arthyperАртериальная гипертензия"Arterial’naya Gipertenziya" ("Arterial Hypertension")1607-419X2411-8524Antihypertensive League10.18705/1607-419X-2017-23-6-498-506arthyper-712Research ArticleОБЗОРREVIEWДВОЙНАЯ БЛОКАДА НЕПРИЛИЗИНА И АТ1-АНГИОТЕНЗИНОВЫХ РЕЦЕПТОРОВ: НОВЫЙ ПОДХОД К АНТИГИПЕРТЕНЗИВНОЙ И НЕФРОПРОТЕКТИВНОЙ ТЕРАПИИ БОЛЬНЫХ С АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИЕЙDUAL NEPRILYSIN AND AT1-ANGIOTENSIN RECEPTOR BLOCKADE: A NOVEL APPROACH FOR ANTIHYPERTENSIVE AND NEPHROPROTECTIVE THERAPYКузьминО. Б.KuzminO. B.

Кузьмин Олег Борисович — доктор медицинских наук, профессор, заведующий кафедрой фармакологии. 

Оренбург.

Oleg B. Kuzmin, MD, PhD, Professor, Chief, Department of Pharmacology.

Orenburg. 

kuzmin.orgma@mail.ruЖежаВ. В.ZhezhaV. V.

Жежа Владислав Викторович — кандидат медицинских наук, доцент кафедры фармакологии. 

Оренбург.

Vladislav V. Zhezha, MD, PhD, Associate Professor, Department of Pharmacology.

Orenburg. 

БелянинВ. В.BelyaninV. V.

Белянин Виталий Васильевич — кандидат медицинских наук, доцент кафедры фармакологии. 

Оренбург.

Vitaly V. Belyanin, MD, PhD, Associate Professor, Department of Pharmacology.

Orenburg. 

БучневаН. В.BuchnevaN. V.

Бучнева Наталья Викторовна — кандидат медицинских наук, доцент кафедры фармакологии. 

Оренбург.

Natalia V. Buchneva, MD, PhD, Associate Professor, Department of Pharmacology.

Orenburg. 

ЛандарьЛ. Н.LandarL. N.

Ландарь Лариса Николаевна — кандидат медицинских наук, доцент кафедры фармакологии. 

Оренбург.

Larisa N. Landar, MD, PhD, Associate Professor, Department of Pharmacology.

Orenburg. 

СердюкС. В.SerdyukS. V.

Сердюк Светлана Владимировна — кандидат медицинских наук, доцент кафедры фармакологии. 

Оренбург.

Svetlana V. Serdyuk, MD, PhD, Associate Professor, Department of Pharmacology.

Orenburg. 

Государственное бюджетное образовательное учреждение  высшего профессионального образования  «Оренбургский государственный медицинский университет»  Министерства здравоохранения Российской Федерации. РоссияOrenburg State Medical University.Russian Federation201711012018236498506Copyright © Кузьмин О.Б., Жежа В.В., Белянин В.В., Бучнева Н.В., Ландарь Л.Н., Сердюк С.В., 20182018Кузьмин О.Б., Жежа В.В., Белянин В.В., Бучнева Н.В., Ландарь Л.Н., Сердюк С.В.Kuzmin O.B., Zhezha V.V., Belyanin V.V., Buchneva N.V., Landar L.N., Serdyuk S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://htn.almazovcentre.ru/jour/article/view/712

