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Emerging Therapy in Hypertension

  • Merrill H. StewartEmail author
  • Carl J. Lavie
  • Hector O. Ventura
Antihypertensive Agents: Mechanisms of Drug Action (Michael E. Ernst, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action

Abstract

Purpose of the Review

Pharmacology remains the mainstay of treatment for hypertension across the globe. In what may seem like a well-trodden field, there are actually an exciting array of new pathways for the treatment of hypertension on the horizon. This review seeks to discuss the most recent research in ongoing areas of drug development in the field of hypertension.

Recent Findings

Novel areas of research in the field of hypertension pharmacology include central nervous system regulators, peripheral noradrenergic inhibitors, gastrointestinal sodium modulators, and a counter-regulatory arm of the renin-angiotensin-aldosterone system.

Summary

This review discusses these pathways in a look into the current status of emerging pharmacological therapies for hypertension.

Keywords

Hypertension Future hypertension therapy Hypertension drugs Pharmacological therapy High blood pressure Hypertension medication 

Abbreviations

ACE

Angiotensin-converting enzyme

ACTH

Adrenocorticotropic hormone

Ang

Angiotensin

Ang I

Angiotensin I

Ang II

Angiotensin II

Ang III

Angiotensin III

AngA

Angiotensin A

ANP

Atrial natriuretic peptide

APA

Aminopeptidase A

ARB

Angiotensin receptor blocker

ASI

Aldosterone synthesis inhibitors

AT1

Angiotensin receptor 1

AT2

Angiotensin receptor 2

BNP

Brain natriuretic peptide

C21

Compound 21

CNS

Central nervous system

DBH

Dopamine-beta-hydroxylase

DIZE

Diminazene aceturate

MrgD

Mas-related G protein–coupled receptor D

NHE3

Sodium/hydrogen exchanger 3

NO

Nitric oxide

RAAS

Renin-angiotensin aldosterone system

SBP

Systolic blood pressure

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global disparities of hypertension prevalence and control. Circulation. 2016;134:441–50.  https://doi.org/10.1161/CIRCULATIONAHA.115.018912.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hrenak J, Paulis L, Simko F. Angiotensin A/Alamandine/MrgD axis: another clue to understanding cardiovascular pathophysiology. Int J Mol Sci. 2016;17.  https://doi.org/10.3390/ijms17071098.CrossRefGoogle Scholar
  3. 3.
    Soltani Hekmat A, Javanmardi K, Kouhpayeh A, Baharamali E, Farjam M. Differences in cardiovascular responses to Alamandine in two-kidney, one clip hypertensive and normotensive rats. Circ J. 2017;81:405–12.CrossRefGoogle Scholar
  4. 4.
    Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017;125:21–38.  https://doi.org/10.1016/j.phrs.2017.06.005.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Stewart MH, Lavie CJ, Ventura HO (2018) Future pharmacological therapy in hypertension. 1–9.CrossRefGoogle Scholar
  6. 6.
    Patel SN, Ali Q, Samuel P, Steckelings UM, Hussain T. Angiotensin II type 2 receptor and receptor mas are colocalized and functionally interdependent in obese zucker rat kidney. Hypertension. 2017;70:831–8.  https://doi.org/10.1161/HYPERTENSIONAHA.117.09679.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Velkoska E, Patel SK, Burrell LM. Angiotensin converting enzyme 2 and diminazene: role in cardiovascular and blood pressure regulation. Curr Opin Nephrol Hypertens. 2016;25:384–95.  https://doi.org/10.1097/MNH.0000000000000254.CrossRefPubMedGoogle Scholar
