Advertisement

New Molecules for Treating Resistant Hypertension: a Clinical Perspective

  • Omar Azzam
  • Marcio G. Kiuchi
  • Jan K. Ho
  • Vance B. Matthews
  • Leslie Marisol Lugo Gavidia
  • Janis M. Nolde
  • Revathy Carnagarin
  • Markus P. SchlaichEmail author
Resistant Hypertension (L Drager, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Resistant Hypertension

Abstract

Purpose of Review

To review the findings of trials evaluating pharmacological treatment approaches for hypertension in general, and resistant hypertension (RH) in particular, and propose future research and clinical directions.

Recent Findings

RH is defined as blood pressure (BP) that remains above target levels despite adherence to at least three antihypertensive medications, including a diuretic. Thus far, clinical trials of pharmacological approaches in RH have focused on older molecules, with spironolactone being demonstrated as the most efficacious fourth-line agent. However, the use of spironolactone in clinical practice is hampered by its side effect profile and the risk of hyperkalaemia in important RH subgroups, such as patients with moderate-severe chronic kidney disease (CKD). Clinical trials of new molecules targeting both well-established and more recently elucidated pathophysiologic mechanisms of hypertension offer a multitude of potential treatment avenues that warrant further evaluation in the context of RH. These include selective mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), activators of the counterregulatory renin-angiotensin-system (RAS), vaccines, neprilysin inhibitors alone and in combined formulations, natriuretic peptide receptor agonists A (NPRA-A) agonists, vasoactive intestinal peptide (VIP) agonists, centrally acting aminopeptidase A (APA|) inhibitors, antimicrobial suppression of central sympathetic outflow (minocycline), dopamine β-hydroxylase (DβH) inhibitors and Na+/H+ Exchanger 3 (NHE3) inhibitors.

Summary

There is a paucity of data from trials evaluating newer molecules for the treatment of RH. Emergent novel molecules for non-resistant forms of hypertension heighten the prospects of identifying new, effective and well-tolerated pharmacological approaches to RH. There is a glaring need to undertake RH-focused trials evaluating their efficacy and clinical applicability.

Keywords

Blood pressure Hypertension Resistant hypertension Treatment Sympathetic nervous system Chronic kidney disease 