В обзоре представлены данные об участии натрийуретических пептидов в фармакодинамике двойного ингибитора неприлизина и АТ1-рецепторов LCZ696 (сакубитрил/валсартан) и результаты клинических исследований, посвященных оценке его клинической эффективности у пациентов с артериальной гипертензией (АГ), включая лиц с нарушенной функцией почек. LCZ696 при назначении в дозах 200–400 мг/сутки в течение 8 недель оказывает клинически значимый антигипертензивный эффект при монотерапии больных эссенциальной гипертензией с АГ 1–2-й степени и при добавлении к лекарственной терапии таких пациентов с АГ 3-й степени. Краткосрочное назначение препарата не сопровождается развитием ангионевротического отека или других опасных побочных эффектов. Результаты этих клинических исследований распространяются преимущественно на больных первичной АГ с относительно сохраненной функцией почек и не страдающих сахарным диабетом, так как лица с содержанием креатинина в сыворотке крови более 133 мкмоль/л и больные сахарным диабетом 1-го и 2-го типов исключались из клинических наблюдений. Данные, полученные у гипертензивных пациентов с АГ 1–2-й степени и С3–С4 стадиями хронической болезни почек, показывают, что LCZ696 в дозах 200–400 мг/сутки в течение 8 недель также способен оказывать выраженный антигипертензивный эффект и в этой популяции больных, который сопровождается умеренным снижением альбуминурии. Для более полной оценки клинической эффективности и безопасности применения LCZ696 у больных АГ, включая пациентов с нарушенной функцией почек, необходимы длительные крупномасштабные клинические исследовани

The review presents data on the role of natriuretic peptides in the pharmacodynamics of LCZ696 (sacubitril/valsartan) and the results of clinical studies evaluating its clinical efficacy in patients with arterial hypertension (HTN), including those with impaired renal function. LCZ696 when administered as monotherapy at doses 200–400 mg/day for 8 weeks causes a clinically significant antihypertensive effect in patients with essential HTN 1–2 degree, as well as when used in combination therapy in HTN 3 degree. Short-term use of the drug is not accompanied by angioedema occurrence or other side effects. These results apply mainly to patients with primary HTN with relatively preserved kidney function and without diabetes mellitus, as subjects with serum creatinine > 133 micromole/L and patients with type 1 and 2 diabetes mellitus were excluded. Available data show that LCZ696 at doses 200–400 mg/day for 8 weeks also provides obvious antihypertensive effect and a moderate decrease in albuminuria in patients with HTN 1–2 degree and chronic kidney disease 3–4 stage. The long-term, large-scale clinical trials are needed for a more complete assessment of the clinical efficacy and safety of LCZ696 in hypertensive patients, including patients with impaired renal function.

