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Pathophysiological Insights in Resistant Hypertension

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Resistant Hypertension in Chronic Kidney Disease

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Abstract

The complex pathophysiological network behind resistant hypertension (RH) is a multifactorial edifice generated by alterations occurring in the equilibrium of key territories. For theoretical purposes, this chapter discusses modern physiopathological aspects regarding the definition and the pathway characterizing each of these elements. Thus, neurogenic (central, sympathetic nervous system and vagal pathways and, peripheral, carotid baroreflex and chemoreceptor involvement, neural kidney regulation, and new theories) as well as renin-angiotensin-aldosterone system mechanisms and contribution of sodium, dopamine, and Na-channels are successively investigated. Supplementary information is provided by the exploration of oxidative stress and inflammation. Interesting insights regarding the genetic background of RH are mentioned. Finally, we highlight particular aspects of RH in obesity and characterize the distinct entity called refractory hypertension. More than the description of mechanisms involved in RH, our aim is to shed light on the authenticity of this disease, as well as on the features which distinguish it from other forms of hypertension.

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References

  1. Esler M, Kaye D. Increased sympathetic nervous system activity and its therapeutic reduction in arterial hypertension, portal hypertension and heart failure. J Auton Nerv Syst. 1998;72(2–3):210–9.

    Article  CAS  PubMed  Google Scholar 

  2. Ozel E, Tastan A, Ozturk A, Ozcan EE. Relationship between sympathetic Overactivity and left ventricular hypertrophy in resistant hypertension. Hellenic J Cardiol HJC Hellenike Kardiologike Epitheorese. 2015;56(6):501–6.

    PubMed  Google Scholar 

  3. Tsioufis C, Kordalis A, Flessas D, Anastasopoulos I, Tsiachris D, Papademetriou V, et al. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. Int J Hypertens. 2011;2011:642416.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Seravalle G, Dimitriadis K, Dell’Oro R, Grassi G. How to assess sympathetic nervous system activity in clinical practice. Curr Clin Pharmacol. 2013;8(3):182–8.

    Article  CAS  PubMed  Google Scholar 

  5. O’Callaghan EL, McBryde FD, Burchell AE, Ratcliffe LE, Nicolae L, Gillbe I, et al. Deep brain stimulation for the treatment of resistant hypertension. Curr Hypertens Rep. 2014;16(11):493.

    Article  PubMed  CAS  Google Scholar 

  6. Kawada T, Sugimachi M. Open-loop static and dynamic characteristics of the arterial baroreflex system in rabbits and rats. J Physiol Sci JPS. 2016;66(1):15–41.

    Article  PubMed  Google Scholar 

  7. Hering D, Schlaich M. The role of central nervous system mechanisms in resistant hypertension. Curr Hypertens Rep. 2015;17(8):58.

    Article  PubMed  Google Scholar 

  8. Morimoto S, Sasaki S, Miki S, Kawa T, Itoh H, Nakata T, et al. Pulsatile compression of the rostral ventrolateral medulla in hypertension. Hypertension. 1997;29(1 Pt 2):514–8.

    Article  CAS  PubMed  Google Scholar 

  9. Rumantir MS, Jennings GL, Lambert GW, Kaye DM, Seals DR, Esler MD. The ‘adrenaline hypothesis’ of hypertension revisited: evidence for adrenaline release from the heart of patients with essential hypertension. J Hypertens. 2000;18(6):717–23.

    Article  CAS  PubMed  Google Scholar 

  10. Presciuttini B, Duprez D, De Buyzere M, Clement DL. How to study sympatho-vagal balance in arterial hypertension and the effect of antihypertensive drugs? Acta Cardiol. 1998;53(3):143–52.

    CAS  PubMed  Google Scholar 

  11. Perini R, Veicsteinas A. Heart rate variability and autonomic activity at rest and during exercise in various physiological conditions. Eur J Appl Physiol. 2003;90(3–4):317–25.

    Article  PubMed  Google Scholar 

  12. Clement DL, De Pue N, Jordaens LJ, Packet L. Adrenergic and vagal influences on blood pressure variability. Clin Exp Hypertens A Theory Practice. 1985;7(2–3):159–66.

    Article  CAS  PubMed  Google Scholar 

  13. Clement DL, Jordaens LJ, Heyndrickx GR. Influence of vagal nervous activity on blood pressure variability. J Hypertens Suppl Off J Int Soc Hypertens. 1984;2(3):S391–3.

    CAS  Google Scholar 

  14. Petkovich BW, Vega J, Thomas S. Vagal modulation of hypertension. Curr Hypertens Rep. 2015;17(4):532.

    Article  PubMed  CAS  Google Scholar 

  15. Plachta DT, Gierthmuehlen M, Cota O, Espinosa N, Boeser F, Herrera TC, et al. Blood pressure control with selective vagal nerve stimulation and minimal side effects. J Neural Eng. 2014;11(3):036011.

    Article  PubMed  Google Scholar 

  16. Lohmeier TE, Iliescu R. Lowering of blood pressure by chronic suppression of central sympathetic outflow: insight from prolonged baroreflex activation. J Appl Physiol (Bethesda, Md : 1985). 2012;113(10):1652–8.

    Article  Google Scholar 

  17. Jordan J, Heusser K, Brinkmann J, Tank J. Electrical carotid sinus stimulation in treatment resistant arterial hypertension. Auton Neurosci Basic Clin. 2012;172(1–2):31–6.

    Article  Google Scholar 

  18. Illig KA, Levy M, Sanchez L, Trachiotis GD, Shanley C, Irwin E, et al. An implantable carotid sinus stimulator for drug-resistant hypertension: surgical technique and short-term outcome from the multicenter phase II Rheos feasibility trial. J Vasc Surg. 2006;44(6):1213–8.

    Article  PubMed  Google Scholar 

  19. Kumar P, Prabhakar NR. Peripheral chemoreceptors: function and plasticity of the carotid body. Compr Physiol. 2012;2(1):141–219.

    PubMed  PubMed Central  Google Scholar 

  20. Iturriaga R, Del Rio R, Idiaquez J, Somers VK. Carotid body chemoreceptors, sympathetic neural activation, and cardiometabolic disease. Biol Res. 2016;49(1):13.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Katayama PL, Castania JA, Dias DP, Patel KP, Fazan R Jr, Salgado HC. Role of chemoreceptor activation in hemodynamic responses to electrical stimulation of the carotid sinus in conscious rats. Hypertension. 2015;66(3):598–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ratcliffe LE, Pijacka W, McBryde FD, Abdala AP, Moraes DJ, Sobotka PA, et al. CrossTalk opposing view: which technique for controlling resistant hypertension? Carotid chemoreceptor denervation/modulation. J Physiol. 2014;592(18):3941–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kopp UC. Role of renal sensory nerves in physiological and pathophysiological conditions. Am J Physiol Regul Integr Comp Physiol. 2015;308(2):R79–95.

