Scholarly article on topic 'Hypertension and physical exercise: The role of oxidative stress'

Hypertension and physical exercise: The role of oxidative stress Academic research paper on "Basic medicine"

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Abstract of research paper on Basic medicine, author of scientific article — Monica Korsager Larsen, Vladimir V. Matchkov

Abstract Oxidative stress is associated with the pathogenesis of hypertension. Decreased bioavailability of nitric oxide (NO) is one of the mechanisms involved in the pathogenesis. It has been suggested that physical exercise could be a potential non-pharmacological strategy in treatment of hypertension because of its beneficial effects on oxidative stress and endothelial function. The aim of this review is to investigate the effect of oxidative stress in relation to hypertension and physical exercise, including the role of NO in the pathogenesis of hypertension. Endothelial dysfunction and decreased NO levels have been found to have the adverse effects in the correlation between oxidative stress and hypertension. Most of the previous studies found that aerobic exercise significantly decreased blood pressure and oxidative stress in hypertensive subjects, but the intense aerobic exercise can also injure endothelial cells. Isometric exercise decreases normally only systolic blood pressure. An alternative exercise, Tai chi significantly decreases blood pressure and oxidative stress in normotensive elderly, but the effect in hypertensive subjects has not yet been studied. Physical exercise and especially aerobic training can be suggested as an effective intervention in the prevention and treatment of hypertension and cardiovascular disease via reduction in oxidative stress.

Academic research paper on topic "Hypertension and physical exercise: The role of oxidative stress"

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Review

Hypertension and physical exercise: The role of oxidative

stress

Monica Korsager Larsen, Vladimir V. Matchkov *

Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark

ABSTRACT

Oxidative stress is associated with the pathogenesis of hypertension. Decreased bioavailability of nitric oxide (NO) is one of the mechanisms involved in the pathogenesis. It has been suggested that physical exercise could be a potential non-pharmacological strategy in treatment of hypertension because of its beneficial effects on oxidative stress and endothelial function. The aim of this review is to investigate the effect of oxidative stress in relation to hypertension and physical exercise, including the role of NO in the pathogenesis of hypertension. Endothelial dysfunction and decreased NO levels have been found to have the adverse effects in the correlation between oxidative stress and hypertension. Most of the previous studies found that aerobic exercise significantly decreased blood pressure and oxidative stress in hypertensive subjects, but the intense aerobic exercise can also injure endothelial cells. Isometric exercise decreases normally only systolic blood pressure. An alternative exercise, Tai chi significantly decreases blood pressure and oxidative stress in normotensive elderly, but the effect in hypertensive subjects has not yet been studied. Physical exercise and especially aerobic training can be suggested as an effective intervention in the prevention and treatment of hypertension and cardiovascular disease via reduction in oxidative stress.

# 2016 The Lithuanian University of Health Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.

org/licenses/by-nc-nd/4.0/).

ARTICLE INFO

Article history:

Received 29 November 2015 Received in revised form 15 January 2016 Accepted 17 January 2016 Available online 29 January 2016

Keywords: Oxidative stress Hypertension Exercise Redox state Nitric oxide

1. Introduction

Hypertension is a major risk factor in the development of cardiovascular diseases, including stroke and coronary artery

disease. Hypertension is defined as a chronic elevation of systolic blood pressure greater than 140 mm Hg and/or diastolic blood pressure greater than 90 mm Hg, and is classified as either essential (primary) or secondary hypertension [1]. Approximately 95% of all cases are categorized as essential

* Corresponding author at: Department of Biomedicine, Faculty of Health, Aarhus University, Ole Worms Alle bygn. 4,1160, Aarhus C 8000, Denmark. Tel.: +45 87167723.

E-mail address: vvm@biomed.au.dk (V.V. Matchkov). Peer review under the responsibility of the Lithuanian University of Health Sciences.

http://dx.doi.org/10.1016/j.medici.2016.01.005

1010-660X/© 2016 The Lithuanian University of Health Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

hypertension which is characterized by a lack of identifiable trigger for blood pressure raise. The remaining 5% of the cases are categorized as secondary hypertension which is caused by various medical conditions, e.g. kidney disease and tumors [2]. It is predicted that the prevalence of hypertension will increase by more than 50% during the next 30 years resulting in an enormous disease burden for society [3]. In line with this ongoing development, the effective treatment of hypertension is becoming increasingly urgent. It is no longer sufficient to depend on pharmacological therapies, when a modest change in lifestyle can be demonstrated to have a beneficial effect.

