Advertisement

Clinical Autonomic Research

, Volume 29, Issue 2, pp 231–243 | Cite as

The renin–angiotensin system in cardiovascular autonomic control: recent developments and clinical implications

  • Amanda J. Miller
  • Amy C. ArnoldEmail author
Review Article

Abstract

Complex and bidirectional interactions between the renin–angiotensin system (RAS) and autonomic nervous system have been well established for cardiovascular regulation under both physiological and pathophysiological conditions. Most research to date has focused on deleterious effects of components of the vasoconstrictor arm of the RAS on cardiovascular autonomic control, such as renin, angiotensin II, and aldosterone. The recent discovery of prorenin and the prorenin receptor have further increased our understanding of RAS interactions in autonomic brain regions. Therapies targeting these RAS components, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are commonly used for treatment of hypertension and cardiovascular diseases, with blood pressure-lowering effects attributed in part to sympathetic inhibition and parasympathetic facilitation. In addition, a vasodilatory arm of the RAS has emerged that includes angiotensin-(1–7), ACE2, and alamandine, and promotes beneficial effects on blood pressure in part by reducing sympathetic activity and improving arterial baroreceptor reflex function in animal models. The role of the vasodilatory arm of the RAS in cardiovascular autonomic regulation in clinical populations, however, has yet to be determined. This review will summarize recent developments in autonomic mechanisms involved in the effects of the RAS on cardiovascular regulation, with a focus on newly discovered pathways and therapeutic targets for this hormone system.

Keywords

Renin–angiotensin system Autonomic nervous system Blood pressure Baroreflex 

Abbreviations

Ang

Angiotensin

ACE

Angiotensin-converting enzyme

AT1

Angiotensin type 1

ARBs

Angiotensin receptor blockers

AT2

Angiotensin type 2

ARC

Arcuate nucleus

CVLM

Caudal ventrolateral medulla

MrgD

Mas-related G-protein coupled receptor D

MR

Mineralocorticoid receptors

NEP

Neutral endopeptidase

OVLT

Organum vasculosum of the lamina terminalis

PRR

Prorenin receptor

PVN

Paraventricular nucleus

RAS

Renin–angiotensin system

RVLM

Rostral ventrolateral medulla

NTS

Nucleus tractus solitarius [solitary tract nucleus]

SFO

Subfornical organ

SNS

Sympathetic nervous system

Notes

Acknowledgements

ACA is supported by NIH grants R00HL122507 and UL1TR002014. AJM is supported by American Heart Association grant 18POST33960087.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