  8. 8.
    De Maria MLA, Araújo LD, Fraga-silva RA, Pereira LAS, Heder J, Menezes GB, et al. Anti-hypertensive effects of diminazene aceturate : an angiotensin-converting enzyme 2 activator in rats. Protein Pept Lett. 2016;23:9–16.CrossRefGoogle Scholar
  9. 9.
    Huskova Z, Kopkan L, Cervenkova L, et al. Intrarenal alterations of the angiotensin-converting enzyme type 2/angiotensin 1-7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats. Clin Exp Pharmacol Physiol. 2016;43:438–49.CrossRefGoogle Scholar
  10. 10.
    Macedo LM, Souza ÁPDS, De Maria MLDA, et al. Cardioprotective effects of diminazene aceturate in pressure-overloaded rat hearts. Life Sci. 2016;155:63–9.  https://doi.org/10.1016/j.lfs.2016.04.036.CrossRefPubMedGoogle Scholar
  11. 11.
    Kuriakose S, Muleme HM, Onyilagha C, Singh R, Jia P, Uzonna JE. Diminazene aceturate (Berenil) modulates the host cellular and inflammatory responses to Trypanosoma congolense infection. PLoS One. 2012;7.  https://doi.org/10.1371/journal.pone.0048696.CrossRefGoogle Scholar
  12. 12.
    Hao Q, Dong X, Chen X, Yan F, Wang X, Shi H, et al. Angiotensin-converting enzyme 2 inhibits angiotensin II-induced abdominal aortic aneurysms in mice. Hum Gene Ther. 2018;29:1387–95.  https://doi.org/10.1089/hum.2016.144.CrossRefGoogle Scholar
  13. 13.
    Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M, et al. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet. 2013;52:783–92.  https://doi.org/10.1007/s40262-013-0072-7.CrossRefPubMedGoogle Scholar
  14. 14.
    Basu R, Poglitsch M, Yogasundaram H, Thomas J, Rowe BH, Oudit GY. Roles of angiotensin peptides and recombinant human ACE2 in heart failure. J Am Coll Cardiol. 2017.  https://doi.org/10.1016/j.jacc.2016.11.064.CrossRefGoogle Scholar
  15. 15.
    Galandrin S, Denis C, Boularan C, et al. Renin – angiotensin system II type 1 receptor. Circulation. 2016.  https://doi.org/10.1161/HYPERTENSIONAHA.116.08118.CrossRefGoogle Scholar
  16. 16.
    Papinska AM, Mordwinkin NM, Meeks CJ, Jadhav SS, Rodgers KE. Angiotensin-(1-7) administration benefits cardiac, renal and progenitor cell function in db/db mice. Br J Pharmacol. 2015;172:4443–53.  https://doi.org/10.1111/bph.13225.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lin S, Pan H, Wu H, Ren D, Lu J. Role of the ACE2Ang(17) Mas axis in blood pressure regulation and its potential as an antihypertensive in functional foods (review). Mol Med Rep. 2017;16:4403–12.CrossRefGoogle Scholar
  18. 18.
    Arnold AC (2018) Blood pressure lowering effects of angiotensin-(1–7) in primary autonomic failure. https://www.clinicaltrials.gov/ct2/show/NCT02591173?term=NCT02591173&rank=1. NCT02591173. Accessed 24 Feb 2018.
  19. 19.
    Biaggioni I (2018) Cardiovascular effects of angiotensin (1–7) in essential hypertension. ClinicalTrials.gov. NCT02245230. Accessed 24 Feb 2019.
  20. 20.
    Wiemer G, Dobrucki LW, Louka FR, Malinski T, Heitsch H. AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium. Hypertension. 2002;40:847–52.  https://doi.org/10.1161/01.HYP.0000037979.53963.8F.CrossRefPubMedGoogle Scholar
  21. 21.
    Ferreira AJ, Jacoby BA, Araujo CAA, Macedo FAFF, Silva GAB, Almeida AP, et al. The nonpeptide angiotensin-(1-7) receptor Mas agonist AVE-0991 attenuates heart failure induced by myocardial infarction. AJP Hear Circ Physiol. 2006;292:H1113–9.  https://doi.org/10.1152/ajpheart.00828.2006.CrossRefGoogle Scholar