артериальная гипертензияфункция почекLCZ696 (сакубитрил/валсартан)ReferencesKusaka H, Sueta D, Koibuchi N, Hasegawa Y, Nakagawa T, Lin B et al. LCZ696, angiotensin II receptor-neprilysin inhibitor, ameliorates high-salt-induced hypertension and cardiovascular injury more than valsartan alone. Am J Hypertens. 2015;28(12):1409– 1417. doi:10.1093/ajh/hpv015Kusaka H, Sueta D, Koibuchi N, Hasegawa Y, Nakagawa T, Lin B et al. LCZ696, angiotensin II receptor-neprilysin inhibitor, ameliorates high-salt-induced hypertension and cardiovascular injury more than valsartan alone. Am J Hypertens. 2015;28(12):1409– 1417. doi:10.1093/ajh/hpv015Ruilope LM, Ducat A, Bohm M, Lacvourcieze Y, Gong J, Lefkovitz MP. Blood pressure reduction with LCZ696, a novel dual-acting inhibitor of angiotensin II receptor and neprilysin: a randomized, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375(9722):1255–1266. doi:10.1016/S0140–6736(09)61966–8Ruilope LM, Ducat A, Bohm M, Lacvourcieze Y, Gong J, Lefkovitz MP. Blood pressure reduction with LCZ696, a novel dual-acting inhibitor of angiotensin II receptor and neprilysin: a randomized, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375(9722):1255–1266. doi:10.1016/S0140–6736(09)61966–8von Lueder TG, Wang BH, Kompa AR, Huang L, Webb R, Jordaan P et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction be reducing cardiac fibrosis and hypertrophy. Circ Heart Fail. 2015;8(1):71–88. doi:10.1161/CIRCHEARTFAILURE.114.001785von Lueder TG, Wang BH, Kompa AR, Huang L, Webb R, Jordaan P et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction be reducing cardiac fibrosis and hypertrophy. Circ Heart Fail. 2015;8(1):71–88. doi:10.1161/CIRCHEARTFAILURE.114.001785Pu Q, Brassard P, Javeshghani DM, Iglarz M, Webb RL, Amiri F et al. Effects of combined AT1 receptor antagonist/ NEP inhibitor on vascular remodeling and cardiac fibrosis in SHRSP. J Hypertens. 2008;26(2):322–333. doi:10.1097/HJH. 0b013e3282f16aafPu Q, Brassard P, Javeshghani DM, Iglarz M, Webb RL, Amiri F et al. Effects of combined AT1 receptor antagonist/ NEP inhibitor on vascular remodeling and cardiac fibrosis in SHRSP. J Hypertens. 2008;26(2):322–333. doi:10.1097/HJH. 0b013e3282f16aafVoors AA, Cori M, Liu LC, Claggett B, Zile MR, Pieske B et al. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserve ejection fraction. Eur J Heart Fail. 2015;17(5):510–517. doi:10.1002/ ejhf.232Voors AA, Cori M, Liu LC, Claggett B, Zile MR, Pieske B et al. Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserve ejection fraction. Eur J Heart Fail. 2015;17(5):510–517. doi:10.1002/ ejhf.232McMurray 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. doi:10.1056/NEJMoa1409077McMurray 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. doi:10.1056/NEJMoa1409077Packer M, McMurray JJ, Desai AS, Cong J, Lefkowitz MP, Rizkala A et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54–61. doi:10.1161/CIRCULATIONAHA.114.013748Packer M, McMurray JJ, Desai AS, Cong J, Lefkowitz MP, Rizkala A et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54–61. doi:10.1161/CIRCULATIONAHA.114.0137482016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975. doi:10.1002/ejhf.5922016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975. doi:10.1002/ejhf.592Potter LR. Natriuretic peptide metabolism, clearance and degradation. FEBS J. 2011;278(11):1808–1817. doi:10.1111/ j.1742–4658.2011.08082.xPotter LR. Natriuretic peptide metabolism, clearance and degradation. FEBS J. 2011;278(11):1808–1817. doi:10.1111/ j.1742–4658.2011.08082.xKerkela R, Ulvila J, Magga J. Natriuretic peptides in the regulation of cardiovascular physiology and metabolic events. J Am Heart Assoc. 