Notes

Compliance with Ethics Guidelines

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.
    Gifford RW Jr. Resistant hypertension. Introduction and definitions. Hypertension. 1988;11(3 Pt 2):II65–6.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51(6):1403–19.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507–20.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Brambilla G, Bombelli M, Seravalle G, Cifkova R, Laurent S, Narkiewicz K, et al. Prevalence and clinical characteristics of patients with true resistant hypertension in central and Eastern Europe: data from the BP-CARE study. J Hypertens. 2013;31(10):2018–24.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. 2011;57(6):1076–80.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635–42.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Sim JJ, Bhandari SK, Shi J, Reynolds K, Calhoun DA, Kalantar-Zadeh K, et al. Comparative risk of renal, cardiovascular, and mortality outcomes in controlled, uncontrolled resistant, and nonresistant hypertension. Kidney Int. 2015;88(3):622–32.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    de la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57(5):898–902.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903–13.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Oliva RV, Bakris GL. Sympathetic activation in resistant hypertension: theory and therapy. Semin Nephrol. 2014;34(5):550–9.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Putnam K, Shoemaker R, Yiannikouris F, Cassis LA. The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am J Physiol Heart Circ Physiol. 2012;302(6):H1219–30.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Sim JJ, Bhandari SK, Shi J, Liu ILA, Calhoun DA, McGlynn EA, et al. Characteristics of resistant hypertension in a large, ethnically diverse hypertension population of an integrated health system. Mayo Clin Proc. 2013;88(10):1099–107.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Irvin MR, Booth JN III, Shimbo D, Lackland DT, Oparil S, Howard G, et al. Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality. J Am Soc Hypertens. 2014;8(6):405–13.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Muntner P, Davis BR, Cushman WC, Bangalore S, Calhoun DA, Pressel SL, et al. Treatment-resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2014;64(5):1012–21.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Acharya T, Tringali S, Singh M, Huang J. Resistant hypertension and associated comorbidities in a veterans affairs population. J Clin Hypertens (Greenwich). 2014;16(10):741–5.CrossRefGoogle Scholar
  16. 16.
    Whelton PK, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and Management of High Blood Pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Hypertension. 2018;71(6):1269–324.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 2015;116(6):1074–95.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Freeman AJ, Vinh A, Widdop RE. Novel approaches for treating hypertension. F1000Res. 2017;6:80.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    PhRMA. 2018 Report: medicines in development for heart disease and stroke 2018 drug list. Available from: http://phrma-docs.phrma.org/files/dmfile/2018_Heart-Disease-and-Stroke_MID-Drug-List.pdf. Accessed 9 Jun 2019.
  20. 20.
    Ubaid-Girioli S, de Souza LA, Yugar-Toledo JC, Cláudio Martins L, Ferreira-Melo S, Rizzi Coelho O, et al. Aldosterone excess or escape: treating resistant hypertension. J Clin Hypertens (Greenwich). 2009;11(5):245–52.CrossRefGoogle Scholar
  21. 21.
    Yugar-Toledo JC, Modolo R, de Faria AP, Moreno H. Managing resistant hypertension: focus on mineralocorticoid-receptor antagonists. Vasc Health Risk Manag. 2017;13:403–11.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Cranston WI, Juel-Jensen BE. The effects of spironolactone and chlorthalidone on arterial pressure. Lancet. 1962;1(7240):1161–4.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059–68.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Krieger EM, Drager LF, Giorgi DMA, Pereira AC, Barreto-Filho JAS, Nogueira AR, et al. Spironolactone versus clonidine as a fourth-drug therapy for resistant hypertension: the ReHOT randomized study (resistant hypertension optimal treatment). Hypertension. 2018;71(4):681–90.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Corvol P, et al. Antiandrogenic effect of spirolactones: mechanism of action. Endocrinology. 1975;97(1):52–8.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Chapman N, Dobson J, Wilson S, Dahlöf B̈, Sever PS, Wedel H, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007;49(4):839–45.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med. 1999;341(10):709–17.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351(6):543–51.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Witham MD, Gillespie ND, Struthers AD. Hyperkalemia after the publication of RALES. N Engl J Med. 2004;351(23):2448–50 author reply 2448-50.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    De Nicola L, et al. Burden of resistant hypertension in hypertensive patients with non-dialysis chronic kidney disease. Kidney Blood Press Res. 2011;34(1):58–67.PubMedCrossRefGoogle Scholar
