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Novel Medical Treatments for Hypertension and Related Comorbidities

  • Jared Davis
  • Suzanne Oparil
Novel Treatments for Hypertension (T Unger, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Novel Treatments for Hypertension

Abstract

Purpose of Review

The purpose of this review is to summarize the most recent data available on advances in development of novel medical treatments for hypertension and related comorbidities.

Recent Findings

Approximately half of all hypertensive patients have not achieved goal blood pressure with current available antihypertensive medications. Recent landmark studies and new hypertension guidelines have called for stricter blood pressure control, creating a need for better strategies for lowering blood pressure. This has led to a shift in focus, in recent years, to the development of combination pills as a means of achieving improved blood pressure control by increasing adherence to prescribed medications along with further research and development of promising novel drugs based on discovery of new molecular targets such as the counter-regulatory renin-angiotensin system.

Summary

Fixed-dose combination pills and novel treatments based on recently discovered pathogenic mechanisms of hypertension that have demonstrated promising results as treatments for hypertension and related comorbidities will be discussed in this review.

Keywords

Hypertension Blood pressure Novel treatments Medications 

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.
    Saklayen MG, Deshpande NV. Timeline of history of hypertension treatment. Front Cardiovasc Med. 2016;3:3.  https://doi.org/10.3389/fcvm.2016.00003.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Administration USDoHaHSFaD. Approved drug products with therapeutic equivalence evaluations (orange book). 38 ed. 2018.Google Scholar
  3. 3.
    •• Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 2015;116(6):1074–95.  https://doi.org/10.1161/CIRCRESAHA.116.303603. This comprehensive review of novel hypertension treatments published in 2015 serves as the basis for our paper outlining updates of these novel treatments.CrossRefPubMedGoogle Scholar
  4. 4.
    •• Group SR, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of Intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103–16.  https://doi.org/10.1056/NEJMoa1511939. The SPRINT trial has provided important new evidence to inform the most recent hypertension guidelines, which recommend lower BP goals in hypertensive patients.CrossRefGoogle Scholar
  5. 5.
    •• Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 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. 2017;  https://doi.org/10.1161/HYP.0000000000000066. The most recent hypertension guidelines in the US which has lowered the target for BP treatment and has lowered the BP threshold for the diagnosis of hypertension.CrossRefPubMedGoogle Scholar
  6. 6.
    Nerenberg KA, Zarnke KB, Leung AA, Dasgupta K, Butalia S, McBrien K, et al. Hypertension Canada's 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children. Can J Cardiol. 2018;34(5):506–25.  https://doi.org/10.1016/j.cjca.2018.02.022.CrossRefPubMedGoogle Scholar
  7. 7.
    Gabb GM, Mangoni AA, Arnolda L. Guideline for the diagnosis and management of hypertension in adults - 2016. Med J Aust. 2017;206(3):141.CrossRefPubMedGoogle Scholar
  8. 8.
    Stiles S. New European HTN Guidelines hit hard with initial therapy, keep 'normal high' label. 2018. https://www.medscape.com/viewarticle/897895.
  9. 9.
    Li YT, Wang HH, Liu KQ, Lee GK, Chan WM, Griffiths SM, et al. Medication adherence and blood pressure control among hypertensive patients with coexisting long-term conditions in primary care settings: a cross-sectional analysis. Medicine (Baltimore). 2016;95(20):e3572.  https://doi.org/10.1097/MD.0000000000003572.CrossRefGoogle Scholar
  10. 10.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation. 2014;129(3):399–410.  https://doi.org/10.1161/01.cir.0000442015.53336.12.CrossRefPubMedGoogle Scholar
  11. 11.
    Neiman AB, Ruppar T, Ho M, Garber L, Weidle PJ, Hong Y, et al. CDC Grand Rounds: Improving Medication Adherence for Chronic Disease Management - Innovations and Opportunities. MMWR Morb Mortal Wkly Rep. 2017;66(45):1248–51.  https://doi.org/10.15585/mmwr.mm6645a2.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Health NIo. ClinicalTrials.gov. National Institutes of Health, Washington D.C. 2018. https://clinicaltrials.gov/. Accessed 4 Apr 2018.