Previous studies suggested that redox imbalance might be associated with pathogenesis of hypertension although it may not be the only cause of blood pressure elevation [4-7]. This occurs due to imbalance between elevated reactive oxygen species (ROS) (e.g. superoxide, hydrogen peroxide and hydroxyl radical) production and/or reduced antioxidant capacity at the systemic level as well as the localized changes in the circulatory regions [8]. ROS are known to play both physiological and pathophysiological roles in the body [5]. At the appropriate concentrations and sub-cellular localization ROS participate in cellular signaling and phenotype regulation. Moreover, ROS are known to modulate numerous pathways important for control of systemic vascular resistance and blood pressure, including decreased bioavailability of nitric oxide (NO), inflammation, imbalance in salt and water homeostasis, hyperactivity of the sympathetic nervous system (SNS) and disturbances of the renin-angiotensin-aldosterone-system (RAAS) [6,9]. Interestingly, physical exercise has been suggested to be beneficial in hypertension by improving the redox state, particularly, in the vascular wall [10,11]. Physical exercise may therefore be of potential importance for prevention or treatment of hypertension or hypertension-associated pathologies besides conventional pharmacological treatment.

This focused review provides an overview for the role of redox imbalance in hypertension and its therapeutic modulation by physical exercise. The focus is especially made on the ROS-dependent reduction of NO bioavailability in hypertensive subjects and the effects of exercise on this endothelium-dependent pathway.

2. Redox state and NO bioavailability

Redox imbalance has been measured in hypertensive subjects as an elevated level of oxidative stress [12-16]. In this context redox imbalance can be seen as outbalanced production/ accumulation of ROS [5]. Along with other pathways, ROS decrease the bioavailability of NO [1]. Hypertension is known to be associated with endothelial dysfunction [17,18] and it might, therefore, be suggested that impairment in hypertension endothelium-dependent vasodilation is the result of oxidative stress [6]. Alternatively, this redox imbalance can be the result of a reduction in antioxidant potential of NO, which occurs secondary to the reduced production of NO. In any of these scenarios, oxidative stress seems to play an important role in hypertension [7,8,19].

Decreased bioavailability of NO is now thought to be one of the critical factors that are common to hypertension [7]. It can involve a number of different mechanisms including a

reduction in endothelial NO synthase (eNOS), an uncoupling of eNOS enzymatic activity, scavenging of NO by ROS as well as the oxidation of the NO targets [20]. The calcium-calmodulin controlled eNOS activates by mechanical and chemical stimuli leading to an increase in endothelial cell calcium, e.g. shear stress, acetylcholine, endothelin, bradykinin and other, are known to stimulate NO production. NO then diffuses from endothelial cells into vascular smooth muscle cells where it leads to relaxation and vasodilatation [7]. Through this mechanism NO is able to decrease total peripheral resistance and lower blood pressure.

ROS, the chemically reactive molecules containing oxygen can be generated in different ways. The nicotinamide adenine dinucleotide phosphate oxidases (Nox) are the primary source of ROS in the vascular wall and have been identified to play a key role in the pathogenesis of hypertension [21]. Importantly, Nox-dependent ROS production can be triggered by numerous pro-contractile neurohumoral factors, e.g. angiotensin II, endothelin-1 and norepinephrine [5]. Xanthine oxidase (XO) is another source for ROS in the vascular wall [22]. Furthermore, functional uncoupling of eNOS resulting in the generation of ROS rather than protective NO [23] also occurs and this pathway has been suggested to be important for hypertension [24]. Finally, damage to the mitochondrial respiratory chain leads to dysfunction of the mitochondrial respiration increasing the mitochondrial ROS formation [25].

Oxygen prematurely and incompletely reduced to superoxide radical (O2~*) is not particularly reactive by itself, but can inactivate enzymes by acting primarily on the cysteine containing proteins or can initiate lipid peroxidation into hydroperoxyl (HO2*), which under normal physiological pH exists in highly aggressive hydroxyl radical. Normally, the level of superoxide is kept low because it is detoxified by the enzyme superoxide dismutase (SOD) into H2O2 and eventually into water. A number of antioxidants including catalase, peroxidases, glutathione and thioredoxin protect cells from the inappropriate elevation of ROS [26].