2015;4: e002423. doi: 10.1161/JAHA.115.002423Kerkela R, Ulvila J, Magga J. Natriuretic peptides in the regulation of cardiovascular physiology and metabolic events. J Am Heart Assoc. 2015;4: e002423. doi: 10.1161/JAHA.115.002423Kuhn M. Molecular physiology of membrane guanylyl cyclase receptors. Physiol. Reviews. 2016;96(2):751–804. doi:10.1152/physrev.00022.2015Kuhn M. Molecular physiology of membrane guanylyl cyclase receptors. Physiol. Reviews. 2016;96(2):751–804. doi:10.1152/physrev.00022.2015Nishikimi T, Maeda N, Matsuoka H. The role of natriuretic peptide in cardioprotection. Cardiovasc Res. 2006;69(2):318–328. doi:10.1016/j.cardiores.2005.10.001Nishikimi T, Maeda N, Matsuoka H. The role of natriuretic peptide in cardioprotection. Cardiovasc Res. 2006;69(2):318–328. doi:10.1016/j.cardiores.2005.10.001Scotland RS, Cohen M, Foster P, Lovell M, Mathur A, Ahluwalia A et al. C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression. Proc Nat Acad Sci USA. 2005;102 (40):14452–14457. doi:10.1073/pnas.0504961102Scotland RS, Cohen M, Foster P, Lovell M, Mathur A, Ahluwalia A et al. C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression. Proc Nat Acad Sci USA. 2005;102 (40):14452–14457. doi:10.1073/pnas.0504961102Ichiki T, Izumi R, Cataliotti A, Larsen AM, Sandberg SM, Burnett JR. Endothelial permeability in vitro and in vivo: protective actions of ANP and omapatrilat in experimental atherosclerosis. Peptides. 2013;48:21–26. doi:10.1016/j.peptides.2013.07.020Ichiki T, Izumi R, Cataliotti A, Larsen AM, Sandberg SM, Burnett JR. Endothelial permeability in vitro and in vivo: protective actions of ANP and omapatrilat in experimental atherosclerosis. Peptides. 2013;48:21–26. doi:10.1016/j.peptides.2013.07.020Theiling F, Wu Q. ANP-induced signaling cascade and its implication in renal pathophysiology. Am J Physiol Renal Physiol. 2015;308(10): F1047-F1055. doi:10.1152/ajprenal.00164.2014Theiling F, Wu Q. ANP-induced signaling cascade and its implication in renal pathophysiology. Am J Physiol Renal Physiol. 2015;308(10): F1047-F1055. doi:10.1152/ajprenal.00164.2014Yoshihara F, Tokudome T, Kishimoto I, Otani K, Kawabara A, Horio T et al. Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor of atrial and B-type natriuretic peptides. Clin Exp Nephrol. 2015;19 (2): 197–207. doi:10.1007/s10157–014–0982–1Yoshihara F, Tokudome T, Kishimoto I, Otani K, Kawabara A, Horio T et al. Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor of atrial and B-type natriuretic peptides. Clin Exp Nephrol. 2015;19 (2): 197–207. doi:10.1007/s10157–014–0982–1Rose RA, Giles WR. Natriuretic peptide C receptor signaling in the heart and vasculature. J Physiol. 2008;586(2):353– 366. doi:10.1113/jphysiol.2007.144253Rose RA, Giles WR. Natriuretic peptide C receptor signaling in the heart and vasculature. J Physiol. 2008;586(2):353– 366. doi:10.1113/jphysiol.2007.144253Volpe M, Rubattu S, Burnett J. Natriuretic peptide in cardiovascular diseases: current use and perspectives. Eur Heart J. 2014;35(7):419–425. doi:10.1093/eurheartj/eht466Volpe M, Rubattu S, Burnett J. Natriuretic peptide in cardiovascular diseases: current use and perspectives. Eur Heart J. 2014;35(7):419–425. doi:10.1093/eurheartj/eht466Wang W, Shen J, Cui Y, Jiang G, Chen S, Peng J et al. Impaired sodium excretion and salt-sensitive hypertension in corin-deficient mice. Kidney Int. 2012;82(1):26–33. doi:10.1038/ ki.2012.41Wang W, Shen J, Cui Y, Jiang G, Chen S, Peng J et al. Impaired sodium excretion and salt-sensitive hypertension in corin-deficient mice. Kidney Int. 2012;82(1):26–33. doi:10.1038/ ki.2012.41Holditch SJ, Schreiber CA, Nini R, Tonne JM, Peng K-W, Geurts A et al. B-type natriuretic peptide deletion leads to progressive hypertension, associated organ damage, and reduced survival. Hypertension. 