  13. 13.
    Toth K, Investigators P. Antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: results of the PIANIST study (perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients). Am J Cardiovasc Drugs. 2014;14(2):137–45.  https://doi.org/10.1007/s40256-014-0067-2.CrossRefPubMedGoogle Scholar
  14. 14.
    Mazza A, Lenti S, Schiavon L, Sacco AP, Dell'Avvocata F, Rigatelli G, et al. Fixed-dose triple combination of antihypertensive drugs improves blood pressure control: from clinical trials to clinical practice. Adv Ther. 2017;34(4):975–85.  https://doi.org/10.1007/s12325-017-0511-1.CrossRefPubMedGoogle Scholar
  15. 15.
    Marazzi G, Pelliccia F, Campolongo G, Cacciotti L, Massaro R, Poggi S, et al. Greater cardiovascular risk reduction with once-daily fixed combination of three antihypertensive agents and statin versus free-drug combination: the ALL-IN-ONE trial. Int J Cardiol. 2016;222:885–7.  https://doi.org/10.1016/j.ijcard.2016.07.163.CrossRefPubMedGoogle Scholar
  16. 16.
    Arif AF, Kadam GG, Joshi C. Treatment of hypertension: postmarketing surveillance study results of telmisartan monotherapy, fixed dose combination of telmisartan + hydrochlorothiazide/amlodipine. J Indian Med Assoc. 2009;107(10):730–3.PubMedGoogle Scholar
  17. 17.
    Sung KC, Oh YS, Cha DH, Hong SJ, Won KH, Yoo KD, et al. Efficacy and tolerability of telmisartan/amlodipine + hydrochlorothiazide versus telmisartan/amlodipine combination therapy for essential hypertension uncontrolled with telmisartan/amlodipine: the phase III, multicenter, randomized, Double-blind TAHYTI Study. Clin Ther. 2018;40(1):50–63 e3.  https://doi.org/10.1016/j.clinthera.2017.11.006.CrossRefPubMedGoogle Scholar
  18. 18.
    Higaki J, Komuro I, Shiki K, Lee G, Taniguchi A, Ikeda H, et al. Effect of hydrochlorothiazide in addition to telmisartan/amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study. Hypertens Res. 2017;40(3):251–8.  https://doi.org/10.1038/hr.2016.124.CrossRefPubMedGoogle Scholar
  19. 19.
    Lee SE, Kim YJ, Lee HY, Yang HM, Park CG, Kim JJ, et al. Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension. Clin Ther. 2012;34(3):552–68, 68 e1–9.  https://doi.org/10.1016/j.clinthera.2012.01.024.CrossRefPubMedGoogle Scholar
  20. 20.
    Lee JH, Yang DH, Hwang JY, Hur SH, Cha TJ, Kim KS, et al. A randomized, double-blind, candesartan-controlled, parallel group comparison clinical trial to evaluate the antihypertensive efficacy and safety of fimasartan in patients with mild to moderate essential hypertension. Clin Ther. 2016;38(6):1485–97.  https://doi.org/10.1016/j.clinthera.2016.04.005.CrossRefPubMedGoogle Scholar
  21. 21.
    Lee HY, Kim YJ, Ahn T, Youn HJ, Chull Chae S, Seog Seo H, et al. A randomized, multicenter, double-blind, placebo-controlled, 3 x 3 factorial design, phase II study to evaluate the efficacy and safety of the combination of fimasartan/amlodipine in patients with essential hypertension. Clin Ther. 2015;37(11):2581–96 e3.  https://doi.org/10.1016/j.clinthera.2015.02.019.CrossRefPubMedGoogle Scholar
  22. 22.