  31. 31.
    Tanner RM, Calhoun DA, Bell EK, Bowling CB, Gutiérrez OM, Irvin MR, et al. Prevalence of apparent treatment-resistant hypertension among individuals with CKD. Clin J Am Soc Nephrol. 2013;8(9):1583–90.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Wolley MJ, Stowasser M. Resistant hypertension and chronic kidney disease: a dangerous liaison. Curr Hypertens Rep. 2016;18(5):36.PubMedCrossRefGoogle Scholar
  33. 33.
    Fagart J, Hillisch A, Huyet J, Bärfacker L, Fay M, Pleiss U, et al. A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule. J Biol Chem. 2010;285(39):29932–40.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Bramlage P, Swift SL, Thoenes M, Minguet J, Ferrero C, Schmieder RE. Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. Eur J Heart Fail. 2016;18(1):28–37.PubMedCrossRefGoogle Scholar
  35. 35.
    Kolkhof P, Delbeck M, Kretschmer A, Steinke W, Hartmann E, Bärfacker L, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64(1):69–78.PubMedCrossRefGoogle Scholar
  36. 36.
    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):2453–63.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884–94.PubMedCrossRefGoogle Scholar
  38. 38.
    Filippatos G, Anker SD, Böhm M, Gheorghiade M, Køber L, Krum H, 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;37(27):2105–14.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Gomez-Sanchez EP, Gomez-Sanchez CE. Central regulation of blood pressure by the mineralocorticoid receptor. Mol Cell Endocrinol. 2012;350(2):289–98.PubMedCrossRefGoogle Scholar
  40. 40.
    Cp, C., et al. Preclinical development of KBP-5074, a novel non-steroidal mineralocorticoid receptor antagonist for the treatment of cardiorenal Diseases. 2018 [cited 4; Available from: https://sciforschenonline.org/journals/drug/article-data/JDRD-4-143/JDRD-4-143.pdf.
  41. 41.
    Pharmacological profile of KBP-5074, a novel non-steroidal, highly selective, mineralocorticoid receptor antagonist (MRA) for the treatment of cardiorenal diseases. Am J Kidney Dis, 2016. 67(5): p. A118.Google Scholar
  42. 42.
    • Connaire, J., et al. Safety, tolerability, and pharmacokinetics of the selective mineralocorticoid receptor antagonist KBP-5074 in hemodialysis and non-hemodialysis patients with severe CKD. 2017; Available from: https://www.asn-online.org/education/kidneyweek/2017/program-abstract.aspx?controlId=2782138. Accessed 9 Jun 2019. The safety data in this study encourages more advanced phase trials of MRA KBP-5074 in the CKD subgroup of patients with RH.
  43. 43.
    •• Carey RM, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72(5):e53–90 Comprehensive evidence-based guidance on on evaluation and management of RH. PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chai W, Danser AH. Why are mineralocorticoid receptor antagonists cardioprotective? Naunyn Schmiedeberg's Arch Pharmacol. 2006;374(3):153–62.CrossRefGoogle Scholar
  45. 45.
    Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006;47(3):312–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Colussi G, Catena C, Sechi LA. Spironolactone, eplerenone and the new aldosterone blockers in endocrine and primary hypertension. J Hypertens. 2013;31(1):3–15.PubMedCrossRefGoogle Scholar
  47. 47.
    Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation. 2011;124(18):1945–55.PubMedCrossRefGoogle Scholar
  48. 48.
    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;15(3):186–92.CrossRefGoogle Scholar
  49. 49.
    • Bogman K, et al. Preclinical and early clinical profile of a highly selective and potent oral inhibitor of aldosterone synthase (CYP11B2). Hypertension. 2017;69(1):189–96 ASI which selectively suppresses aldosterone production but spares cortisol production. PubMedCrossRefGoogle Scholar
  50. 50.
