ, et al. British hypertension society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ. 2004;328(7440):634–40.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    DeSouza CA, Shapiro LF, Clevenger CM, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation. 2000;102(12):1351–7.CrossRefPubMedGoogle Scholar
  138. 138.
    Taddei S, Galetta F, Virdis A, et al. Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation. 2000;101(25):2896–901.CrossRefPubMedGoogle Scholar
  139. 139.
    McCall DO, McGartland CP, McKinley MC, 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.CrossRefPubMedGoogle Scholar
  140. 140.
    Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH collaborative research group. N Engl J Med. 1997;336(16):1117–24.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    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.CrossRefPubMedGoogle Scholar
  142. 142.
    Widlansky ME, Duffy SJ, Hamburg NM, 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.CrossRefPubMedGoogle Scholar
  143. 143.
    Appel LJ, Brands MW, Daniels SR, et al. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension. 2006;47(2):296–308.CrossRefPubMedGoogle Scholar
  144. 144.
    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.CrossRefPubMedGoogle Scholar
  145. 145.
    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.CrossRefGoogle Scholar
  146. 146.
    Langford HG, Blaufox MD, Oberman A, et al. Dietary therapy slows the return of hypertension after stopping prolonged medication. JAMA. 1985;253(5):657–64.CrossRefPubMedGoogle Scholar
  147. 147.
    Whelton PK, Appel LJ, Espeland MA, 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.CrossRefPubMedGoogle Scholar
  148. 148.
    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.CrossRefPubMedGoogle Scholar
  149. 149.
    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.CrossRefPubMedGoogle Scholar
  150. 150.
    Kopkan L, Majid DSA. Superoxide contributes to development of salt sensitivity and hypertension induced by nitric oxide deficiency. Hypertension. 2005;46(4):1026–31.CrossRefPubMedGoogle Scholar
  151. 151.
    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.CrossRefPubMedGoogle Scholar
  152. 152.
    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.CrossRefPubMedGoogle Scholar
  153. 153.
    Gates PE, Tanaka H, Hiatt WR, Seals DR. Dietary sodium restriction rapidly improves large elastic artery compliance in older adults with systolic hypertension. Hypertension. 2004;44(1):35–41.CrossRefPubMedGoogle Scholar
  154. 154.
    Cogswell ME, Mugavero K, Bowman BA, Frieden TR. Dietary sodium and cardiovascular disease risk--measurement matters. N Engl J Med. 2016;375(6):580–6.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    O'Donnell M, Mente A, Yusuf S. Sodium and cardiovascular disease. N Engl J Med. 2014;371(22):2137–8.PubMedGoogle Scholar
  156. 156.
    Mozaffarian D, Fahimi S, Singh GM, et al. Global sodium consumption and death from cardiovascular causes. N Engl J Med. 2014;371(7):624–34.CrossRefPubMedGoogle Scholar
  157. 157.
    Mancia G, Oparil S, Whelton PK, et al. The technical report on sodium intake and cardiovascular disease in low- and middle-income countries by the joint working group of the world heart federation, the European Society of Hypertension and the European public health association. Eur Heart J. 2017;38(10):712–9.PubMedGoogle Scholar
  158. 158.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Alan C. Cameron
    • 1
  • Giacomo Rossitto
    • 1
  • Ninian N. Lang
    • 1
  • Rhian M. Touyz
    • 1
    Email author
  1. 1.Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Reserach CentreUniversity of GlasgowGlasgowUK

Personalised recommendations