Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCtkFQ9MYX7SY8gwKYbhtQHZy00452S0066-782X2021000400452abc.2020116410.36660/abc.20201164MinieditorialNovas Perspectivas no Tratamento da Hipertensão0000-0002-9591-3093LopesHeno F.1Universidade de São Paulo Instituto do Coração – CardiopneumologiaSão PauloSPBrasilUniversidade de São Paulo Instituto do Coração – Cardiopneumologia, São Paulo, SP – Brasil.Correspondência: Heno F. Lopes • Universidade de São Paulo Instituto do Coração – Cardiopneumologia - Av. Dr. Eneas de C. Aguiar, 44 Bloco 2, sala 8. CEP 05403-900, São Paulo, SP – Brasil. E-mail: hipheno@gmail.com230420210320211163452453This is an open-access article distributed under the terms of the Creative Commons Attribution LicensePalavras-chaveHipertensão/tendênciasPressão ArterialDiuréticos/uso terapêutico; Doenças Cardiovasculares/complicaçõesTratamento Farmacológico/tendências
A hipertensão arterial é certamente o maior fator de risco para doenças cardiovasculares. Tiocianatos, barbitúricos, brometos e bismuto foram testados no tratamento da hipertensão arterial no início da década de 1940.1 O uso dessas drogas foi interrompido por se mostrarem ineficazes e com diversos efeitos colaterais. Em meados da década de 1950, bloqueadores ganglionares como hexametônio, pentolínio, mecamilamina e substâncias simpatolíticas de ação periférica (guanetidina) foram testadas no tratamento da hipertensão arterial e mostraram-se eficazes na sua redução, mas pouco toleradas.2 Novos medicamentos foram introduzidos para este fim na década de 1950, incluindo diuréticos.3
Em 1956, em estudo observacional, Moser e Magaulay acompanharam 106 pacientes hipertensos que receberam rauwolfia, hidralazina, reserpina, mecamilamina e clorotiazida como tratamento para hipertensão arterial, isoladamente ou em combinação. A dose de clorotiazida utilizada neste estudo variou de 0,5 a 1,5 gramas e a combinação de clorotiazida resultou em melhor controle da pressão arterial. Desde esse estudo observacional até os dias atuais, vários estudos relacionados ao tratamento farmacológico da hipertensão foram realizados.4 O primeiro estudo randomizado e controlado por placebo realizado foi o Veteran Administration (VA), publicado em 1967.5 É importante notar que o critério de inclusão do estudo para o tratamento ativo versus placebo foi a pressão diastólica entre 115 e 129 mmHg. Após a publicação do estudo VA-I em 19675 e do VA-II em 19706, diversos estudos randomizados controlados abordando o tratamento da hipertensão arterial foram realizados. O foco inicial do tratamento para hipertensão arterial foi a excreção renal de sódio, uma vez que se pensava inicialmente que as doenças renais fossem a principal causa da hipertensão. Posteriormente, os mecanismos fisiopatológicos da hipertensão foram elucidados e a terapia foi direcionada aos principais deles. A ativação do sistema nervoso simpático como importante mecanismo fisiopatológico da hipertensão já havia sido percebida na década de 1950, e várias formas de bloqueio do sistema nervoso simpático e até simpatectomia foram então testadas.7 A partir da década de 1980, com a introdução da microneurografia e a técnica de spillover de norepinefrina, a importância da ativação do sistema nervoso simpático na fisiopatologia da hipertensão tornou-se ainda mais evidente.8,9 Embora mal tolerados, os bloqueadores adrenérgicos centrais e periféricos sempre fizeram parte do tratamento da hipertensão arterial.10 A ativação do sistema renina-angiotensina aldosterona (SRA) e a curva de pressão da natriurese alterada são dois outros mecanismos importantes na fisiopatologia da hipertensão arterial. Atualmente, o uso de diuréticos para correção da curva alterada de pressão da natriurese e de inibidores do sistema renina-angiotensina aldosterona, que atuam em diferentes locais, tem sido rotina no tratamento da hipertensão arterial.11
O sistema nervoso simpático e o sistema renina-angiotensina aldosterona estão envolvidos diretamente nos mecanismos fisiopatológicos da hipertensão arterial. Um aspecto importante nesse sentido é que a ativação desses dois sistemas está relacionada a um processo inflamatório no paciente hipertenso.12 Eles interagem com citocinas inflamatórias, como a interleucina-6 (IL-6) e o fator de necrose tumoral alfa (TNF-α). O sistema nervoso simpático estimula a secreção de citocinas pró-inflamatórias e, ao mesmo tempo, funciona como fonte de citocinas.13 A angiotensina-II é um importante fator pró-inflamatório. Está relacionada à produção de TNF-α e IL-6 e estimula a proteína-1 quimioatraente de monócitos (MCP-1) e o fator nuclear B.14,15 Por outro lado, o tipo de droga utilizada no tratamento de pacientes hipertensos pode reduzir o processo inflamatório relacionado à hipertensão. O uso de moxonidina simpatolítica de ação central no tratamento de mulheres hipertensas na pós-menopausa resultou em uma redução do TNF-α.16