2015;66(1):199–210. doi:10.1161/ HYPERTENSIONAHA.115.05610Holditch SJ, Schreiber CA, Nini R, Tonne JM, Peng K-W, Geurts A et al. B-type natriuretic peptide deletion leads to progressive hypertension, associated organ damage, and reduced survival. Hypertension. 2015;66(1):199–210. doi:10.1161/ HYPERTENSIONAHA.115.05610Moyes AJ, Khambata RS, Villar I, Bubb KJ, Baliga RS, Lumsden VG et al. Endothelial C-type natriuretic peptide maintains vascular homeostasis. J Clin Invest. 2014;124(9):4039– 4051. doi:10.1172/JCI74281Moyes AJ, Khambata RS, Villar I, Bubb KJ, Baliga RS, Lumsden VG et al. Endothelial C-type natriuretic peptide maintains vascular homeostasis. J Clin Invest. 2014;124(9):4039– 4051. doi:10.1172/JCI74281Kasahara M, Mukoyama M, Sugawara A, Makino H, Suganami T, Ogawa Y et al. Ameliorated glomeruli injury in mice overexpressing brain natriuretic peptide with renal oblation. Am J Soc Nephrol. 2000;11(9):1691–1701.Kasahara M, Mukoyama M, Sugawara A, Makino H, Suganami T, Ogawa Y et al. Ameliorated glomeruli injury in mice overexpressing brain natriuretic peptide with renal oblation. Am J Soc Nephrol. 2000;11(9):1691–1701.Dong N, Fang C, Jiang Y, Zhou T, Liu M, Zhou J et al. Corin mutation R539C from hypertensive patients impairs zymogen activation and generates of inactive alternative ectodomain fragment. J Biol Chem. 2013;288(11):7867–7874. doi:10.1074/jbc. M112.411512Dong N, Fang C, Jiang Y, Zhou T, Liu M, Zhou J et al. Corin mutation R539C from hypertensive patients impairs zymogen activation and generates of inactive alternative ectodomain fragment. J Biol Chem. 2013;288(11):7867–7874. doi:10.1074/jbc. M112.411512Newton-Cheh C, Larsson MG, Vasan RS, Levy D, Block KD, Surti A et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet. 2009;41(3):348–353. doi:10.1038/ng.328Newton-Cheh C, Larsson MG, Vasan RS, Levy D, Block KD, Surti A et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet. 2009;41(3):348–353. doi:10.1038/ng.328Belluardo P, Cataliotti A, Bonaiuto L, Giuffre E, Maugeri E, Noto P et al. Lack of activation of molecular forms of the BNP system in human grade 1 hypertension and relationship to cardiac hypertrophy. Am J Physiol Heart Physiol. 2006;291(4): H1529-H1535. doi:10.1152/ajpheart.00107.2006Belluardo P, Cataliotti A, Bonaiuto L, Giuffre E, Maugeri E, Noto P et al. Lack of activation of molecular forms of the BNP system in human grade 1 hypertension and relationship to cardiac hypertrophy. Am J Physiol Heart Physiol. 2006;291(4): H1529-H1535. doi:10.1152/ajpheart.00107.2006Macheret F, Heublein D, Costello-Boerrigter LC, Boerrigter G, McKie P, Bellavia D et al. Human hypertension is characterized by a lack of activation of the antihypertensive cardiac hormones ANP and BNP. J Am Coll Cardiol. 2012;60(16):1558–1565. doi:10.1016/j. jacc.2012.05.049Macheret F, Heublein D, Costello-Boerrigter LC, Boerrigter G, McKie P, Bellavia D et al. Human hypertension is characterized by a lack of activation of the antihypertensive cardiac hormones ANP and BNP. J Am Coll Cardiol. 2012;60(16):1558–1565. doi:10.1016/j. jacc.2012.05.049Hu W, Zhou PH, Zhang XB, Xu CG, Wang W. Plasma concentrations of adrenomedullin and natriuretic peptides in patients with essential hypertension. Exp Ther Med. 2015; 9(5):1901–1908. doi:10.3892/etm.2015.2345Hu W, Zhou PH, Zhang XB, Xu CG, Wang W. Plasma concentrations of adrenomedullin and natriuretic peptides in patients with essential hypertension. Exp Ther Med. 2015; 9(5):1901–1908. doi:10.3892/etm.2015.2345Richards 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):407–416.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):407–416.