    Rhee MY, Ahn T, Chang K, Chae SC, Yang TH, Shim WJ, et al. The efficacy and safety of co-administration of fimasartan and rosuvastatin to patients with hypertension and dyslipidemia. BMC Pharmacol Toxicol. 2017;18(1):2.  https://doi.org/10.1186/s40360-016-0112-7.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    • McMurray JJ, 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(11):993–1004.  https://doi.org/10.1056/NEJMoa1409077. This RCT showed the mortality and morbidity benefit of Entresto in patients with HFrEF compared to enalapril. This article served as the basis on which Entresto gained approval for the treatment of HFrEF. CrossRefPubMedGoogle Scholar
  24. 24.
    Gervasini G, Robles NR. Potential beneficial effects of sacubitril-valsartan in renal disease: a new field for a new drug. Expert Opin Investig Drugs. 2017;26(5):651–9.  https://doi.org/10.1080/13543784.2017.1317345.CrossRefPubMedGoogle Scholar
  25. 25.
    Chrysant SG. Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/valsartan. J Am Soc Hypertens. 2017;11(7):461–8.  https://doi.org/10.1016/j.jash.2017.04.012.CrossRefPubMedGoogle Scholar
  26. 26.
    Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2017;5(5):333–40.  https://doi.org/10.1016/S2213-8587(17)30087-6.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Engeli S, Stinkens R, Heise T, May M, Goossens GH, Blaak EE, et al. Effect of sacubitril/valsartan on exercise-induced lipid metabolism in patients with obesity and hypertension. Hypertension. 2018;71(1):70–7.  https://doi.org/10.1161/HYPERTENSIONAHA.117.10224.CrossRefPubMedGoogle Scholar
  28. 28.
    • Williams B, Cockcroft JR, Kario K, Zappe DH, Brunel PC, Wang Q, et al. Effects of sacubitril/valsartan versus olmesartan on central hemodynamics in the elderly with systolic hypertension: the PARAMETER study. Hypertension. 2017;69(3):411–20.  https://doi.org/10.1161/HYPERTENSIONAHA.116.08556. This is the first major study to evaluate Entresto for hypertension and showed greater reduction in BP compared to olmesartan. CrossRefPubMedGoogle Scholar
  29. 29.
    Izzo JL Jr, 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(6):374–81.  https://doi.org/10.1097/FJC.0000000000000485.CrossRefPubMedGoogle Scholar
  30. 30.
    Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326(7404):1419–0.  https://doi.org/10.1136/bmj.326.7404.1419.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA. 2013;310(9):918–29.  https://doi.org/10.1001/jama.2013.277064.CrossRefPubMedGoogle Scholar
  32. 32.
    Singh K, Crossan C, Laba TL, Roy A, Hayes A, Salam A, et al. Cost-effectiveness of a fixed dose combination (polypill) in secondary prevention of cardiovascular diseases in India: within-trial cost-effectiveness analysis of the UMPIRE trial. Int J Cardiol. 2018;262:71–8.  https://doi.org/10.1016/j.ijcard.2018.03.082.CrossRefPubMedGoogle Scholar
  33. 33.
    •• Chow CK, Thakkar J, Bennett A, Hillis G, Burke M, Usherwood T, et al. Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review. Lancet. 2017;389(10073):1035–42.  https://doi.org/10.1016/S0140-6736(17)30260-X. This RCT showed the benefit of low-dose multi-target FDCP (polypill) as initial treatment of hypertension. CrossRefPubMedGoogle Scholar
  34. 34.
    Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther. 2008;30(4):587–604.CrossRefPubMedGoogle Scholar
  35. 35.
    Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713–9.  https://doi.org/10.1016/j.amjmed.2006.08.033.CrossRefPubMedGoogle Scholar
  36. 36.
    Shahid N, Adnan S, Farooq M, Ali S, Shabbir M, Masood Z, et al. Development of compressed coated polypill with mucoadhesive core comprising of atorvastatin/clopidogrel/aspirin using compression coating technique. Acta Pol Pharm. 2017;74(2):477–87.PubMedGoogle Scholar
  37. 37.
