Recent Developments in Drug Targets and Combination Therapy for the Clinical Management of Hypertension

Howard, G.; Banach, M.; Cushman, M.; Goff, D.C.; Howard, V.J.; Lackland, D.T.; McVay, J.; Meschia, J.F.; Muntner, P.; Oparil, S.; Rightmyer, M.; Taylor, H.A. Is blood pressure control for stroke prevention the correct goal? The lost opportunity of preventing hypertension. Stroke, 2015, 46(6), 1595-1600.
[http://dx.doi.org/10.1161/STROKEAHA.115.009128] [PMID: 25953369]

Peters, S.A.E.; Huxley, R.R.; Woodward, M. Comparison of the sex-specific associations between systolic blood pressure and the risk of cardiovascular disease: A systematic review and meta-analysis of 124 cohort studies, including 1.2 million individuals. Stroke, 2013, 44(9), 2394-2401.
[http://dx.doi.org/10.1161/STROKEAHA.113.001624] [PMID: 23821229]

Gradman, A.H.; Basile, J.N.; Carter, B.L.; Bakris, G.L. Combination therapy in hypertension. J. Am. Soc. Hypertens., 2010, 4(1), 42-50.
[http://dx.doi.org/10.1016/j.jash.2010.02.005] [PMID: 20374950]

Hypertension - World Heart Federation. Available from: https://world-heart-federation.org/what-we-do/hypertension/ (Accessed on: 2023-05-31).

Ministry of Health & Family Welfare. Screening, Diagnosis, Assessment, and Management of Primary Hypertension in Adults in India. 2016. Available from: https://clinicalestablishments.gov.in/WriteReadData/5191.pdf

Williams, B.; Mancia, G.; Spiering, W.; Agabiti Rosei, E.; Azizi, M.; Burnier, M.; Clement, D.L.; Coca, A.; de Simone, G.; Dominiczak, A.; Kahan, T.; Mahfoud, F.; Redon, J.; Ruilope, L.; Zanchetti, A.; Kerins, M.; Kjeldsen, S.E.; Kreutz, R.; Laurent, S.; Lip, G.Y.H.; McManus, R.; Narkiewicz, K.; Ruschitzka, F.; Schmieder, R.E.; Shlyakhto, E.; Tsioufis, C.; Aboyans, V.; Desormais, I.; De Backer, G.; Heagerty, A.M.; Agewall, S.; Bochud, M.; Borghi, C.; Boutouyrie, P.; Brguljan, J.; Bueno, H.; Caiani, E.G.; Carlberg, B.; Chapman, N.; Cífková, R.; Cleland, J.G.F.; Collet, J-P.; Coman, I.M.; de Leeuw, P.W.; Delgado, V.; Dendale, P.; Diener, H-C.; Dorobantu, M.; Fagard, R.; Farsang, C.; Ferrini, M.; Graham, I.M.; Grassi, G.; Haller, H.; Hobbs, F.D.R.; Jelakovic, B.; Jennings, C.; Katus, H.A.; Kroon, A.A.; Leclercq, C.; Lovic, D.; Lurbe, E.; Manolis, A.J.; McDonagh, T.A.; Messerli, F.; Muiesan, M.L.; Nixdorff, U.; Olsen, M.H.; Parati, G.; Perk, J.; Piepoli, M.F.; Polonia, J.; Ponikowski, P.; Richter, D.J.; Rimoldi, S.F.; Roffi, M.; Sattar, N.; Seferovic, P.M.; Simpson, I.A.; Sousa-Uva, M.; Stanton, A.V.; van de Borne, P.; Vardas, P.; Volpe, M.; Wassmann, S.; Windecker, S.; Zamorano, J.L.; Windecker, S.; Aboyans, V.; Agewall, S.; Barbato, E.; Bueno, H.; Coca, A.; Collet, J-P.; Coman, I.M.; Dean, V.; Delgado, V.; Fitzsimons, D.; Gaemperli, O.; Hindricks, G.; Iung, B.; Jüni, P.; Katus, H.A.; Knuuti, J.; Lancellotti, P.; Leclercq, C.; McDonagh, T.A.; Piepoli, M.F.; Ponikowski, P.; Richter, D.J.; Roffi, M.; Shlyakhto, E.; Simpson, I.A.; Sousa-Uva, M.; Zamorano, J.L.; Tsioufis, C.; Lurbe, E.; Kreutz, R.; Bochud, M.; Rosei, E.A.; Jelakovic, B.; Azizi, M.; Januszewics, A.; Kahan, T.; Polonia, J.; van de Borne, P.; Williams, B.; Borghi, C.; Mancia, G.; Parati, G.; Clement, D.L.; Coca, A.; Manolis, A.; Lovic, D.; Benkhedda, S.; Zelveian, P.; Siostrzonek, P.; Najafov, R.; Pavlova, O.; De Pauw, M.; Dizdarevic-Hudic, L.; Raev, D.; Karpettas, N.; Linhart, A.; Olsen, M.H.; Shaker, A.F.; Viigimaa, M.; Metsärinne, K.; Vavlukis, M.; Halimi, J-M.; Pagava, Z.; Schunkert, H.; Thomopoulos, C.; Páll, D.; Andersen, K.; Shechter, M.; Mercuro, G.; Bajraktari, G.; Romanova, T.; Trušinskis, K.; Saade, G.A.; Sakalyte, G.; Noppe, S.; DeMarco, D.C.; Caraus, A.; Wittekoek, J.; Aksnes, T.A.; Jankowski, P.; Polonia, J.; Vinereanu, D.; Baranova, E.I.; Foscoli, M.; Dikic, A.D.; Filipova, S.; Fras, Z.; Bertomeu-Martínez, V.; Carlberg, B.; Burkard, T.; Sdiri, W.; Aydogdu, S.; Sirenko, Y.; Brady, A.; Weber, T.; Lazareva, I.; Backer, T.D.; Sokolovic, S.; Jelakovic, B.; Widimsky, J.; Viigimaa, M.; Pörsti, I.; Denolle, T.; Krämer, B.K.; Stergiou, G.S.; Parati, G.; Trušinskis, K.; Miglinas, M.; Gerdts, E.; Tykarski, A.; de Carvalho Rodrigues, M.; Dorobantu, M.; Chazova, I.; Lovic, D.; Filipova, S.; Brguljan, J.; Segura, J.; Gottsäter, A.; Pechère-Bertschi, A.; Erdine, S.; Sirenko, Y.; Brady, A. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur. Heart J., 2018, 39(33), 3021-3104.
[http://dx.doi.org/10.1093/eurheartj/ehy339] [PMID: 30165516]

Paul, K. 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: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension, 2018.

Mancia, G.; De Backer, G.; Dominiczak, A.; Cifkova, R.; Fagard, R.; Germano, G.; Grassi, G.; Heagerty, A.M.; Kjeldsen, S.E.; Laurent, S.; Narkiewicz, K.; Ruilope, L.; Rynkiewicz, A.; Schmieder, R.E.; Boudier, H.A.J.S.; Zanchetti, A.; Vahanian, A.; Camm, J.; De Caterina, R.; Dean, V.; Dickstein, K.; Filippatos, G.; Funck-Brentano, C.; Hellemans, I.; Kristensen, S.D.; McGregor, K.; Sechtem, U.; Silber, S.; Tendera, M.; Widimsky, P.; Zamorano, J.L.; Erdine, S.; Kiowski, W.; Agabiti-Rosei, E.; Ambrosioni, E.; Lindholm, L.H.; Viigimaa, M.; Adamopoulos, S.; Agabiti-Rosei, E.; Ambrosioni, E.; Bertomeu, V.; Clement, D.; Erdine, S.; Farsang, C.; Gaita, D.; Lip, G.; Mallion, J.M.; Manolis, A.J.; Nilsson, P.M.; O’Brien, E.; Ponikowski, P.; Redon, J.; Ruschitzka, F.; Tamargo, J.; van Zwieten, P.; Waeber, B.; Williams, B. 2007 guidelines for the management of arterial hypertension. J. Hypertens., 2007, 25(6), 1105-1187.
[http://dx.doi.org/10.1097/HJH.0b013e3281fc975a] [PMID: 17563527]

Hypertension. Available from: https://www.who.int/news-room/fact-sheets/detail/hypertension (Accessed on: 2023-05-17).

