Effect of Physical Training on Nitric Oxide Levels in Patients with Arterial Hypertension: An Integrative Review

Tábata de Paula Facioli Mariana Colombini Buranello Eloisa Maria Gatti Regueiro Renata Pedrolongo Basso-Vanelli Marina de Toledo Durand About the authors

Abstract

The regular practice of physical exercise as a non-pharmacological treatment of arterial hypertension (AH) has been encouraged due to causing a series of physiological responses in the cardiovascular system, such as the production of vasoactive substances, including nitric oxide (NO). NO is a relaxation factor released by the endothelium, and the decrease in its bioavailability is related to coronary and arterial diseases, such as AH. This study aimed to perform an integrative literature review to elucidate the effect of physical training on NO levels in patients with AH and to establish a relationship between these levels and blood pressure (BP) control. A literature review was was performed by searching PubMed / MEDLINE, Lilacs, Scielo, Cinahl and Embase databases. The search string used was ("arterial hypertension" OR hypertension) AND (exercise OR "physical exercise" OR "aerobic exercise" OR "exercise training" or "physical activity") AND ("nitric oxide"). We included fully available controlled and uncontrolled clinical trials published in English and Portuguese languages in the last 10 years. The review consisted of 16 articles, of which 13 reported an increase in NO production after the physical training intervention, and three studies found no change. In addition, 15 studies observed a reduction in BP after the intervention. In conclusion, regular practice of physical exercises, advocating moderate intensity, can improve NO bioavailability in pre-hypertensive and hypertensive individuals, which seems to be one of the mechanisms responsible for BP reduction.

Blood Pressure; Hypertension; Exercise; Physical Conditioning Human; Nitric Oxide; Endothelium Dependent Relaxing Factors; Vasoactive Substances; Cardiovascular System

Introduction

Arterial hypertension (AH) is characterized as a multifactorial clinical condition and considered one of the main risk factors for cardiovascular morbidity and mortality. In addition to a sustained elevation in blood pressure (BP), AH is also associated with metabolic disorders and functional and structural changes in target organs, which can be aggravated by the presence of other risk factors and is responsible for several other complications.11. Malachias MVB, Souza WK, Plavnik FL, Rodrigues CIS, Brandão AA, Neves MF, et al.Sociedade Brasileira de Cardiologia. 7a.Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol, 2016;107(3):1-83.

The practice of physical exercise as a non-pharmacological therapeutic approach to AH has been increasingly encouraged by health professionals, as it causes many physiological responses in body systems, especially in the cardiovascular system.22. Rondon MUPB, Brum PC. Exercício físico como tratamento não farmacológico da hipertensão arterial. Rev Bras Hipertens.2003;10:134-7. Physical training, when performed regularly, causes important autonomic and hemodynamic adaptations, as well as humoral changes related to the production of vasoactive substances, such as nitric oxide (NO).33. Faria TeO, Targueta GP, Angeli JK, Almeida EA, Stefanon I, Vassallo DV, et al. Acute resistance exercise reduces blood pressure and vascular reactivity, and increases endothelium-dependent relaxation in spontaneously hypertensive rats. Eur J Appl Physiol. 2010;110(2):359-66. These changes are responsible for the reduction or even normalization of the BP levels in patients with mild to moderate hypertension, using or not using medications.11. Malachias MVB, Souza WK, Plavnik FL, Rodrigues CIS, Brandão AA, Neves MF, et al.Sociedade Brasileira de Cardiologia. 7a.Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol, 2016;107(3):1-83. , 44. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2002;136(7):493-503. , 55. Pescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA, Ray CA, et al. American College of Sports Medicine position stand. Exercise and hypertension. Med Sci Sports Exerc. 2004;36(3):533-53.

NO, a relaxation factor released by the endothelium,66. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288(5789):373-60. is a gaseous mediator responsible for a variety of physiological phenomena,77. Garthwaite J, Charles SL, Chess-William SR. Endothelium-derived relaxing factor release on activation of nmda receptors suggests role as intercellular messenger in the brain. Nature. 1988; 336(6197):385-88. and a decrease in its bioavailability is related to coronary and arterial diseases, among others. In systemic AH, the increase in oxidative stress and endothelial dysfunction promotes a reduction in the bioavailability of NO and its action on the vascular wall, affecting vascular relaxation.88. Portaluppi F, Boari B, Manfredini R. Oxidative stress in essential hypertension. Curr Pharm Des. 2004;10(14):1695-8. , 99. Ward NC, Hodgson JM, Puddey IB, Mori TA, Beilin LJ, Croft KD. Oxidative stress in human hypertension: association with antihypertensive treatment, gender, nutrition, and lifestyle. Free Radic Biol Med. 2004;36(2):226-32.