    Working Group on the Summit on Combination Therapy for CVD, Yusuf S, Attaran A, Bosch J, Joseph P, Lonn E, et al. Combination pharmacotherapy to prevent cardiovascular disease: present status and challenges. Eur Heart J. 2014;35(6):353–64.  https://doi.org/10.1093/eurheartj/eht407.CrossRefGoogle Scholar
  38. 38.
    Yusuf S, Lonn E, Pais P, Bosch J, Lopez-Jaramillo P, Zhu J, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med. 2016;374(21):2032–43.  https://doi.org/10.1056/NEJMoa1600177.CrossRefPubMedGoogle Scholar
  39. 39.
    Chrysant SG, Chrysant GS. Future of polypill use for the prevention of cardiovascular disease and strokes. Am J Cardiol. 2014;114(4):641–5.  https://doi.org/10.1016/j.amjcard.2014.05.049.CrossRefPubMedGoogle Scholar
  40. 40.
    Khonputsa P, Veerman LJ, Bertram M, Lim SS, Chaiyakunnaphruk N, Vos T. Generalized cost-effectiveness analysis of pharmaceutical interventions for primary prevention of cardiovascular disease in Thailand. Value Health Reg Issues. 2012;1(1):15–22.  https://doi.org/10.1016/j.vhri.2012.03.019.CrossRefPubMedGoogle Scholar
  41. 41.
    • Webster R, Castellano JM, Onuma OK. Putting polypills into practice: challenges and lessons learned. Lancet. 2017;389(10073):1066–74.  https://doi.org/10.1016/S0140-6736(17)30558-5. This article outlines the reasons for the difficulty in acceptance and use of polypill in clinical practice.CrossRefPubMedGoogle Scholar
  42. 42.
    Nansseu JR, Tankeu AT, Kamtchum-Tatuene J, Noubiap JJ. Fixed-dose combination therapy to reduce the growing burden of cardiovascular disease in low- and middle-income countries: feasibility and challenges. J Clin Hypertens (Greenwich). 2018;20(1):168–73.  https://doi.org/10.1111/jch.13162.CrossRefGoogle Scholar
  43. 43.
    Jaisser F, Farman N. Emerging roles of the mineralocorticoid receptor in pathology: toward new paradigms in clinical pharmacology. Pharmacol Rev. 2016;68(1):49–75.  https://doi.org/10.1124/pr.115.011106.CrossRefPubMedGoogle Scholar
  44. 44.
    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.  https://doi.org/10.1056/NEJM199909023411001.CrossRefPubMedGoogle Scholar
  45. 45.
    • 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.  https://doi.org/10.1016/S0140-6736(15)00257-3. This article showed a benefit of adding spironolactone over bisoprolol and doxazosin as fourth-line agent in resistant hypertension.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol Cell Endocrinol. 2012;350(2):310–7.  https://doi.org/10.1016/j.mce.2011.06.025.CrossRefPubMedGoogle Scholar
  47. 47.
    Fagart J, Hillisch A, Huyet J, Barfacker 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.  https://doi.org/10.1074/jbc.M110.131342.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    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.  https://doi.org/10.1093/eurheartj/eht187.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    • Filippatos G, Anker SD, Bohm M, Gheorghiade M, Kober 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.  https://doi.org/10.1093/eurheartj/ehw132. This article outlines the improved efficacy of finerenone compared to eplerenone in patients with HF and diabetic CKD. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Lattenist L, Lechner SM, Messaoudi S, Le Mercier A, El Moghrabi S, Prince S, et al. Nonsteroidal mineralocorticoid receptor antagonist finerenone protects against acute kidney injury-mediated chronic kidney disease: role of oxidative stress. Hypertension. 2017;69(5):870–8.  https://doi.org/10.1161/HYPERTENSIONAHA.116.08526.CrossRefPubMedGoogle Scholar
  51. 51.