ROS may exert dual effects on signaling in vascular smooth muscle cells. It may be detrimental as well as acting as endogenous signaling molecules. The interaction between NO/cGMP and inositol trisphosphate (IP3) pathways has been suggested in this regard [27]. Thus, IP3-induced intracellular calcium release from sarcoplasmic reticulum has been shown to be facilitated by superoxide [28] and this might be mediated via the decreased cross-inhibition of IP3 pathway by cGMP in vascular smooth muscle cells [27]. Under normal physiological conditions this might be used for well-tuned regulation of vascular resistance. However, if the level of superoxide is increased, the interaction with NO/cGMP dependent pathway will be imbalanced and this can be detected through the decreased NO bioavailability leading to pathological vasoconstriction. The consequent reduction of tissue perfusion will result in a further increasing ROS production and thereby coupling the process into a malignant cycle of the disease [29].

3. Redox imbalance in hypertension

The importance of redox imbalance in the development of hypertension is clearly demonstrated in experimental animal

Table 1 - Reviewed studies addressing the role of oxidative stress in exercise-induced changes of blood pressure. Studies focused on association between blood pressure control and redox state. The association was analyzed under control conditions and as a response to different forms of exercise in humans and animal studies.

Reference Design, study population

Measured parameters

Results

Case-control; controls vs. hypertensive patients

Vascular sources of oxidative stress, including COX-1, COX-2, and Nox

Double-blind randomized; controls vs. essential hypertensive patients

Aerobic exercise

Normotensive vs. mild hypertension patients

Case-control; aerobic training (>12 months) vs. sedentary controls

Walking exercise (12 weeks of 40-50 min three times/ week) of patients with metabolic syndrome

6 months of aerobic exercise training; pre-hypertensive and hypertensive subjects

Isometric exercise

[42] Cohort study; bilateral/

unilateral IHG training (four 2 min 3 times/week for 8 weeks)

[43] Controlled prospective

cohort study; hypertensive individuals (training 3 times/week for 6 weeks)

Alternative exercise

[44] Case-control; non-

hypertensive elderly (12 months Tai chi vs. control)

Could the calcium antagonist (lacidipine) increase antioxidant activity and restore NO bioavailability?

Effect of 12 weeks aerobic exercise on endothelial function

Does the moderate-intensity exercise reduce oxidative stress in type 2 diabetes

Short-term effects of moderate intensity

To determine whether the p22phox subunit polymorphisms is associated with the oxidative stress

Effect of IHG training on endothelial function and blood pressure

Effect of short-term isometric exercise training in hypertensive individuals

Effect of alternative (Tai chi) exercise in elderly

Superoxide - fluorescent detection with dihydroethidium; Western blot - COX-1 and COX-2 expression in small arteries

Forearm blood flow; ROS - measured by 2,7-dichloro-fluorescin-diacetate oxidation; NO - vasoconstriction to l-NMMA

Forearm blood flow response to acetylcholine

Urinary 8-OHdG measurements

Blood pressure and heart rate;

O2 consumption; Inflammatory and metabolic parameters TAC in blood plasma; NOx in urine; 8-iso-GF2a in urine

Forearm blood flow/FMD -measured in both arms

Blood pressure measurements; ROS measured by electron spin resonance spectroscopy in plasma

Antioxidant activity in blood samples: GPx, SOD, CAT, MDA; Nutrient intake: FFQ

In hypertensive patients:

• vascular oxidative stress enhanced;

• COX-2 and Nox upregulation in the vascular media

• endothelial dysfunction through the reduction of NO availability

Lacidipine:

• restores NO bioavailability;

• increases endothelium-dependent vasodilation;

• decreased markers of oxidative stress

Long-term exercise improves vasorelaxation through an increase in NO release in normotensive as well as hypertensive patients

Aerobic exercise improved glycemic control and reduced oxidative stress in patients with diabetes Systolic and diastolic blood pressures reduced by exercise

Aerobic exercise increases antioxidant levels but decrease in NO and increase in oxidative stress

IHG training improved FMD only in trained arm; Systolic blood pressure significantly reduced after both bi- and unilateral IHG training;

Diastolic blood pressure remained unchanged Short-term exercise lowers systolic but not diastolic blood pressure in hypertensive individuals; Decrease in the exercise-induced oxygen centered radicals