In this sense, moderate physical exercise can be an effective non-pharmacological medicated means to increase NO bioavailability and, hence, mediate positive adjustments in the tissues. The main functions of NO in the cardiovascular system include regulation of vascular tone by the vasodilating action on smooth muscle cells; inhibition of platelet activity; leukocyte aggregation; and proliferation of smooth muscle cells in the vascular endothelium,1010. Ramachandran A, Levonen AL, Brookes PS, Ceaser E, Shiva S, Barone MC, et al. Mitochondria, nitric oxide, and cardiovascular dysfunction. Free Radic Biol Med. 2002;33(11):1465-74. which altogether contribute to BP control and prevention or control of cardiovascular diseases.33. Faria TeO, Targueta GP, Angeli JK, Almeida EA, Stefanon I, Vassallo DV, et al. Acute resistance exercise reduces blood pressure and vascular reactivity, and increases endothelium-dependent relaxation in spontaneously hypertensive rats. Eur J Appl Physiol. 2010;110(2):359-66. , 1111. Cubbon RM, Murgatroyd SR, Ferguson C, Bowen TS, Rakobowchuk M, Baliga V, et al. Human exercise-induced circulating progenitor cell mobilization is nitric oxide-dependent and is blunted in South Asian men. Arterioscler Thromb Vasc Biol. 2010;30(4):878-84. , 1212. Mastelari RB, de Souza HC, Lenhard A, de Aguiar Corrêa FM, Martins-Pinge MC. Nitric oxide inhibition in paraventricular nucleus on cardiovascular and autonomic modulation after exercise training in unanesthetized rats. Brain Res. 2011;1375:68-76.

Therefore, for an effective clinical application of physical training in the management of hypertensive individuals, it is necessary to know the effect of different physical exercises on NO and BP levels. In this regard, defining the study population and clarifying issues related to exercise – type (aerobic or anaerobic), intensity and training duration33. Faria TeO, Targueta GP, Angeli JK, Almeida EA, Stefanon I, Vassallo DV, et al. Acute resistance exercise reduces blood pressure and vascular reactivity, and increases endothelium-dependent relaxation in spontaneously hypertensive rats. Eur J Appl Physiol. 2010;110(2):359-66. , 1212. Mastelari RB, de Souza HC, Lenhard A, de Aguiar Corrêa FM, Martins-Pinge MC. Nitric oxide inhibition in paraventricular nucleus on cardiovascular and autonomic modulation after exercise training in unanesthetized rats. Brain Res. 2011;1375:68-76.

13. Augeri AL, Tsongalis GJ, Van Heest JL, Maresh CM, Thompson PD, Pescatello LS. The endothelial nitric oxide synthase -786 T>C polymorphism and the exercise-induced blood pressure and nitric oxide responses among men with elevated blood pressure. Atherosclerosis. 2009;204(2):e28-34.
- 1414. Allen JD, Stabler T, Kenjale A, Ham KL, Robbins JL, Duscha BD, et al. Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3 months of exercise training. Free Radic Biol Med. 2010;49(6):1138-44. is crucial to guide the therapeutic approach by health professionals. Therefore, this study aimed to conduct a literature review to elucidate the effect of physical training on NO levels in patients with AH and to establish a relationship between NO levels and BP control in this population.

Methods

An integrative review was performed by searching PubMed / MEDLINE, Lilacs, Scielo, Cinahl and Embase databases, using terms indexed in the DeCS – Health Sciences Descriptors – which was developed from the Medical Subject Headings of the US National Library of Medicine, to allow the use of common terminology in Portuguese, English and Spanish. The search string used in all databases was ("arterial hypertension" OR hypertension) AND (exercise OR "physical exercise" OR "aerobic exercise" OR "exercise training" or "physical activity") AND "nitric oxide".

The search was conducted between October 2019 and April 2020, covering studies published in the last 10 years, i.e., from October 2009 until the present moment. Fully available controlled and uncontrolled clinical trials published in English and Portuguese languages were included in the review. We selected articles that evaluated the effect of physical training on blood / urinary concentrations of NO or its metabolites, activity of the enzyme nitric oxide synthase (NOS), or BP levels of pre-hypertensive or hypertensive individuals. Studies on acute physical training only and those that included individuals with pulmonary hypertension were excluded.

Two independent researchers participated in the four steps of the review: literature search; duplicate analysis; reading of titles and abstracts; and full reading of each article. In the 3rd and 4th steps, each researcher classified the articles in a binary way, with zero (0) for articles that did not meet the inclusion criteria or had any of the exclusion criteria and one (1) for articles that fulfilled the inclusion criteria. Articles that scored one (1) from both researchers carried on to the next step, and those articles that were already at the fourth step were included immediately. Articles that scored zero from both researchers were immediately excluded. Articles that were assigned zero from one researcher and one (1) from the other researcher were evaluated by a third reviewer to ultimately determine if the article would be included (or moved to the next step) or not.

Results

Figure 1 presents the flow diagram of identification and selection of the articles included in this review, according to the PRISMA flow diagram.1515. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al.The prisma statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Plos med. 2009; 6(7): e1000100. doi:10.1371/journal.pmed.1000100. A total of 16 articles were included, with the main results described in Table 1 .

Figure 1
– PRISMA Flow diagram of article selection and inclusion/exclusion process.