  22. 22.
    Raffai G, Lombard JH. Angiotensin-(1-7) selectively induces relaxation and modulates endothelium-dependent dilation in mesenteric arteries of salt-fed rats. J Vasc Res. 2016;53:105–18.  https://doi.org/10.1159/000448714.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ma Y, Huang H, Jiang J, Wu L, Lin C, Tang A, et al. AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress. Biochem Biophys Res Commun. 2016;474:621–5.CrossRefGoogle Scholar
  24. 24.
    Skiba DS, Nosalski R, Mikolajczyk TP, et al. Anti-atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque in fl ammation in early atherosclerosis. Br J Pharmacol. 2017.  https://doi.org/10.1111/bph.13685.CrossRefGoogle Scholar
  25. 25.
    Qaradakhi T, Apostolopoulos V, Zulli A. Angiotensin (1-7) and Alamandine: similarities and differences. Pharmacol Res. 2016;111:820–6.CrossRefGoogle Scholar
  26. 26.
    Soares ER, Barbosa CM, Campagnole-Santos MJ, Santos RAS, Alzamora AC. Hypotensive effect induced by microinjection of Alamandine, a derivative of angiotensin-(1–7), into caudal ventrolateral medulla of 2K1C hypertensive rats. Peptides. 2017;96:67–75.  https://doi.org/10.1016/j.peptides.2017.09.005.CrossRefPubMedGoogle Scholar
  27. 27.
    de Jesus ICG, Scalzo S, Alves F, Marques K, Rocha-Resende C, Bader M, et al. Alamandine acts via MrgD to induce AMPK/NO activation against ANG II hypertrophy in cardiomyocytes. Am J Physiol Cell Physiol. 2018;314:C702–11.CrossRefGoogle Scholar
  28. 28.
    Park BM, Phuong HTA, Yu L, Kim SH. Alamandine protects the heart against reperfusion injury via the MrgD receptor. Circ J. 2018;82:2584–93.CrossRefGoogle Scholar
  29. 29.
    Liu C, Yang CX, Chen XR, Liu BX, Li Y, Wang XZ, et al. Alamandine attenuates hypertension and cardiac hypertrophy in hypertensive rats. Amino Acids. 2018;50:1071–81.CrossRefGoogle Scholar
  30. 30.
    Whitebread S, Mele M, Kamber B, de Gasparo M. Preliminary biochemical characterization of two angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989;163:284–91.  https://doi.org/10.1016/0006-291X(89)92133-5.CrossRefPubMedGoogle Scholar
  31. 31.
    Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature. 1995;377:748–50.  https://doi.org/10.1038/377748a0.CrossRefPubMedGoogle Scholar
  32. 32.
    Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest. 1999;104:925–35.  https://doi.org/10.1172/JCI7886.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Henrion D, Kubis N, Lévy BI. Physiological and pathophysiological functions of the AT2subtype receptor of angiotensin II from large arteries to the microcirculation. Hypertension. 2001;38:1150–7.  https://doi.org/10.1161/hy1101.096109.CrossRefPubMedGoogle Scholar
  34. 34.
    Lo M, Liu KL, Lantelme P, Sassard J. Subtype 2 of angiotensin II receptors controls pressure-natriuresis in rats. J Clin Invest. 1995;95:1394–7.  https://doi.org/10.1172/JCI117792.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Whitebread SE, Taylor V, Bottari SP, Kamber B, de Gasparo M. Radioiodinated CGP 42111A: A novel high affinity and highly selective ligand for the characterization of angiotensin AT2receptors. Biochem Biophys Res Commun. 1991;181:1365–71.  https://doi.org/10.1016/0006-291X(91)92089-3.CrossRefPubMedGoogle Scholar