    Article  CAS  PubMed  Google Scholar 

  24. Johns EJ. The neural regulation of the kidney in hypertension and renal failure. Exp Physiol. 2014;99(2):289–94.

    Article  PubMed  Google Scholar 

  25. Polimeni A, Curcio A, Indolfi C. Renal sympathetic denervation for treating resistant hypertension. Circ J Off J Jpn Circ Soc. 2013;77(4):857–63.

    CAS  Google Scholar 

  26. Volpe M, Rosei EA, Ambrosioni E, Cottone S, Cuspidi C, Borghi C, et al. Renal artery denervation for treating resistant hypertension : definition of the disease, patient selection and description of the procedure. High Blood Press Cardiovasc Prev Off J Ital Soc Hypertens. 2012;19(4):237–44.

    Article  CAS  Google Scholar 

  27. Williams JM, Murphy S, Burke M, Roman RJ. 20-hydroxyeicosatetraeonic acid: a new target for the treatment of hypertension. J Cardiovasc Pharmacol. 2010;56(4):336–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev. 2002;82(1):131–85.

    Article  CAS  PubMed  Google Scholar 

  29. Wainford RD, Carmichael CY, Pascale CL, Kuwabara JT. Galphai2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension. Hypertension. 2015;65(1):178–86.

    Article  CAS  PubMed  Google Scholar 

  30. Santisteban MM, Ahmari N, Carvajal JM, Zingler MB, Qi Y, Kim S, et al. Involvement of bone marrow cells and neuroinflammation in hypertension. Circ Res. 2015;117(2):178–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shi P, Diez-Freire C, Jun JY, Qi Y, Katovich MJ, Li Q, et al. Brain microglial cytokines in neurogenic hypertension. Hypertension. 2010;56(2):297–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lazartigues E. Is microglia the new target for the treatment of resistant hypertension? Hypertension. 2015;66(2):265–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shen XZ, Li Y, Li L, Shah KH, Bernstein KE, Lyden P, et al. Microglia participate in neurogenic regulation of hypertension. Hypertension. 2015;66(2):309–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Desir GV. Regulation of blood pressure and cardiovascular function by renalase. Kidney Int. 2009;76(4):366–70.

    Article  CAS  PubMed  Google Scholar 

  35. Desir GV. Role of renalase in the regulation of blood pressure and the renal dopamine system. Curr Opin Nephrol Hypertens. 2011;20(1):31–6.

    Article  CAS  PubMed  Google Scholar 

  36. Mell B, Jala VR, Mathew AV, Byun J, Waghulde H, Zhang Y, et al. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol Genomics. 2015;47(6):187–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Davern PJ, Chowdhury S, Jackson KL, Nguyen-Huu TP, Head GA. GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice. J Hypertens. 2014;32(2):352–62.

    Article  CAS  PubMed  Google Scholar 

  38. Brown NJ. This is not Dr. Conn’s aldosterone anymore. Trans Am Clin Climatol Assoc. 2011;122:229–43.

    PubMed  PubMed Central  Google Scholar 

  39. Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther Sponsored Int Soc Cardiovasc Pharmacother. 1995;9(1):145–9.

    Article  CAS  Google Scholar 

  40. Duprez D, De Buyzere M, Rietzschel ER, Clement DL. Aldosterone and vascular damage. Curr Hypertens Rep. 2000;2(3):327–34.

    Article  CAS  PubMed  Google Scholar 

  41. Sato A, Saruta T. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res. 2001;29(1):13–21.

    Article  CAS  PubMed  Google Scholar 

  42. Shamkhlova M, Trubitsyna NP, Katsaia GV, Goncharov NP, Malysheva NM, Il’in AV, et al. The angiotensin II inhibition escape phenomenon in patients with type 2 diabetes and diabetic nephropathy. Ter Arkh. 2008;80(1):49–52.

    PubMed  Google Scholar 

  43. Jansen PM, Hofland J, van den Meiracker AH, de Jong FH, Danser AH. Renin and prorenin have no direct effect on aldosterone synthesis in the human adrenocortical cell lines H295R and HAC15. J Renin Angiotensin Aldosterone Syst JRAAS. 2012;13(3):360–6.

    Article  CAS  PubMed  Google Scholar 

  44. Athyros VG, Mikhailidis DP, Kakafika AI, Tziomalos K, Karagiannis A. Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution? Expert Opin Pharmacother. 2007;8(5):529–35.

    Article  CAS  PubMed  Google Scholar 

  45. Cherney DZ, Lai V, Miller JA, Scholey JW, Reich HN. The angiotensin II receptor type 2 polymorphism influences haemodynamic function and circulating RAS mediators in normotensive humans. Nephrol Dial, Transplant Off Publ Eur Dial Transplant Assoc Eur Renal Assoc. 2010;25(12):4093–6.

    CAS  Google Scholar 

  46. Cicoira M, Zanolla L, Rossi A, Golia G, Franceschini L, Cabrini G, et al. Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype. J Am Coll Cardiol. 2001;37(7):1808–12.

    Article  CAS  PubMed  Google Scholar 

  47. Otani H, Otsuka F, Inagaki K, Suzuki J, Makino H. Roles of bone morphogenetic protein-6 in aldosterone regulation by adrenocortical cells. Acta Med Okayama. 2010;64(4):213–8.

    Google Scholar 

  48. Otani H, Otsuka F, Inagaki K, Suzuki J, Miyoshi T, Kano Y, et al. Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: possible involvement of bone morphogenetic protein-6 actions. Endocrinology. 2008;149(6):2816–25.

    Article  CAS  PubMed  Google Scholar 

  49. Rossi GP. Aldosterone breakthrough during RAS blockade: a role for endothelins and their antagonists? Curr Hypertens Rep. 2006;8(3):262–8.

    Article  CAS  PubMed  Google Scholar 

  50. Rossi GP, Cavallin M, Nussdorfer GG, Pessina AC. The endothelin-aldosterone axis and cardiovascular diseases. J Cardiovasc Pharmacol. 2001;38(Suppl 2):S49–52.

    Article  CAS  PubMed  Google Scholar 

  51. Turban S, Wang XY, Knepper MA. Regulation of NHE3, NKCC2, and NCC abundance in kidney during aldosterone escape phenomenon: role of NO. Am J Physiol Ren Physiol. 2003;285(5):F843–51.

    Article  CAS  Google Scholar 

  52. Granger JP, Burnett JC Jr, Romero JC, Opgenorth TJ, Salazar J, Joyce M. Elevated levels of atrial natriuretic peptide during aldosterone escape. Am J Phys. 1987;252(5 Pt 2):R878–82.

    CAS  Google Scholar 

  53. Wang C, Chao J, Chao L. Adenovirus-mediated human prostasin gene delivery is linked to increased aldosterone production and hypertension in rats. Am J Physiol Regul Integr Comp Physiol. 2003;284(4):R1031–6.

    Article  CAS  PubMed  Google Scholar 

  54. Raizada V, Skipper B, Luo W, Griffith J. Intracardiac and intrarenal renin-angiotensin systems: mechanisms of cardiovascular and renal effects. J Invest Med Off Publ Am Fed Clin Res. 2007;55(7):341–59.