References

  1. 1.
    Kurtz A (2011) Renin release: sites, mechanisms, and control. Annu Rev Physiol 73:377–399Google Scholar
  2. 2.
    Lavoie JL, Sigmund CD (2003) Minireview: overview of the renin-angiotensin system–an endocrine and paracrine system. Endocrinology 144(6):2179–2183Google Scholar
  3. 3.
    Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AH (2015) Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res 116(6):960–975Google Scholar
  4. 4.
    Lavoie JL, Liu X, Bianco RA, Beltz TG, Johnson AK, Sigmund CD (2006) Evidence supporting a functional role for intracellular renin in the brain. Hypertension 47(3):461–466Google Scholar
  5. 5.
    Li XC, Zhu D, Zheng X, Zhang J, Zhuo JL (2018) Intratubular and intracellular renin-angiotensin system in the kidney: a unifying perspective in blood pressure control. Clin Sci (Lond) 132(13):1383–1401Google Scholar
  6. 6.
    Uehara Y, Miura S, Yahiro E, Saku K (2013) Non-ACE pathway-induced angiotensin II production. Curr Pharm Des 19(17):3054–3059Google Scholar
  7. 7.
    Zhuo JL, Li XC (2011) New insights and perspectives on intrarenal renin-angiotensin system: focus on intracrine/intracellular angiotensin II. Peptides 32(7):1551–1565Google Scholar
  8. 8.
    Lemarie CA, Schiffrin EL (2010) The angiotensin II type 2 receptor in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 11(1):19–31Google Scholar
  9. 9.
    Yugandhar VG, Clark MA (2013) Angiotensin III: a physiological relevant peptide of the renin angiotensin system. Peptides 46:26–32Google Scholar
  10. 10.
    Dupont AG, Brouwers S (2010) Brain angiotensin peptides regulate sympathetic tone and blood pressure. J Hypertens 28(8):1599–1610Google Scholar
  11. 11.
    Ferrario CM, Ahmad S, Nagata S, Simington SW, Varagic J, Kon N, Dell’italia LJ (2014) An evolving story of angiotensin-II-forming pathways in rodents and humans. Clin Sci (Lond) 126(7):461–469Google Scholar
  12. 12.
    Campbell DJ (2008) Critical review of prorenin and (pro)renin receptor research. Hypertension 51(5):1259–1264Google Scholar
  13. 13.
    Santos RA (2014) Angiotensin-(1–7). Hypertension 63(6):1138–1147Google Scholar
  14. 14.
    Leonhardt J, Villela DC, Teichmann A, Munter LM, Mayer MC, Mardahl M, Kirsch S, Namsolleck P, Lucht K, Benz V, Alenina N, Daniell N, Horiuchi M, Iwai M, Multhaup G, Schulein R, Bader M, Santos RA, Unger T, Steckelings UM (2017) Evidence for heterodimerization and functional interaction of the angiotensin type 2 receptor and the receptor MAS. Hypertension 69(6):1128–1135Google Scholar
  15. 15.
    Gaidarov I, Adams J, Frazer J, Anthony T, Chen X, Gatlin J, Semple G, Unett DJ (2018) Angiotensin (1–7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor. Cell Signal 50:9–24Google Scholar
  16. 16.
    Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, Jankowski J, Jankowski V, Sousa F, Alzamora A, Soares E, Barbosa C, Kjeldsen F, Oliveira A, Braga J, Savergnini S, Maia G, Peluso AB, Passos-Silva D, Ferreira A, Alves F, Martins A, Raizada M, Paula R, Motta-Santos D, Klempin F, Pimenta A, Alenina N, Sinisterra R, Bader M, Campagnole-Santos MJ, Santos RA (2013) Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res 112(8):1104–1111Google Scholar
  17. 17.
    Villela DC, Passos-Silva DG, Santos RA (2014) Alamandine: a new member of the angiotensin family. Curr Opin Nephrol Hypertens 23(2):130–134Google Scholar
  18. 18.
    Iliescu R, Lohmeier TE, Tudorancea I, Laffin L, Bakris GL (2015) Renal denervation for the treatment of resistant hypertension: review and clinical perspective. Am J Physiol Renal Physiol 309(7):F583–F594Google Scholar
  19. 19.
    Hong MN, Li XD, Chen DR, Ruan CC, Xu JZ, Chen J, Wu YJ, Ma Y, Zhu DL, Gao PJ (2016) Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension. Oncotarget 7(42):67828–67840Google Scholar
  20. 20.