Table 1
Characteristics of the included studies

Population

The number of individuals studied ranged from 112929. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17. to 60,2323. Patil SG, Aithala MR, Das KK. Effect of yoga on arterial stiffness in elderly subjects with increased pulse pressure: a randomized controlled study. ComplemEnt ther Med. 2015;23(4):562-9. and mean age was equal to or older than 50 years in eleven articles,1616. Jo EA, Cho KI, Park JJ, Im DS, Choi JH, Kim BJ. Effects of high-intensity interval training versus moderate-intensity continuous training on epicardial fat thickness and endothelial function in hypertensive metabolic syndrome. Metab Syndr relat Disord. 2020;18(2): 96-102. , 1818. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3).

19. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55.

20. Tomeleri CM, Marcori AJ, Ribeiro AS, Gerage AM, Padilha CS, Schiavoni D, et al. Chronic Blood Pressure Reductions and Increments in Plasma Nitric Oxide Bioavailability. Int J Sports Med. 2017;38(4):290-9.

21. Cruz LG, Bocchi EA, Grassi G, Guimaraes GV. Neurohumoral and Endothelial Responses to Heated Water-Based Exercise in Resistant Hypertensive Patients. Circ J. 2017;81(3):339-45.
- 2222. Wong A, Alvarez-Alvarado S, Jaime SJ, Kinsey AW, Spicer MT, Madzima TA, et al. Combined whole-body vibration training and l-citrulline supplementation improves pressure wave reflection in obese postmenopausal women. Appl Physiol Nutr Metab. 2016;41(3):292-7. , 2424. Pan X, Zhang Y, Tao S. Effects of tai chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. Clin Exp Hypertens. 2015;37(1):8-14. , 2626. Turky K, Elnahas N, Oruch R. Effects of exercise training on postmenopausal hypertension: implications on nitric oxide levels. Med J Malaysia. 2013; 68(6):459-464. , 2929. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17.

30. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9.
- 3131. de Meirelles LR, Mendes-Ribeiro AC, Mendes MA, da Silva MN, Ellory JC, Mann GE, et al. Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway. Scand J Med Sci Sports. 2009;19(1):67-74. between 40 and 50 years in three2525. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10. , 2727. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94. , 2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. and below 30 years in one study.1717. Wong A, Figueroa A, Fischer SM, Bagheri R, Park SY. The effects of mat pilates training on vascular function and body fatness in obese young women with elevated blood pressure. Am J Hypertens. 2020; hpaa026. doi:10.1093/ajh/hpaa026. The studies included individuals with stage I or II hypertension (nine articles1616. Jo EA, Cho KI, Park JJ, Im DS, Choi JH, Kim BJ. Effects of high-intensity interval training versus moderate-intensity continuous training on epicardial fat thickness and endothelial function in hypertensive metabolic syndrome. Metab Syndr relat Disord. 2020;18(2): 96-102. , 1818. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3). , 1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. , 2222. Wong A, Alvarez-Alvarado S, Jaime SJ, Kinsey AW, Spicer MT, Madzima TA, et al. Combined whole-body vibration training and l-citrulline supplementation improves pressure wave reflection in obese postmenopausal women. Appl Physiol Nutr Metab. 2016;41(3):292-7.

23. Patil SG, Aithala MR, Das KK. Effect of yoga on arterial stiffness in elderly subjects with increased pulse pressure: a randomized controlled study. ComplemEnt ther Med. 2015;23(4):562-9.
- 2424. Pan X, Zhang Y, Tao S. Effects of tai chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. Clin Exp Hypertens. 2015;37(1):8-14. , 2929. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17.

30. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9.
- 3131. de Meirelles LR, Mendes-Ribeiro AC, Mendes MA, da Silva MN, Ellory JC, Mann GE, et al. Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway. Scand J Med Sci Sports. 2009;19(1):67-74. ), prehypertensive and hypertensive individuals (two articles2020. Tomeleri CM, Marcori AJ, Ribeiro AS, Gerage AM, Padilha CS, Schiavoni D, et al. Chronic Blood Pressure Reductions and Increments in Plasma Nitric Oxide Bioavailability. Int J Sports Med. 2017;38(4):290-9. , 3131. de Meirelles LR, Mendes-Ribeiro AC, Mendes MA, da Silva MN, Ellory JC, Mann GE, et al. Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway. Scand J Med Sci Sports. 2009;19(1):67-74. ), normotensive and hypertensive (three articles2727. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94.

28. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9.
- 2929. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17. ), prehypertensive, hypertensive and normotensive individuals2525. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10. and only prehypertensive individuals.1717. Wong A, Figueroa A, Fischer SM, Bagheri R, Park SY. The effects of mat pilates training on vascular function and body fatness in obese young women with elevated blood pressure. Am J Hypertens. 2020; hpaa026. doi:10.1093/ajh/hpaa026.

Intervention

Aerobic exercise was the most common intervention, identified in 11 of the 16 articles included,1616. Jo EA, Cho KI, Park JJ, Im DS, Choi JH, Kim BJ. Effects of high-intensity interval training versus moderate-intensity continuous training on epicardial fat thickness and endothelial function in hypertensive metabolic syndrome. Metab Syndr relat Disord. 2020;18(2): 96-102. , 1818. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3). , 1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. , 2121. Cruz LG, Bocchi EA, Grassi G, Guimaraes GV. Neurohumoral and Endothelial Responses to Heated Water-Based Exercise in Resistant Hypertensive Patients. Circ J. 2017;81(3):339-45. , 2525. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10.