    • Sloan-Lancaster J, et al. LY3045697: results from two randomized clinical trials of a novel inhibitor of aldosterone synthase. J Renin-Angiotensin-Aldosterone Syst. 2017;18(3):1470320317717883 Another ASI demonstrating selectivity and worth evaluating in hypertension trials. PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–60.PubMedCrossRefGoogle Scholar
  53. 53.
    Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Yusuf S, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59.PubMedCrossRefGoogle Scholar
  55. 55.
    Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892–903.PubMedCrossRefGoogle Scholar
  56. 56.
    Parving HH, Brenner BM, McMurray JJV, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–13.PubMedCrossRefGoogle Scholar
  57. 57.
    • Ionis Pharmaceuticals. In: Our antisense-powered pipeline. 2019; Available from: https://www.ionispharma.com/ionis-innovation/pipeline/. Accessed 9 Jun 2019. One of several molecules developed in this innovative antisense technology that undergoing multiple simultaneous trials to address a broad range of diseases. Watch the space.
  58. 58.
    Hoogwerf BJ. Renin-angiotensin system blockade and cardiovascular and renal protection. Am J Cardiol. 2010;105(1 Suppl):30A–5A.PubMedCrossRefGoogle Scholar
  59. 59.
    Donoghue M, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87(5):E1–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Keidar S, Kaplan M, Gamliel-Lazarovich A. ACE2 of the heart: from angiotensin I to angiotensin (1-7). Cardiovasc Res. 2007;73(3):463–9.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res. 2016;118(8):1313–26.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Yamazato M, Yamazato Y, Sun C, Diez-Freire C, Raizada MK. Overexpression of angiotensin-converting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats. Hypertension. 2007;49(4):926–31.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Rentzsch B, Todiras M, Iliescu R, Popova E, Campos LA, Oliveira ML, et al. Transgenic angiotensin-converting enzyme 2 overexpression in vessels of SHRSP rats reduces blood pressure and improves endothelial function. Hypertension. 2008;52(5):967–73.PubMedCrossRefGoogle Scholar
  64. 64.
    Ye M, Wysocki J, Gonzalez-Pacheco FR, Salem M, Evora K, Garcia-Halpin L, et al. Murine recombinant angiotensin-converting enzyme 2: effect on angiotensin II-dependent hypertension and distinctive angiotensin-converting enzyme 2 inhibitor characteristics on rodent and human angiotensin-converting enzyme 2. Hypertension. 2012;60(3):730–40.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Lo J, Patel VB, Wang Z, Levasseur J, Kaufman S, Penninger JM, et al. Angiotensin-converting enzyme 2 antagonizes angiotensin II-induced pressor response and NADPH oxidase activation in Wistar-Kyoto rats and spontaneously hypertensive rats. Exp Physiol. 2013;98(1):109–22.PubMedCrossRefGoogle Scholar
  66. 66.
    • Liu P, et al. Novel ACE2-Fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation. Kidney Int. 2018;94(1):114–25 Encouraging Preclinical Findings.PubMedCrossRefGoogle Scholar
  67. 67.
    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(9):783–92.PubMedCrossRefGoogle Scholar
  68. 68.
    Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Hemnes AR, et al. A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J. 2018;51(6).  https://doi.org/10.1183/13993003.02638-2017.PubMedCrossRefGoogle Scholar
  70. 70.
    Kluskens LD, Nelemans SA, Rink R, de Vries L, Meter-Arkema A, Wang Y, et al. Angiotensin-(1-7) with thioether bridge: an angiotensin-converting enzyme-resistant, potent angiotensin-(1-7) analog. J Pharmacol Exp Ther. 2009;328(3):849–54.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Marques FD, et al. Beneficial effects of long-term administration of an oral formulation of angiotensin-(1-7) in infarcted rats. Int J Hypertens. 2012;2012:795452.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Koenen J, et al. Abstract P309: safety, tolerability and pharmacokinetic data of the novel orally active formulation of angiotensin- (1-7), Hydroxypropyl-β-cyclodextrin/ Ang- (1-7), in healthy volunteers- a randomized double-blinded controlled pilot study. Hypertension. 2016;68(suppl_1):AP309–9.Google Scholar
  73. 73.