    Averill DB, Diz DI (2000) Angiotensin peptides and baroreflex control of sympathetic outflow: pathways and mechanisms of the medulla oblongata. Brain Res Bull 51(2):119–128Google Scholar
  21. 21.
    Reid IA (1992) Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol 262(6 Pt 1):E763–E778Google Scholar
  22. 22.
    Lohmeier TE (2012) Angiotensin II infusion model of hypertension: is there an important sympathetic component? Hypertension 59(3):539–541Google Scholar
  23. 23.
    Leenen FH (2014) Actions of circulating angiotensin II and aldosterone in the brain contributing to hypertension. Am J Hypertens 27(8):1024–1032Google Scholar
  24. 24.
    Allen AM, Zhuo J, Mendelsohn FA (2000) Localization and function of angiotensin AT1 receptors. Am J Hypertens 13(1 Pt 2):31S–38SGoogle Scholar
  25. 25.
    Hirooka Y, Kishi T, Ito K, Sunagawa K (2013) Potential clinical application of recently discovered brain mechanisms involved in hypertension. Hypertension 62(6):995–1002Google Scholar
  26. 26.
    Huber G, Schuster F, Raasch W (2017) Brain renin-angiotensin system in the pathophysiology of cardiovascular diseases. Pharmacol Res 125(Pt A):72–90Google Scholar
  27. 27.
    de Queiroz TM, Monteiro MM, Braga VA (2013) Angiotensin-II-derived reactive oxygen species on baroreflex sensitivity during hypertension: new perspectives. Front Physiol 4:105Google Scholar
  28. 28.
    Schaich CL, Shaltout HA, Grabenauer M, Thomas BF, Gallagher PE, Howlett AC, Diz DI (2015) Alterations in the medullary endocannabinoid system contribute to age-related impairment of baroreflex sensitivity. J Cardiovasc Pharmacol 65(5):473–479Google Scholar
  29. 29.
    Pellegrino PR, Schiller AM, Haack KK, Zucker IH (2016) Central angiotensin-II increases blood pressure and sympathetic outflow via rho kinase activation in conscious rabbits. Hypertension 68(5):1271–1280Google Scholar
  30. 30.
    Arnold AC, Isa K, Shaltout HA, Nautiyal M, Ferrario CM, Chappell MC, Diz DI (2010) Angiotensin-(1–12) requires angiotensin converting enzyme and AT1 receptors for cardiovascular actions within the solitary tract nucleus. Am J Physiol Heart Circ Physiol 299(3):H763–H771Google Scholar
  31. 31.
    Houghton BL, Huang C, Johns EJ (2010) Influence of dietary sodium on the blood pressure and renal sympathetic nerve activity responses to intracerebroventricular angiotensin II and angiotensin III in anaesthetized rats. Exp Physiol 95(2):282–295Google Scholar
  32. 32.
    Marc Y, Llorens-Cortes C (2011) The role of the brain renin-angiotensin system in hypertension: implications for new treatment. Prog Neurobiol 95(2):89–103Google Scholar
  33. 33.
    Huang BS, Ahmad M, White RA, Marc Y, Llorens-Cortes C, Leenen FH (2013) Inhibition of brain angiotensin III attenuates sympathetic hyperactivity and cardiac dysfunction in rats post-myocardial infarction. Cardiovasc Res 97(3):424–431Google Scholar
  34. 34.
    Kokje RJ, Wilson WL, Brown TE, Karamyan VT, Wright JW, Speth RC (2007) Central pressor actions of aminopeptidase-resistant angiotensin II analogs: challenging the angiotensin III hypothesis. Hypertension 49(6):1328–1335Google Scholar
  35. 35.
    Matsukawa T, Gotoh E, Minamisawa K, Kihara M, Ueda S, Shionoiri H, Ishii M (1991) Effects of intravenous infusions of angiotensin II on muscle sympathetic nerve activity in humans. Am J Physiol 261(3 Pt 2):R690–R696Google Scholar
  36. 36.
    Sayk F, Wobbe I, Twesten C, Meusel M, Wellhoner P, Derad I, Dodt C (2015) Prolonged blood pressure elevation following continuous infusion of angiotensin II-a baroreflex study in healthy humans. Am J Physiol Regul Integr Comp Physiol 309(11):R1406–R1414Google Scholar
  37. 37.
    Goldsmith SR, Hasking GJ, Miller E (1993) Angiotensin II and sympathetic activity in patients with congestive heart failure. J Am Coll Cardiol 21(5):1107–1113Google Scholar
  38. 38.