  36. 36.
    Wan Y, Wallinder C, Plouffe B, Beaudry H, Mahalingam AK, Wu X, et al. Design, synthesis, and biological evaluation, of the first selective nonpeptide AT2 receptor agonist. J Med Chem. 2004;47:5995–6008.  https://doi.org/10.1021/jm049715t.CrossRefPubMedGoogle Scholar
  37. 37.
    Padia SH, Carey RM. AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function. Pflugers Arch Eur J Physiol. 2013;465:99–110.  https://doi.org/10.1007/s00424-012-1146-3.CrossRefGoogle Scholar
  38. 38.
    Kemp BA, Howell NL, Keller SR, Gildea JJ, Padia SH, Carey RM. AT2 receptor activation prevents sodium retention and reduces blood pressure in angiotensin II-dependent hypertension. Circ Res. 2016;119:532–43.  https://doi.org/10.1161/CIRCRESAHA.116.308384.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lange C, Sommerfeld M, Namsolleck P, Kintscher U, Unger T, Kaschina E. AT2R (angiotensin AT2 receptor) agonist, compound 21, prevents abdominal aortic aneurysm progression in the rat. Hypertension. 2018.  https://doi.org/10.1161/HYPERTENSIONAHA.118.11168.
  40. 40.
    Chow BSM, Koulis C, Krishnaswamy P, Steckelings UM, Unger T, Cooper ME, et al. The angiotensin II type 2 receptor agonist compound 21 is protective in experimental diabetes-associated atherosclerosis. Diabetologia 2016;59(8):1778–90.  https://doi.org/10.1007/s00125-016-3977-5.CrossRefGoogle Scholar
  41. 41.
    Castoldi G, di Gioia CRT, Roma F, Carletti R, Manzoni G, Stella A, et al. Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats. Acta Diabetol. 2018.  https://doi.org/10.1007/s00592-018-1220-1.CrossRefGoogle Scholar
  42. 42.
    BOLTE E, VERDY M, MARC-AURELE J, BROUILLET J, BEAUREGARD P, GENEST J. Studies on new diuretic compounds: spirolactone and chlorothiazide. Can Med Assoc J. 1958;79:881–8.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Williams B, Macdonald TM, Morant S, Webb DJ, Sever P, Mcinnes G, et al. British Hypertension Society's PATHWAY Studies Group. 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):2059–2068.  https://doi.org/10.1016/S0140-6736(15)00257-3.CrossRefGoogle Scholar
  44. 44.
    Amar L, Azizi M, Watson C. Aldosterone synthase inhibition with LCI699 A proof-of-concept study in patients with primary aldosteronism. Hypertension. 2010.  https://doi.org/10.1161/HYPERTENSIONAHA.110.157271.CrossRefGoogle Scholar
  45. 45.
    Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, et al. Effects of a novel aldosterone synthase inhibitor for phase 2 trial. Circulation. 2011.  https://doi.org/10.1161/CIRCULATIONAHA.111.029892.CrossRefGoogle Scholar
  46. 46.
    Karns AD, Bral JM, Hartman D, Peppard T, Schumacher C. Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. J Clin Hypertens (Greenwich). 2013.  https://doi.org/10.1111/jch.12051.CrossRefGoogle Scholar
  47. 47.
    Weldon SM, Cerny MA, Gueneva-boucheva K, Cogan D, Guo X, Moss N et al. Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. J Pharmacol Exp Ther. 2016;359(1):142–150.  https://doi.org/10.1124/jpet.116.236463.CrossRefGoogle Scholar
  48. 48.
    •• Sloan-lancaster J, Raddad E, Flynt A, Jin Y, Voelker J, Miller JW. LY3045697 : Results from two randomized clinical trials of a novel inhibitor of aldosterone synthase. J Renin Angiotensin Aldosterone Syst. 2017.  https://doi.org/10.1177/1470320317717883 Phase I trial of a novel selective inhibitor of the enzyme CYP11B2, aldosterone synthase. Previous drugs in this class failed due to homology with cortisol synthase, but new selective inhibitors hold much promise. CrossRefGoogle Scholar