Carey, R.M.; Cutler, J.; Friedewald, W. The 1984 report of the joint national committee on detection, evaluation, and treatment of high blood pressure. Arch. Intern. Med., 1984, 144(5), 1045-1057.
[http://dx.doi.org/10.1001/archinte.1984.00350170211032] [PMID: 6143542]

Domanski, M.; Mitchell, G.; Pfeffer, M.; Neaton, J.D.; Norman, J.; Svendsen, K.; Grimm, R.; Cohen, J.; Stamler, J. Pulse pressure and cardiovascular disease-related mortality: Follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA, 2002, 287(20), 2677-2683.
[http://dx.doi.org/10.1001/jama.287.20.2677] [PMID: 12020303]

Seravalle, G.; Grassi, G. Essential Hypertension. In: Primer on the Autonomic Nervous System, 4th ed.; StatPearls Publishing, 2023;, pp. 467-470.
[http://dx.doi.org/10.1016/B978-0-323-85492-4.00096-X]

Hypertension. Available from: https://www.who.int/news-room/fact-sheets/detail/hypertension (Accessed on: 2023-07-31).

Types of Hypertension-Stanford Health Care. Available from: https://stanfordhealthcare.org/medical-conditions/blood-heart-circulation/resistant-hypertension/types.html (Accessed on: 2023-07-31).

Paz Ocaranza, M.; Riquelme, J.A.; García, L.; Jalil, J.E.; Chiong, M.; Santos, R.A.S.; Lavandero, S. Counter-regulatory renin–angiotensin system in cardiovascular disease. Nat. Rev. Cardiol., 2019, 17(2), 116-129.
[http://dx.doi.org/10.1038/s41569-019-0244-8]

Oparil, S.; Schmieder, R.E. New approaches in the treatment of hypertension. Circ. Res., 2015, 116(6), 1074-1095.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.303603] [PMID: 25767291]

Mehta, P.K.; Griendling, K.K.; Angiotensin, I.I. Angiotensin II cell signaling: Physiological and pathological effects in the cardiovascular system. Am. J. Physiol. Cell Physiol., 2007, 292(1), C82-C97.
[http://dx.doi.org/10.1152/ajpcell.00287.2006] [PMID: 16870827]

Kumar, U.; Wettersten, N.; Garimella, P.S. Cardiorenal syndrome. Cardiol. Clin., 2019, 37(3), 251-265.
[http://dx.doi.org/10.1016/j.ccl.2019.04.001] [PMID: 31279419]

Gradman, A.H. Strategies for combination therapy in hypertension. Curr. Opin. Nephrol. Hypertens., 2012, 21(5), 486-491.
[http://dx.doi.org/10.1097/MNH.0b013e328356c551] [PMID: 22871676]

Hypertension. Available from: https://www.who.int/news-room/fact-sheets/detail/hypertension (Accessed on: 2023-05-20).

Guerrero-García, C.; Rubio-Guerra, F. Combination therapy in the treatment of hypertension. Drugs Context, 2018, 7, 1-9.
[http://dx.doi.org/10.7573/dic.212531] [PMID: 29899755]

Chobanian, A.V.; Bakris, G.L.; Black, H.R.; Cushman, W.C.; Green, L.A.; Izzo, J.L., Jr; Jones, D.W.; Materson, B.J.; Oparil, S.; Wright, J.T., Jr; Roccella, E.J.; Lenfant, C.; Carter, B.L.; Cohen, J.D.; Colman, P.J.; Cziraky, M.J.; Davis, J.J.; Ferdinand, K.C.; Gifford, R.W.; Glick, M.; Havas, S.; Hostetter, T.H.; Kirby, L.; Kolasa, K.M.; Linas, S.; Manger, W.M.; Marshall, E.C.; Merchant, J.; Miller, N.H.; Moser, M.; Nickey, W.A.; Randall, O.S.; Reed, J.W.; Shaughnessy, L.; Sheps, S.G.; Snyder, D.B.; Sowers, J.R.; Steiner, L.M.; Stout, R.; Strickland, R.D.; Vallbona, C.; Weiss, H.S.; Whisnant, J.P.; Wilson, G.J.; Winston, M.; Karimbakas, J. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA, 2003, 289(19), 2560-2572.
[http://dx.doi.org/10.1001/jama.289.19.2560] [PMID: 12748199]

Mancia, G.; Fagard, R.; Narkiewicz, K.; Redón, J.; Zanchetti, A.; Böhm, M.; Christiaens, T.; Cifkova, R.; De Backer, G.; Dominiczak, A.; Galderisi, M.; Grobbee, D.E.; Jaarsma, T.; Kirchhof, P.; Kjeldsen, S.E.; Laurent, S.; Manolis, A.J.; Nilsson, P.M.; Ruilope, L.M.; Schmieder, R.E.; Sirnes, P.A.; Sleight, P.; Viigimaa, M.; Waeber, B.; Zannad, F. 2013 ESH/ESC Guidelines for the management of arterial hypertension. J. Hypertens., 2013, 31(7), 1281-1357.
[http://dx.doi.org/10.1097/01.hjh.0000431740.32696.cc] [PMID: 23817082]

Mancia, G.; Rea, F.; Corrao, G.; Grassi, G. Two-drug combinations as first-step antihypertensive treatment. Circ. Res., 2019, 124(7), 1113-1123.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.313294] [PMID: 30920930]

Spirk, D.; Noll, S.; Burnier, M.; Rimoldi, S.; Noll, G.; Sudano, I. First line combination therapy in the treatment of stage II and III hypertension (FLASH). Front. Cardiovasc. Med., 2020, 7, 46.
[http://dx.doi.org/10.3389/fcvm.2020.00046] [PMID: 32292790]

Rubio-Guerra, A.; Castro-Serna, D.; Barrera, C.I.; Ramos-Brizuela, L.M. Current concepts in combination therapy for the treatment of hypertension: Combined calcium channel blockers and RAAS inhibitors. Integr. Blood Press. Control, 2009, 2, 55-62.
[http://dx.doi.org/10.2147/IBPC.S6232] [PMID: 21949615]

Burnier, M. Antihypertensive combination treatment: State of the art. Curr. Hypertens. Rep., 2015, 17(7), 51.
[http://dx.doi.org/10.1007/s11906-015-0562-0] [PMID: 26068654]

Lu, Y.; Van Zandt, M.; Liu, Y.; Li, J.; Wang, X.; Chen, Y.; Chen, Z.; Cho, J.; Dorajoo, S.R.; Feng, M.; Hsu, M.H.; Hsu, J.C.; Iqbal, U.; Jonnagaddala, J.; Li, Y.C.; Liaw, S.T.; Lim, H.S.; Ngiam, K.Y.; Nguyen, P.A.; Park, R.W.; Pratt, N.; Reich, C.; Rhee, S.Y.; Sathappan, S.M.K.; Shin, S.J.; Tan, H.X.; You, S.C.; Zhang, X.; Krumholz, H.M.; Suchard, M.A.; Xu, H. Analysis of dual combination therapies used in treatment of hypertension in a multinational cohort. JAMA Netw. Open, 2022, 5(3), e223877-e223877.
[http://dx.doi.org/10.1001/jamanetworkopen.2022.3877] [PMID: 35323951]

Nguyen, Q.; Dominguez, J.; Nguyen, L.; Gullapalli, N. Hypertension management: An update. Am. Health Drug Benefits, 2010, 3(1), 47-56.
[PMID: 25126308]

Steckelings, U.M.; Paulis, L.; Unger, T.; Bader, M. Emerging drugs which target the renin–angiotensin–aldosterone system. Expert Opin. Emerg. Drugs, 2011, 16(4), 619-630.
[http://dx.doi.org/10.1517/14728214.2011.618495] [PMID: 21905943]

Jorde, U.P.; Ennezat, P.V.; Lisker, J.; Suryadevara, V.; Infeld, J.; Cukon, S.; Hammer, A.; Sonnenblick, E.H.; Le Jemtel, T.H. Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation, 2000, 101(8), 844-846.
[http://dx.doi.org/10.1161/01.CIR.101.8.844] [PMID: 10694521]

Kalra, S.; Kalra, B.; Agrawal, N. Combination therapy in hypertension: An update. Diabetol. Metab. Syndr., 2010, 2(1), 44.
[http://dx.doi.org/10.1186/1758-5996-2-44] [PMID: 20576135]