    • 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.  https://doi.org/10.1001/jama.2015.10081. This RCT showed a beneficial effect of finerenone on renal protection indexed by albuminuria in diabetic nephropathy. CrossRefPubMedGoogle Scholar
  52. 52.
    •• Oparil S, Haber E. The renin-angiotensin system (first of two parts). N Engl J Med. 1974;291(8):389–401.  https://doi.org/10.1056/NEJM197408222910805. This article is part 1 of 2 which demonstrated the RAS pathway and how it can be inhibited to treat hypertension.CrossRefPubMedGoogle Scholar
  53. 53.
    •• Oparil S, Haber E. The renin-angiotensin system (second of two parts). N Engl J Med. 1974;291(9):446–57.  https://doi.org/10.1056/NEJM197408292910905. This article is part 2 of 2 which demonstrated the RAS pathway and how it can be inhibited to treat hypertension.CrossRefPubMedGoogle Scholar
  54. 54.
    Lee H, Kim KS, Chae SC, Jeong MH, Kim DS, Oh BH. Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension. Clin Ther. 2013;35(9):1337–49.  https://doi.org/10.1016/j.clinthera.2013.06.021.CrossRefPubMedGoogle Scholar
  55. 55.
    Youn JC, Ihm SH, Bae JH, Park SM, Jeon DW, Jung BC, et al. Efficacy and safety of 30-mg fimasartan for the treatment of patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, phase III clinical study. Clin Ther. 2014;36(10):1412–21.  https://doi.org/10.1016/j.clinthera.2014.07.004.CrossRefPubMedGoogle Scholar
  56. 56.
    Li Y, Li XH, Huang ZJ, Yang GP, Zhang GG, Zhao SP, et al. A randomized, double blind, placebo-controlled, multicenter phase II trial of allisartan isoproxil in essential hypertensive population at low-medium risk. PLoS One. 2015;10(2):e0117560.  https://doi.org/10.1371/journal.pone.0117560.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ferreira AJ, Bader M, Santos RA. Therapeutic targeting of the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas cascade in the renin-angiotensin system: a patent review. Expert Opin Ther Pat. 2012;22(5):567–74.  https://doi.org/10.1517/13543776.2012.682572.CrossRefPubMedGoogle Scholar
  58. 58.
    Clarke C, Flores-Munoz M, McKinney CA, Milligan G, Nicklin SA. Regulation of cardiovascular remodeling by the counter-regulatory axis of the renin-angiotensin system. Futur Cardiol. 2013;9(1):23–38.  https://doi.org/10.2217/fca.12.75.CrossRefGoogle Scholar
  59. 59.
    •• Fraga-Silva RA, Ferreira AJ, Dos Santos RA. Opportunities for targeting the angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor pathway in hypertension. Curr Hypertens Rep. 2013;15(1):31–8.  https://doi.org/10.1007/s11906-012-0324-1. This article outlines the optimal targets for development of novel antihypertensive agents in the counter-regulatory RAS pathway. CrossRefPubMedGoogle Scholar
  60. 60.
    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.  https://doi.org/10.1007/s40262-013-0072-7.CrossRefPubMedGoogle Scholar
  61. 61.
    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.  https://doi.org/10.1186/s13054-017-1823-x.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kittana N. Angiotensin-converting enzyme 2-angiotensin 1-7/1-9 system: novel promising targets for heart failure treatment. Fundam Clin Pharmacol. 2018;32(1):14–25.  https://doi.org/10.1111/fcp.12318.CrossRefPubMedGoogle Scholar
  63. 63.
    Marques FD, Melo MB, Souza LE, Irigoyen MC, Sinisterra RD, de Sousa FB, et al. Beneficial effects of long-term administration of an oral formulation of angiotensin-(1-7) in infarcted rats. Int J Hypertens. 2012;2012:795452–12.  https://doi.org/10.1155/2012/795452.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    • Santos SH, Andrade JM. Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome. Peptides. 2014;59:34–41.  https://doi.org/10.1016/j.peptides.2014.07.002. This review of pertinent studies demonstrates the beneficial effect of Ang (1–7) on lipid and glucose metabolism by reducing Ang II activity.CrossRefPubMedGoogle Scholar
  65. 65.