    Singh Y, Singh K, Sharma PL. Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA-salt-induced hypertension in rats. Mol Cell Biochem. 2013;373(1–2):189–94.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Savergnini SQ, Ianzer D, Carvalho MBL, Ferreira AJ, Silva GAB, Marques FD, et al. The novel Mas agonist, CGEN-856S, attenuates isoproterenol-induced cardiac remodeling and myocardial infarction injury in rats. PLoS One. 2013;8(3):e57757.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Jankowski V, Vanholder R, van der Giet M, Tölle M, Karadogan S, Gobom J, et al. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol. 2007;27(2):297–302.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013;112(8):1104–11.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    • Liu C, et al. Alamandine attenuates hypertension and cardiac hypertrophy in hypertensive rats. Amino Acids. 2018;50(8):1071–81 Encouraging preclinical findings. PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    de Souza-Neto FP, Silva MM, Santuchi MC, de Alcântara-Leonídio TC, Motta-Santos D, Oliveira AC, et al. Alamandine attenuates arterial remodelling induced by transverse aortic constriction in mice. Clin Sci (Lond). 2019;133(5):629–43.CrossRefGoogle Scholar
  79. 79.
    Steckelings UM, Paulis L, Unger T, Bader M. Emerging drugs which target the renin-angiotensin-aldosterone system. Expert Opin Emerg Drugs. 2011;16(4):619–30.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Foulquier S, Steckelings UM, Unger T. Impact of the AT(2) receptor agonist C21 on blood pressure and beyond. Curr Hypertens Rep. 2012;14(5):403–9.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    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(24):5995–6008.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Ali Q, Patel S, Hussain T. Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats. Am J Physiol Ren Physiol. 2015;308(12):F1379–85.CrossRefGoogle Scholar
  83. 83.
    • Steckelings U, Lindblad L, Leisvuori A, Lovro Z, Vainio P, Graens J, et al. [PP.02.17] successful completion of a pHASE I, randomized, double-blind, placebo controlled, single ascending dose trial for the first in class angiotensin AT2-receptor agonist compound 21. J Hypertens. 2017;35:e105–6.CrossRefGoogle Scholar
  84. 84.
    Steckelings UM, Paulis L, Namsolleck P, Unger T. AT2 receptor agonists: hypertension and beyond. Curr Opin Nephrol Hypertens. 2012;21(2):142–6.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Pandey KN. Biology of natriuretic peptides and their receptors. Peptides. 2005;26(6):901–32.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Nakagami H, Morishita R. Therapeutic vaccines for hypertension: a new option for clinical practice. Curr Hypertens Rep. 2018;20(3):22.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Tissot AC, Maurer P, Nussberger J, Sabat R, Pfister T, Ignatenko S, et al. Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet. 2008;371(9615):821–7.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Business Wire. 2018. Resistant Hypertension Drug Development Pipeline Study, H1 2018 - ResearchAndMarkets.com. 9 June 2019]; Available from: https://www.businesswire.com/news/home/20180612006405/en/Resistant-Hypertension-Drug-Development-Pipeline-Study-H1. Accessed 10 Jun 2019.
  89. 89.
    Brown MJ. Success and failure of vaccines against renin-angiotensin system components. Nat Rev Cardiol. 2009;6(10):639–47.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Chen X, Qiu Z, Yang S, Ding D, Chen F, Zhou Y, et al. Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals. Hypertension. 2013;61(2):408–16.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Li LD, Tian M, Liao YH, Zhou ZH, Wei F, Zhu F, et al. Effect of active immunization against angiotensin II type 1 (AT1) receptor on hypertension & arterial remodelling in spontaneously hypertensive rats (SHR). Indian J Med Res. 2014;139(4):619–24.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Corti R, Burnett Jr JC, Rouleau JL, Ruschitzka F, Lüscher TF. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation. 2001;104(15):1856–62.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Richards AM, Wittert GA, Crozier IG, Espiner EA, Yandle TG, Ikram H, et al. Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II. J Hypertens. 1993;11(4):407–16.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Kostis JB, et al. Omapatrilat and enalapril in patients with hypertension: the omapatrilat cardiovascular treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103–11.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Weber MA. Vasopeptidase inhibitors. Lancet. 2001;358(9292):1525–32.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Sagnella GA. Vasopeptidase inhibitors. J Renin-Angiotensin-Aldosterone Syst. 2002;3(2):90–5.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    •• Yi BA, et al. Abstract 12892: safety and efficacy of LHW090 in patients with resistant hypertension: results of a randomized, double blind, parallel group, placebo-controlled study. Circulation. 2018;138(Suppl_1):A12892-A12892 Very encouraging findings which warrant a phase III trial. Google Scholar