Altun, B.; Arici, M. Nergizoğlu, G.; Derici, Ü.; Karatan, O.; Turgan, Ç.; Sindel, Ş.; Erbay, B.; Hasanoğlu, E.; Çağlar, Ş. Prevalence, awareness, treatment and control of hypertension in Turkey (the PatenT study) in 2003. J. Hypertens., 2005, 23(10), 1817-1823.
[http://dx.doi.org/10.1097/01.hjh.0000176789.89505.59] [PMID: 16148604]

Mancia, G.; Laurent, S.; Agabiti-Rosei, E.; Ambrosioni, E.; Burnier, M.; Caulfield, M.J.; Cifkova, R.; Clément, D.; Coca, A.; Dominiczak, A.; Erdine, S.; Fagard, R.; Farsang, C.; Grassi, G.; Haller, H.; Heagerty, A.; Kjeldsen, S.E.; Kiowski, W.; Mallion, J.M.; Manolis, A.; Narkiewicz, K.; Nilsson, P.; Olsen, M.H.; Rahn, K.H.; Redon, J.; Rodicio, J.; Ruilope, L.; Schmieder, R.E.; Struijker-Boudier, H.A.J.; van Zwieten, P.A.; Viigimaa, M.; Zanchetti, A. Reappraisal of European guidelines on hypertension management: A European Society of Hypertension Task Force document. J. Hypertens., 2009, 27(11), 2121-2158.
[http://dx.doi.org/10.1097/HJH.0b013e328333146d] [PMID: 19838131]

Salam, A.; Kanukula, R.; Atkins, E.; Wang, X.; Islam, S.; Kishore, S.P.; Jaffe, M.G.; Patel, A.; Rodgers, A. Efficacy and safety of dual combination therapy of blood pressure-lowering drugs as initial treatment for hypertension. J. Hypertens., 2019, 37(9), 1768-1774.
[http://dx.doi.org/10.1097/HJH.0000000000002096] [PMID: 30986788]

Davis, J.; Oparil, S. Novel medical treatments for hypertension and related comorbidities. Curr. Hypertens. Rep., 2018, 20(10), 90.
[http://dx.doi.org/10.1007/s11906-018-0890-y] [PMID: 30145617]

Telmisartan/Amlodipine (80/10) vs. Telmisartan/Amlodipine (40/10) vs. amlodipine10 in Resistant Hypertension. Available from: https://clinicaltrials.gov/ct2/show/NCT00553267

Dunlay, M.C.; Fitzpatrick, V.; Chrysant, S.; Francischetti, E.A.; Goldberg, A.I.; Sweet, C.S. Losartan potassium as initial therapy in patients with severe hypertension. J. Hum. Hypertens., 1995, 9(11), 861-867.
[PMID: 8583463]

Oparil, S.; Ripley, E. E101 Candesartan cilexetil enhances blood pressure reduction in severe (stage 3, JNC-VI) hypertensive patients inadequately controlled with HCTZ. Am. J. Hypertens., 1998, 11(4), 121A-121A.
[http://dx.doi.org/10.1016/S0895-7061(97)91163-8]

Hansson, L.; Zanchetti, A.; Carruthers, S.G.; Dahlöf, B.; Elmfeldt, D.; Julius, S.; Ménard, J.; Rahn, K.H.; Wedel, H.; Westerling, S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet, 1998, 351(9118), 1755-1762.
[http://dx.doi.org/10.1016/S0140-6736(98)04311-6] [PMID: 9635947]

Larochelle, P.; Flack, J.M.; Marbury, T.C.; Sareli, P.; Krieger, E.M.; Reeves, R.A. Effects and tolerability of irbesartan versus enalapril in patients with severe hypertension. Am. J. Cardiol., 1997, 80(12), 1613-1615.
[http://dx.doi.org/10.1016/S0002-9149(97)00784-4] [PMID: 9416950]

Weir, M.R.; Bakris, G.L. Combination therapy with Renin-Angiotensin-aldosterone receptor blockers for hypertension: How far have we come? J. Clin. Hypertens., 2008, 10(2), 146-152.
[http://dx.doi.org/10.1111/j.1751-7176.2008.07439.x] [PMID: 18256579]

Karmakar, P.S.; Chandra, A. Combination therapy in management of hypertension. In: Drugs and Therapeutics: Hypertension; Knowledge Bridge; , 2021;, pp. 1-12.

van der Vring, J.A.F.M.; Daniëls, M.C.G.; Holwerda, N.J.H.; Withagen, P.J.A.M.; Schelling, A.; Cleophas, T.J.; Hendriks, M.G.C. Combination of calcium channel blockers and beta blockers for patients with exercise-induced angina pectoris: A double-blind parallel-group comparison of different classes of calcium channel blockers. Angiology, 1999, 50(6), 447-454.
[http://dx.doi.org/10.1177/000331979905000602] [PMID: 10378820]

Haria, M.; Plosker, G.L.; Markham, A. Felodipine/Metoprolol. Drugs, 2000, 59(1), 141-157.
[http://dx.doi.org/10.2165/00003495-200059010-00011] [PMID: 10718104]

Chrysant, S.G. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Arch. Intern. Med., 1994, 154(7), 737-743.
[http://dx.doi.org/10.1001/archinte.1994.00420070047005] [PMID: 8147677]

Dahlöf, B.; Devereux, R.B.; Kjeldsen, S.E.; Julius, S.; Beevers, G.; de Faire, U.; Fyhrquist, F.; Ibsen, H.; Kristiansson, K.; Lederballe-Pedersen, O.; Lindholm, L.H.; Nieminen, M.S.; Omvik, P.; Oparil, S.; Wedel, H. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet, 2002, 359(9311), 995-1003.
[http://dx.doi.org/10.1016/S0140-6736(02)08089-3] [PMID: 11937178]

Wald, D.S.; Law, M.; Morris, J.K.; Bestwick, J.P.; Wald, N.J. Combination therapy versus monotherapy in reducing blood pressure: Meta-analysis on 11,000 participants from 42 trials. Am. J. Med., 2009, 122(3), 290-300.
[http://dx.doi.org/10.1016/j.amjmed.2008.09.038] [PMID: 19272490]

Unger, T.; Borghi, C.; Charchar, F.; Khan, N.A.; Poulter, N.R.; Prabhakaran, D.; Ramirez, A.; Schlaich, M.; Stergiou, G.S.; Tomaszewski, M.; Wainford, R.D.; Williams, B.; Schutte, A.E. 2020 International society of hypertension global hypertension practice guidelines. Hypertension, 2020, 75(6), 1334-1357.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15026] [PMID: 32370572]

Sahoo, S.K.; Pathni, A.K.; Krishna, A.; Moran, A.E.; Cohn, J.; Bhatia, S.; Maheshwari, N.; Sharma, B. Research Letter: Antihypertensive drugs market in India: An insight on size, trends, and prescribing preferences in the private health sector, 2016–2018. Glob. Heart, 2021, 16(1), 51.
[http://dx.doi.org/10.5334/gh.999] [PMID: 34381673]

Shah, S. N.; Munjal, Y. P.; Kamath, S. A.; Wander, G. S.; Mehta, N.; Mukherjee, S.; Kirpalani, A.; Gupta, P.; Shah, H.; Rohatgi, R.; Billimoria, A.R.; Maiya, M.; Das, M. K.; Goswami, K. C.; Sharma, R.; Rajapurkar, M. M.; Chawla, R.; Saboo, B.; Jha, V. Indian guidelines on hypertension-IV (2019). J. Hum. Hypertens., 2020, 34(11), 745-758.
[http://dx.doi.org/10.1038/s41371-020-0349-x]

James, P.A.; Oparil, S.; Carter, B.L.; Cushman, W.C.; Dennison-Himmelfarb, C.; Handler, J.; Lackland, D.T.; LeFevre, M.L.; MacKenzie, T.D.; Ogedegbe, O.; Smith, S.C., Jr; Svetkey, L.P.; Taler, S.J.; Townsend, R.R.; Wright, J.T., Jr; Narva, A.S.; Ortiz, E. 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), 507-520.
[http://dx.doi.org/10.1001/jama.2013.284427] [PMID: 24352797]

DiPette, D.J.; Skeete, J.; Ridley, E.; Campbell, N.R.C.; Lopez-Jaramillo, P.; Kishore, S.P.; Jaffe, M.G.; Coca, A.; Townsend, R.R.; Ordunez, P. Fixed‐dose combination pharmacologic therapy to improve hypertension control worldwide: Clinical perspective and policy implications. J. Clin. Hypertens., 2019, 21(1), 4-15.
[http://dx.doi.org/10.1111/jch.13426] [PMID: 30480368]