Tai Chi exercise stimulates endogenous antioxidant enzymes and reduced oxidative stress markers. Systolic blood pressure lowered in Tai Chi subjects

Table 1 (Continued )

Reference Design, study population Aim Measured parameters Results

Animal experiments

[45] Acute (2 weeks) or chronic Effects of exercise on Tail-cuff blood pressure Endurance training enhance

(6 weeks) treadmill running endothelium-dependent measurements; endothelium-dependent

of rats at moderate vasodilation and eNOS/ In vitro function of thoracic relaxation;

intensity, or intense iNOS and HO-1/HO-2 aorta; Intense training resulted in

training of high volume Western blot/immune- mild hypertension with

histochemistry - content/ impairment in vasodilation

localization of HO-1/HO-2,

and eNOS/iNOS

[11] 12 weeks treadmill Effects of aerobic exercise Tail-cuff blood pressure In SHR exercise reduced:

training; (WKY vs. SHR) training in hypertension measurements; • vascular stiffness;

associated vascular NO production - • normalized the responses

remodeling diaminofluorescein to apocynin and l-NAME;

diacetate; • normalized superoxide

Superoxide production - production;

dihydroethidium; • reduced superoxide

In vitro contraction and dismutase expression;

acetylcholine relaxation; • increased NO production

Western blot

8-iso-PGF2a, 8-iso-prostaglandine F2a; 8-OHdG, 8-hydroxy-2'-deoxyguanosine; CAT, catalase; COX, cyclooxygenase; eNOS, endothelial nitric oxide synthase; HO, heme oxygenase; FFQ, food frequency questionnaire; FMD, flow-mediated dilation; GPx, glutathione peroxidase; IHG, isometric handgrip; iNOS, inducible nitric oxide synthase; l-NAME, non-selective NOS inhibitor, N-nitro-l-arginine methyl ester; l-NMMA, monomethyl-l-arginine, monoacetate salt; NO, nitric oxide; NOx, nitric oxide metabolites; Nox, superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; MDA, malondialdehyde; ROS, reactive oxygen species; SOD, superoxide dismutase; SHR, spontaneously hypertensive rats; TAC, total antioxidant capacity; WKY, normotensive Wistar Kyoto rats.

models [30,31]. However, the results from clinical studies are less clear since many antioxidant trials have failed to show beneficial effects [32]. Nevertheless, it is appreciated that, in patients with essential hypertension, blood pressure positively correlates with biomarkers of oxidative stress and negatively correlates with the level of antioxidants [33-36]. A number of epidemiological studies clearly indicate the relationship between hypertension, oxidative stress and exercise (Table 1). Oxidative stress has been measured experimentally in several ways. It was indirectly evaluated noninvasively as an endothelial function using brachial artery flow-mediated vasodilation [46]. Moreover, many biomarkers listed in Table 2 have been used to determine oxidative stress in various cell types, tissues, urine, blood, etc. [1].

Redox imbalance evaluated as an elevated level of oxidative stress has been measured in both humans and experimental animals. Importantly, experimental animal studies clearly demonstrate a well-documented association between high blood pressure and oxidative stress [1,21,47]. Accordingly, pro-hypertensive treatment of normotensive rats with angiotensin II is known to stimulate the production of ROS by Nox and raise blood pressure [48]. A pharmacological improvement of mitochondrial respiratory chain dysfunctions has been shown to produce an antihypertensive effect in hypertensive rats [49]. Metabolic syndrome in hypertensive rats [50] is suggested to be one of the reasons for the association between elevated blood pressure and redox imbalance, ROS-mediated inactivation of NO and decreased NO availability. Moreover, blood pressure,

Table 2 - Some of oxidative stress markers discussed in review.