26. Turky K, Elnahas N, Oruch R. Effects of exercise training on postmenopausal hypertension: implications on nitric oxide levels. Med J Malaysia. 2013; 68(6):459-464.

27. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94.

28. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9.

29. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17.

30. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9.
- 3131. de Meirelles LR, Mendes-Ribeiro AC, Mendes MA, da Silva MN, Ellory JC, Mann GE, et al. Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway. Scand J Med Sci Sports. 2009;19(1):67-74. three of which addressed high-intensity aerobic training.1616. Jo EA, Cho KI, Park JJ, Im DS, Choi JH, Kim BJ. Effects of high-intensity interval training versus moderate-intensity continuous training on epicardial fat thickness and endothelial function in hypertensive metabolic syndrome. Metab Syndr relat Disord. 2020;18(2): 96-102. , 1818. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3). , 1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. In addition, two studies performed resistance exercise,2020. Tomeleri CM, Marcori AJ, Ribeiro AS, Gerage AM, Padilha CS, Schiavoni D, et al. Chronic Blood Pressure Reductions and Increments in Plasma Nitric Oxide Bioavailability. Int J Sports Med. 2017;38(4):290-9. , 2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. one of which combined aerobic and resistance exercises.2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. Four studies addressed training with different techniques such as vibrating platform,2222. Wong A, Alvarez-Alvarado S, Jaime SJ, Kinsey AW, Spicer MT, Madzima TA, et al. Combined whole-body vibration training and l-citrulline supplementation improves pressure wave reflection in obese postmenopausal women. Appl Physiol Nutr Metab. 2016;41(3):292-7. yoga,2323. Patil SG, Aithala MR, Das KK. Effect of yoga on arterial stiffness in elderly subjects with increased pulse pressure: a randomized controlled study. ComplemEnt ther Med. 2015;23(4):562-9. Tai Chi practice2424. Pan X, Zhang Y, Tao S. Effects of tai chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. Clin Exp Hypertens. 2015;37(1):8-14. and mat Pilates.1717. Wong A, Figueroa A, Fischer SM, Bagheri R, Park SY. The effects of mat pilates training on vascular function and body fatness in obese young women with elevated blood pressure. Am J Hypertens. 2020; hpaa026. doi:10.1093/ajh/hpaa026.

In the studies that used aerobic physical training, different parameters and percentages were used to measure training intensity, ranging from 60% to 100% of maximum heart rate (HRmax),2323. Patil SG, Aithala MR, Das KK. Effect of yoga on arterial stiffness in elderly subjects with increased pulse pressure: a randomized controlled study. ComplemEnt ther Med. 2015;23(4):562-9. , 2525. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10. , 2727. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94. , 3030. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9. 30% to 100% of maximum oxygen consumption (VO2max),1818. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3). , 2424. Pan X, Zhang Y, Tao S. Effects of tai chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. Clin Exp Hypertens. 2015;37(1):8-14. , 2727. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94. , 2929. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17. 50% to 90% of HRmax reserve1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. , 2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. , 3131. de Meirelles LR, Mendes-Ribeiro AC, Mendes MA, da Silva MN, Ellory JC, Mann GE, et al. Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway. Scand J Med Sci Sports. 2009;19(1):67-74. and between 11 and 13 points on Borg’s rating scale of perceived exertion.2121. Cruz LG, Bocchi EA, Grassi G, Guimaraes GV. Neurohumoral and Endothelial Responses to Heated Water-Based Exercise in Resistant Hypertensive Patients. Circ J. 2017;81(3):339-45.

Duration of exercise training varied between six1818. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3). , 1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. and 24 weeks,2525. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10. , 2929. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17. , 3030. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9. most often three to four days a week,1616. Jo EA, Cho KI, Park JJ, Im DS, Choi JH, Kim BJ. Effects of high-intensity interval training versus moderate-intensity continuous training on epicardial fat thickness and endothelial function in hypertensive metabolic syndrome. Metab Syndr relat Disord. 2020;18(2): 96-102.

17. Wong A, Figueroa A, Fischer SM, Bagheri R, Park SY. The effects of mat pilates training on vascular function and body fatness in obese young women with elevated blood pressure. Am J Hypertens. 2020; hpaa026. doi:10.1093/ajh/hpaa026.

18. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3).
- 1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. , 2121. Cruz LG, Bocchi EA, Grassi G, Guimaraes GV. Neurohumoral and Endothelial Responses to Heated Water-Based Exercise in Resistant Hypertensive Patients. Circ J. 2017;81(3):339-45. , 2222. Wong A, Alvarez-Alvarado S, Jaime SJ, Kinsey AW, Spicer MT, Madzima TA, et al. Combined whole-body vibration training and l-citrulline supplementation improves pressure wave reflection in obese postmenopausal women. Appl Physiol Nutr Metab. 2016;41(3):292-7. , 2525. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10.

26. Turky K, Elnahas N, Oruch R. Effects of exercise training on postmenopausal hypertension: implications on nitric oxide levels. Med J Malaysia. 2013; 68(6):459-464.

27. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94.

28. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9.

29. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17.

30. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9.
- 3131. de Meirelles LR, Mendes-Ribeiro AC, Mendes MA, da Silva MN, Ellory JC, Mann GE, et al. Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway. Scand J Med Sci Sports. 2009;19(1):67-74. with sessions from 20 min2525. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10. , 2626. Turky K, Elnahas N, Oruch R. Effects of exercise training on postmenopausal hypertension: implications on nitric oxide levels. Med J Malaysia. 2013; 68(6):459-464. to 60 minutes.1717. Wong A, Figueroa A, Fischer SM, Bagheri R, Park SY. The effects of mat pilates training on vascular function and body fatness in obese young women with elevated blood pressure. Am J Hypertens. 2020; hpaa026. doi:10.1093/ajh/hpaa026. , 2222. Wong A, Alvarez-Alvarado S, Jaime SJ, Kinsey AW, Spicer MT, Madzima TA, et al. Combined whole-body vibration training and l-citrulline supplementation improves pressure wave reflection in obese postmenopausal women. Appl Physiol Nutr Metab. 2016;41(3):292-7.

23. Patil SG, Aithala MR, Das KK. Effect of yoga on arterial stiffness in elderly subjects with increased pulse pressure: a randomized controlled study. ComplemEnt ther Med. 2015;23(4):562-9.
- 2424. Pan X, Zhang Y, Tao S. Effects of tai chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. Clin Exp Hypertens. 2015;37(1):8-14. , 2929. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17. , 3131. de Meirelles LR, Mendes-Ribeiro AC, Mendes MA, da Silva MN, Ellory JC, Mann GE, et al. Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway. Scand J Med Sci Sports. 2009;19(1):67-74.

Outcomes

Regarding the effect of physical exercise on NO, 13 out of the 16 studies analyzed reported an increase in NO or NOS production after the intervention.1616. Jo EA, Cho KI, Park JJ, Im DS, Choi JH, Kim BJ. Effects of high-intensity interval training versus moderate-intensity continuous training on epicardial fat thickness and endothelial function in hypertensive metabolic syndrome. Metab Syndr relat Disord. 2020;18(2): 96-102.

17. Wong A, Figueroa A, Fischer SM, Bagheri R, Park SY. The effects of mat pilates training on vascular function and body fatness in obese young women with elevated blood pressure. Am J Hypertens. 2020; hpaa026. doi:10.1093/ajh/hpaa026.

18. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3).

19. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55.

20. Tomeleri CM, Marcori AJ, Ribeiro AS, Gerage AM, Padilha CS, Schiavoni D, et al. Chronic Blood Pressure Reductions and Increments in Plasma Nitric Oxide Bioavailability. Int J Sports Med. 2017;38(4):290-9.

21. Cruz LG, Bocchi EA, Grassi G, Guimaraes GV. Neurohumoral and Endothelial Responses to Heated Water-Based Exercise in Resistant Hypertensive Patients. Circ J. 2017;81(3):339-45.

22. Wong A, Alvarez-Alvarado S, Jaime SJ, Kinsey AW, Spicer MT, Madzima TA, et al. Combined whole-body vibration training and l-citrulline supplementation improves pressure wave reflection in obese postmenopausal women. Appl Physiol Nutr Metab. 2016;41(3):292-7.

23. Patil SG, Aithala MR, Das KK. Effect of yoga on arterial stiffness in elderly subjects with increased pulse pressure: a randomized controlled study. ComplemEnt ther Med. 2015;23(4):562-9.

24. Pan X, Zhang Y, Tao S. Effects of tai chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. Clin Exp Hypertens. 2015;37(1):8-14.

25. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10.
- 2626. Turky K, Elnahas N, Oruch R. Effects of exercise training on postmenopausal hypertension: implications on nitric oxide levels. Med J Malaysia. 2013; 68(6):459-464. , 2929. Zaros PR, Pires CE, Bacci M, Moraes C, Zanesco A. Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women. BMC Womens Health. 2009;9:17. , 3131. de Meirelles LR, Mendes-Ribeiro AC, Mendes MA, da Silva MN, Ellory JC, Mann GE, et al. Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway. Scand J Med Sci Sports. 2009;19(1):67-74. In these cases, exercise modality, time and intensity was not homogeneous throughout the studies. The other three studies found no change.2727. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94. , 2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. , 3030. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9.

With respect to BP, only one article carried out with African American individuals did not report a reduction in this variable after the intervention, most likely because the parameters of normotensive and hypertensive individuals were analyzed together. Despite this, there was an increase in plasma NO levels and an improvement in vascular structure and function after training.2525. Feairheller DL, Diaz KM, Kashem MA, Thakkar SR, Veerabhadrappa P, Sturgeon KM, et al. Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. J Clin Hypertens (Greenwich). 2014;16(7):504-10. On the other hand, three studies showed a decrease in BP, but unrelated to changes in NO or NOS production.2727. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94. , 2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. , 3030. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9. In these studies, the hypotensive effect was associated with an improvement in the balance between vasodilator and vasoconstrictor factors, with changes in prostanoids levels,2727. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94. , 2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. increased hydrogen sulfide-producing enzyme (cystathionine gamma-lyase) and reduced thromboxane,2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. or with decreased levels of total cholesterol and LDL.3030. Sturgeon KM, Fenty-Stewart NM, Diaz KM, Brinkley TE, Dowling TC, Brown MD. The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training. Blood Press. 2009;18(4):171-9.