Rahimi, K.; Emdin, C.A.; MacMahon, S. The epidemiology of blood pressure and its worldwide management. Circ. Res., 2015, 116(6), 925-936.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.304723] [PMID: 25767281]

Hall, J.E.; do Carmo, J.M.; da Silva, A.A.; Wang, Z.; Hall, M.E. Obesity-induced hypertension. Circ. Res., 2015, 116(6), 991-1006.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.305697] [PMID: 25767285]

Padmanabhan, S.; Caulfield, M.; Dominiczak, A.F. Genetic and molecular aspects of hypertension. Circ. Res., 2015, 116(6), 937-959.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.303647] [PMID: 25767282]

te Riet, L.; van Esch, J.H.M.; Roks, A.J.M.; van den Meiracker, A.H.; Danser, A.H. J. Hypertension. Circ. Res., 2015, 116(6), 960-975.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.303587] [PMID: 25767283]

Nishizaka, M. K.; Zaman, M. A.; Calhoun, D. A. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am. J. Hypertens., 2003, 16(11 Pt 1), 925-930.
[http://dx.doi.org/10.1016/S0895-7061(03)01032-X]

Oparil, S. ME-1: Role of mineralocorticoid receptor blockers in resistant and refractory hypertension. J. Hypertens., 2023, 41(Suppl. 1), e11.
[http://dx.doi.org/10.1097/01.hjh.0000912792.66742.45]

Tezuka, Y.; Ito, S. The time to reconsider mineralocorticoid receptor blocking strategy: Arrival of nonsteroidal mineralocorticoid receptor blockers. Curr. Hypertens. Rep., 2022, 24(7), 215-224.
[http://dx.doi.org/10.1007/s11906-022-01177-6]

Malek, V.; Gaikwad, A.B. Neprilysin inhibitors: A new hope to halt the diabetic cardiovascular and renal complications? Biomed. Pharmacother., 2017, 90, 752-759.
[http://dx.doi.org/10.1016/j.biopha.2017.04.024] [PMID: 28419972]

Mills, J.; Vardeny, O. The role of neprilysin inhibitors in cardiovascular disease. Curr. Heart Fail. Rep., 2015, 12(6), 389-394.
[http://dx.doi.org/10.1007/s11897-015-0270-8] [PMID: 26466607]

Solomon, S.D.; McMurray, J.J.V.; Anand, I.S.; Ge, J.; Lam, C.S.P.; Maggioni, A.P.; Martinez, F.; Packer, M.; Pfeffer, M.A.; Pieske, B.; Redfield, M.M.; Rouleau, J.L.; van Veldhuisen, D.J.; Zannad, F.; Zile, M.R.; Desai, A.S.; Claggett, B.; Jhund, P.S.; Boytsov, S.A.; Comin-Colet, J.; Cleland, J.; Düngen, H.D.; Goncalvesova, E.; Katova, T.; Kerr Saraiva, J.F.; Lelonek, M.; Merkely, B.; Senni, M.; Shah, S.J.; Zhou, J.; Rizkala, A.R.; Gong, J.; Shi, V.C.; Lefkowitz, M.P. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N. Engl. J. Med., 2019, 381(17), 1609-1620.
[http://dx.doi.org/10.1056/NEJMoa1908655] [PMID: 31475794]

Ruilope, L.M.; Dukat, A.; Böhm, M.; Lacourcière, Y.; Gong, J.; Lefkowitz, M.P. 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), 1255-1266.
[http://dx.doi.org/10.1016/S0140-6736(09)61966-8] [PMID: 20236700]

Khder, Y.; Shi, V.; McMurray, J.J.V.; Lefkowitz, M.P. Sacubitril/Valsartan (LCZ696) in heart failure. Handb. Exp. Pharmacol., 2016, 243, 133-165.
[http://dx.doi.org/10.1007/164_2016_77] [PMID: 28004291]

Grant, P.J.; Cosentino, F. The 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart J., 2019, 40(39), 3215-3217.
[http://dx.doi.org/10.1093/eurheartj/ehz687] [PMID: 31608951]

Fournie-Zaluski, M.C.; Fassot, C.; Valentin, B.; Djordjijevic, D.; Reaux-Le Goazigo, A.; Corvol, P.; Roques, B.P.; Llorens-Cortes, C. Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension. Proc. Natl. Acad. Sci. USA, 2004, 101(20), 7775-7780.
[http://dx.doi.org/10.1073/pnas.0402312101] [PMID: 15136730]

Ferreira, A.J.; Raizada, M.K.; Aminopeptidase, A.; Aminopeptidase, A. Hypertension, 2008, 51(5), 1273-1274.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.109561] [PMID: 18362227]

Petkov, V.; Mosgoeller, W.; Ziesche, R.; Raderer, M.; Stiebellehner, L.; Vonbank, K.; Funk, G.C.; Hamilton, G.; Novotny, C.; Burian, B.; Block, L.H. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J. Clin. Invest., 2003, 111(9), 1339-1346.
[http://dx.doi.org/10.1172/JCI17500] [PMID: 12727925]

Henning, R.; Sawmiller, D.R. Vasoactive intestinal peptide: Cardiovascular effects. Cardiovasc. Res., 2001, 49(1), 27-37.
[http://dx.doi.org/10.1016/S0008-6363(00)00229-7] [PMID: 11121793]

Li, Y.; Xie, Z.; Lin, W.; Cai, W.; Wen, C.; Guan, Y.; Mo, X.; Wang, J.; Wang, Y.; Peng, P.; Chen, X.; Hong, W.; Xiao, G.; Liu, J.; Zhang, L.; Hu, F.; Li, F.; Zhang, F.; Deng, X.; Li, L. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: An exploratory randomized controlled trial. Med., 2020, 1(1), 105-113.e4.
[http://dx.doi.org/10.1016/j.medj.2020.04.001]

Safety, tolerability, pharmacokinetics and pharmacodynamics response of vasomera (PB1046) injection following a single subcutaneous dose in subjects with stage 1 or 2 essential hypertension- ClinicalTrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT01523067 (Accessed on: on: 2023-05-23).

Nwia, S.M.; Li, X.C.; Leite, A.P.O.; Hassan, R.; Zhuo, J.L. The Na+/H+ exchanger 3 in the intestines and the proximal tubule of the kidney: Localization, physiological function, and key roles in angiotensin II-induced hypertension. Front. Physiol., 2022, 13, 861659.
[http://dx.doi.org/10.3389/fphys.2022.861659] [PMID: 35514347]

Dominguez Rieg, J.A.; De La, S.; Chavez, M.; 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-R1191.
[http://dx.doi.org/10.1152/ajpregu.00372.2016]

Spencer, A.G.; Labonte, E.D.; Rosenbaum, D.P.; Plato, C.F.; Carreras, C.W.; Leadbetter, M.R.; Kozuka, K.; Kohler, J.; Koo-McCoy, S.; He, L.; Bell, N.; Tabora, J.; Joly, K.M.; Navre, M.; Jacobs, J.W.; Charmot, D. 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.
[http://dx.doi.org/10.1126/scitranslmed.3007790] [PMID: 24622516]

Linz, D.; Wirth, K.; Linz, W.; Heuer, H.O.O.; Frick, W.; Hofmeister, A.; Heinelt, U.; Arndt, P.; Schwahn, U.; Böhm, M.; Ruetten, H. Antihypertensive and laxative effects by pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut. Hypertension, 2012, 60(6), 1560-1567.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.201590] [PMID: 23108657]

Hynynen, M.; Khalil, R. The vascular endothelin system in hypertension--recent patents and discoveries. Recent Adv. Cardiovasc. Drug Discov., 2006, 1(1), 95-108.
[http://dx.doi.org/10.2174/157489006775244263] [PMID: 17200683]

Black, H.R.; Bakris, G.L.; Weber, M.A.; Weiss, R.; Shahawy, M.E.; Marple, R.; Tannoury, G.; Linas, S.; Wiens, B.L.; Linseman, J.V.; Roden, R.; Gerber, M.J. Efficacy and safety of darusentan in patients with resistant hypertension: Results from a randomized, double-blind, placebo-controlled dose-ranging study. J. Clin. Hypertens., 2007, 9(10), 760-769.
[http://dx.doi.org/10.1111/j.1524-6175.2007.07244.x] [PMID: 17917503]

