Refractory arterial hypertension: hyperactivity of the sympathetic nervous system, kidney and approaches to antihypertensive drug therapy
https://doi.org/10.18705/1607-419X-2022-28-5-600-608
Abstract
Improving blood pressure (BP) control and reducing the risk of developing unfavorable cardiovascular and renal outcomes in patients with refractory hypertension (HTN) is an urgent problem of cardiology. According to clinical studies, patients with refractory HTN receiving intensive diuretic therapy with chlorthalidone and a mineralcorticoid receptor antagonist differ from patients with refractory HTN by a higher sympathetic nervous system (SNS) activity. Overactivity of sympathetic nerves may be one of the key pathogenetic factors that is involved in the kidney in the formation of refractory HTN, exerting a direct stimulating effect on the type 3 Na+ / H+ exchanger (NHE3) and type 2 sodium glucose cotransporter (SGLT2), which are involved in BP control by mechanism of pressure natriuresis. The review presents data on the peculiarities of sympathetic regulation of sodium tubular transport and the results of studies devoted the elucidating in the patients with resistant and refractory HTN the clinical efficacy of SGLT2 inhibitors glyflozins, sympatholytic reserpine and brain aminopeptidase A inhibitor firibastat, which suppresses the activity of central structures of SNS.
About the Authors
O. B. KuzminRussian Federation
Oleg B. Kuzmin, MD, PhD, Professor, Head, Department of Pharmacology
7 Park Avenue, Orenburg, 460000
V. V. Zhezha
Russian Federation
Vladislav V. Zhezha, MD, PhD, Associate Professor, Department of Pharmacology
Orenburg
N. V. Buchneva
Russian Federation
Nataliya N. Buchneva, MD, PhD, Associate Professor, Department of Pharmacology
Orenburg
L. N. Landar
Russian Federation
Larisa N. Landar, MD, PhD, Associate Professor, Department of Pharmacology
Orenburg
References
1. Buhnerkempe MG, Botchway A, Prakash V, Al-Akhar M, Nalonso-Morales CE, Calhoun DA et al. Prevalence of refractory hypertension in the United States from 1999 to 2014. J Hypertens. 2019;37(9):1797–1804. doi:10.1097/HJH.0000000000002103
2. Armario P, Calhoun DA, Oliveras A, Blanch P, Vinyoles E, Banegas JR et al. Prevalence and clinical characteristics of refractory hypertension. J Am Heart Assoc. 2017;6(12):e007365. doi:10.1161/JAHA.117.007365
3. Chedier B, Cortez AF, Roderjan CN, Cavalcanti AH, de Carvalho-Carlos FO, Moreira Dos Santos BD et al. Prevalence and clinical profile of refractory hypertension in a large cohort of patients with resistant hypertension. J Hum Hypertens. 2021;35(8):709–717. doi:10.1038/s41341-020-00406-2
4. Cardoso CR, Salles JF. Refractory hypertension and risks of adverse cardiovascular events and mortality in patients with resistant hypertension: a prospective cohort study. J Am Heart Assoc. 2020;9(17):e017634. doi:10.1161/JAHA.120.017634
5. Buhnerkempe MG, Prakas V, Botchway A, Adekola B, Cohen JB, Rahman M et al. Adverse health outcomes associated with refractory and treatment-resistant hypertension in the Chronic Renal Insufficiency Cohort. Hypertension. 2021;77(1):72–81. doi:10.1161/HYPERTENSIONAHA.120.15064
6. Dudenbostel T, Acelajado MC, Pisoni R, Li P, Oparil S, Calhoun DA. Refractory hypertension: evidence of heightened sympathetic activity as a cause of antihypertensive treatment failure. Hypertension. 2015;66(1):126–133. doi:10.1161/HYPERTENSIONAHA.115.05449
7. Kuzmin OB, Buchneva NV, Zhezha VV, Serdyuk SV. Uncontrolled arterial hypertension: kidney, neurohormonal imbalance, and approaches to antihypertensive drug therapy. Kardiologiia = Cardiology. 2019;59(12):64–71. In Russian. doi:10.18087/cardio.2019.n547
8. Falkovskaya AYu, Mordovin VF, Pekarskiy SE, Manukyan MA, Ripp TM, Zyubanova IV et al. Refractory and resistant hypertension in patients with type 2 diabetes mellitus: different response to renal denervation. Kardiologiia = Cardiology. 2021;61(2):54–61. In Russian]. doi:10.18087/cardio.2021.n1102
9. Guyton AC. Blood pressure control — special role of the kidneys and body fluids. Science. 1991;252(5014):1813–1816. doi:10.1126/science.2063193
10. Kuzmin OB, Pugaeva MO, Chub SV. Landar L.N. Renal mechanisms of essential hypertension. Nephrology (Saint-Peterburg). 2005;9(2):23–29. In Russian.
11. Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E et al. Hypertension: physiology and pathophysiology. Compr Physiol. 2012;2(4):2393–2402. doi:10.1002/cphy.c110058
12. Calhoun DA, Booth JN, Oparil S, Irvin MR, Shimbo D, Lackland DT et al. Refractory hypertension: determination, prevalence, risk factors, and comorbidities in a large populationbased cohort. Hypertension. 2014;63(3):451–458. doi:10.1161/HYPERTENSIONAHA.113.02026
13. Velasco A, Siddiqui M, Kreps E, Kolakalapudi P, Dudenbostel T, Arora G et al. Refractory hypertension is not attributable to intravascular fluid retention as determined by intracardiac volumes. Hypertension. 2018;72(2):343–349. doi:10.1161/HYPERTENSIONAHA.118.10965
14. Pontes RB, Crajoinas RO, Nishi EE, Oliveira-Sales EB, Girardi AC, Campos RR et al. Renal nerve stimulation leads to the activation of the Na+/H+ exchanger isoform 3 via angiotensin II type 1 receptor. Am J Physiol Renal Physiol. 2015;308(8):F848– 856. doi:10.1152/ajprenal.00515.2014
15. Osborn JW, Tyshynsky R, Vulchanova L. Function of renal nerves in kidney physiology and pathophysiology. Annu Rev Physiol. 2021;83:439–450. doi:10.1146/annurevphysiol031620-091656
16. Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in the regulation of the sodium-glucose cotransporter 2. J Hypertens. 2017;35(10):2059–2068. doi:10.1097/HJH.0000000000001434
17. Duan X-P, Gu L, Xiao Y, Gao Z-H, Wu P, Zhang Y-H et al. Norepinephrine-induced stimulation of Kir4.1/Kir5.1 is required for the activation of the NaCl cotransporter in distal convoluted tubule. Hypertension. 2019;73(1):112–120. doi:10.1161/HYPERTENSIONAHA.118.11621
18. Puleo F, Kim K, Frame AA, Walsh KR, Ferdaus MZ, Moreira JD et al. Sympathetic regulation of the NCC (sodium chloride cotransporter) in Dahl salt sensitive hypertension. Hypertension. 2020;76(5):1461–1469. doi:10.1161/HYPERTENSIONAHA.120.15928
19. 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 (PATHWAY2): a randomized, double-blind, crossover trial. Lancet. 2015;386(10008):2059–2068. doi:10.1016/S0140-6736(15)00257-3
20. Kriger EM, Drager LF, Giorgi DM, Pereira AC, Barreto-Filho JA, Nogueira AR et al. Spironolactone versus clonidine as a fourths-drug therapy for resistant hypertension: the ReHOT randomized study (Resistant Hypertension Optimal Treatment). Hypertension. 2018;71(4):681–690. doi:10.1161/HYPERTENSIONAHA.117.10662
21. Siddiqui M, Bhatt H, Judd EK, Oparil S, Calhoun DA. Reserpine substantially lowers blood pressure in patients with refractory hypertension: a proof of concept study. Am J Hypertens. 2020;33(8):741–747. doi:10.1093/ajh/hpaa042
22. Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75(1):33–59. doi:10.1007/s40265-014-0337-y
23. McGuire DK, Shin WJ, Cosentino F, Charbonnel B, Cherney DZ, Dagogo-Jack S et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6(2):148–158. doi:10.1001/jamacardio.2020.4511
24. Kuzmin OB, Belyanin VV, Buchneva NV, Landar LN, Serdyuk SV. Sodium and glucose cotransporter type 2 inhibitors: a new class of drugs for treatment of diabetic and non-diabetic nephropathy. Nephrology (SaintPetersburg). 2021;24(4):33–41. In Russian. doi:10.36485/1561-6274-2021-25-4-33-41
25. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Methieu C et al. Update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020;43(2):487–493. doi:10.2337/dci19-0066
26. Sha S, Polidori D, Heise T, Natarajan J, Farrel K, Wang SS et al. Effect of sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087–1895. doi:10.1111/dom.12322
27. Solini A, Giannini L, Seghiery M, Vitolo E, Taddei S, Ghiadoni L et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16(1):138. doi:10.1186/s12933-017-0621-8
28. De Stefano A, Tesauro M, Di Daniele N, Vizioli G, Schinzari F et al. Mechanisms of SGLT2 (sodium-glucose transporter type 2) inhibition-induced relaxation in arteries from human visceral adipose tissue. Hypertension. 2021;77(2):729–738. doi:10.1161/HYPERTENSIONAHA.120.16466