Em um estudo envolvendo pacientes com hipertensão resistente, Barbaro et al. encontraram valores mais elevados de TNF-α em pacientes com hipertensão resistente em comparação com o grupo normotenso.17 Os resultados apontam para TNF-α como um possível mediador de dano vascular em pacientes com hipertensão resistente. Bautista et al.,18 encontraram associação dos níveis de IL-6 e TNF-α com os valores da pressão arterial, independentemente da idade, sexo, índice de massa corporal, história familiar de hipertensão e outras citocinas pró-inflamatórias. No estudo,19 os autores avaliaram o infliximabe, medicamento inibidor do TNF-α, para o tratamento de hipertensos resistentes. O infliximabe em dose única de 3 mg/kg (infusão) resultou em queda de 6,3 mmHg na pressão arterial média e 4,9 mmHg na pressão diastólica. Este efeito agudo do infliximabe na pressão arterial abre uma nova perspectiva no tratamento da hipertensão arterial. Independentemente da queda da pressão arterial, o uso de anti-TNF-α bloqueia um fator que pode ser agravante nas lesões vasculares. Sabe-se que a gravidade da hipertensão está relacionada a um ciclo vicioso decorrente da ativação dos sistemas pressóricos (sistema nervoso simpático e sistema renina-angiotensina-aldosterona).20 A interrupção desse ciclo é essencial para a proteção do organismo e para uma melhor ação de drogas hipotensoras já bem conhecidas.
Minieditorial referente ao artigo: Efeitos da Terapia com Anti-TNF-Α na Pressão Arterial em Pacientes com Hipertensão Resistente: Um Estudo Piloto Randomizado, Duplo-Cego e Controlado por Placebo
ReferênciasMoserMHistorical Perspectives on the Management of HypertensionJ Clin Hypertens20068Suppl 215201. Moser M. Historical Perspectives on the Management of Hypertension. J Clin Hypertens. 2006;8(Suppl 2):15–20.MoserMMattinglyTWCritical evaluation of drug therapy of hypertensionPostgraduate medicine19551753513612. Moser M, Mattingly TW. Critical evaluation of drug therapy of hypertension - Postgraduate medicine 1955;17(5):351-61.MoserMMagaulayAIChlorothiazide as an Adiunct in the Treatment of Essential HypertensionAm J Cardiol1959322142193. Moser M, and Magaulay AI. Chlorothiazide as an Adiunct in the Treatment of Essential Hypertension. Am J Cardiol 1959;3(2):214-9.SaklayenMGDeshpandeNVTimeline of History of Hypertension TreatmentFront Cardiovasc Med201633310.3389/fcvm.2016.000034. Saklayen MG and Deshpande NV. Timeline of History of Hypertension Treatment. Front Cardiovasc Med. 2016;3(:3. doi: 10.3389/fcvm.2016.00003.Veterans Administration Cooperative Study Group on Antihypertensive AgentsEffect of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm HgJAMA196720211102810345. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effect of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA. 1967;202(11):1028–34.Veterans Administration Cooperative Study Group on Antihypertensive AgentsEffects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm HgJAMA19702137114311526. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213(7):1143–52.MoserMMattinglyTWCritical evaluation of drug therapy of hypertensionPostgrad Med19551753513617. Moser M, Mattingly TW. Critical evaluation of drug therapy of hypertension - Postgrad Med. 1955;17(5):351-61.AndersonEASinkeyCALawtonWJMarkALElevated sympathetic nerve activity in borderline hypertensive humans: evidence from direct intraneural recordingsHypertension1988142127712838. Anderson EA, Sinkey CA, Lawton WJ, Mark AL. Elevated sympathetic nerve activity in borderline hypertensive humans: evidence from direct intraneural recordings. Hypertension. 1988;14(2):1277-83.EslerMLambertGJenningsGIncreased regional sympathetic nervous activity in human hypertension: causes and consequencesJ Hypertens199087S53S579. Esler M, Lambert G, Jennings G. Increased regional sympathetic nervous activity in human hypertension: causes and consequences. J Hypertens. 