Marker Sample type

Cells Tissue Blood Urine Other

Lipid peroxidation

Malondialdehyde (MDA) x x x x

8-iso-Prostaglandine F2a (8-iso-PGF2a) x x x x

DNA/RNA damage

8-Hydroxydeoxyguanosine (8-OHdG) x x x x

Reactive oxygen species

Nitric oxide (NO) x x x x

Hydrogen peroxidase (H2O2) x x x x

Antioxidants

Total antioxidant capacity (TAC) x x x x Food sample

Catalase (CAT) x x x

Glutathione peroxidase (GPx) x x x x

Superoxide dismutase (SOD) x x x

redox state and NO availability have been shown to improve 2 months after switching animals from prodiabetic to normal diet [50]. Several contributory factors can influence oxidative stress in hypertensive subjects. For example, a study of immobilizing stress in rats demonstrated that psychical stress can also lead to redox imbalance [51]. Redox imbalance was also shown in association with chronic mild stress in rats [52]. It has been found that arterial eNOS and NO decreased by psychical stress leading to reduced acetylcholine-induced relaxation [52,53], and that this was associated with an increase in plasma malondialdehyde (MDA) suggesting elevated oxidative stress (Table 2).

Experimental results from animal studies have received substantial support from the clinical studies in hypertensive patients where redox state was evaluated [6,37]. An association between oxidative stress and essential hypertension in humans was identified [5]. The importance of redox imbalance in hypertension has also been demonstrated in many population-based studies where reduced level of antioxidant protection was correlated to high blood pressure [14,54,55]. Direct measurements in vascular smooth muscle cells derived from resistance arteries of hypertensive patients demonstrated the elevated level of ROS at rest and after angiotensin II stimulation in comparison with normotensive controls [56]. In the study by Taddei and coauthors, it is assumed that essential hypertension is associated with impaired endothelium-de-pendent vasodilation caused by ROS-induced NO breakdown. It was suggested that, since calcium antagonists can improve endothelial function, the potential beneficial effect can relate to restoration of NO availability caused by antioxidant activity [37]. Accordingly, they have found that the calcium channel blocker lacidipine increases endothelium-dependent vasodila-tionbyrestoringNO availability possibly via antioxidant activity (Table 1). Thus, the reduction of ROS by lacidipine was suggested to have a beneficial mechanism mainly because it might prevent the formation of the peroxynitrite anion (ONOO~) (Figure). In the follow up study resistance arteries from patient biopsies were studied in vitro for endothelium-dependent

D Catalase -=> H202-H20 + 02

NAD(P)H Oxidase

Xanthine oxidase Lipoxygenase Cyclooxygenase P-450 monooxygenase Mitochondrial oxidative phosphorylation

Figure - A schematic interaction of endothelial nitric oxide (NO) and reactive oxygen species (ROS). cGMP, cyclic guanosine monophosphate; sGC, soluble guanylate cyclase; eNOS, endothelial NO synthase; SOD, superoxide dismutase; NAD(P)H, nicotinamide adenine dinucleotide (phosphate) hydrogen, ONOO", peroxynitrite anion.

(acetylcholine-induced) and endothelium-independent (sodium nitroprusside induced) relaxations after the preconstriction with noradrenaline [6]. It was found that resistance arteries of hypertensive subjects showed a significant impairment of the endothelium-dependent relaxation compared with normoten-sive subjects due to overexpression of cyclooxygenase-2 (COX-2) and Nox. Since both these enzymes are sources for generating ROS (Figure), an elevation of oxidative stress was suggested to be responsible for the reduced availability of NO [6].

4. Redox state and physical exercise

The hypothesis about the importance of redox imbalance for hypertension pathology suggests that oxidative stress may be a possible target and focus for therapeutic intervention in the treatment of hypertension. A number of different therapeutic strategies including physical exercise have been suggested [4,5]. The beneficial effects of exercise in hypertensive subjects are thought to be mediated by an improvement of the redox state [57]. Since hypertension is known to be associated with endothelial dysfunction - an early feature of vascular diseases in humans - lifestyle modifications, including exercise, are expected to prevent cardiovascular complications and appear to be an effective nonpharmacological therapy for prevention and control of hypertension [11].

It has been shown that exercise improves endothelial function in animal experimental models of hypertension and in patients with essential hypertension (Table 3). In normo-tensive humans exercise is also shown to have a beneficial effect on cardiovascular control and particularly for endothe-lial function [38]. Although the mechanisms underlying the antihypertensive effects of exercise have not yet been fully clarified, it has been suggested that the improvement of endothelium-dependent relaxation, endothelial adaptation, is mainly mediated by a significant increase in vascular NO production and/or decrease in NO scavenging by ROS [57,58]. This endothelial adaptation has been suggested to be, at least in part, a product of exercise-induced changes in shear stress [59]. Thus, this increase in NO bioavailability, mainly through the reduction of oxidative stress, is an important contributor to the improvement of endothelial function observed as a result of exercise. Moreover, exercise has also been demonstrated to normalize the levels and/or expression of proinflammatory cytokines that decrease NO bioavailability by stimulation of ROS production [57].