    Goldsmith SR, Hasking GJ (1995) Angiotensin II inhibits the forearm vascular response to increased arterial pressure in humans. J Am Coll Cardiol 25(1):246–250Google Scholar
  39. 39.
    Townend JN, Al-Ani M, West JN, Littler WA, Coote JH (1995) Modulation of cardiac autonomic control in humans by angiotensin II. Hypertension 25(6):1270–1275Google Scholar
  40. 40.
    Ruhs S, Nolze A, Hubschmann R, Grossmann C (2017) 30 years of the mineralocorticoid receptor: nongenomic effects via the mineralocorticoid receptor. J Endocrinol 234(1):T107–T124Google Scholar
  41. 41.
    Downey RM, Mizuno M, Mitchell JH, Vongpatanasin W, Smith SA (2017) Mineralocorticoid receptor antagonists attenuate exaggerated exercise pressor reflex responses in hypertensive rats. Am J Physiol Heart Circ Physiol 313(4):H788–H794Google Scholar
  42. 42.
    Yee KM, Struthers AD (1998) Aldosterone blunts the baroreflex response in man. Clin Sci (Lond) 95(6):687–692Google Scholar
  43. 43.
    Schmidt BM, Montealegre A, Janson CP, Martin N, Stein-Kemmesies C, Scherhag A, Feuring M, Christ M, Wehling M (1999) Short term cardiovascular effects of aldosterone in healthy male volunteers. J Clin Endocrinol Metab 84(10):3528–3533Google Scholar
  44. 44.
    Heindl S, Holzschneider J, Hinz A, Sayk F, Fehm HL, Dodt C (2006) Acute effects of aldosterone on the autonomic nervous system and the baroreflex function in healthy humans. J Neuroendocrinol 18(2):115–121Google Scholar
  45. 45.
    Monahan KD, Leuenberger UA, Ray CA (2007) Aldosterone impairs baroreflex sensitivity in healthy adults. Am J Physiol Heart Circ Physiol 292(1):H190–H197Google Scholar
  46. 46.
    Cuadra AE, Shan Z, Sumners C, Raizada MK (2010) A current view of brain renin-angiotensin system: is the (pro)renin receptor the missing link? Pharmacol Ther 125(1):27–38Google Scholar
  47. 47.
    Li W, Peng H, Cao T, Sato R, McDaniels SJ, Kobori H, Navar LG, Feng Y (2012) Brain-targeted (pro)renin receptor knockdown attenuates angiotensin II-dependent hypertension. Hypertension 59(6):1188–1194Google Scholar
  48. 48.
    Shan Z, Shi P, Cuadra AE, Dong Y, Lamont GJ, Li Q, Seth DM, Navar LG, Katovich MJ, Sumners C, Raizada MK (2010) Involvement of the brain (pro)renin receptor in cardiovascular homeostasis. Circ Res 107(7):934–938Google Scholar
  49. 49.
    Huber MJ, Basu R, Cecchettini C, Cuadra AE, Chen QH, Shan Z (2015) Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats. Am J Physiol Heart Circ Physiol 309(5):H880–H887Google Scholar
  50. 50.
    Li W, Peng H, Mehaffey EP, Kimball CD, Grobe JL, van Gool JM, Sullivan MN, Earley S, Danser AH, Ichihara A, Feng Y (2014) Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension. Hypertension 63(2):316–323Google Scholar
  51. 51.
    Li W, Sullivan MN, Zhang S, Worker CJ, Xiong Z, Speth RC, Feng Y (2015) Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension. Hypertension 65(2):352–361Google Scholar
  52. 52.
    Shi P, Grobe JL, Desland FA, Zhou G, Shen XZ, Shan Z, Liu M, Raizada MK, Sumners C (2014) Direct pro-inflammatory effects of prorenin on microglia. PLoS One 9(10):e92937Google Scholar
  53. 53.
    Pitra S, Feng Y, Stern JE (2016) Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. Mol Metab 5(10):858–868Google Scholar
  54. 54.
    Gironacci MM, Cerniello FM, Longo Carbajosa NA, Goldstein J, Cerrato BD (2014) Protective axis of the renin-angiotensin system in the brain. Clin Sci (Lond) 127(5):295–306Google Scholar
  55. 55.
    de Souza-Neto FP, Carvalho Santuchi M, de Morais ESM, Campagnole-Santos MJ, da Silva RF (2018) Angiotensin-(1–7) and alamandine on experimental models of hypertension and atherosclerosis. Curr Hypertens Rep 20(2):17Google Scholar
  56. 56.
    Shangguan W, Shi W, Li G, Wang Y, Li J, Wang X (2017) Angiotensin-(1–7) attenuates atrial tachycardia-induced sympathetic nerve remodeling. J Renin Angiotensin Aldosterone Syst 18(3):1470320317729281Google Scholar