    CAS  Google Scholar 

  55. Grubler MR, Kienreich K, Gaksch M, Verheyen N, Hartaigh BO, Fahrleitner-Pammer A, et al. Aldosterone-to-renin ratio is associated with reduced 24-hour heart rate variability and QTc prolongation in hypertensive patients. Medicine. 2016;95(8):e2794.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Stowasser M. Aldosterone excess and resistant hypertension: investigation and treatment. Curr Hypertens Rep. 2014;16(7):439.

    Article  PubMed  CAS  Google Scholar 

  57. Sartori M, Calo LA, Mascagna V, Realdi A, Macchini L, Ciccariello L, et al. Aldosterone and refractory hypertension: a prospective cohort study. Am J Hypertens. 2006;19(4):373–9; discussion 380.

    Google Scholar 

  58. Shibata H, Itoh H. Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension. Am J Hypertens. 2012;25(5):514–23.

    Article  CAS  PubMed  Google Scholar 

  59. Semplicini A, Strapazzon G, Papparella I, Sartori M, Realdi A, Macchini L, et al. RGS2 expression and aldosterone: renin ratio modulate response to drug therapy in hypertensive patients. J Hypertens. 2010;28(5):1104–8.

    Article  CAS  PubMed  Google Scholar 

  60. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008;168(11):1159–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ames MK, Atkins CE, Lantis AC, Zum Brunnen J. Evaluation of subacute change in RAAS activity (as indicated by urinary aldosterone:creatinine, after pharmacologic provocation) and the response to ACE inhibition. J Renin Angiotensin Aldosterone Syst JRAAS. 2016;17(1). http://journals.sagepub.com/doi/abs/10.1177/1470320316633897?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

  62. Ichihara A. (pro)renin receptor and vacuolar H(+)-ATPase. Keio J Med. 2012;61(3):73–8.

    Article  CAS  PubMed  Google Scholar 

  63. Oshima Y, Morimoto S, Ichihara A. Roles of the (pro)renin receptor in the kidney. World J Nephrol. 2014;3(4):302–7.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Shi P, Grobe JL, Desland FA, Zhou G, Shen XZ, Shan Z, et al. Direct pro-inflammatory effects of prorenin on microglia. PLoS One. 2014;9(10):e92937.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Nguyen G. Renin and prorenin receptor in hypertension: what’s new? Curr Hypertens Rep. 2011;13(1):79–85.

    Article  CAS  PubMed  Google Scholar 

  66. Prieto MC, Botros FT, Kavanagh K, Navar LG. Prorenin receptor in distal nephron segments of 2-kidney, 1-clip goldblatt hypertensive rats. Ochsner J. 2013;13(1):26–32.

    PubMed  PubMed Central  Google Scholar 

  67. Ando T, Ichihara A. Novel approach to cardiovascular diseases: a promising probability of (pro)renin receptor [(P)RR]. Curr Pharm Des. 2014;20(14):2371–6.

    Article  CAS  PubMed  Google Scholar 

  68. Gonzalez AA, Womack JP, Liu L, Seth DM, Prieto MC. Angiotensin II increases the expression of (pro)renin receptor during low-salt conditions. Am J Med Sci. 2014;348(5):416–22.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Gonzalez AA, Green T, Luffman C, Bourgeois CR, Gabriel Navar L, Prieto MC. Renal medullary cyclooxygenase-2 and (pro)renin receptor expression during angiotensin II-dependent hypertension. Am J Physiol Ren Physiol. 2014;307(8):F962–70.

    Article  CAS  Google Scholar 

  70. Wang F, Lu X, Peng K, Du Y, Zhou SF, Zhang A, et al. Prostaglandin E-prostanoid4 receptor mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla. Hypertension. 2014;64(2):369–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gonzalez AA, Prieto MC. Renin and the (pro)renin receptor in the renal collecting duct: role in the pathogenesis of hypertension. Clin Exp Pharmacol Physiol. 2015;42(1):14–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Li W, Peng H, Mehaffey EP, Kimball CD, Grobe JL, van Gool JM, et al. Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension. Hypertension. 2014;63(2):316–23.

    Article  CAS  PubMed  Google Scholar 

  73. Bracquart D, Cousin C, Contrepas A, Nguyen G. The prorenin receptor. J Soc Biol. 2009;203(4):303–10.

    Article  CAS  PubMed  Google Scholar 

  74. Utsunomiya H, Nakamura M, Kakudo K, Inagami T, Tamura M. Angiotensin II AT2 receptor localization in cardiovascular tissues by its antibody developed in AT2 gene-deleted mice. Regul Pept. 2005;126(3):155–61.

    Article  CAS  PubMed  Google Scholar 

  75. Hsieh PS, Tai YH, Loh CH, Shih KC, Cheng WT, Chu CH. Functional interaction of AT1 and AT2 receptors in fructose-induced insulin resistance and hypertension in rats. Metab Clin Exp. 2005;54(2):157–64.

    Article  CAS  PubMed  Google Scholar 

  76. Strehlow K, Nickenig G, Roeling J, Wassmann S, Zolk O, Knorr A, et al. AT(1) receptor regulation in salt-sensitive hypertension. Am J Phys. 1999;277(5 Pt 2):H1701–7.

    CAS  Google Scholar 

  77. Harrison-Bernard LM, Schulman IH, Raij L. Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension. 2003;42(6):1157–63.

    Article  CAS  PubMed  Google Scholar 

  78. Szombathy T, Szalai C, Katalin B, Palicz T, Romics L, Csaszar A. Association of angiotensin II type 1 receptor polymorphism with resistant essential hypertension. Clinica Chimica Acta Int J Clin Chem. 1998;269(1):91–100.

    Article  Google Scholar 

  79. Hunyady L, Turu G. The role of the AT1 angiotensin receptor in cardiac hypertrophy: angiotensin II receptor or stretch sensor? Trends Endocrinol Metab TEM. 2004;15(9):405–8.

    Article  CAS  PubMed  Google Scholar 

  80. Liao Y, Husain A. The chymase-angiotensin system in humans: biochemistry, molecular biology and potential role in cardiovascular diseases. Can J Cardiol. 1995;11(Suppl F):13f–9f.

    CAS  PubMed  Google Scholar 

  81. Mangiapane ML, Rauch AL, MacAndrew JT, Ellery SS, Hoover KW, Knight DR, et al. Vasoconstrictor action of angiotensin I-convertase and the synthetic substrate (Pro11,D-Ala12)-angiotensin I. Hypertension. 1994;23(6 Pt 2):857–60.

    Article  CAS  PubMed  Google Scholar 

  82. Nagata S, Varagic J, Kon ND, Wang H, Groban L, Simington SW, et al. Differential expression of the angiotensin-(1-12)/chymase axis in human atrial tissue. Ther Adv Cardiovasc Dis. 2015;9(4):168–80.

    Article  CAS  PubMed  Google Scholar 

  83. Park S, Bivona BJ, Ford SM Jr, Xu S, Kobori H, de Garavilla L, et al. Direct evidence for intrarenal chymase-dependent angiotensin II formation on the diabetic renal microvasculature. Hypertension. 2013;61(2):465–71.