29. Sano M, Chen S, Imazeki H, Ochiai H, Seino Y. Changes in heart rate in patients with type 2 diabetes mellitus after treatment with luseogliflozin: subanalysis of placebo-controlled, double-blind clinical trials. J Diabetes Investig. 2018;9(3):638–641. doi:10.1111/jdi.12726
30. Scheen AJ. Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure. Curr Cardiol Rep. 2019;21(8):70. doi:10.1007/s11886-019-1165-1
31. Jordan J, Tank J, Heusser K, Heise T, Wanner C, Heer M et al. The effect of empagliflozin on muscle sympathetic nerve activity in patients with type 2 diabetes mellitus. J Am Soc Hypertens. 2017;11(9):604–612. doi:10.1016/j.jash.2017.07.005
32. Kiuchi S, Hisatake S, Kabuki T, Oka T, Dobashi S, Hashimoto H et al. Long-term use of ipragliflozin improved cardiac sympathetic nerve activity in patients with heart failure: a case report. Drug Discov Ther. 2018;12(1):51–54. doi:10.5582/ddt.2017.01069
33. Lymperopouos A, Borges JI, Cora N, Sizova A. Sympatholytic mechanisms for the beneficial cardiovascular effects of SGLT2 inhibitors: a research hypothesis for dapagliflozin’s effects in adrenal gland. Int J Mol Sci. 2021;22(14):7684. doi:10.3390/ijms22147684
34. Ferreira JP, Fitchett D, Ofstad AP, Kraus BJ, Wanner C, Zwiener I et al. Empagliflozin for patients with presumed resistant hypertension: a post-hos analysis of the EMPA-REG-OUTCOME trial. Am J Hypertens. 2020;33(12):1092–1101. doi:10.1093/ajh/hpaa073
35. Ye N, Jardine MJ, Oshima M, Hoekman G. Blood pressure effects of canagliflozin and clinical outcomes in type 2 diabetes and chronic kidney disease. Circulation. 2021;143(18):1735–1749. doi:10.1161/CIRCULATIONAHA.120.048740
36. Alomar SA, Alghabban SA, Alharbi HA, Almoqati MF, Alduraibi Y, Abu-Zaid A. Firibastat, the first-in-class brain aminopeptidase inhibitor, in the management of hypertension: a review of clinical trials. Avicenna J Med. 2021;11(1):1–7. doi:10.4103/ajm.ajm_117_20
37. Su C, Xue J, Ye C, Chen A. Role of the central reninangiotensin system in hypertension. Int J Mol Med. 2021;47(6):95. doi:10.3892/ijmm.2021.4928
38. Hmazzou R, Mare Y, Flahault A, Gerbier R, De Mota N, Llorens-Cortes C. Brain ACE2 activation following brain aminopeptidase A blockade by firibastat in salt-dependent hypertension. Clin Sci (London). 2021;35(6):775–791. doi:10.1042/CS20201385
39. Marc Y, Hmazzou R, Balavoine F, Flahault A, LlorensCortes C. Central antihypertensive effects of chronic treatment with RB 150: an orally active aminopeptidase A inhibitor in desoxycorticosterone acetate-salt rats. J Hypertens. 2018;36(3):641– 650. doi:10.1097/HJH.0000000000001563
40. Ferdinand KC, Balavoine F, Besse B, Black HR, Desbrandes S, Dittrich HC et al. Efficacy and safety of firibastat, a first-inclass brain aminopeptidase A inhibitor, in hypertensive overweight patients of multiple ethnic origins. Circulation. 2019;140(2):138– 146. doi:10.1161/CIRCULATIONAHA.119.040070
41. Firibastat in Treatment-resistant Hypertension (FRESH). ClinicalTrials.gov. NCT04277884
42. Yaffe D, Forrest LR, Schuldiner S. The ins and outs of vesicular monoamine transportes. J Gen Physiol. 2018;150(5):671– 682. doi:10.1085/jgp201711980
43. Shamon SD, Perez MI. Blood pressure-lowering efficacy of reserpine for primary hypertension. Cochrane Database Syst Rev. 2016;12(12): CD007655. doi:10.1002/14651858.CD007655
44. Siddiqui M, Bhatt H, Judd EK, Oparil S, Calhoun DA. Reserpine substantially lowers blood pressure in patients with refractory hypertension: proof-of concept study. Am J Hypertens. 2020;33(8):741–747. doi:10.1093/ajh/hpaa042
Supplementary files
Review
For citations:
Kuzmin O.B., Zhezha V.V., Buchneva N.V., Landar L.N. Refractory arterial hypertension: hyperactivity of the sympathetic nervous system, kidney and approaches to antihypertensive drug therapy. "Arterial’naya Gipertenziya" ("Arterial Hypertension"). 2022;28(5):600-608. (In Russ.) https://doi.org/10.18705/1607-419X-2022-28-5-600-608