  57. 57.
    Martins Lima A, Xavier CH, Ferreira AJ, Raizada MK, Wallukat G, Velloso EP, dos Santos RA, Fontes MA (2013) Activation of angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis attenuates the cardiac reactivity to acute emotional stress. Am J Physiol Heart Circ Physiol 305(7):H1057–H1067Google Scholar
  58. 58.
    de Moura MM, dos Santos RA, Campagnole-Santos MJ, Todiras M, Bader M, Alenina N, Haibara AS (2010) Altered cardiovascular reflexes responses in conscious angiotensin-(1–7) receptor Mas-knockout mice. Peptides 31(10):1934–1939Google Scholar
  59. 59.
    Bilodeau MS, Leiter JC (2018) Angiotensin 1–7 in the rostro-ventrolateral medulla increases blood pressure and splanchnic sympathetic nerve activity in anesthetized rats. Respir Physiol Neurobiol 247:103–111Google Scholar
  60. 60.
    Ren X, Zhang F, Zhao M, Zhao Z, Sun S, Fraidenburg DR, Tang H, Han Y (2017) Angiotensin-(1–7) in paraventricular nucleus contributes to the enhanced cardiac sympathetic afferent reflex and sympathetic activity in chronic heart failure rats. Cell Physiol Biochem 42(6):2523–2539Google Scholar
  61. 61.
    Xia H, Lazartigues E (2010) Angiotensin-converting enzyme 2: central regulator for cardiovascular function. Curr Hypertens Rep 12(3):170–175Google Scholar
  62. 62.
    Shen YH, Chen XR, Yang CX, Liu BX, Li P (2018) Alamandine injected into the paraventricular nucleus increases blood pressure and sympathetic activation in spontaneously hypertensive rats. Peptides 103:98–102Google Scholar
  63. 63.
    Leenen FH, Ruzicka M, Floras JS (2012) Central sympathetic inhibition by mineralocorticoid receptor but not angiotensin II type 1 receptor blockade: are prescribed doses too low? Hypertension 60(2):278–280Google Scholar
  64. 64.
    Ferrario CM, Mullick AE (2017) Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. Pharmacol Res 125(Pt A):57–71Google Scholar
  65. 65.
    Grassi G (2016) Sympathomodulatory effects of antihypertensive drug treatment. Am J Hypertens 29(6):665–675Google Scholar
  66. 66.
    Abuissa H, Jones PG, Marso SP, O’Keefe JH Jr (2005) Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 46(5):821–826Google Scholar
  67. 67.
    Yang Y, Wei RB, Wang ZC, Wang N, Gao YW, Li MX, Qiu Q (2015) A meta-analysis of the effects of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers on insulin sensitivity in hypertensive patients without diabetes. Diabetes Res Clin Pract 107(3):415–423Google Scholar
  68. 68.
    Robles NR, Cerezo I, Hernandez-Gallego R (2014) Renin-angiotensin system blocking drugs. J Cardiovasc Pharmacol Ther 19(1):14–33Google Scholar
  69. 69.
    Benter IF, Yousif MH, Al-Saleh FM, Raghupathy R, Chappell MC, Diz DI (2011) Angiotensin-(1–7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-l-arginine methyl ester. J Cardiovasc Pharmacol 57(5):559–567Google Scholar
  70. 70.
    Kucharewicz I, Pawlak R, Matys T, Pawlak D, Buczko W (2002) Antithrombotic effect of captopril and losartan is mediated by angiotensin-(1–7). Hypertension 40(5):774–779Google Scholar
  71. 71.
    Yousif MH, Dhaunsi GS, Makki BM, Qabazard BA, Akhtar S, Benter IF (2012) Characterization of angiotensin-(1–7) effects on the cardiovascular system in an experimental model of type-1 diabetes. Pharmacol Res 66(3):269–275Google Scholar
  72. 72.
    Lang CC, Stein CM, He HB, Wood AJ (1996) Angiotensin converting enzyme inhibition and sympathetic activity in healthy subjects. Clin Pharmacol Ther 59(6):668–674Google Scholar
  73. 73.
    Azevedo ER, Mak S, Floras JS, Parker JD (2017) Acute effects of angiotensin-converting enzyme inhibition versus angiotensin II receptor blockade on cardiac sympathetic activity in patients with heart failure. Am J Physiol Regul Integr Comp Physiol 313(4):R410–R417Google Scholar