    Li P, Zhang F, Sun HJ, Zhang F, Han Y. Angiotensin-(1-7) enhances the effects of angiotensin II on the cardiac sympathetic afferent reflex and sympathetic activity in rostral ventrolateral medulla in renovascular hypertensive rats. J Am Soc Hypertens. 2015;9(11):865–77.  https://doi.org/10.1016/j.jash.2015.08.005.CrossRefPubMedGoogle Scholar
  66. 66.
    Bertagnolli M, Casali KR, De Sousa FB, Rigatto K, Becker L, Santos SH, et al. An orally active angiotensin-(1-7) inclusion compound and exercise training produce similar cardiovascular effects in spontaneously hypertensive rats. Peptides. 2014;51:65–73.  https://doi.org/10.1016/j.peptides.2013.11.006.CrossRefPubMedGoogle Scholar
  67. 67.
    Lin L, Liu X, Xu J, Weng L, Ren J, Ge J, et al. Mas receptor mediates cardioprotection of angiotensin-(1-7) against angiotensin II-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress. J Cell Mol Med. 2016;20(1):48–57.  https://doi.org/10.1111/jcmm.12687.CrossRefPubMedGoogle Scholar
  68. 68.
    Lu W, Kang J, Hu K, Tang S, Zhou X, Yu S, et al. Angiotensin-(1-7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis. Braz J Med Biol Res. 2017;50(1):e5594.  https://doi.org/10.1590/1414-431X20165594.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Shi Y, Lo CS, Padda R, Abdo S, Chenier I, Filep JG, et al. Angiotensin-(1-7) prevents systemic hypertension, attenuates oxidative stress and tubulointerstitial fibrosis, and normalizes renal angiotensin-converting enzyme 2 and Mas receptor expression in diabetic mice. Clin Sci (Lond). 2015;128(10):649–63.  https://doi.org/10.1042/CS20140329.CrossRefGoogle Scholar
  70. 70.
    Zhao J, Liu T, Liu E, Li G, Qi L, Li J. The potential role of atrial natriuretic peptide in the effects of angiotensin-(1-7) in a chronic atrial tachycardia canine model. J Renin-Angiotensin-Aldosterone Syst. 2016;17(1):1470320315627409.  https://doi.org/10.1177/1470320315627409.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Santiago NM, Guimaraes PS, Sirvente RA, Oliveira LA, Irigoyen MC, Santos RA, et al. Lifetime overproduction of circulating angiotensin-(1-7) attenuates deoxycorticosterone acetate-salt hypertension-induced cardiac dysfunction and remodeling. Hypertension. 2010;55(4):889–96.  https://doi.org/10.1161/HYPERTENSIONAHA.110.149815.CrossRefPubMedGoogle Scholar
  72. 72.
    Papinska AM, Soto M, Meeks CJ, Rodgers KE. Long-term administration of angiotensin (1-7) prevents heart and lung dysfunction in a mouse model of type 2 diabetes (db/db) by reducing oxidative stress, inflammation and pathological remodeling. Pharmacol Res. 2016;107:372–80.  https://doi.org/10.1016/j.phrs.2016.02.026.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Savergnini SQ, Beiman M, Lautner RQ, de Paula-Carvalho V, Allahdadi K, Pessoa DC, et al. Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor. Hypertension. 2010;56(1):112–20.  https://doi.org/10.1161/HYPERTENSIONAHA.110.152942.CrossRefPubMedGoogle Scholar
  74. 74.
    Savergnini SQ, Ianzer D, Carvalho MB, Ferreira AJ, Silva GA, 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.  https://doi.org/10.1371/journal.pone.0057757.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    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.  https://doi.org/10.1007/s11010-012-1489-2.CrossRefPubMedGoogle Scholar
  76. 76.