1990;8(7):S53–57.DeQuattroVLiDSympatholytic therapy in primary hypertension: a user friendly role for the futureJournal of Human Hypertension200216Suppl 1S118S12310. DeQuattro V and Li D. Sympatholytic therapy in primary hypertension: a user friendly role for the future. Journal of Human Hypertension 2002; 16(Suppl 1):S118–S123.ReboussinDMAllenNBGriswoldMEGuallarEHongYLacklandDTSystematic Review for the 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 GuidelinesHypertension2018716e116e13511. Reboussin DM, Allen NB, Griswold ME, Guallar E, Hong Y, Lackland DT, et al. Systematic Review for the 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;71(6):e116-e135.ChaeCULeeRTRifaiNRidkerPMBlood pressure and inflammation in apparently healthy menHypertension200138339940312. Chae CU, Lee RT, Rifai N, and Ridker PM. Blood pressure and inflammation in apparently healthy men. Hypertension 2001;38(3): 399 – 403.ZhangZHWeiSGFrancisJFelderRBCardiovascular and renal sympathetic activation by blood-borne TNF in rat: the role of central prostaglandinsAm J Physiol Regul Integr Comp Physiol20032844R916R92713. Zhang ZH, Wei SG, Francis J, and Felder RB. Cardiovascular and renal sympathetic activation by blood-borne TNF in rat: the role of central prostaglandins. Am J Physiol Regul Integr Comp Physiol. 2003;284(4):R916 – R927.HanYRungeMSBraiserARAngiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-B transcription factorsCirc Res199984669570314. Han Y, Runge MS, and Braiser AR. Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-B transcription factors. Circ Res. 1999;84(6): 695– 703.Ruiz-OrtegaMRuperezMLorenzoOEstebanVBlancoJMezzanoSEgidoJAngiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidneyKidney Int200282SupplS12S2215. Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, and Egido J. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int. 2002;82(Suppl):S12–S22.Poyhonen-AlhoMKManhemKKatzmanPKibarskisAAntikainenRLErkkolaRUCentral sympatholytic therapy has anti-inflammatory properties in hypertensive postmenopausal womenJ Hypertens200826122445244916. Poyhonen-Alho MK, Manhem K, Katzman P, Kibarskis A, Antikainen RL, Erkkola RU, et al. Central sympatholytic therapy has anti-inflammatory properties in hypertensive postmenopausal women. J Hypertens. 2008; 26(12):2445–9.BarbaroNRAraújoTMTanus-SantosJEAnhêGFFontanaVMorenoHVascular Damage in Resistant Hypertension: TNF-Alpha Inhibition Effects on Endothelial CellsBioMed Res Internat201520151-863159417. Barbaro NR, Araújo TM, Tanus-Santos JE, Anhê GF, Fontana V, Moreno H Vascular Damage in Resistant Hypertension: TNF-Alpha Inhibition Effects on Endothelial Cells. BioMed Res Internat. 2015;2015:1-8.631594BautistaLEVeraLMArenasIAGamarraGIndependent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-a) and essential hypertensionJournal of Human Hypertension200519214915418. Bautista LE, Vera LM, Arenas IA, and Gamarra G. Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-a) and essential hypertension. Journal of Human Hypertension 2005;19(2):149–54.FariaAPRitterAMVSanta-CatharinaASouzaDPEstephNaseriEPBertoloManoel B.Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo- Controlled Pilot StudyArq Bras Cardiol2021116344345119. Faria AP, Ritter AMV, Santa-Catharina A, Souza DP, EstephNaseri EP, Manoel B. Bertolo, et al. Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo- Controlled Pilot Study. Arq Bras Cardiol. 2021; 116(3):443-451.MatsukawaTManoTGotohEIshiiMElevated Sympathetic Nerve Activity in Patients with Accelerated Essential HypertensionJ Clin Invest1993921252820. Matsukawa T, Mano T, Gotoh E, Ishii M. Elevated Sympathetic Nerve Activity in Patients with Accelerated Essential Hypertension. J Clin Invest. 1993;92(1):25-8.Short EditorialNew Perspectives in the Treatment of Hypertension0000-0002-9591-3093LopesHeno F.1São PauloSPBrazilUniversidade de São Paulo Instituto do Coração – Cardiopneumologia, São Paulo, SP – Brazil.Mailing Address: Heno F. Lopes • Universidade de São Paulo Instituto do Coração – Cardiopneumologia - Av. Dr. Eneas de C. Aguiar, 44 Bloco 2, sala 8. Postal Code 05403-900, São Paulo, SP – Brazil. E-mail: hipheno@gmail.comKeywordsHypertension/trendsBlood PressureDiuretics/therapeutic useCardiovascular Diseases/complicationsDrug Therapy/trends
Arterial hypertension is by far the biggest risk factor for cardiovascular diseases. Thiocyanates, barbiturates, bromides and bismuth were tested in the treatment of arterial hypertension in the early 1940s.1 The use of these drugs was discontinued because they were proven ineffective and had several side effects. In the mid-1950s, ganglion blockers such as hexamethonium, pentolinium, mecamylamine and peripherally acting sympatholytic substances (guanethidine) were tested as treatment of arterial hypertension and were shown effective in reducing blood pressure, but little tolerated.2 New drugs were introduced to treat hypertension in the 1950s, including diuretics.3