Rivera-Lebron, B.N.; Risbano, M.G. Ambrisentan: A review of its use in pulmonary arterial hypertension. Ther. Adv. Respir. Dis., 2017, 11(6), 233-244.
[http://dx.doi.org/10.1177/1753465817696040] [PMID: 28425346]

Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.; Kobayashi, M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature, 1988, 332(6163), 411-415.
[http://dx.doi.org/10.1038/332411a0] [PMID: 2451132]

Hunter, P.G.; Chapman, F.A.; Dhaun, N. Hypertension: Current trends and future perspectives. Br. J. Clin. Pharmacol., 2021, 87(10), 3721-3736.
[http://dx.doi.org/10.1111/bcp.14825] [PMID: 33733505]

Verweij, P.; Danaietash, P.; Flamion, B.; Ménard, J.; Bellet, M. Randomized dose-response study of the new dual endothelin receptor antagonist aprocitentan in hypertension. Hypertension, 2020, 75(4), 956-965.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14504] [PMID: 32063059]

Angeli, F.; Verdecchia, P.; Reboldi, G. Aprocitentan, a dual endothelin receptor antagonist under development for the treatment of resistant hypertension. Cardiol. Ther., 2021, 10(2), 397-406.
[http://dx.doi.org/10.1007/s40119-021-00233-7] [PMID: 34251649]

Trensz, F.; Bortolamiol, C.; Kramberg, M.; Wanner, D.; Hadana, H.; Rey, M.; Strasser, D.S.; Delahaye, S.; Hess, P.; Vezzali, E.; Mentzel, U.; Ménard, J.; Clozel, M.; Iglarz, M. Pharmacological characterization of aprocitentan, a dual endothelin receptor antagonist, alone and in combination with blockers of the renin angiotensin system, in two models of experimental hypertension. J. Pharmacol. Exp. Ther., 2019, 368(3), 462-473.
[http://dx.doi.org/10.1124/jpet.118.253864] [PMID: 30622171]

Bartunek, J.; Weinberg, E.O.; Tajima, M.; Rohrbach, S.; Katz, S.E.; Douglas, P.S.; Lorell, B.H.; Chronic, N. Chronic N(G)-nitro-L-arginine methyl ester-induced hypertension: Novel molecular adaptation to systolic load in absence of hypertrophy. Circulation, 2000, 101(4), 423-429.
[http://dx.doi.org/10.1161/01.CIR.101.4.423] [PMID: 10653835]

Kumar, S.; Prahalathan, P.; Raja, B. Syringic acid ameliorates l-NAME-induced hypertension by reducing oxidative stress. Naunyn Schmiedebergs Arch. Pharmacol., 2012, 385(12), 1175-1184.
[http://dx.doi.org/10.1007/s00210-012-0802-7] [PMID: 23079793]

Yang, L.; Ma, J.; Tan, Y.; Zheng, Q.; Dong, M.; Guo, W.; Xiong, L.; Yang, J.; Ren, J. Cardiac-specific overexpression of metallothionein attenuates L-NAME-induced myocardial contractile anomalies and apoptosis. J. Cell. Mol. Med., 2019, 23(7), 4640-4652.
[http://dx.doi.org/10.1111/jcmm.14375] [PMID: 31104354]

Tettey, A.; Jiang, Y.; Li, X.; Li, Y. Therapy for pulmonary arterial hypertension: Glance on nitric oxide pathway. Front. Pharmacol., 2021, 12, 767002.
[http://dx.doi.org/10.3389/fphar.2021.767002] [PMID: 34867394]

Garay-Gutiérrez, N.F.; Hernandez-Fuentes, C.P.; García-Rivas, G.; Lavandero, S.; Guerrero-Beltrán, C.E. Vaccines against components of the renin–angiotensin system. Heart Fail. Rev., 2021, 26(3), 711-726.
[http://dx.doi.org/10.1007/s10741-020-10033-1] [PMID: 32995973]

Downham, M.R.; Auton, T.R.; Rosul, A.; Sharp, H.L.; Sjöström, L.; Rushton, A.; Richards, J.P.; Mant, T.G.K.; Gardiner, S.M.; Bennett, T.; Glover, J.F. Evaluation of two carrier protein–angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man. Br. J. Clin. Pharmacol., 2003, 56(5), 505-512.
[http://dx.doi.org/10.1046/j.1365-2125.2003.01926.x] [PMID: 14651724]

O’Donnell, J.A.; Zheng, T.; Meric, G.; Marques, F.Z. The gut microbiome and hypertension. Nat. Rev. Nephrol., 2023, 19(3), 153-167.
[http://dx.doi.org/10.1038/s41581-022-00654-0]

Avery, E.G.; Bartolomaeus, H.; Maifeld, A.; Marko, L.; Wiig, H.; Wilck, N.; Rosshart, S.P.; Forslund, S.K.; Müller, D.N. The gut microbiome in hypertension. Circ. Res., 2021, 128(7), 934-950.
[http://dx.doi.org/10.1161/CIRCRESAHA.121.318065] [PMID: 33793332]

Chen, L.; He, F.J.; Dong, Y.; Huang, Y.; Wang, C.; Harshfield, G.A.; Zhu, H. Modest sodium reduction increases circulating short-chain fatty acids in untreated hypertensives. Hypertension, 2020, 76(1), 73-79.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14800] [PMID: 32475312]

Cookson, T.A. Bacterial-induced blood pressure reduction: mechanisms for the treatment of hypertension via the gut. Front. Cardiovasc. Med., 2021, 8, 721393.
[http://dx.doi.org/10.3389/fcvm.2021.721393] [PMID: 34485420]

Bravo, P.E.; Morse, S.; Borne, D.M.; Aguilar, E.A.; Reisin, E. Leptin and hypertension in obesity. Vasc. Health Risk Manag., 2006, 2(2), 163-169.
[http://dx.doi.org/10.2147/vhrm.2006.2.2.163] [PMID: 17319461]

Faulkner, J.L.; Bruder-Nascimento, T.; Belin de Chantemèle, E.J. The regulation of aldosterone secretion by leptin. Curr. Opin. Nephrol. Hypertens., 2018, 27(2), 63-69.
[http://dx.doi.org/10.1097/MNH.0000000000000384] [PMID: 29135585]

Mendoza, M.F.; Kachur, S.M.; Lavie, C.J. Hypertension in obesity. Curr. Opin. Cardiol., 2020, 35(4), 389-396.
[http://dx.doi.org/10.1097/HCO.0000000000000749] [PMID: 32398606]

von Schnurbein, J.; Manzoor, J.; Brandt, S.; Denzer, F.; Kohlsdorf, K.; Fischer-Posovszky, P.; Weißenberger, M.; Frank-Podlech, S.; Mahmood, S.; Wabitsch, M. Leptin is not essential for obesity-associated hypertension. Obes. Facts, 2019, 12(4), 460-475.
[http://dx.doi.org/10.1159/000501319] [PMID: 31357197]

Gao, Q.; Xu, L.; Cai, J. New drug targets for hypertension: A literature review. Biochim. Biophys. Acta Mol. Basis Dis., 2021, 1867(3), 166037.
[http://dx.doi.org/10.1016/j.bbadis.2020.166037] [PMID: 33309796]

Azizi, M.; Courand, P.Y.; Denolle, T.; Delsart, P.; Zhygalina, V.; Amar, L.; Lantelme, P.; Mounier-Vehier, C.; De Mota, N.; Balavoine, F.; Llorens-Cortes, C. 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.
[http://dx.doi.org/10.1097/HJH.0000000000002092] [PMID: 30882604]

Phase IIa study of the product QGC001 compared with placebo in patients with essential hypertension. Available from: https://clinicaltrials.gov/ct2/show/NCT02322450 (Accessed on: 2023-05-27).