  74. 74.
    Krum H, Lambert E, Windebank E, Campbell DJ, Esler M (2006) Effect of angiotensin II receptor blockade on autonomic nervous system function in patients with essential hypertension. Am J Physiol Heart Circ Physiol 290(4):H1706–H1712Google Scholar
  75. 75.
    de Champlain J, Karas M, Assouline L, Nadeau R, LeBlanc AR, Dube B, Larochelle P (2007) Effects of valsartan or amlodipine alone or in combination on plasma catecholamine levels at rest and during standing in hypertensive patients. J Clin Hypertens (Greenwich) 9(3):168–178Google Scholar
  76. 76.
    Ajayi AA, Reid JL (1988) Renin-angiotensin modulation of sympathetic reflex function in essential hypertension and in the elderly. Int J Clin Pharmacol Res 8(5):327–333Google Scholar
  77. 77.
    Stupin A, Drenjancevic I, Rasic L, Cosic A, Stupin M (2017) A cross-talk between the renin-angiotensin and adrenergic systems in cardiovascular health and disease. SEEMEDJ 1(1):90–107Google Scholar
  78. 78.
    Arnold AC, Okamoto LE, Gamboa A, Shibao C, Raj SR, Robertson D, Biaggioni I (2013) Angiotensin II, independent of plasma renin activity, contributes to the hypertension of autonomic failure. Hypertension 61(3):701–706Google Scholar
  79. 79.
    Cabandugama PK, Gardner MJ, Sowers JR (2017) The renin angiotensin aldosterone system in obesity and hypertension: roles in the cardiorenal metabolic syndrome. Med Clin N Am 101(1):129–137Google Scholar
  80. 80.
    Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM (2005) Weight loss and the renin-angiotensin-aldosterone system. Hypertension 45(3):356–362Google Scholar
  81. 81.
    Masuo K, Mikami H, Ogihara T, Tuck ML (2001) Weight reduction and pharmacologic treatment in obese hypertensives. Am J Hypertens 14(6 Pt 1):530–538Google Scholar
  82. 82.
    Floras JS, Ponikowski P (2015) The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur Heart J 36(30):1974–1982bGoogle Scholar
  83. 83.
    Neumann J, Ligtenberg G, Klein IH, Boer P, Oey PL, Koomans HA, Blankestijn PJ (2007) Sympathetic hyperactivity in hypertensive chronic kidney disease patients is reduced during standard treatment. Hypertension 49(3):506–510Google Scholar
  84. 84.
    Pantzaris ND, Karanikolas E, Tsiotsios K, Velissaris D (2017) Renin inhibition with aliskiren: a decade of clinical experience. J Clin Med 6(6):61Google Scholar
  85. 85.
    Huang BS, White RA, Bi L, Leenen FH (2012) Central infusion of aliskiren prevents sympathetic hyperactivity and hypertension in Dahl salt-sensitive rats on high salt intake. Am J Physiol Regul Integr Comp Physiol 302(7):R825–R832Google Scholar
  86. 86.
    Siddiqi L, Oey PL, Blankestijn PJ (2011) Aliskiren reduces sympathetic nerve activity and blood pressure in chronic kidney disease patients. Nephrol Dial Transplant 26(9):2930–2934Google Scholar
  87. 87.
    Okada Y, Jarvis SS, Best SA, Bivens TB, Adams-Huet B, Levine BD, Fu Q (2013) Chronic renin inhibition lowers blood pressure and reduces upright muscle sympathetic nerve activity in hypertensive seniors. J Physiol 591(23):5913–5922Google Scholar
  88. 88.
    Jarvis SS, Okada Y, Levine BD, Fu Q (2015) Central integration and neural control of blood pressure during the cold pressor test: a comparison between hydrochlorothiazide and aliskiren. Physiol Rep 3(9):e12502Google Scholar
  89. 89.
    Fogari R, Zoppi A, Mugellini A, Maffioli P, Lazzari P, Monti C, Derosa G (2011) Effect of aliskiren addition to amlodipine on ankle edema in hypertensive patients: a three-way crossover study. Expert Opin Pharmacother 12(9):1351–1358Google Scholar
  90. 90.
    Maser RE, Lenhard MJ, Kolm P, Edwards DG (2013) Direct renin inhibition improves parasympathetic function in diabetes. Diabetes Obes Metab 15(1):28–34Google Scholar
  91. 91.