Discussion

In the present review it was verified that physical training was able to increase NO production and reduce BP in hypertensive and prehypertensive individuals. Most studies used an exercise intensity ranging from 60% to 100% of HRmax, 50% to 100% of VO2max, 30% to 90% of HRmax reserve, and between 11 and 13 points on the scale of perceived exertion (Borg). Based on analysis of the relationship between these parameters, we can verify that exercises of intensities of 60-79% of HRmax, 50-74% of VO2max or reserve of HRmax and Borg of 12-13 are considered of moderate intensity.3232. American College of Sports Medicine (ACSM). A quantidade e o tipo recomendados de exercícios para o desenvolvimento e a manutenção da aptidão cardiorrespiratória e muscular em adultos saudáveis. Rev Bras Med Esporte. 1998;4(3):96-106. , 3333. Borg, G, Ottoson, D. The perception of exertion in physical work. London, England: The Macmillan Press, Ltd. 1986.p.4-7.

Based on the literature, approximately 75% of hypertensive individuals when submitted to physical training, mainly of moderate intensity, have reduced BP levels.3434. Hagberg JM, Park JJ, Brown MD. The role of exercise training in the treatment of hypertension: an update. Sports Med. 2000;30(3):193-206. The practice of physical exercise may be responsible for promoting several adaptations, such as attenuation of vascular and cardiac sympathetic activity, decrease in serum levels of vasoconstrictor factors and increase in endothelial dilating factors, resulting in a reduction of peripheral vascular resistance.3535. Higashi Y, Yoshizumi M. Exercise and endothelial function: role of endothelium-derived nitric oxide and oxidative stress in healthy subjects and hypertensive patients. Pharmacol ther. 2004;102(1):87-96. , 3636. Cornelissen VA, Fagard RH. Effects of endurance training on blood pressure, blood pressure-regulating mechanisms, and cardiovascular risk factors. Hypertension. 2005;46(4):667-7.

The time, frequency and duration of training are also important factors to be considered. Despite the great discrepancy between the training protocols of the selected studies, ranging from 20 to 60 min per session, three to four days per week, and from six to 24 weeks, this did not affect the results on NO concentrations. In this context, the Brazilian Society of Cardiology ( Sociedade Brasileira de Cardiologia ) recommends that individuals diagnosed with AH initiate regular exercise programs, three to five times a week, in sessions of at least 30 min, with ideal duration between 40 and 50 minutes.11. Malachias MVB, Souza WK, Plavnik FL, Rodrigues CIS, Brandão AA, Neves MF, et al.Sociedade Brasileira de Cardiologia. 7a.Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol, 2016;107(3):1-83. Furthermore, aerobic exercises are preferred, of light to moderate intensity, between 60% and 80% of HRmax, or between 50% and 70% of VO2max, and complemented by resistance exercises.11. Malachias MVB, Souza WK, Plavnik FL, Rodrigues CIS, Brandão AA, Neves MF, et al.Sociedade Brasileira de Cardiologia. 7a.Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol, 2016;107(3):1-83. , 44. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2002;136(7):493-503. , 3737. Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;104(14):1694-740.51

Dynamic or isotonic resistance training should be performed with caution, since there are still few randomized and controlled studies with this type of exercise in AH, and its isolated effect on resting BP is not yet well established.3838. Fagard RH. Exercise therapy in hypertensive cardiovascular disease. Prog cardiovasc Dis. 2011;53(6):404-11. , 3939. Pescatello LS, MacDonald HV, Lamberti L, Johnson BT. Exercise for Hypertension: A Prescription Update Integrating Existing Recommendations with Emerging Research. Curr Hypertens Rep. 2015;17(11):87. In this case, it is recommended an overload of up to 50-60% of one-repetition maximum (1RM) from two to three times a week, one to three series, 8 to 15 repetitions up to moderate fatigue, and passive breaks of 90 to 120 seconds.11. Malachias MVB, Souza WK, Plavnik FL, Rodrigues CIS, Brandão AA, Neves MF, et al.Sociedade Brasileira de Cardiologia. 7a.Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol, 2016;107(3):1-83. In this sense, the study by Tomeleri et al.,2020. Tomeleri CM, Marcori AJ, Ribeiro AS, Gerage AM, Padilha CS, Schiavoni D, et al. Chronic Blood Pressure Reductions and Increments in Plasma Nitric Oxide Bioavailability. Int J Sports Med. 2017;38(4):290-9. evaluated the effect of resisted exercise – series of 10 to 15 repetitions according to 1RM, twice a week – in pre- and hypertensive women. Although they did not specify the length of breaks and the percentage of RM, the parameters used in this study were consistent with the recommendations of the Hypertension Guideline11. Malachias MVB, Souza WK, Plavnik FL, Rodrigues CIS, Brandão AA, Neves MF, et al.Sociedade Brasileira de Cardiologia. 7a.Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol, 2016;107(3):1-83. and indicated an increase in plasma NO levels with resistance training.