Balavoine, F.; Azizi, M.; Bergerot, D.; De Mota, N.; Patouret, R.; Roques, B.P.; Llorens-Cortes, C. Randomised, double-blind, placebo-controlled, dose-escalating phase I study of QGC001, a centrally acting aminopeptidase a inhibitor prodrug. Clin. Pharmacokinet., 2014, 53(4), 385-395.
[http://dx.doi.org/10.1007/s40262-013-0125-y] [PMID: 24337978]

Brown, M.J.; Coltart, J.; Gunewardena, K.; Ritter, J.M.; Auton, T.R.; Glover, J.F. Randomized double-blind placebo-controlled study of an angiotensin immunotherapeutic vaccine (PMD3117) in hypertensive subjects. Clin. Sci., 2004, 107(2), 167-173.
[http://dx.doi.org/10.1042/CS20030381] [PMID: 15040783]

Weber, M.A.; Black, H.; Bakris, G.; Krum, H.; Linas, S.; Weiss, R.; Linseman, J.V.; Wiens, B.L.; Warren, M.S.; Lindholm, L.H. 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), 1423-1431.
[http://dx.doi.org/10.1016/S0140-6736(09)61500-2] [PMID: 19748665]

Drug Approval Package: Brand Name (Generic Name) NDA. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204410Orig1s000TOC.cfm (Accessed on: 2023-05-28).

Cohen, H.; Chahine, C.; Hui, A.; Mukherji, R. Bosentan therapy for pulmonary arterial hypertension. Am. J. Health Syst. Pharm., 2004, 61(11), 1107-1119.
[http://dx.doi.org/10.1093/ajhp/61.11.1107] [PMID: 15237563]

A research study to show the effect of aprocitentan in the treatment of difficult to control (resistant) high blood pressure (hypertension) and find out more about its safety. Available from: https://clinicaltrials.gov/ct2/show/NCT03541174 (accessed 2023-05-28).

Schlaich, M.P.; Bellet, M.; Weber, M.A.; Danaietash, P.; Bakris, G.L.; Flack, J.M.; Dreier, R.F.; Sassi-Sayadi, M.; Haskell, L.P.; Narkiewicz, K.; Wang, J.G.; Reid, C.; Schlaich, M.; Katz, I.; Ajani, A.; Biswas, S.; Esler, M.; Elder, G.; Roger, S.; Colquhoun, D.; Mooney, J.; De Backer, T.; Persu, A.; Chaumont, M.; Krzesinski, J.M.; Vanassche, T.; Girard, G.; Pliamm, L.; Schiffrin, E.; Merali, F.; Dresser, G.; Vallee, M.; Jolly, S.; Chow, S.; Wang, J.; Mu, J.; Yu, J.; Yuan, H.; Feng, Y.; Zhang, X.; Xie, J.; Lin, L.; Soucek, M.; Widimsky, J.; Cifkova, R.; Vaclavik, J.; Ullrych, M.; Lukac, M.; Rychlik, I.; Guldager Lauridsen, T.; Kantola, I.; Taurio, J.; Ukkola, O.; Ormezzano, O.; Gosse, P.; Azizi, M.; Courand, P-Y.; Delsart, P.; Tartiere, J.M.; Mahfoud, F.; Schmieder, R.; Stegbauer, J.; Lurz, P.; Koziolek, M.; Ott, C.; Toursarkissian, N.; Tsioufis, K.; Kyfnidis, K.; Manolis, A.; Patsilinakos, S.; Zebekakis, P.; Karavidas, A.; Denes, P.; Bezzegh, K.; Zsom, M.; Kovacs, L.; Sharabi, Y.; Elias, M.; Sukholutsky, I.; Yosefy, C.; Kenis, I.; Atar, S.; Volpe, M.; Maria Lorenza, M.; Taddei, S.; Grassi, G.; Veglio, F.; Son, J.W.; Kim, J-Y.; Park, J-I.; Lee, C.H.; Lee, H-Y.; Raugaliene, R.; Marcinkeviciene, J.E.; Kavaliauskiene, R.; Deinum, J.; Kroon, A.; van den Born, B-J.; Januszewicz, A.; Tykarski, A.; Walczewska, J.; Gaciong, Z.; Wiecek, A.; Chrostowska, M.; Kleinrok, A.; Krekora, J.; Kania, G.; Podrazka-Szczepaniak, A.; Golawski, C.; Podziewski, M.; Kaczmarek, B.; Skoczylas, G.; Wilkolaski, A.; Wozniak, I.; Janik-Palazzolo, M.; Rewerska, B.; Konradi, A.; Shvarts, Y.; Pecherina, T.; Nikolaev, K.; Liudmila, G.; Orlikova, O.; Mordovin, V.; Petrochenkova, N.; Kamalov, G.; Kosmacheva, E.; Nikolaev, K.; Tyrenko, V.; Gorbunov, V.; Obrezan, A.; Supryadkina, T.; Ler, I.; Kotenko, O.; Kuzin, A.; Martínez García, F.; Redon, J.; Oliveras, A.; Beltran Romero, L.; Shatylo, V.; Rudenko, L.; Bazylevych, A.; Rudyk, Y.; Karpenko, O.; Stanislavchuk, M.; Tseluyko, V.; Kushnir, M.; Asanov, E.; Sirenko, Y.; Yagensky, A.; Collier, D.; Gupta, P.; Webb, D.; MacLeod, M.; McLay, J.; Peace, A.; Arora, S.; Buchanan, P.; Harris, R.; Degarmo, R.; Guillen, M.; Karns, A.; Neutel, J.; Paliwal, Y.; Pettis, K.; Toth, P.D.; Wayne, J.M.; Butcher, M.B.; Diller, P.M.; Oparil, S.; Calhoun, D.; Brautigam, D.; Flack, J.; Goldman, J.M.; Rashidi, A.; Aslam, N.; Haley, W.; Andrawis, N.; Lang, B.; Miller, R.; Powell, J.; Dewhurst, R.; Pritchard, J.; Khanna, D.; Tang, D.; Gabra, N.; Park, J.; Jones, C.; Scott, C.; Luna, B.; Mussaji, M.; Bhagwat, R.; Bauer, M.; McGinty, J.; Nambiar, R.; Sangrigoli, R.; Davis, W.R.; Eaves, W.; McGrew, F.; Awad, A.; Bolster, E.; Scott, D.; Kalirao, P.; Dabel, P.; Calhoun, W.; Gouge, S.; Warren, M.; Lawrence, M.K.; Jamal, A.; El-Shahawy, M.; Mercado, C.; Kumar, J.; Velasquez-Mieyer, P.; Busch, R.; Lewis, T.; Rich, L. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): A multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet, 2022, 400(10367), 1927-1937.
[http://dx.doi.org/10.1016/S0140-6736(22)02034-7] [PMID: 36356632]

Clemmensen, C.; Smajilovic, S.; Smith, E.P.; Woods, S.C.; Bräuner-Osborne, H.; Seeley, R.J.; D’Alessio, D.A.; Ryan, K.K. Oral L-arginine stimulates GLP-1 secretion to improve glucose tolerance in male mice. Endocrinology, 2013, 154(11), 3978-3983.
[http://dx.doi.org/10.1210/en.2013-1529] [PMID: 23959939]

Sharif Kashani, B.; Tahmaseb Pour, P.; Malekmohammad, M.; Behzadnia, N.; Sheybani-Afshar, F.; Fakhri, M.; Chaibakhsh, S.; Naghashzadeh, F.; Aidenlou, S. Oral l-citrulline malate in patients with idiopathic pulmonary arterial hypertension and Eisenmenger Syndrome: A clinical trial. J. Cardiol., 2014, 64(3), 231-235.
[http://dx.doi.org/10.1016/j.jjcc.2014.01.003] [PMID: 24525046]

Yargiçoğlu, P.; Yaraş, N.; Aǧar, A.; Gümüşlü, S.; Abidin, İ.; Bilmen, S. Effects of N-nitro L -arginine methyl ester (L -NAME), a potent nitric oxide synthase inhibitor, on visual evoked potentials of rats exposed to different experimental stress models. Acta Physiol. Scand., 2004, 180(3), 307-316.
[http://dx.doi.org/10.1111/j.0001-6772.2003.01254.x] [PMID: 14962013]

Steven, S.; Oelze, M.; Brandt, M.; Ullmann, E.; Kröller-Schön, S.; Heeren, T.; Tran, L.P.; Daub, S.; Dib, M.; Stalleicken, D.; Wenzel, P.; Münzel, T.; Daiber, A. Pentaerythritol tetranitrate in vivo treatment improves oxidative stress and vascular dysfunction by suppression of endothelin-1 signaling in monocrotaline-induced pulmonary hypertension. Oxid. Med. Cell. Longev., 2017, 2017, 1-13.
[http://dx.doi.org/10.1155/2017/4353462] [PMID: 28337251]