    Article  CAS  PubMed  Google Scholar 

  84. Leckie BJ. Targeting the renin-angiotensin system: what’s new? Curr Med Chem Cardiovasc Hematol Agents. 2005;3(1):23–32.

    Article  CAS  PubMed  Google Scholar 

  85. Leung PS. The peptide hormone angiotensin II: its new functions in tissues and organs. Curr Protein Pept Sci. 2004;5(4):267–73.

    Article  CAS  PubMed  Google Scholar 

  86. Re RN. The clinical implication of tissue renin angiotensin systems. Curr Opin Cardiol. 2001;16(6):317–27.

    Article  CAS  PubMed  Google Scholar 

  87. Zhuo JL, Li XC. New insights and perspectives on intrarenal renin-angiotensin system: focus on intracrine/intracellular angiotensin II. Peptides. 2011;32(7):1551–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kumar R, Thomas CM, Yong QC, Chen W, Baker KM. The intracrine renin-angiotensin system. Clin Sci (London, England: 1979). 2012;123(5):273–84.

    Article  CAS  Google Scholar 

  89. Re RN. Intracellular renin and the nature of intracrine enzymes. Hypertension. 2003;42(2):117–22.

    Article  CAS  PubMed  Google Scholar 

  90. De Mello WC, Danser AH. Angiotensin II and the heart : on the intracrine renin-angiotensin system. Hypertension. 2000;35(6):1183–8.

    Article  PubMed  Google Scholar 

  91. Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes. 2008;57(12):3297–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Deliu E, Brailoiu GC, Eguchi S, Hoffman NE, Rabinowitz JE, Tilley DG, et al. Direct evidence of intracrine angiotensin II signaling in neurons. Am J Physiol Cell Physiol. 2014;306(8):C736–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ellis B, Li XC, Miguel-Qin E, Gu V, Zhuo JL. Evidence for a functional intracellular angiotensin system in the proximal tubule of the kidney. Am J Physiol Regul Integr Comp Physiol. 2012;302(5):R494–509.

    Article  CAS  PubMed  Google Scholar 

  94. Ferrao FM, Lara LS, Lowe J. Renin-angiotensin system in the kidney: what is new? World J Nephrol. 2014;3(3):64–76.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Zhuo JL, Li XC. Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells. J Renin Angiotensin Aldosterone Syst JRAAS. 2007;8(1):23–33.

    Article  CAS  PubMed  Google Scholar 

  96. Haznedaroglu IC, Beyazit Y. Pathobiological aspects of the local bone marrow renin-angiotensin system: a review. J Renin Angiotensin Aldosterone Syst JRAAS. 2010;11(4):205–13.

    Article  CAS  PubMed  Google Scholar 

  97. Goker H, Haznedaroglu IC, Beyazit Y, Aksu S, Tuncer S, Misirlioglu M, et al. Local umbilical cord blood renin-angiotensin system. Ann Hematol. 2005;84(5):277–81.

    Article  CAS  PubMed  Google Scholar 

  98. Huang J, Hara Y, Anrather J, Speth RC, Iadecola C, Pickel VM. Angiotensin II subtype 1A (AT1A) receptors in the rat sensory vagal complex: subcellular localization and association with endogenous angiotensin. Neuroscience. 2003;122(1):21–36.

    Article  CAS  PubMed  Google Scholar 

  99. Glass MJ, Huang J, Speth RC, Iadecola C, Pickel VM. Angiotensin II AT-1A receptor immunolabeling in rat medial nucleus tractus solitarius neurons: subcellular targeting and relationships with catecholamines. Neuroscience. 2005;130(3):713–23.

    Article  CAS  PubMed  Google Scholar 

  100. Leung PS. The physiology of a local renin-angiotensin system in the pancreas. J Physiol. 2007;580(Pt 1):31–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Eggena P, Zhu JH, Sereevinyayut S, Giordani M, Clegg K, Andersen PC, et al. Hepatic angiotensin II nuclear receptors and transcription of growth-related factors. J Hypertens. 1996;14(8):961–8.

    Article  CAS  PubMed  Google Scholar 

  102. Carretero OA, Scicli AG. Local hormonal factors (intracrine, autocrine, and paracrine) in hypertension. Hypertension. 1991;18(3 Suppl):I58–69.

    Article  CAS  PubMed  Google Scholar 

  103. Wu Y, Takahashi H, Suzuki E, Kruzliak P, Soucek M, Uehara Y. Impaired response of regulator of Galphaq signaling-2 mRNA to angiotensin II and hypertensive renal injury in Dahl salt-sensitive rats. Hypertens Res Off J Jpn Soc Hypertens. 2016;39(4):210–6.

    Article  CAS  Google Scholar 

  104. Muscogiuri G, Chavez AO, Gastaldelli A, Perego L, Tripathy D, Saad MJ, et al. The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. Curr Vasc Pharmacol. 2008;6(4):301–12.

    Article  CAS  PubMed  Google Scholar 

  105. Papparella I, Ceolotto G, Lenzini L, Mazzoni M, Franco L, Sartori M, et al. Angiotensin II-induced over-activation of p47phox in fibroblasts from hypertensives: which role in the enhanced ERK1/2 responsiveness to angiotensin II? J Hypertens. 2005;23(4):793–800.

    Article  CAS  PubMed  Google Scholar 

  106. Baritono E, Ceolotto G, Papparella I, Sartori M, Ciccariello L, Iori E, et al. Abnormal regulation of G protein alpha(i2) subunit in skin fibroblasts from insulin-resistant hypertensive individuals. J Hypertens. 2004;22(4):783–92.

    Article  CAS  PubMed  Google Scholar 

  107. Burns KD, Li N. The role of angiotensin II-stimulated renal tubular transport in hypertension. Curr Hypertens Rep. 2003;5(2):165–71.

    Article  PubMed  Google Scholar 

  108. Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension. 2000;35(1 Pt 2):155–63.

    Article  CAS  PubMed  Google Scholar 

  109. Hilliard LM, Chow CL, Mirabito KM, Steckelings UM, Unger T, Widdop RE, et al. Angiotensin type 2 receptor stimulation increases renal function in female, but not male, spontaneously hypertensive rats. Hypertension. 2014;64(2):378–83.

    Article  CAS  PubMed  Google Scholar 

  110. Tallant EA, Diz DI, Ferrario CM. State-of-the-art lecture. Antiproliferative actions of angiotensin-(1-7) in vascular smooth muscle. Hypertension. 1999;34(4 Pt 2):950–7.

    Article  CAS  PubMed  Google Scholar 

  111. Meinert C, Gembardt F, Bohme I, Tetzner A, Wieland T, Greenberg B, et al. Identification of intracellular proteins and signaling pathways in human endothelial cells regulated by angiotensin-(1-7). J Proteome. 2016;130:129–39.

    Article  CAS  Google Scholar 

  112. de Almeida PW, Melo MB, Lima Rde F, Gavioli M, Santiago NM, Greco L, et al. Beneficial effects of angiotensin-(1-7) against deoxycorticosterone acetate-induced diastolic dysfunction occur independently of changes in blood pressure. Hypertension. 2015;66(2):389–95.