    Mengal V, Silva PH, Tiradentes RV, Santuzzi CH, de Almeida SA, Sena GC, Bissoli NS, Abreu GR, Gouvea SA (2016) Aliskiren and l-arginine treatments restore depressed baroreflex sensitivity and decrease oxidative stress in renovascular hypertension rats. Hypertens Res 39(11):769–776Google Scholar
  92. 92.
    DuPont JJ, Hill MA, Bender SB, Jaisser F, Jaffe IZ (2014) Aldosterone and vascular mineralocorticoid receptors: regulators of ion channels beyond the kidney. Hypertension 63(4):632–637Google Scholar
  93. 93.
    Brown NJ (2003) Eplerenone: cardiovascular protection. Circulation 107(19):2512–2518Google Scholar
  94. 94.
    Dudenbostel T, Calhoun DA (2017) Use of aldosterone antagonists for treatment of uncontrolled resistant hypertension. Am J Hypertens 30(2):103–109Google Scholar
  95. 95.
    Arnold AC, Okamoto LE, Gamboa A, Black BK, Raj SR, Elijovich F, Robertson D, Shibao CA, Biaggioni I (2016) Mineralocorticoid receptor activation contributes to the supine hypertension of autonomic failure. Hypertension 67(2):424–429Google Scholar
  96. 96.
    Lincevicius GS, Shimoura CG, Nishi EE, Perry JC, Casarini DE, Gomes GN, Bergamaschi CT, Campos RR (2015) Aldosterone contributes to sympathoexcitation in renovascular hypertension. Am J Hypertens 28(9):1083–1090Google Scholar
  97. 97.
    Marques Neto SR, Silva AD, Santos MD, Ferraz EF, Nascimento JH (2013) The blockade of angiotensin AT1 and aldosterone receptors protects rats from synthetic androgen-induced cardiac autonomic dysfunction. Acta Physiol (Oxf) 208(2):166–171Google Scholar
  98. 98.
    Davies JI, Witham MD, Struthers AD (2005) Autonomic effects of spironolactone and MR blockers in heart failure. Heart Fail Rev 10(1):63–69Google Scholar
  99. 99.
    Gomez-Sanchez EP (2016) Third-generation mineralocorticoid receptor antagonists: why do we need a fourth? J Cardiovasc Pharmacol 67(1):26–38Google Scholar
  100. 100.
    Kaplinsky E (2016) Sacubitril/valsartan in heart failure: latest evidence and place in therapy. Ther Adv Chronic Dis 7(6):278–290Google Scholar
  101. 101.
    Ye L, Wang J, Chen Q, Yang X (2017) LCZ696, a promising novel agent in treating hypertension (a meta-analysis of randomized controlled trials). Oncotarget 8(64):107991–108005Google Scholar
  102. 102.
    Engeli S, Stinkens R, Heise T, May M, Goossens GH, Blaak EE, Havekes B, Jax T, Albrecht D, Pal P, Tegtbur U, Haufe S, Langenickel TH, Jordan J (2018) Effect of sacubitril/valsartan on exercise-induced lipid metabolism in patients with obesity and hypertension. Hypertension 71(1):70–77Google Scholar
  103. 103.
    Menendez JT (2016) The mechanism of action of LCZ696. Card Fail Rev 2(1):40–46Google Scholar
  104. 104.
    Kusaka H, Sueta D, Koibuchi N, Hasegawa Y, Nakagawa T, Lin B, Ogawa H, Kim-Mitsuyama S (2015) LCZ696, angiotensin II receptor-neprilysin inhibitor, ameliorates high-salt-induced hypertension and cardiovascular injury more than valsartan alone. Am J Hypertens 28(12):1409–1417Google Scholar
  105. 105.
    Ferrario CM, Martell N, Yunis C, Flack JM, Chappell MC, Brosnihan KB, Dean RH, Fernandez A, Novikov SV, Pinillas C, Luque M (1998) Characterization of angiotensin-(1–7) in the urine of normal and essential hypertensive subjects. Am J Hypertens 11(2):137–146Google Scholar
  106. 106.
    Touyz RM, Montezano AC (2018) Angiotensin-(1–7) and vascular function: the clinical context. Hypertension 71(1):68–69Google Scholar
  107. 107.
    Machado-Silva A, Passos-Silva D, Santos RA, Sinisterra RD (2016) Therapeutic uses for angiotensin-(1–7). Expert Opin Ther Pat 26(6):669–678Google Scholar
  108. 108.
    Ho JK, Nation DA (2018) Cognitive benefits of angiotensin IV and angiotensin-(1–7): a systematic review of experimental studies. Neurosci Biobehav Rev 92:209–225Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Neural and Behavioral SciencesPennsylvania State University College of MedicineHersheyUSA

Personalised recommendations