Xu, D.; Guo, H.; Xu, X.; Lu, Z.; Fassett, J.; Hu, X.; Xu, Y.; Tang, Q.; Hu, D.; Somani, A.; Geurts, A.M.; Ostertag, E.; Bache, R.J.; Weir, E.K.; Chen, Y. Exacerbated pulmonary arterial hypertension and right ventricular hypertrophy in animals with loss of function of extracellular superoxide dismutase. Hypertension, 2011, 58(2), 303-309.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.166819] [PMID: 21730301]

Flierl, U.; Fraccarollo, D.; Widder, J.D.; Micka, J.; Neuser, J.; Bauersachs, J.; Schäfer, A. The nitric oxide donor pentaerythritol tetranitrate reduces platelet activation in congestive heart failure. PLoS One, 2015, 10(4), e0123621.
[http://dx.doi.org/10.1371/journal.pone.0123621] [PMID: 25928879]

Tissot, A.C.; Maurer, P.; Nussberger, J.; Sabat, R.; Pfister, T.; Ignatenko, S.; Volk, H.D.; Stocker, H.; Müller, P.; Jennings, G.T.; Wagner, F.; Bachmann, M.F. 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), 821-827.
[http://dx.doi.org/10.1016/S0140-6736(08)60381-5] [PMID: 18328929]

Chen, X.; Qiu, Z.; Yang, S.; Ding, D.; Chen, F.; Zhou, Y.; Wang, M.; Lin, J.; Yu, X.; Zhou, Z.; Liao, Y. Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals. Hypertension, 2013, 61(2), 408-416.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.201020] [PMID: 23184378]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors-FDA 2018. Available from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/sodium-glucose-cotransporter-2-sglt2-inhibitors (Accessed on: 2023-05-27).

Cantalupo, A.; Gargiulo, A.; Dautaj, E.; Liu, C.; Zhang, Y.; Hla, T.; Di Lorenzo, A. S1PR1 (Sphingosine-1-Phosphate Receptor 1) signaling regulates blood flow and pressure. Hypertension, 2017, 70(2), 426-434.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09088] [PMID: 28607130]

Free, A.; Brazg, R.; Matson, M.; Smith, W.; Chuck, L.; Georgopoulos, L. A phase 1, multi-center, randomized, double-blind, placebo controlled study to evaluate the safety/tolerability, pharmacokinetic and hemodynamic response following single ascending subcutaneous doses of PB1046 (VasomeraTM) in subjects With. Circulation, 2014, 130(Suppl. 2), A19112.

Mason, W. Efficacy and safety of EGT0001442 in patients with type 2 diabetes mellitus., 2011. Available from: https://clinicaltrials.gov/ct2/show/NCT01377844 (accessed 2023-05-28).

Nakayama, J. Daiichi Sankyo initiates phase 3 study of CS-3150, a novel mineralocorticoid receptor antagonist for treatment of essential hypertension-Press Releases-Media-Daiichi Sankyo; Tokyo, Japan. 2016. Available from: https://www.daiichisankyo.com/media/press_release/detail/index_3409.html

Ito, S.; Itoh, H.; Rakugi, H.; Okuda, Y.; Yoshimura, M.; Yamakawa, S. Double-blind randomized phase 3 study comparing esaxerenone (CS-3150) and eplerenone in patients with essential hypertension (ESAX-HTN Study). Hypertension., 2020, 75(1), 51-58.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13569]

Keith, C. Firibastat-first-in-class-hypertension en monothérapie-quantum genomics; , 2017. Available from: https://quantum-genomics.com/science/firibastat-first-in-classhypertensionen-monotherapie/ (Accessed on: 2023-05-28).

Clinical efficacy and safety evaluation of HCP1904-1 in essential hypertension patients. 2021. Available from: https://clinicaltrials.gov/ct2/show/NCT04820907

Manson, J.E.; Bassuk, S.S.; Lee, I.M.; Cook, N.R.; Albert, M.A.; Gordon, D.; Zaharris, E.; MacFadyen, J.G.; Danielson, E.; Lin, J.; Zhang, S.M.; Buring, J.E. The VITamin D and OmegA-3 TriaL (VITAL): Rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp. Clin. Trials, 2012, 33(1), 159-171.
[http://dx.doi.org/10.1016/j.cct.2011.09.009] [PMID: 21986389]

Cataliotti, A. Nesiritide in Hypertension, 2015. Available from: https://clinicaltrials.gov/ct2/show/NCT02608996 (Accessed on: 2023-05-28).

Study Details-clinical trial to evaluate the efficacy and safety of CKD-333 tablet. 2019. Available from: https://clinicaltrials.gov/study/NCT03583905 (Accessed on: 2023-10-21).

Bayer extends clinical development program for finerenone with Phase II study investigating the initial combination therapy with empagliflozin in patients with chronic kidney disease and type 2 diabetes. Available from: https://www.bayer.com/en/ca/bayer-extends-clinical-development-program-for-finerenone-with-phase-ii-study-investigating-the (Accessed on: 2023-05-28).

Ahmed, H.A.; Ishrat, T.; Pillai, B.; Bunting, K.M.; Vazdarjanova, A.; Waller, J.L.; Ergul, A.; Fagan, S.C. Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study. Behav. Brain Res., 2019, 359, 560-569.
[http://dx.doi.org/10.1016/j.bbr.2018.10.010] [PMID: 30296528]

Study Record. Available from: https://beta.clinicaltrials.gov/study/NCT03198793 (Accessed on: 2023-05-28).

Pemziviptadil (PB1046), a Long-acting, Sustained Release Human VIP Analogue, Intended to Provide Clinical Improvement to Hospitalized COVID-19 Patients at High Risk for Rapid Clinical Deterioration and Acute Respiratory Distress Syndrome (ARDS). Available from: https://clinicaltrials.gov/ct2/show/NCT04433546 (Accessed on:2023-05-28)

Youn, J.C.; Ihm, S.H.; Bae, J.H.; Park, S.M.; Jeon, D.W.; Jung, B.C.; Park, T.H.; Lee, N.H.; Song, J.M.; Yoon, Y.W.; Shin, E.S.; Sung, K.C.; Jung, I.H.; Pyun, W.B.; Joo, S.J.; Park, W.J.; Shin, J.H.; Kang, S.M. 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), 1412-1421.
[http://dx.doi.org/10.1016/j.clinthera.2014.07.004] [PMID: 25092393]

Citterio, L.; Bianchi, G.; Scioli, G.A.; Glorioso, N.; Bigazzi, R.; Cusi, D.; Staessen, J.A.; Cavuto, S.; Ferrandi, M.; Lanzani, C.; Li, X.; Lau, L.F.; Chiang, C.E.; Wang, T.D.; Wang, K.L.; Ferrari, P.; Manunta, P. Antihypertensive treatment guided by genetics: PEARL-HT, the randomized proof-of-concept trial comparing rostafuroxin with losartan. Pharmacogenomics J., 2021, 21(3), 346-358.
[http://dx.doi.org/10.1038/s41397-021-00214-y] [PMID: 33649520]

Efficacy and safety of HL-040XC in essential hypertension and hyperlipidemia. Available from: https://clinicaltrials.gov/ct2/show/NCT01541943 (Accessed on:2023-05-28).

Intervention for high-normal blood pressure in adults with type 2 diabetes-renal Substudy. Available from: https://clinicaltrials.gov/ct2/show/NCT04978649 (Accessed on: 2023-05-28).

Duowell® vs. Telmisartan Monotherapy in Mild Dyslipidemia Patients With Hypertension. Available from: https://clinicaltrials.gov/ct2/show/NCT03267329 (Accessed on:2023-05-28).

Kim, K.; Shin, M.S.; Ihm, S.H.; Youn, H.J.; Sung, K.C.; Chae, S.C.; Nam, C.W.; Seo, H.S.; Park, S.M.; Rhee, M.Y.; Kim, M.H.; Cha, K.S.; Kim, Y.J.; Kim, J.J.; Chun, K.J.; Yoo, B.S.; Park, S.; Shin, E.S.; Kim, D.S.; Il Kim, D.; Kim, K.H.; Joo, S.J.; Jeong, J.O.; Shin, J.; Kim, C.H. A randomized, double-blind, multicenter, phase III study to evaluate the efficacy and safety of fimasartan/amlodipine combined therapy versus fimasartan monotherapy in patients with essential hypertension unresponsive to fimasartan monotherapy. Clin. Ther., 2016, 38(10), 2159-2170.
[http://dx.doi.org/10.1016/j.clinthera.2016.07.008] [PMID: 27502326]

Study for the recording of adherence to treatment with perindopril/indapamide/amlodipine fixed dose combination. Available from: https://clinicaltrials.gov/ct2/show/NCT02655029 (Accessed on:2023-05-28).