  98. 98.
    Packer M, Califf RM, Konstam MA, Krum H, McMurray J, Rouleau JL, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE). Circulation. 2002;106(8):920–6.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Coats AJ. Omapatrilat--the story of overture and octave. Int J Cardiol. 2002;86(1):1–4.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    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(9722):1255–66.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    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(4):698–705.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387–95.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    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 (Greenwich). 2016;18(4):308–14.CrossRefGoogle Scholar
  105. 105.
    Dhaun N, Goddard J, Kohan DE, Pollock DM, Schiffrin EL, Webb DJ. Role of endothelin-1 in clinical hypertension: 20 years on. Hypertension. 2008;52(3):452–9.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Tikkanen I, Tikkanen T, Cao Z, Allen TJ, Davis BJ, Lassila M, et al. Combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes. J Hypertens. 2002;20(4):707–14.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Parvanova A, van der Meer IM, Iliev I, Perna A, Gaspari F, Trevisan R, et al. Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2013;1(1):19–27.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Feldstein C, Romero C. Role of endothelins in hypertension. Am J Ther. 2007;14(2):147–53.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Black HR, Bakris GL, Weber MA, Weiss R, Shahawy ME, Marple R, et al. Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study. J Clin Hypertens (Greenwich). 2007;9(10):760–9.CrossRefGoogle Scholar
  110. 110.
    Weber MA, Black H, Bakris G, Krum H, Linas S, Weiss R, et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9699):1423–31.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019;393(10184):1937–47.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Sica D, Jordan R, Fischkoff SA. Phase IIa study of the NPR-A agonist, PL-3994, in healthy adult volunteers with controlled hypertension. J Card Fail. 2009;15(6):S67.CrossRefGoogle Scholar
  113. 113.
    Chen Y, Huntley BK, Iyer SR, Sangaralingham JS, Burnett JC Jr. ZD100: a novel pGC-A activator for the treatment of resistant hypertension: in vitro resistance to neprilysin degradation. J Am Soc Hypertens. 2016;10(4):e22–3.CrossRefGoogle Scholar
  114. 114.
    Frase LL, Gaffney FA, Lane LD, Buckey JC, Said SI, Blomqvist CG, et al. Cardiovascular effects of vasoactive intestinal peptide in healthy subjects. Am J Cardiol. 1987;60(16):1356–61.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    PhaseBio Pharmaceuticals Inc. 2015. PB1046 (Vasomera™) in: clinical development pipeline. Available from: http://phasebio.com/clinical-development-pipeline/vasomera/. Accessed 5 Jun 2019.
  116. 116.
    Gao J, Marc Y, Iturrioz X, Leroux V, Balavoine F, Llorens-Cortes C. A new strategy for treating hypertension by blocking the activity of the brain renin-angiotensin system with aminopeptidase A inhibitors. Clin Sci (Lond). 2014;127(3):135–48.CrossRefGoogle Scholar
  117. 117.
    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;53(4):385–95.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Ferdinand KC, et al. Efficacy and safety of firibastat, a first-in-class brain aminopeptidase a inhibitor, in hypertensive overweight patients of multiple ethnic origins a phase 2, open-label, multicenter, dose-titrating study. Circulation. 2019.Google Scholar
  119. 119.
    •• Azizi M, et al. A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension. J Hypertens. 2019;37(8):1722-1728. The results of this study justify a larger powered trial to assess safety and efficacy in hypertension. PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Bautista LE, Vera LM, Arenas IA, Gamarra G. Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. J Hum Hypertens. 2005;19(2):149–54.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Zubcevic J, et al. Functional neural-bone marrow pathways: implications in hypertension and cardiovascular disease. Hypertension. 2014;63(6):e129–39.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Singh MV, Chapleau MW, Harwani SC, Abboud FM. The immune system and hypertension. Immunol Res. 2014;59(1–3):243–53.