  49. 49.
    • Cypb S, Bogman K, Schwab D, et al. Aldosterone synthase inhibitor preclinical and early clinical profile of a highly selective and potent oral inhibitor of aldosterone. Hypertension. 2016.  https://doi.org/10.1161/HYPERTENSIONAHA.116.07716 Another phase I trial of a novel selective CYP11B2 inhibitor, a new class of medications. CrossRefGoogle Scholar
  50. 50.
    Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013;34(31):2453–2463.  https://doi.org/10.1093/eurheartj/eht187.CrossRefGoogle Scholar
  51. 51.
    • Sato N, Ajioka M, Yamada T, et al. A randomized controlled study of finerenone vs. eplerenone in japanese patients with worsening chronic heart failure and diabetes and/or chronic kidney disease. Circ J. 2016.  https://doi.org/10.1253/circj.CJ-16-0122. New mineralcorticoid antagonist with specificity for cardiac over renal tissue, designed for vasoactive effects without potential renal injury. Finerenone is showing promise in heart failure trials but a dose depdent blood pressure reduction has also been noted. CrossRefGoogle Scholar
  52. 52.
    Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016.  https://doi.org/10.1093/eurheartj/ehw132.CrossRefGoogle Scholar
  53. 53.
    Macdonald PS. Combined angiotensin receptor/neprilysin inhibitors: a review of the new paradigm in the management of chronic heart failure. Clin Ther. 2015;37:2199–205.  https://doi.org/10.1016/j.clinthera.2015.08.013.CrossRefPubMedGoogle Scholar
  54. 54.
    McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.  https://doi.org/10.1056/NEJMoa1409077.CrossRefPubMedGoogle Scholar
  55. 55.
    Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375:1255–66.  https://doi.org/10.1016/S0140-6736(09)61966-8.CrossRefPubMedGoogle Scholar
  56. 56.
    Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A, et al. Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension. 2014;63:698–705.  https://doi.org/10.1161/HYPERTENSIONAHA.113.02002.CrossRefPubMedGoogle Scholar
  57. 57.
    Supasyndh O, Sun N, Kario K, Hafeez K, Zhang J. Long-term (52-week) safety and efficacy of sacubitril/valsartan in Asian patients with hypertension. Hypertens Res. 2017;40:472–6.CrossRefGoogle Scholar
  58. 58.
    Kario K, Tamaki Y, Okino N, Gotou H, Zhu M, Zhang J. LCZ696, a first-in-class angiotensin receptor-neprilysin inhibitor: the first clinical experience in patients with severe hypertension. J Clin Hypertens. 2016;18:308–14.  https://doi.org/10.1111/jch.12667.CrossRefGoogle Scholar
  59. 59.
    Izzo JLJ, Zappe DH, Jia Y, Hafeez K, Zhang J. Efficacy and safety of crystalline valsartan/sacubitril (LCZ696) compared with placebo and combinations of free valsartan and sacubitril in patients with systolic hypertension: the RATIO study. J Cardiovasc Pharmacol. 2017;69:374–81.CrossRefGoogle Scholar
  60. 60.
    Schmieder RE, Wagner F, Mayr M, Delles C, Ott C, Keicher C, et al. The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study. Eur Heart J. 2017;38:3308–17.CrossRefGoogle Scholar
  61. 61.
    Igreja B, Pires NM, Bonifácio MJ, Loureiro AI, Fernandes-Lopes C, Wright LC, et al. Blood pressure-decreasing effect of etamicastat alone and in combination with antihypertensive drugs in the spontaneously hypertensive rat. Hypertens Res. 2015;38:30–8.  https://doi.org/10.1038/hr.2014.143.CrossRefPubMedGoogle Scholar