The Special Drug Use-Results Survey on Long-Term Use of Telmisartan 80 Mg/Amlodipine 5 Mg/Hydrochlorothiazide 12.5 Mg Fixed Dose Combination Tablets in Patients with Hypertension. 2015. Available from: https://clinicaltrials.gov/ProvidedDocs/65/NCT03021265/Prot_000.pdf

Observational Study to Evaluate the Safety and Efficacy for Levacalm Tab. Versus Valsartan/Amlodipine Combination Therapy in Essential Hypertension Patients | Clinical Research Trial Listing (Orthostatic Hypertension | Lower Leg Edema) (NCT02415192). Available from: https://www.centerwatch.com/clinical-trials/listings/71814/lower-leg-edema-observational-study-evaluate-safety/ (Accessed on: 2023-05-29).

Muñoz, D.; Uzoije, P.; Reynolds, C.; Miller, R.; Walkley, D.; Pappalardo, S.; Tousey, P.; Munro, H.; Gonzales, H.; Song, W.; White, C.; Blot, W.J.; Wang, T.J. Polypill for cardiovascular disease prevention in an underserved population. N. Engl. J. Med., 2019, 381(12), 1114-1123.
[http://dx.doi.org/10.1056/NEJMoa1815359] [PMID: 31532959]

Fereidoon Shahidi, Y. Z. Bioactive peptides. J. AOAC Int., 2008, 91(4), 914-931.

Pihlanto-Leppälä, A. Bioactive peptides derived from bovine whey proteins. Trends Food Sci. Technol., 2000, 11(9-10), 347-356.
[http://dx.doi.org/10.1016/S0924-2244(01)00003-6]

Tong, L.T.; Fujimoto, Y.; Shimizu, N.; Tsukino, M.; Akasaka, T.; Kato, Y.; Iwamoto, W.; Shiratake, S.; Imaizumi, K.; Sato, M. Rice α-globulin decreases serum cholesterol concentrations in rats fed a hypercholesterolemic diet and ameliorates atherosclerotic lesions in apolipoprotein E-deficient mice. Food Chem., 2012, 132(1), 194-200.
[http://dx.doi.org/10.1016/j.foodchem.2011.10.056] [PMID: 26434280]

Bamdad, F.; Sun, X.; Guan, L.L.; Chen, L. Preparation and characterization of antimicrobial cationized peptides from barley (Hordeum vulgare L.) proteins. Lebensm. Wiss. Technol., 2015, 63(1), 29-36.
[http://dx.doi.org/10.1016/j.lwt.2015.03.012]

Power, O.; Jakeman, P.; FitzGerald, R.J. Antioxidative peptides: Enzymatic production, in vitro and in vivo antioxidant activity and potential applications of milk-derived antioxidative peptides. Amino Acids, 2013, 44(3), 797-820.
[http://dx.doi.org/10.1007/s00726-012-1393-9] [PMID: 22968663]

de Oliveira Filho, J.G.; Rodrigues, J.M.; Valadares, A.C.F.; de Almeida, A.B.; Valencia-Mejia, E.; Fernandes, K.F.; Lemes, A.C.; Alves, C.C.F.; Sousa, H.A.F.; da Silva, E.R.; Egea, M.B.; Dyszy, F.H. Bioactive properties of protein hydrolysate of cottonseed byproduct: Antioxidant, antimicrobial, and Angiotensin-Converting Enzyme (ACE) inhibitory activities. Waste Biomass Valoriz., 2021, 12(3), 1395-1404.
[http://dx.doi.org/10.1007/s12649-020-01066-6]

Shimizu, M.; Sawashita, N.; Morimatsu, F.; Ichikawa, J.; Taguchi, Y.; Ijiri, Y.; Yamamoto, J. Antithrombotic papain-hydrolyzed peptides isolated from pork meat. Thromb. Res., 2009, 123(5), 753-757.
[http://dx.doi.org/10.1016/j.thromres.2008.07.005] [PMID: 18930309]

Stadtman, E.R. Protein oxidation and aging. Free Radic. Res., 2006, 40(12), 1250-1258.
[http://dx.doi.org/10.1080/10715760600918142] [PMID: 17090414]

Rojas-Humpire, R.; Olarte-Durand, M.; Medina-Ramirez, S.; Gutierrez-Ajalcriña, R.; Canaza, J.F.; Huancahuire-Vega, S. Insulin resistance indexes as biomarkers of lifetime cardiovascular risk among adults from Peru. J. Nutr. Metab., 2021, 2021, 1-8.
[http://dx.doi.org/10.1155/2021/6633700] [PMID: 33833874]

Okagu, I.U.; Ezeorba, T.P.C.; Aham, E.C.; Aguchem, R.N.; Nechi, R.N. Recent findings on the cellular and molecular mechanisms of action of novel food-derived antihypertensive peptides. Food Chem.: Mol. Sci., 2022, 4, 100078.
[http://dx.doi.org/10.1016/j.fochms.2022.100078] [PMID: 35415696]

Ghatage, T.; Goyal, S.G.; Dhar, A.; Bhat, A. Novel therapeutics for the treatment of hypertension and its associated complications: Peptide- and nonpeptide-based strategies. Hypertension Research, 2021, 44(7), 740-755.
[http://dx.doi.org/10.1038/s41440-021-00643-z]

A dose-escalation study in subjects with pulmonary arterial hypertension (PAH). Available from: https://clinicaltrials.gov/ct2/show/NCT03177603 (Accessed on: 2023-05-28).

Mechanisms of pregnancy vascular adaptations. Available from: https://clinicaltrials.gov/ct2/show/NCT03806283 (Accessed on: 2023-05-28).

Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a treatment for patients with COVID-19. Available from: https://clinicaltrials.gov/ct2/show/NCT04335136 (Accessed on: 2023-05-28).

Angiotensin 1-7 in Obesity Hypertension. Available from: https://clinicaltrials.gov/ct2/show/NCT03604289 (Accessed on: 2023-05-28).

Angiotensin-(1-7) in peripheral arterial disease. Available from: https://clinicaltrials.gov/ct2/show/NCT03240068 (Accessed on: 2023-05-28).

MANP in Hypertension and Metabolic Syndrome. Available from: https://clinicaltrials.gov/ct2/show/NCT03781739 (Accessed on: 2023-05-28).

Observation on the effect of sacubitril/valsartan in advanced Chronic Kidney Disease CKD patients with heart failure. Available from: https://clinicaltrials.gov/ct2/show/NCT03771729 (Accessed on: 2023-05-28).

Safety and efficacy of ANX-042 in human cardiorenal syndrome. Available from: https://clinicaltrials.gov/ct2/show/NCT03019653 (Accessed on: 2023-05-28).

Safety study of cenderitide in chronic stable heart failure with moderate renal impairment. Available from: https://clinicaltrials.gov/ct2/show/NCT02603614 (Accessed on: 2023-05-30).

Riociguat in children with Pulmonary Arterial Hypertension (PAH). Available from: https://clinicaltrials.gov/ct2/show/NCT02562235 (Accessed on:2023-05-30).

Patient-reported Outcomes in Vericiguat-treated Patients With HFpEF. Available from: https://clinicaltrials.gov/ct2/show/NCT03547583 (Accessed on: 2023-05-30).

A study of the effect of IW-1973 on the exercise capacity of patients with heart failure with preserved ejection fraction (HFpEF). Available from: https://clinicaltrials.gov/ct2/show/NCT03254485 (Accessed on:2023-05-30).

A study to evaluate the soluble guanylate cyclase (sGC) stimulator IW-1973 in diabetic nephropathy/diabetic kidney disease as measured by albuminuria. Available from: https://clinicaltrials.gov/ct2/show/NCT03217591 (Accessed on: 2023-05-30).

Vitamin D and Omega-3 hypertension trial (VITAL Hypertension). Available from: https://clinicaltrials.gov/ct2/show/NCT01653678 (Accessed on: 2023-05-30).

The effect of antioxidants on skin blood flow during local heating. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03680638 (Accessed on: 2023-05-30).

The Effect of Local Antioxidant Therapy on Racial Differences in Vasoconstriction. Available from: https://clinicaltrials.gov/ct2/show/NCT03680404 (Accessed on: 2023-05-30).