    Article  PubMed  CAS  Google Scholar 

  113. Giani JF, Munoz MC, Mayer MA, Veiras LC, Arranz C, Taira CA, et al. Angiotensin-(1-7) improves cardiac remodeling and inhibits growth-promoting pathways in the heart of fructose-fed rats. Am J Physiol Heart Circ Physiol. 2010;298(3):H1003–13.

    Article  CAS  PubMed  Google Scholar 

  114. Katovich MJ, Grobe JL, Raizada MK. Angiotensin-(1-7) as an antihypertensive, antifibrotic target. Curr Hypertens Rep. 2008;10(3):227–32.

    Article  CAS  PubMed  Google Scholar 

  115. Singh N, Joshi S, Guo L, Baker MB, Li Y, Castellano RK, et al. ACE2/Ang-(1-7)/Mas axis stimulates vascular repair-relevant functions of CD34+ cells. Am J Physiol Heart Circ Physiol. 2015;309(10):H1697–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Dilauro M, Burns KD. Angiotensin-(1-7) and its effects in the kidney. ScientificWorldJournal. 2009;9:522–35.

    Article  CAS  PubMed  Google Scholar 

  117. Patel VB, Takawale A, Ramprasath T, Das SK, Basu R, Grant MB, et al. Antagonism of angiotensin 1–7 prevents the therapeutic effects of recombinant human ACE2. J Mol Med (Berlin, Germany). 2015;93(9):1003–13.

    Article  CAS  Google Scholar 

  118. Tom B, Dendorfer A, Danser AH. Bradykinin, angiotensin-(1-7), and ACE inhibitors: how do they interact? Int J Biochem Cell Biol. 2003;35(6):792–801.

    Article  CAS  PubMed  Google Scholar 

  119. Bjorkholt Andersen L, Herse F, Christesen HT, Dechend R, Muller D. PP005. Vitamin D depletion aggravates hypertension in transgenic rats. Pregnancy Hypertens. 2013;3(2):69.

    Article  PubMed  Google Scholar 

  120. Garcia IM, Altamirano L, Mazzei L, Fornes M, Cuello-Carrion FD, Ferder L, et al. Vitamin D receptor-modulated Hsp70/AT1 expression may protect the kidneys of SHRs at the structural and functional levels. Cell Stress Chaperones. 2014;19(4):479–91.

    Article  CAS  PubMed  Google Scholar 

  121. Xue B, Pamidimukkala J, Lubahn DB, Hay M. Estrogen receptor-alpha mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice. Am J Physiol Heart Circ Physiol. 2007;292(4):H1770–6.

    Article  CAS  PubMed  Google Scholar 

  122. Wei LH, Huang XR, Zhang Y, Li YQ, Chen HY, Heuchel R, et al. Deficiency of Smad7 enhances cardiac remodeling induced by angiotensin II infusion in a mouse model of hypertension. PLoS One. 2013;8(7):e70195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Qiu Y, Tao L, Lei C, Wang J, Yang P, Li Q, et al. Downregulating p22phox ameliorates inflammatory response in angiotensin II-induced oxidative stress by regulating MAPK and NF-kappaB pathways in ARPE-19 cells. Sci Rep. 2015;5:14362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tain YL, Sheen JM, Yu HR, Chen CC, Tiao MM, Hsu CN, et al. Maternal melatonin therapy rescues prenatal dexamethasone and postnatal high-fat diet induced programmed hypertension in male rat offspring. Front Physiol. 2015;6:377.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Scholkens BA. Kinins in the cardiovascular system. Immunopharmacology. 1996;33(1–3):209–16.

    Article  CAS  PubMed  Google Scholar 

  126. Natarajan AR, Eisner GM, Armando I, Browning S, Pezzullo JC, Rhee L, et al. The renin-angiotensin and renal dopaminergic systems interact in normotensive humans. J Am Soc Nephrol JASN. 2016;27(1):265–79.

    Article  PubMed  Google Scholar 

  127. Jose PA, Eisner GM, Felder RA. Dopaminergic defect in hypertension. Pediatr Nephrol (Berlin, Germany). 1993;7(6):859–64.

    Article  CAS  Google Scholar 

  128. Sakamoto T, Chen C, Lokhandwala MF. Lack of renal dopamine production during acute volume expansion in Dahl salt-sensitive rats. Clin Exp Hypertens (New York, NY: 1993). 1994;16(2):197–206.

    CAS  Google Scholar 

  129. Armando I, Villar VA, Jose PA. Dopamine and renal function and blood pressure regulation. Compr Physiol. 2011;1(3):1075–117.

    PubMed  Google Scholar 

  130. Choi MR, Kouyoumdzian NM, Rukavina Mikusic NL, Kravetz MC, Roson MI, Rodriguez Fermepin M, et al. Renal dopaminergic system: pathophysiological implications and clinical perspectives. World J Nephrol. 2015;4(2):196–212.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Sanada H, Jose PA, Hazen-Martin D, Yu PY, Xu J, Bruns DE, et al. Dopamine-1 receptor coupling defect in renal proximal tubule cells in hypertension. Hypertension. 1999;33(4):1036–42.

    Article  CAS  PubMed  Google Scholar 

  132. Hussain T, Kansra V, Lokhandwala MF. Renal dopamine receptor signaling mechanisms in spontaneously hypertensive and Fischer 344 old rats. Clin Exp Hypertens (New York, NY: 1993). 1999;21(1–2):25–36.

    CAS  Google Scholar 

  133. Yu P, Asico LD, Luo Y, Andrews P, Eisner GM, Hopfer U, et al. D1 dopamine receptor hyperphosphorylation in renal proximal tubules in hypertension. Kidney Int. 2006;70(6):1072–9.

    Article  CAS  PubMed  Google Scholar 

  134. Yu P, Asico LD, Eisner GM, Hopfer U, Felder RA, Jose PA. Renal protein phosphatase 2A activity and spontaneous hypertension in rats. Hypertension. 2000;36(6):1053–8.

    Article  CAS  PubMed  Google Scholar 

  135. Salomone LJ, Howell NL, McGrath HE, Kemp BA, Keller SR, Gildea JJ, et al. Intrarenal dopamine D1-like receptor stimulation induces natriuresis via an angiotensin type-2 receptor mechanism. Hypertension. 2007;49(1):155–61.

    Article  CAS  PubMed  Google Scholar 

  136. Jose PA, Eisner GM, Drago J, Carey RM, Felder RA. Dopamine receptor signaling defects in spontaneous hypertension. Am J Hypertens. 1996;9(4 Pt 1):400–5.

    Article  CAS  PubMed  Google Scholar 

  137. Gurich RW, Beach RE. Abnormal regulation of renal proximal tubule Na(+)-K(+)-ATPase by G proteins in spontaneously hypertensive rats. Am J Phys. 1994;267(6 Pt 2):F1069–75.