Three articles included in the present review showed improvement in NO levels and consequent decrease in BP due to increased vascular mechanical stress imposed by high-intensity interval training (HIIT) in hypertensive patients.1616. Jo EA, Cho KI, Park JJ, Im DS, Choi JH, Kim BJ. Effects of high-intensity interval training versus moderate-intensity continuous training on epicardial fat thickness and endothelial function in hypertensive metabolic syndrome. Metab Syndr relat Disord. 2020;18(2): 96-102. , 1818. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3). , 1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. HIIT consists of alternating short periods of high-intensity aerobic exercise (85-100% VO2max) with active periods of moderate to low intensity exercise. Hence, blood flow varies between high and low intensities, representing a greater challenge to the heart, improving cardiorespiratory fitness.1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. The authors justify that in this type of training, the increase in shear stress induces an increase in the apelin pathway, which is positively correlated to the increase in NO production, generating a vasodilatation with a consequent reduction in BP.1919. Izadi MR, Ghardashi Afousi A, Asvadi Fard M, Babaee Bigi MA. High-intensity interval training lowers blood pressure and improves apelin and nox plasma levels in older treated hypertensive individuals. J Physiol Biochem. 2018;74(1):47-55. Nevertheless, this type of training is still best suited to healthy adult individuals, as described by the Update of the Cardiovascular Prevention Guideline of the Brazilian Society of Cardiology.4040. Précoma D, Oliveira GM, Simão AF, Dutra OP, Coelho DR, Izar MC, et al. Sociedade Brasileira de Cardiologia. Atualização da diretriz de prevenção cardiovascular da sociedade brasileira de cardiologia. Arq Bras Cardiol. 2019;113(4):787-891

The shear stress caused by the increased unidirectional blood flow during physical exercise is the main mechanism of improvement of endothelial function.3333. Borg, G, Ottoson, D. The perception of exertion in physical work. London, England: The Macmillan Press, Ltd. 1986.p.4-7. , 4141. Kingwell BA. Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. Faseb J. 2000;14(12):1685-96. This mechanical stress produced by the friction between red blood cells and endothelial cells activates endothelial NOS, increasing the production of NO. NO diffuses into the underlying vascular smooth muscle and activates the enzyme guanylate cyclase. This, in turn, induces the cGMP production that activates the metabolic pathways of cGMP-dependent protein kinase G (PKG), causing vascular relaxation.4242. Noble A. The cardiovascular system. Edinburgh; New York: Churchill Livingstone, 2005. Thus, shear stress is considered a powerful stimulus for the release of vasodilator factors produced by the vascular endothelium.4141. Kingwell BA. Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. Faseb J. 2000;14(12):1685-96.

In addition to its potent vasodilating action, NO can induce other important vascular, renal and cardiac effects, including inhibition of platelet aggregation, modulation of glomerular filtration rate, and an effect on vascular and cardiac remodeling.4343. Bartunek J, Weinberg EO, Tajima M, Rohrbach S, Katz SE, Douglas PS, et al. Chronic N (G)-nitro-L-arginine methyl ester-induced hypertension: novel molecular adaptation to systolic load in absence of hypertrophy. Circulation. 2000;101(4):423-9. On the other hand, the endogenous reduction of NO synthesis is related to several pathophysiological disorders or associated conditions, such as reduction of endothelium-dependent vasodilation in patients with hypertension, hypercholesterolemia, diabetes or arteriosclerosis.4444. Moncada S, Higgs A. The l-arginine-nitric oxide pathway. N Engl J Med. 1993;329(27):2002-12.

Studies have shown that the responses in BP control are related to humoral mechanisms, especially with involvement of NO. In fact, in the studies by Firoenza et al.,1818. Fiorenza M, Gunnarsson TP, Ehlers TS, Bangsbo J. High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension. Acta Physiologica.2019; 225(3). Pan et al.,2424. Pan X, Zhang Y, Tao S. Effects of tai chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. Clin Exp Hypertens. 2015;37(1):8-14. Nyberg et al.,2727. Nyberg M, Jensen LG, Thaning P, Hellsten Y, Mortensen SP. Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training. J Physiol. 2012;590(6):1481-94. and Hansen et al.,2828. Hansen AH, Nyberg M, Bangsbo J, Saltin B, Hellsten Y. Exercise training alters the balance between vasoactive compounds in skeletal muscle of individuals with essential hypertension. Hypertension. 2011;58(5):943-9. it was observed that hypertensive individuals had lower levels of muscle eNOS and plasma NO compared to normotensive individuals. In addition, Pan et al.2424. Pan X, Zhang Y, Tao S. Effects of tai chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. Clin Exp Hypertens. 2015;37(1):8-14. and Tomeleri et al.2020. Tomeleri CM, Marcori AJ, Ribeiro AS, Gerage AM, Padilha CS, Schiavoni D, et al. Chronic Blood Pressure Reductions and Increments in Plasma Nitric Oxide Bioavailability. Int J Sports Med. 2017;38(4):290-9. demonstrated a negative correlation between NO and BP values. Also, there is evidence that one cause of AH is the presence of products analogous to endothelial L-arginine, which hampers its action on eNOS, resulting in a substantial decrease in NO production.4545. Togashi H, Togashi I, Yoshioka M, Kobayashi T, Yasuda H, Kitabatake A, et al. A central nervous system action of nitric oxide in blood pressure regulation. J Pharmacol Exp Ther. 1992;262(1):343-7. Furthermore, the increase in BP is not only caused by elimination of the vasodilating action of NO, but also by elimination of its influence in central regions of the autonomic cardiovascular control, especially of the sympathetic nervous system.4545. Togashi H, Togashi I, Yoshioka M, Kobayashi T, Yasuda H, Kitabatake A, et al. A central nervous system action of nitric oxide in blood pressure regulation. J Pharmacol Exp Ther. 1992;262(1):343-7.