    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(4):621–5.  https://doi.org/10.1016/j.bbrc.2015.09.050.CrossRefPubMedGoogle Scholar
  77. 77.
    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.  https://doi.org/10.1161/CIRCRESAHA.113.301077.CrossRefPubMedGoogle Scholar
  78. 78.
    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(3):405–12.  https://doi.org/10.1253/circj.CJ-16-0958.CrossRefPubMedGoogle Scholar
  79. 79.
    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
  80. 80.
    Bosnyak S, Welungoda IK, Hallberg A, Alterman M, Widdop RE, Jones ES. Stimulation of angiotensin AT2 receptors by the non-peptide agonist, compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats. Br J Pharmacol. 2010;159(3):709–16.  https://doi.org/10.1111/j.1476-5381.2009.00575.x.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Moltzer E, Verkuil AV, van Veghel R, Danser AH, van Esch JH. Effects of angiotensin metabolites in the coronary vascular bed of the spontaneously hypertensive rat: loss of angiotensin II type 2 receptor-mediated vasodilation. Hypertension. 2010;55(2):516–22.  https://doi.org/10.1161/HYPERTENSIONAHA.109.145037.CrossRefPubMedGoogle Scholar
  82. 82.
    Gao L, Zucker IH. AT2 receptor signaling and sympathetic regulation. Curr Opin Pharmacol. 2011;11(2):124–30.  https://doi.org/10.1016/j.coph.2010.11.004.CrossRefPubMedGoogle Scholar
  83. 83.
    • 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.  https://doi.org/10.1007/s11906-012-0291-6. This review highlights the anti-inflammatory and anti-apoptotic effects of C21 on renal and vascular tissue in animal models.CrossRefPubMedGoogle Scholar
  84. 84.
    Rehman A, Leibowitz A, Yamamoto N, Rautureau Y, Paradis P, Schiffrin EL. Angiotensin type 2 receptor agonist compound 21 reduces vascular injury and myocardial fibrosis in stroke-prone spontaneously hypertensive rats. Hypertension. 2012;59(2):291–9.  https://doi.org/10.1161/HYPERTENSIONAHA.111.180158.CrossRefPubMedGoogle Scholar
  85. 85.
    Pandey A, Gaikwad AB. AT2 receptor agonist compound 21: a silver lining for diabetic nephropathy. Eur J Pharmacol. 2017;815:251–7.  https://doi.org/10.1016/j.ejphar.2017.09.036.CrossRefPubMedGoogle Scholar
  86. 86.
    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;60(2):411–8.  https://doi.org/10.1161/HYPERTENSIONAHA.112.190942.CrossRefPubMedGoogle Scholar
  87. 87.
    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.  https://doi.org/10.1042/CS20130396.CrossRefGoogle Scholar
  88. 88.
    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(3):641–50.  https://doi.org/10.1097/HJH.0000000000001563.CrossRefPubMedGoogle Scholar
  89. 89.
    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.  https://doi.org/10.1007/s40262-013-0125-y.CrossRefPubMedGoogle Scholar
  90. 90.
    Couvineau A, Laburthe M. VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins. Br J Pharmacol. 2012;166(1):42–50.  https://doi.org/10.1111/j.1476-5381.2011.01676.x.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    del Rio CL, Kloepfer RGP, Ueyama Y, Youngblood B, Georgopoulos L, Arnold S, et al. Vasomera, a novel VPAC2-selective vasoactive intestinal peptide agonist, improves arterial elastance and ventriculo-arterial coupling in rats with induced diastolic dysfunction via renoprival hypertension. J Am Coll Cardiol. 2013;61(10):Supplement E645.  https://doi.org/10.1016/S0735-1097(13)60645-2.CrossRefGoogle Scholar
  92. 92.