    CAS  Google Scholar 

  138. Hussain T, Lokhandwala MF. Dopamine-1 receptor G-protein coupling and the involvement of phospholipase A2 in dopamine-1 receptor mediated cellular signaling mechanisms in the proximal tubules of SHR. Clin Exp Hypertens (New York, NY : 1993). 1997;19(1–2):131–40.

    Google Scholar 

  139. Yu PY, Eisner GM, Yamaguchi I, Mouradian MM, Felder RA, Jose PA. Dopamine D1A receptor regulation of phospholipase C isoform. J Biol Chem. 1996;271(32):19503–8.

    Article  CAS  PubMed  Google Scholar 

  140. Damasceno A, Santos A, Serrao P, Caupers P, Soares-da-Silva P, Polonia J. Deficiency of renal dopaminergic-dependent natriuretic response to acute sodium load in black salt-sensitive subjects in contrast to salt-resistant subjects. J Hypertens. 1999;17(12 Pt 2):1995–2001.

    Article  CAS  PubMed  Google Scholar 

  141. Mironova E, Boiko N, Bugaj V, Kucher V, Stockand JD. Regulation of Na+ excretion and arterial blood pressure by purinergic signalling intrinsic to the distal nephron: consequences and mechanisms. Acta Physiol (Oxf). 2015;213(1):213–21.

    Article  CAS  Google Scholar 

  142. Drummond HA. Nontubular epithelial Na+ channel proteins in cardiovascular regulation. Phys Rep. 2015;3(5):e12404. doi:10.14814/phy2.12404.

    Article  Google Scholar 

  143. Leenen FH, Hou X, Wang HW, Ahmad M. Enhanced expression of epithelial sodium channels causes salt-induced hypertension in mice through inhibition of the alpha2-isoform of Na+, K+−ATPase. Phys Rep. 2015;3(5):e12383. doi:10.14814/phy2.12383.

    Article  CAS  Google Scholar 

  144. Hanukoglu I, Hanukoglu A. Epithelial sodium channel (ENaC) family: phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene. 2016;579(2):95–132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Qadri YJ, Rooj AK, Fuller CM. ENaCs and ASICs as therapeutic targets. Am J Physiol Cell Physiol. 2012;302(7):C943–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Wang Q, Song B, Jiang S, Liang C, Chen X, Shi J, et al. Hydrogen sulfide prevents advanced glycation end-products induced activation of the epithelial sodium channel. Oxidative Med Cell Longev. 2015;2015:976848.

    Google Scholar 

  147. Mansley MK, Neuhuber W, Korbmacher C, Bertog M. Norepinephrine stimulates the epithelial Na+ channel in cortical collecting duct cells via alpha2-adrenoceptors. Am J Physiol Ren Physiol. 2015;308(5):F450–8.

    Article  CAS  Google Scholar 

  148. Bao HF, Song JZ, Duke BJ, Ma HP, Denson DD, Eaton DC. Ethanol stimulates epithelial sodium channels by elevating reactive oxygen species. Am J Physiol Cell Physiol. 2012;303(11):C1129–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Snyder PM. Intoxicated Na(+) channels. Focus on "ethanol stimulates epithelial sodium channels by elevating reactive oxygen species". Am J Physiol Cell Physiol. 2012;303(11):C1125–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Pochynyuk O, Kucher V, Boiko N, Mironova E, Staruschenko A, Karpushev AV, et al. Intrinsic voltage dependence of the epithelial Na+ channel is masked by a conserved transmembrane domain tryptophan. J Biol Chem. 2009;284(38):25512–21. Kashlan OB, Blobner BM, Zuzek Z, Tolino M, Kleyman TR. Na+ inhibits the epithelial Na+ channel by binding to a site in an extracellular acidic cleft. J Biol Chem. 2015;290(1):568–76.

    Google Scholar 

  151. Blaustein MP, Leenen FH, Chen L, Golovina VA, Hamlyn JM, Pallone TL, et al. How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension. Am J Physiol Heart Circ Physiol. 2012;302(5):H1031–49.

    Article  CAS  PubMed  Google Scholar 

  152. Hamlyn JM, Linde CI, Gao J, Huang BS, Golovina VA, Blaustein MP, et al. Neuroendocrine humoral and vascular components in the pressor pathway for brain angiotensin II: a new axis in long term blood pressure control. PLoS One. 2014;9(9):e108916.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Fedorova OV, Agalakova NI, Talan MI, Lakatta EG, Bagrov AY. Brain ouabain stimulates peripheral marinobufagenin via angiotensin II signalling in NaCl-loaded Dahl-S rats. J Hypertens. 2005;23(8):1515–23.

    Article  CAS  PubMed  Google Scholar 

  154. Fedorova OV, Talan MI, Agalakova NI, Lakatta EG, Bagrov AY. Endogenous ligand of alpha(1) sodium pump, marinobufagenin, is a novel mediator of sodium chloride – dependent hypertension. Circulation. 2002;105(9):1122–7.

    Google Scholar 

  155. Gatti G, Lanzani C, Citterio L, Messaggio E, Carpini SD, Simonini M, et al. 6C.06: genes involved in blood pressure response to acute and chronic salt modifications: identification of a new pathway. J Hypertens. 2015;33(Suppl 1):e80–1.

    Article  PubMed  Google Scholar 

  156. Manunta P, Ferrandi M, Messaggio E, Ferrari P. A new antihypertensive agent that antagonizes the prohypertensive effect of endogenous ouabain and adducin. Cardiovasc Hematol Agents Med Chem. 2006;4(1):61–6.

    Article  CAS  PubMed  Google Scholar 

  157. Chen L, Song H, Wang Y, Lee JC, Kotlikoff MI, Pritchard TJ, et al. Arterial alpha2-Na+ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific alpha2 mice. Am J Physiol Heart Circ Physiol. 2015;309(5):H958–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Jin C, Sun J, Stilphen CA, Smith SM, Ocasio H, Bermingham B, et al. HV1 acts as a sodium sensor and promotes superoxide production in medullary thick ascending limb of Dahl salt-sensitive rats. Hypertension. 2014;64(3):541–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Touyz RM. The Neuroimmune Axis in the kidney: role in hypertension. Circ Res. 2015;117(6):487–9.

    Article  CAS  PubMed  Google Scholar 

  160. Pober JS. Is hypertension an autoimmune disease? J Clin Invest. 2014;124(10):4234–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Itani HA, Xiao L, Saleh MA, Wu J, Pilkinton MA, Dale BL, et al. CD70 exacerbates blood pressure elevation and renal damage in response to repeated hypertensive stimuli. Circ Res. 2016;118:1233–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Harrison DG. The immune system in hypertension. Trans Am Clin Climatol Assoc. 2014;125:130–8; discussion 138–40.

    Google Scholar 

  163. Harrison DG, Vinh A, Lob H, Madhur MS. Role of the adaptive immune system in hypertension. Curr Opin Pharmacol. 2010;10(2):203–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, et al. DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest. 2014;124(10):4642–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Traitanon O, Gorbachev A, Bechtel JJ, Keslar KS, Baldwin WM 3rd, Poggio ED, et al. IL-15 induces alloreactive CD28(−) memory CD8 T cell proliferation and CTLA4-Ig resistant memory CD8 T cell activation. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2014;14(6):1277–89.