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Jun JY, Zubcevic J, Qi Y, Afzal A, Carvajal JM, Thinschmidt JS, et al. Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension. Hypertension. 2012;60(5):1316–23.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Zubcevic J, Jun JY, Kim S, Perez PD, Afzal A, Shan Z, et al. Altered inflammatory response is associated with an impaired autonomic input to the bone marrow in the spontaneously hypertensive rat. Hypertension. 2014;63(3):542–50.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, et al. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487(7407):325–9.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Yellowlees Douglas J, Bhatwadekar AD, Li Calzi S, Shaw LC, Carnegie D, Caballero S, et al. Bone marrow-CNS connections: implications in the pathogenesis of diabetic retinopathy. Prog Retin Eye Res. 2012;31(5):481–94.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Beliaev A, Learmonth DA, Soares-da-Silva P. Synthesis and biological evaluation of novel, peripherally selective chromanyl imidazolethione-based inhibitors of dopamine beta-hydroxylase. J Med Chem. 2006;49(3):1191–7.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    • Igreja B, et al. Blood pressure-decreasing effect of etamicastat alone and in combination with antihypertensive drugs in the spontaneously hypertensive rat. Hypertens Res. 2015;38(1):30–8 Promising preclinical findings worth evaluating in clinical trials as both monotherapy and as an add-on therapy, including in RH. PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    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 beta-hydroxylase inhibition with etamicastat. Hypertens Res. 2015;38(9):605–12.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Nunes T, et al. Safety, tolerability, and pharmacokinetics of etamicastat, a novel dopamine-beta-hydroxylase inhibitor, in a rising multiple-dose study in young healthy subjects. Drugs R D. 2010;10(4):225–42.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Almeida L, Nunes T, Costa R, Rocha JF, Vaz-da-Silva M, Soares-da-Silva P. Etamicastat, a novel dopamine beta-hydroxylase inhibitor: tolerability, pharmacokinetics, and pharmacodynamics in patients with hypertension. Clin Ther. 2013;35(12):1983–96.PubMedCrossRefGoogle Scholar
  133. 133.
    Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks FM, et al. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension. 2006;47(2):296–308.PubMedCrossRefGoogle Scholar
  134. 134.
    Linz D, Wirth K, Linz W, Heuer HOO, Frick W, Hofmeister A, et al. Antihypertensive and laxative effects by pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut. Hypertension. 2012;60(6):1560–7.PubMedCrossRefGoogle Scholar
  135. 135.
    Rosenbaum DP, Yan A, Jacobs JW. Pharmacodynamics, safety, and tolerability of the NHE3 inhibitor tenapanor: two trials in healthy volunteers. Clin Drug Investig. 2018;38(4):341–51.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Singer DR, Markandu ND, Sugden AL, Miller MA, MacGregor GA. Sodium restriction in hypertensive patients treated with a converting enzyme inhibitor and a thiazide. Hypertension. 1991;17(6 Pt 1):798–803.PubMedGoogle Scholar
  137. 137.
    Lobo MD, Sobotka PA, Dolan E, Witkowski A, Schmieder RE. Central arteriovenous anastomosis and hypertension - authors' reply. Lancet. 2015;386(10006):1821–2.PubMedCrossRefGoogle Scholar
  138. 138.
    Lobo MD, Ott C, Sobotka PA, Saxena M, Stanton A, Cockcroft JR, et al. Central iliac arteriovenous anastomosis for uncontrolled hypertension: one-year results from the ROX CONTROL HTN trial. Hypertension. 2017;70(6):1099–105.PubMedCrossRefGoogle Scholar
  139. 139.
    Schlaich MP, Azzam O, Sata Y. Hypertension on the ROX: durable blood pressure lowering with central iliac arteriovenous anastomosis. Hypertension. 2017;70(6):1084–6.PubMedCrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Omar Azzam
    • 1
    • 2
  • Marcio G. Kiuchi
    • 2
  • Jan K. Ho
    • 2
  • Vance B. Matthews
    • 2
  • Leslie Marisol Lugo Gavidia
    • 2
  • Janis M. Nolde
    • 2
  • Revathy Carnagarin
    • 2
  • Markus P. Schlaich
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Internal MedicineRoyal Perth HospitalPerthAustralia
  2. 2.Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research FoundationUniversity of Western AustraliaPerthAustralia
  3. 3.Departments of Cardiology and NephrologyRoyal Perth HospitalPerthAustralia
  4. 4.Neurovascular Hypertension & Kidney Disease LaboratoryBaker Heart and Diabetes InstituteMelbourneAustralia

Personalised recommendations