  62. 62.
    Igreja B, Wright LC, Soares-Da-Silva P. Sustained high blood pressure reduction with etamicastat, a peripheral selective dopamine β-hydroxylase inhibitor. J Am Soc Hypertens. 2016;10:207–16.  https://doi.org/10.1016/j.jash.2015.12.011.CrossRefPubMedGoogle Scholar
  63. 63.
    Pires NM, Igreja B, Moura E, Wright LC, Serrão MP, Soares-da-Silva P. Blood pressure decrease in spontaneously hypertensive rats following renal denervation or dopamine β-hydroxylase inhibition with etamicastat. Hypertens Res. 2015;38:605–12.  https://doi.org/10.1038/hr.2015.50.CrossRefPubMedGoogle Scholar
  64. 64.
    •• Almeida L, Nunes T, Costa R, Rocha JF, Vaz-da-Silva M, Soares-da-Silva P. Etamicastat, a novel dopamine β-hydroxylase inhibitor: tolerability, pharmacokinetics, and pharmacodynamics in patients with hypertension. Clin Ther. 2013.  https://doi.org/10.1016/j.clinthera.2013.10.012 Phase I trial of a novel class of medications inhibiting the peripheral conversion of dopamine to noradrenaline.CrossRefGoogle Scholar
  65. 65.
    • Igreja B, Pires NM, Wright LC, Soares-da-Silva P. Effects of zamicastat treatment in a genetic model of salt-sensitive hypertension and heart failure. Eur J Pharmacol. 2019.  https://doi.org/10.1016/j.ejphar.2018.10.030 Preclinical study of the newest iteration of dopamine B-hydoxylase inhibitors. Previous versions were well tolerated in phase I trials and represent a new class of medications for the treatment of hypertension. CrossRefGoogle Scholar
  66. 66.
    Bial-Portela, C S.A. Safety, tolerability, pharmacokinetics and pharmacodynamics of BIA 5-1058. In: ClinicalTrials.gov. 2018. https://clinicaltrials.gov/ct2/show/NCT03708146. Accessed 24 Feb 2019.
  67. 67.
    Tani S, Kushiro T, Takahashi A, Kawamata H, Ohkubo K, Nagao K, et al. Antihypertensive efficacy of the direct renin inhibitor Aliskiren as add-on therapy in patients with poorly controlled hypertension. Intern Med. 2016;55:427–35.CrossRefGoogle Scholar
  68. 68.
    McMurray JJV, Krum H, Abraham WT, et al. Aliskiren, Enalapril, or Aliskiren and Enalapril in heart failure. N Engl J Med. 2016;374:1521–32.  https://doi.org/10.1056/NEJMoa1514859.CrossRefPubMedGoogle Scholar
  69. 69.
    Parving H-H, Brenner BM, McMurray JJV, et al. Cardiorenal end points in a trial of Aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204–13.  https://doi.org/10.1056/NEJMoa1208799.CrossRefPubMedGoogle Scholar
  70. 70.
    Zheng SL, Roddick AJ, Ayis S. Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes and cardiovascular disease or risk: a systematic review and meta-analysis of 13,395 patients. Diab Vasc Dis Res. 2017.  https://doi.org/10.1177/1479164117715854.CrossRefGoogle Scholar
  71. 71.
    Fu S, Wen X, Han F, Long Y, Xu G. Aliskiren therapy in hypertension and cardiovascular disease : a systematic review and a meta-analysis. Oncotarget. 2017;8:89364–74.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Kristensen SL, Mogensen UM, Tarnesby G, et al. Aliskiren alone or in combination with enalapril vs. enalapril among patients with chronic heart failure with and without diabetes: a subgroup analysis from the ATMOSPHERE trial. Eur J Heart Fail. 2018.  https://doi.org/10.1002/ejhf.896.CrossRefGoogle Scholar
  73. 73.