    Article  CAS  Google Scholar 

  166. Barbaro NR, Fontana V, Modolo R, De Faria AP, Sabbatini AR, Fonseca FH, et al. Increased arterial stiffness in resistant hypertension is associated with inflammatory biomarkers. Blood Press. 2015;24(1):7–13.

    Article  CAS  PubMed  Google Scholar 

  167. Barbaro NR, de Araujo TM, Tanus-Santos JE, Anhe GF, Fontana V, Moreno H. Vascular damage in resistant hypertension: TNF-alpha inhibition effects on endothelial cells. Biomed Res Int. 2015;2015:631594.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. de La Sierra A, Larrousse M, Oliveras A, Armario P, Hernandez-Del Rey R, Poch E, et al. Abnormalities of vascular function in resistant hypertension. Blood Press. 2012;21(2):104–9.

    Article  CAS  Google Scholar 

  169. Itani HA, Harrison DG. Memories that last in hypertension. Am J Physiol Ren Physiol. 2015;308(11):F1197–9.

    Article  CAS  Google Scholar 

  170. Campbell DJ. Vaccination against high blood pressure. Curr Pharm Des. 2012;18(7):1005–10.

    Article  CAS  PubMed  Google Scholar 

  171. de Faria AP, Fontana V, Modolo R, Barbaro NR, Sabbatini AR, Pansani IF, et al. Plasma 8-isoprostane levels are associated with endothelial dysfunction in resistant hypertension. Clinica chimica acta. Int J Clin Chem. 2014;433:179–83.

    Google Scholar 

  172. 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.

    Google Scholar 

  173. Montezano AC, Touyz RM. Reactive oxygen species and endothelial function – role of nitric oxide synthase uncoupling and Nox family nicotinamide adenine dinucleotide phosphate oxidases. Basic Clin Pharmacol Toxicol. 2012;110(1):87–94.

    Google Scholar 

  174. Virdis A, Bacca A, Colucci R, Duranti E, Fornai M, Materazzi G, et al. Endothelial dysfunction in small arteries of essential hypertensive patients: role of cyclooxygenase-2 in oxidative stress generation. Hypertension. 2013;62(2):337–44.

    Google Scholar 

  175. Magen E, Mishal J, Paskin J, Glick Z, Yosefy C, Kidon M, et al. Resistant arterial hypertension is associated with higher blood levels of complement C3 and C-reactive protein. J Clin Hypertens (Greenwich, Conn). 2008;10(9):677–83.

    Article  CAS  Google Scholar 

  176. Ferri C, Croce G, Cofini V, De Berardinis G, Grassi D, Casale R, et al. C-reactive protein: interaction with the vascular endothelium and possible role in human atherosclerosis. Curr Pharm Des. 2007;13(16):1631–45.

    Article  CAS  PubMed  Google Scholar 

  177. Andrikou I, Tsioufis C, Dimitriadis K, Syrseloudis D, Valenti P, Almiroudi M, et al. Similar levels of low-grade inflammation and arterial stiffness in masked and white-coat hypertension: comparisons with sustained hypertension and normotension. Blood Press Monit. 2011;16(5):218–23.

    Article  PubMed  Google Scholar 

  178. Tan J, Hua Q, Xing X, Wen J, Liu R, Yang Z. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res Off J Jpn Soc Hypertens. 2007;30(10):959–63.

    Article  CAS  Google Scholar 

  179. Dorr O, Liebetrau C, Mollmann H, Mahfoud F, Ewen S, Gaede L, et al. Beneficial effects of renal sympathetic denervation on cardiovascular inflammation and remodeling in essential hypertension. Clin Res Cardiol Off J German Cardiac Soc. 2015;104(2):175–84.

    Article  CAS  Google Scholar 

  180. Eikelis N, Hering D, Marusic P, Sari C, Walton A, Phillips S, et al. The effect of renal denervation on endothelial function and inflammatory markers in patients with resistant hypertension. Int J Cardiol. 2015;188:96–8.

    Article  CAS  PubMed  Google Scholar 

  181. Xiao L, Kirabo A, Wu J, Saleh MA, Zhu L, Wang F, et al. Renal denervation prevents immune cell activation and renal inflammation in angiotensin II-induced hypertension. Circ Res. 2015;117(6):547–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. El Rouby N, Cooper-DeHoff RM. Genetics of resistant hypertension: a novel pharmacogenomics phenotype. Curr Hypertens Rep. 2015;17(9):583.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Trotta R, Donati MB, Iacoviello L. Trends in pharmacogenomics of drugs acting on hypertension. Pharmacol Res. 2004;49(4):351–6.

    Article  CAS  PubMed  Google Scholar 

  184. Johnson JA. Advancing management of hypertension through pharmacogenomics. Ann Med. 2012;44(Suppl 1):S17–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Tabara Y, Kohara K, Miki T. Hunting for genes for hypertension: the millennium genome project for hypertension. Hypertens Res Off J Jpn Soc Hypertens. 2012;35(6):567–73.

    Article  CAS  Google Scholar 

  186. Yugar-Toledo JC, Martin JF, Krieger JE, Pereira AC, Demacq C, Coelho OR, et al. Gene variation in resistant hypertension: multilocus analysis of the angiotensin 1-converting enzyme, angiotensinogen, and endothelial nitric oxide synthase genes. DNA Cell Biol. 2011;30(8):555–64.

    Article  CAS  PubMed  Google Scholar 

  187. Doris PA. Hypertension genetics, single nucleotide polymorphisms, and the common disease:common variant hypothesis. Hypertension. 2002;39(2 Pt 2):323–31.

    Article  CAS  PubMed  Google Scholar 

  188. Turner ST, Boerwinkle E, O’Connell JR, Bailey KR, Gong Y, Chapman AB, et al. Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide. Hypertension. 2013;62(2):391–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Johnson JA, Boerwinkle E, Zineh I, Chapman AB, Bailey K, Cooper-DeHoff RM, et al. Pharmacogenomics of antihypertensive drugs: rationale and design of the Pharmacogenomic evaluation of antihypertensive responses (PEAR) study. Am Heart J. 2009;157(3):442–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Fontana V, McDonough CW, Gong Y, El Rouby NM, Sa AC, Taylor KD, et al. Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension. J Am Heart Assoc. 2014;3(6):e001398.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Lynch AI, Irvin MR, Davis BR, Ford CE, Eckfeldt JH, Arnett DK. Genetic and adverse health outcome associations with treatment resistant hypertension in GenHAT. Int J Hypertens. 2013;2013:578578.

    Article  PubMed  PubMed Central  Google Scholar 

  192. Hirawa N, Fujiwara A, Umemura S. ATP2B1 and blood pressure: from associations to pathophysiology. Curr Opin Nephrol Hypertens. 2013;22(2):177–84.

    Article  CAS  PubMed  Google Scholar 

  193. Kato N. Ethnic differences in genetic predisposition to hypertension. Hypertens Res Off J Jpn Soc Hypertens. 2012;35(6):574–81.