Therefore, characteristics of physical exercise, i.e., its intensity, duration, frequency, and the muscle groups involved (larger or smaller muscle groups), can be determinant in the greater production of NO and in the control of BP in hypertensive patients.4646. Maiorana A, O’Driscoll G, Dembo L, Cheetham C, Goodman C, Taylor R, et al. Effect of aerobic and resistance exercise training on vascular function in heart failure. Am J Physiol Heart Circ Physiol. 2000;279:H1999-H2005. , 4747. Green DJ, Maiorana A, O’Driscoll G, Taylor R. Effect of exercise training on endothelium derived nitric oxide function in humans. J Physiol. 2004;561(1):1-25. The increase in NO bioavailability promotes relaxation of smooth muscle cells in the blood vessel wall, leading to an increase in its diameter and a decrease of vascular resistance and systemic BP.66. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288(5789):373-60. Besides, the decrease in sympathetic activity induced by physical exercise also suggests that the increase in NO production promotes a buffering action to the low-frequency oscillations in BP, acting in opposition to the vascular sympathetic modulation.4848. DiCarlo SE, Zheng H, Collins HL, Rodenbaugh DW, Patel KP. Daily exercise normalizes the number of diaphorase (NOS) positive neurons in the hypothalamus of hypertensive rats. Brain Res. 2002;955(1-2):153-60.

49. Zucker IH, Patel KP, Schultz HD, Li YF, Wang W, Pkiquett RU.Exxercise training in experimental heart failure. Exerc Sport Sci Rev. 2004;32(3):107-11.
- 5050. Higa-Taniguchi KT, Silva FC, Silva HM, Michelini LC, Stern JE. Exercise training-induced remodeling of paraventricular nucleus (nor)adrenergic innervation in normotensive and hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):R1717-27.

In 2018, Pagan et al.5151. Pagan LU, Gomes MJ, Okoshi MP. Função endotelial e exercício físico. Arq Bras Cardiol. 2018;111(4):540-1. published an editorial addressing the role of exercise in endothelial function, with emphasis on NO, and discussed the studies with animal models that obtained improvement of this function associated with increased levels of NO,5252. Martinez JE, Taipeiro EF, Chies AB. Effects of continuous and accumulated exercise on endothelial function in rat aorta. Arq Bras Cardiol. 2017;108(4):315-22. , 5353. Mota MM, Silva TLTBD, Macedo FN, Mesquita TRR, Quintans LJJ, Santana-filho VJ, et al. Effects of a single bout of resistance exercise in different volumes on endothelium adaptations in healthy animals. Arq Bras Cardiol. 2017;108(5):436-42. also in hypertensive animals.5454. Faria TO, Angeli JK, Mello LGM, Pinto GC, Stefanon i, Vassallo DV, et al. A single resistance exercise session improves aortic endothelial function in hypertensive rats. Arq Bras Cardiol. 2017;108(3):228-36. The authors emphasized the need to establish better training intensity, type, and duration for this objective. In the present integrative review, a diversity of training parameters in humans was found, as also pointed out by Pagan et al.5151. Pagan LU, Gomes MJ, Okoshi MP. Função endotelial e exercício físico. Arq Bras Cardiol. 2018;111(4):540-1. Therefore, among the limitations of this review, we can point out the lack of information and standardization of tests and training protocols, which made it difficult to interpret the effectiveness of exercise intervention on NO bioavailability.

Therefore, we concluded that the regular practice of physical exercises in pre-hypertensive and hypertensive individuals can increase the bioavailability of NO and, consequently, cause a hypotensive effect. Thus, we can establish a relationship between NO levels and BP control in hypertensive individuals, that is, the greater the NO production, the lower the BP values. However, it is important to note that the higher bioavailability of NO depends on the type – different by controlled, and of moderate intensity – of physical exercise and the muscle mass involved.

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  • Study Association
    This article is part of the thesis of lato sensu specialization submitted by Tábata P. Facioli, from Universidade de Ribeirão Preto.
  • Ethics approval and consent to participate
    This article does not contain any studies with human participants or animals performed by any of the authors.

  • Sources of Funding: This study was partially funded by Universidade de Ribeirão Preto.

Publication Dates

  • Publication in this collection
    09 June 2021
  • Date of issue
    Mar-Apr 2022

History

  • Received
    13 Aug 2020
  • Reviewed
    19 Nov 2020
  • Accepted
    10 Jan 2021
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