    Jia Y, Jia G. Role of intestinal Na + / H + exchanger inhibition in the prevention of cardiovascular and kidney disease. Ann Transl Med. 2015;3:2–4.Google Scholar
  74. 74.
    Spencer AG, Labonte ED, Rosenbaum DP, et al. Intestinal inhibition of the Na + / H + exchanger 3 prevents cardiorenal damage in rats and inhibits Na + uptake in humans. Sci Transl Med. 2014;6:1–12.CrossRefGoogle Scholar
  75. 75.
    Rosenbaum DP. Pharmacodynamics, safety, and tolerability of the NHE3 inhibitor tenapanor: two trials in healthy volunteers. Clin Drug Investig. 2018;38:341–51.  https://doi.org/10.1007/s40261-017-0614-0.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Ardelyx. A 26-week study to evaluate the efficacy and safety of tenapanor in IBS-C (T3MPO-2). 2018. https://www.clinicaltrials.gov/ct2/show/NCT02686138?term=A+26-week+study+to+evaluate+the+efficacy+and+safety+of++tenapanor+in+IBS-C+%28T3MPO-2%29.&rank=1. NCT02686138. Accessed 24 Feb 2018
  77. 77.
    Linz B, Hohl M, Reil JC, Böhm M, Linz D. Inhibition of NHE3-mediated sodium absorption in the gut reduced cardiac end-organ damage without deteriorating renal function in obese spontaneously hypertensive rats. J Cardiovasc Pharmacol. 2016;67:225–31.  https://doi.org/10.1097/FJC.0000000000000336.CrossRefPubMedGoogle Scholar
  78. 78.
    Wright JW, Mizutani S, Harding JW. Focus on brain angiotensin III and aminopeptidase A in the control of hypertension. 2012. doi:  https://doi.org/10.1155/2012/124758.CrossRefGoogle Scholar
  79. 79.
    Fournie-Zaluski M-C, Fassot C, Valentin B, Djordjijevic D, Reaux-Le Goazigo A, Corvol P, et al. Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension. Proc Natl Acad Sci. 2004;101:7775–80.  https://doi.org/10.1073/pnas.0402312101.CrossRefPubMedGoogle Scholar
  80. 80.
    Marc Y, Gao J, Balavoine F, Michaud A, Roques BP, Llorens-cortes C. Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats. Hypertension. 2012.  https://doi.org/10.1161/HYPERTENSIONAHA.112.190942.CrossRefGoogle Scholar
  81. 81.
    •• Balavoine F, Azizi M, Bergerot D, De Mota N, Patouret R, Roques BP, et al. Randomised, double-blind, placebo-controlled, dose-escalating phase i study of qgc001, a centrally acting aminopeptidase a inhibitor prodrug. Clin Pharmacokinet. 2014.  https://doi.org/10.1007/s40262-013-0125-y Sucessful phase I trial of a centrally acting inhibitor of aminopeptidase A and thereby the production of angiotensin III. This demonstrates the role of the renin-angiotensin aldosterone cacasde within the central nervous system. CrossRefGoogle Scholar
  82. 82.
    SA QG. Phase IIa study of the product QGC001 compared with placebo in patients with essential hypertension (2QG1). ClinicalTrials.gov. 2016. Accessed 24 Feb 2019.
  83. 83.
    Marc Y, Hmazzou R, Balavoine F, Flahault A, Llorens-Cortes C. Central antihypertensive effects of chronic treatment with RB150: an orally active aminopeptidase A inhibitor in deoxycorticosterone acetate-salt rats. J Hypertens. 2018;36:641–50.  https://doi.org/10.1097/HJH.0000000000001563.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Merrill H. Stewart
    • 1
    Email author
  • Carl J. Lavie
    • 1
  • Hector O. Ventura
    • 1
  1. 1.John Ochsner Heart and Vascular Institute, Ochsner Clinical SchoolThe University of Queensland School of MedicineNew OrleansUSA

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