In 1956, in an observational study, Moser and Magaulay followed up 106 hypertensive patients who received rauwolfia, hydralazine, reserpine, mecamylamine and chlorothiazide as treatment for arterial hypertension, alone or in combination. The dose of chlorothiazide used in this study ranged from 0.5 to 1.5 grams and the combination of chlorothiazide resulted in better control of blood pressure. Since that observational study by Moser and Magaulay to the present day, several studies related to the pharmacological treatment of hypertension have been carried out.4 The first randomized, placebo-controlled study conducted on the treatment of arterial hypertension was the Veterans Administration (VA), published in 1967.5 It is worth noting that the study inclusion criterion for active versus placebo treatment was diastolic pressure between 115 and 129 mmHg. After the publication of the VA-I study in 19675 and the VA-II in 1970,6 several randomized controlled studies addressing the treatment of arterial hypertension were carried out. The initial focus of treatment for arterial hypertension was renal sodium excretion, as renal disorders were initially thought to be the main cause of hypertension. Subsequently, the pathophysiological mechanisms of hypertension were elucidated and the therapy was directed to the main pathophysiological mechanisms. The activation of the sympathetic nervous system as an important pathophysiological mechanism of hypertension had already been perceived in the 1950s, and various forms of sympathetic nervous system block and even sympathectomy were then attempted.7 Beginning in the 1980s, with the introduction of the microneurography and the norepinephrine spillover technique, the importance of activation of the sympathetic nervous system in the pathophysiology of hypertension was even more evident.8,9 Although poorly tolerated, central and peripheral adrenergic blockers have always been part of the treatment of arterial hypertension.10 The activation of the renin-angiotensin aldosterone system (RAS) and the altered natriuresis pressure curve are two other important mechanisms in the pathophysiology of arterial hypertension. Currently, the use of diuretics to correct the altered natriuresis pressure curve and inhibitors of the renin-angiotensin aldosterone system, which act at different sites, has been routine in the treatment of arterial hypertension.11
The sympathetic nervous system and the renin-angiotensin aldosterone system are involved directly in the pathophysiological mechanisms of arterial hypertension. An important aspect in this sense is that the activation of these two systems is related to an inflammatory process in the hypertensive patient.12 They interact with inflammatory cytokines such as interleukin-6 (IL-6) and the tumor necrosis factor-alpha (TNF-α). The sympathetic nervous system stimulates the secretion of proinflammatory cytokines and at the same time it functions as a source of cytokines.13 Angiotensin-II is an important proinflammatory factor. It is related to the production of TNF-α and IL-6 and stimulates the monocyte chemoattractant protein-1 (MCP-1) and the nuclear factor-B.14,15 On the other hand, the type of drug used in the treatment of hypertensive patients can reduce the inflammatory process related to hypertension. The use of centrally acting sympatholytic moxonidine in the treatment of postmenopausal hypertensive women resulted in a reduction in TNF-α.16
In a study involving patients with resistant hypertension, Barbaro et al.17 found higher TNF-α values in patients with resistant hypertension compared to the normotensive group.17 The results point to TNF-α as a possible mediator of vascular damage in patients with resistant hypertension. Bautista et al.18 found an association of IL-6 and TNF-α levels with blood pressure values, regardless of age, sex, body mass index, family history of hypertension and other proinflammatory cytokines. In the study,19 the authors evaluated Infliximab, a drug that inhibits TNF-α, for the treatment of resistant hypertensive patients. Infliximab in a single dose of 3 mg/kg (infusion) resulted in a drop of 6.3 mmHg in mean arterial pressure and 4.9 mmHg in diastolic pressure. This acute effect of Infliximab on blood pressure opens a new perspective in the treatment of arterial hypertension. Regardless of the drop in blood pressure, using anti-TNF-α blocks a factor that can be aggravating in vascular injuries. It is known that the severity of hypertension is related to a vicious circle resulting from the activation of pressure systems (sympathetic nervous system and renin-angiotensin aldosterone system).20 The interruption of this circle is essential to protect the organism and for a better action of hypotensive drugs already well known.
Short Editorial related to the article: Effects of Anti-TNF-Α Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Study