    Dominguez Rieg JA, de la Mora CS, Rieg T. Novel developments in differentiating the role of renal and intestinal sodium hydrogen exchanger 3. Am J Physiol Regul Integr Comp Physiol. 2016;311(6):R1186–R91.  https://doi.org/10.1152/ajpregu.00372.2016.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Linz D, Wirth K, Linz W, Heuer HO, 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.  https://doi.org/10.1161/HYPERTENSIONAHA.112.201590.CrossRefPubMedGoogle Scholar
  94. 94.
    Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, 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(227):227ra36.  https://doi.org/10.1126/scitranslmed.3007790.CrossRefPubMedGoogle Scholar
  95. 95.
    Spencer AG, Greasley PJ. Pharmacologic inhibition of intestinal sodium uptake: a gut centric approach to sodium management. Curr Opin Nephrol Hypertens. 2015;24(5):410–6.  https://doi.org/10.1097/MNH.0000000000000154.CrossRefPubMedGoogle Scholar
  96. 96.
    Labonte ED, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, et al. Gastrointestinal inhibition of sodium-hydrogen exchanger 3 reduces phosphorus absorption and protects against vascular calcification in CKD. J Am Soc Nephrol. 2015;26(5):1138–49.  https://doi.org/10.1681/ASN.2014030317.CrossRefPubMedGoogle Scholar
  97. 97.
    Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial. Am J Gastroenterol. 2017;112(5):763–74.  https://doi.org/10.1038/ajg.2017.41.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Park BG, Shin WS, Oh S, Park GM, Kim NI, Lee S. A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca(2+) channel blocker and endothelin A/B2 receptor antagonist. Bioorg Med Chem. 2017;25(17):4649–55.  https://doi.org/10.1016/j.bmc.2017.07.002.CrossRefPubMedGoogle Scholar
  99. 99.
    Lingrel JB. The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na. K-ATPase Annu Rev Physiol. 2010;72:395–412.  https://doi.org/10.1146/annurev-physiol-021909-135725.CrossRefPubMedGoogle Scholar
  100. 100.
    Blanco G, Wallace DP. Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney disease. Am J Physiol Renal Physiol. 2013;305(6):F797–812.  https://doi.org/10.1152/ajprenal.00248.2013.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Wenceslau CF, Rossoni LV. Rostafuroxin ameliorates endothelial dysfunction and oxidative stress in resistance arteries from deoxycorticosterone acetate-salt hypertensive rats: the role of Na+K+-ATPase/cSRC pathway. J Hypertens. 2014;32(3):542–54.  https://doi.org/10.1097/HJH.0000000000000059.CrossRefPubMedGoogle Scholar
  102. 102.
    • 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.  https://doi.org/10.1161/HYPERTENSIONAHA.112.201020. This article shows that the ATRQß-001 vaccine reduces BP and prevents target organ damage in SHR and Ang II-induced hypertensive rats.CrossRefPubMedGoogle Scholar
  103. 103.
    Nakagami F, Koriyama H, Nakagami H, Osako MK, Shimamura M, Kyutoku M, et al. Decrease in blood pressure and regression of cardiovascular complications by angiotensin II vaccine in mice. PLoS One. 2013;8(3):e60493.  https://doi.org/10.1371/journal.pone.0060493.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    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
  105. 105.
    Ou X, Guo L, Wu J, Mi K, Yin N, Zhang G, et al. Construction, expression and immunogenicity of a novel anti-hypertension angiotensin II vaccine based on hepatitis A virus-like particle. Hum Vaccin Immunother. 2013;9(6):1191–9.  https://doi.org/10.4161/hv.23940.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Ding D, Du Y, Qiu Z, Yan S, Chen F, Wang M, et al. Vaccination against type 1 angiotensin receptor prevents streptozotocin-induced diabetic nephropathy. J Mol Med (Berl). 2016;94(2):207–18.  https://doi.org/10.1007/s00109-015-1343-6.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.UAB Vascular Biology and Hypertension Program, Division of Cardiovascular DiseaseUniversity of Alabama at BirminghamBirminghamUSA

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