    Article  Google Scholar 

  194. Hong KW, Go MJ, Jin HS, Lim JE, Lee JY, Han BG, et al. Genetic variations in ATP2B1, CSK, ARSG and CSMD1 loci are related to blood pressure and/or hypertension in two Korean cohorts. J Hum Hypertens. 2010;24(6):367–72.

    Article  CAS  PubMed  Google Scholar 

  195. Cooper-DeHoff RM, Johnson JA. Hypertension pharmacogenomics: in search of personalized treatment approaches. Nat Rev Nephrol. 2016;12(2):110–22.

    Article  CAS  PubMed  Google Scholar 

  196. Bramlage P, Pittrow D, Wittchen HU, Kirch W, Boehler S, Lehnert H, et al. Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am J Hypertens. 2004;17(10):904–10.

    Article  PubMed  Google Scholar 

  197. Isaksson H, Cederholm T, Jansson E, Nygren A, Ostergren J. Therapy-resistant hypertension associated with central obesity, insulin resistance, and large muscle fibre area. Blood Press. 1993;2(1):46–52.

    Article  CAS  PubMed  Google Scholar 

  198. Hall WD. Resistant hypertension, secondary hypertension, and hypertensive crises. Cardiol Clin. 2002;20(2):281–9.

    Article  PubMed  Google Scholar 

  199. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC guidelines for the Management of Arterial Hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159–219.

    Article  PubMed  Google Scholar 

  200. Romero R, Bonet J, de la Sierra A, Aguilera MT. Undiagnosed obesity in hypertension: clinical and therapeutic implications. Blood Press. 2007;16(6):347–53.

    Article  PubMed  Google Scholar 

  201. 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.

    Article  CAS  PubMed  Google Scholar 

  202. Id D, Bertog SC, Ziegler AK, Hornung M, Hofmann I, Vaskelyte L, et al. Predictors of blood pressure response: obesity is associated with a less pronounced treatment response after renal denervation. Catheter Cardiovasc Interv Off J Soc Cardiac Angiography Interv. 2016;87:E30–8.

    Article  Google Scholar 

  203. Stevens VJ, Obarzanek E, Cook NR, Lee IM, Appel LJ, Smith West D, et al. Long-term weight loss and changes in blood pressure: results of the trials of hypertension prevention, phase II. Ann Intern Med. 2001;134(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  204. Redon J, Cifkova R, Laurent S, Nilsson P, Narkiewicz K, Erdine S, et al. The metabolic syndrome in hypertension: European society of hypertension position statement. J Hypertens. 2008;26(10):1891–900.

    Article  CAS  PubMed  Google Scholar 

  205. Simonenko VB, Goriutskii VN, Dulin PA. The role of insulin resistance in pathogenesis of arterial hypertension. Klin Med. 2014;92(9):27–33.

    CAS  Google Scholar 

  206. Redon J, Cifkova R, Laurent S, Nilsson P, Narkiewicz K, Erdine S, et al. Mechanisms of hypertension in the cardiometabolic syndrome. J Hypertens. 2009;27(3):441–51.

    Article  CAS  PubMed  Google Scholar 

  207. de Faria AP, Modolo R, Fontana V, Moreno H. Adipokines: novel players in resistant hypertension. J Clin Hypertens (Greenwich, Conn). 2014;16(10):754–9.

    Article  CAS  Google Scholar 

  208. Yiannikouris F, Gupte M, Putnam K, Cassis L. Adipokines and blood pressure control. Curr Opin Nephrol Hypertens. 2010;19(2):195–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Bulcao C, Ferreira SR, Giuffrida FM, Ribeiro-Filho FF. The new adipose tissue and adipocytokines. Curr Diabetes Rev. 2006;2(1):19–28.

    Article  CAS  PubMed  Google Scholar 

  210. Sabbatini AR, Fontana V, Laurent S, Moreno H. An update on the role of adipokines in arterial stiffness and hypertension. J Hypertens. 2015;33(3):435–44.

    Article  CAS  PubMed  Google Scholar 

  211. Lago F, Dieguez C, Gomez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol. 2007;3(12):716–24.

    Article  CAS  PubMed  Google Scholar 

  212. Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines: the missing link between insulin resistance and obesity. Diabete Metab. 2008;34(1):2–11.

    Article  CAS  PubMed  Google Scholar 

  213. Qi Y, Rathinasabapathy A, Huo T, Zhang J, Shang H, Katz A, et al. 7A.04: dl adipose stem cell is linked to obesity, elevated inflammatory cytokines and resistant hypertension. J Hypertens. 2015;33(Suppl 1):e90.

    Article  PubMed  Google Scholar 

  214. Cao Y, Tao L, Yuan Y, Jiao X, Lau WB, Wang Y, et al. Endothelial dysfunction in adiponectin deficiency and its mechanisms involved. J Mol Cell Cardiol. 2009;46(3):413–9.

    Article  CAS  PubMed  Google Scholar 

  215. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol. 2005;115(5):911–9; quiz 920.

    Google Scholar 

  216. Popko K, Gorska E, Stelmaszczyk-Emmel A, Plywaczewski R, Stoklosa A, Gorecka D, et al. Proinflammatory cytokines Il-6 and TNF-alpha and the development of inflammation in obese subjects. Eur J Med Res. 2010;15(Suppl 2):120–2.

    PubMed  PubMed Central  Google Scholar 

  217. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm. 2006;74:443–77.

    Article  CAS  PubMed  Google Scholar 

  218. How JM, Wardak SA, Ameer SI, Davey RA, Sartor DM. Blunted sympathoinhibitory responses in obesity-related hypertension are due to aberrant central but not peripheral signalling mechanisms. J Physiol. 2014;592(7):1705–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Nakamura M, Yamazaki O, Shirai A, Horita S, Satoh N, Suzuki M, et al. Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome. Kidney Int. 2015;87(3):535–42.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Interventional Cardiology, Cardiovascular Diseases Institute – Iaşi, Iaşi, Romania

    Alexandru Burlacu

  2. Professor Internal Medicine & Nephrology, Grigore T. Popa University of Medicine, Iaşi, Romania

    Adrian Covic

Authors
  1. Alexandru Burlacu
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  2. Adrian Covic
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Correspondence to Alexandru Burlacu .

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Editors and Affiliations

  1. Grigore T. Popa University of Medicine, Iaşi, Romania

    Adrian Covic

  2. Department of Medicine, Division of Nephrology, University School of Medicine, Istanbul, Turkey

    Mehmet Kanbay

  3. Section of Nephrology, University of Illinois at Chicago College of Medicine/Advocate Christ Medical Center, Oak Lawn, Illinois, USA

    Edgar V. Lerma

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Burlacu, A., Covic, A. (2017). Pathophysiological Insights in Resistant Hypertension. In: Covic, A., Kanbay, M., Lerma, E. (eds) Resistant Hypertension in Chronic Kidney Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-56827-0_7

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  • DOI: https://doi.org/10.1007/978-3-319-56827-0_7

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  • Publisher Name: Springer, Cham

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  • Online ISBN: 978-3-319-56827-0

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