Кузьмин О. Б., Жежа В. В., Белянин В. В., Ландарь Л. Н. Гломерулярная гипертензия: молекулярные механизмы повреждения подоцитов и мезангиальных клеток. Нефрология. 2016;20(4):39–45. [Kuzmin OB, Zhezha VV, Belyanin VV, Landar LN. Glomerular hypertension: molecular mechanisms of podocyte and mesangial cells damage. Nefrologiya = Nephrology. 2016;20(4):39–45. In Russian].Кузьмин О. Б., Жежа В. В., Белянин В. В., Ландарь Л. Н. Гломерулярная гипертензия: молекулярные механизмы повреждения подоцитов и мезангиальных клеток. Нефрология. 2016;20(4):39–45. [Kuzmin OB, Zhezha VV, Belyanin VV, Landar LN. Glomerular hypertension: molecular mechanisms of podocyte and mesangial cells damage. Nefrologiya = Nephrology. 2016;20(4):39–45. In Russian].Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103–111. doi:10.1016/j.amjhyper. 2003.09.014Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103–111. doi:10.1016/j.amjhyper. 2003.09.014Gu J, Noe A, Chandra P, Al-Fayoumi S, Liqueros-Saylan M, Sarangapani R et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010;50(4):401–414. doi:10.1177/ 0091270009343932Gu J, Noe A, Chandra P, Al-Fayoumi S, Liqueros-Saylan M, Sarangapani R et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010;50(4):401–414. doi:10.1177/ 0091270009343932Hegde LG, Yu C, Renner P, Thibodeaux H, Armstrong SR, Park T et al. Concomitant angiotensin AT1 receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal Japanese plasma extravasation in the rat. J Cardiovasc Pharmacol. 2011;57(4):495–504. doi:10.1097/ FJC.0b01e318210fc7eHegde LG, Yu C, Renner P, Thibodeaux H, Armstrong SR, Park T et al. Concomitant angiotensin AT1 receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal Japanese plasma extravasation in the rat. J Cardiovasc Pharmacol. 2011;57(4):495–504. doi:10.1097/ FJC.0b01e318210fc7eVolpe M, Carnovali M, Mastromarino V. The natriuretic peptide system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci. 2015;170(2):57–77. doi:10. 1042/Cs20150469Volpe M, Carnovali M, Mastromarino V. The natriuretic peptide system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci. 2015;170(2):57–77. doi:10. 1042/Cs20150469Katsuya T, IshikawaK, Sugimoto K, Rakugi H, Ogihara T. Salt sensitivity in Japanese from the viewpoint of gene polymorphism. Hypertens Res. 2003;26(7):521–525. doi:10. 1291/hypres.26.521Katsuya T, IshikawaK, Sugimoto K, Rakugi H, Ogihara T. Salt sensitivity in Japanese from the viewpoint of gene polymorphism. Hypertens Res. 2003;26(7):521–525. doi:10. 1291/hypres.26.521Kario K, Sun N, Chiang FT, Supasyndt O, Back CH, Inubishi-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. doi:10.1161/HYPERTENSIONAHA.113.02002Kario K, Sun N, Chiang FT, Supasyndt O, Back CH, Inubishi-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. doi:10.1161/HYPERTENSIONAHA.113.02002Kario K, Tamaki Y, Okino N, Gotou H, Zhu M, Zhang J. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor: the first experience in patients with severe hypertension. J Clin Hypertens (Greenwich). 2016;18(4):308–314. doi:10.1111/ jch.12667Kario K, Tamaki Y, Okino N, Gotou H, Zhu M, Zhang J. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor: the first experience in patients with severe hypertension. J Clin Hypertens (Greenwich). 2016;18(4):308–314. doi:10.1111/ jch.12667Ito S, Satoh M, Tamaki Y, Gotou H, Charney A, Okino N et al. Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Hypertens Res. 2015;38(4):269–275. doi:10.1038/hr.2015.1Ito S, Satoh M, Tamaki Y, Gotou H, Charney A, Okino N et al. Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Hypertens Res. 2015;38(4):269–275. doi:10.1038/hr.2015.1

The authors declare that there are no conflicts of interest present.