Importantly, endothelial adaptations are also reported for vascular beds of skeletal muscles and other organs which are not active or less active during exercise [60,61]. These endothelial adaptations beyond the active muscular beds suggest that other than shear stress factors are involved in linking physical activity and endothelial function. These might include the whole body shear stress profile changes and humoral factors, e.g. insulin [for review see: 59]. Moreover, active muscles suggested releasing several cytokines and other peptides, termed myokines, and exerting anti-inflammatory action [62] which in turn increases NO bioavailability via decrease of ROS production [57]. In general, the phenomenon of endothelial adaptation supports the systemic effect of exercise on redox state of the whole body suggesting it

Table 3 - Exercise interventions and the effects on vascular redox state.

Subject Analyzed tissue Benefit Training program Reference

Rats Aorta "eNOS "NO Treadmill run for 2 or 6 weeks at 50% VO2max: • 2 h/d (endurance training, moderate volume) • 3 h/d (intense training high volume) [45]

Rats Coronary/mesenteric #O2* Treadmill run: [11]

arteries "SOD expression "NO "NOS expression 1 h/day 5 days/week for 12 weeks at 55%-65% VO2max

Humans Forearm artery "BP (systolic and diastolic) "Norepinephrine "NO Aerobic exercise: 30-min walking 5-7 times/week for 12 weeks [38]

Humans Plasma " O2* "Glycemic control Aerobic exercise: min. 30 min 3 days/week for 12 months at 50% VO2max [39]

Humans Plasma "Antioxidant capacity "Urinary NO "Oxidative stress Aerobic exercise: 1 h/day 3 days/week for 6 months at 60%-70% VO2max [41]

Humans Plasma "DNA damage "HR "Systolic BP Tai Chi: 1 h twice a week for 12 months [44]

Humans Brachial artery "BA FMD in trained arm "Systolic BP IHG contractions: 4 x 2 min 3 times/week for 8 weeks at 30% VO2max [42]

Humans Brachial artery/plasma "ROS "Antioxidants "Systolic BP IET: 10 min/day 3 days/week for 6 weeks at 50% MVC [43]

BA FMD, brachial artery flow-mediated-dilation; BP, blood pressure; eNOS, endothelial nitric oxide synthase; IHG, isometric hand grip; IET,

isometric exercise training; HR, heart rate; MVC, maximum voluntary contraction; NO, nitric oxide; NOS, nitric oxide synthase; O2' ', superoxide;

SOD, superoxide dismutase; VO2, oxygen consumption.

significance for nonexercising vascular beds [63,64]. Overall, two large groups of exercise are usually distinguished: aerobic and resistance training. Aerobic exercise includes a broad spectrum of training performed at moderate level of intensity for extended period and involves or improves oxygen consumption to sufficiently meet energy demands during exercise [65]. One of the common forms for resistance training is isometric exercise where high-intensity, short-duration muscle contractions are mechanically opposed. Over the past two decades the effects of different forms of exercise in both animal models and humans have been intensively studied. An overview of the subjects, tissue, programs and benefits in the redox state achieved by the exercise interventions are provided in Table 3.

5. Aerobic exercise

Aerobic exercise has been shown to be effective in a significant reduction of ROS and in a decrease of the occurrence of ROSassociated diseases, including hypertension [11]. It has been suggested that aerobic exercise enhances the adaptation to oxidative stress by increasing level of antioxidants [66]. Accordingly, improved eNOS phosphorylation and increased antioxidant enzyme expression have been observed in diabetic mice after aerobic exercise [67]. Moreover, rats subjected to acute and chronic aerobic training demonstrated an increased blood flow and augmented sheer stress induced endothelium-dependent vasodilation [45]. This was associated with an upregulation of eNOS leading to the greater bioavailability of NO. Furthermore, it has been shown that 12 weeks of moderate aerobic treadmill running improved

mechanical and functional properties of coronary arteries and resistance arteries in hypertensive rats [11]. This benefit appears to be mainly due to similar mechanisms, i.e. the increased expression of eNOS, the elevated NO bioavailability and the reduced levels of superoxide.

These results have received support from the patient studies (Table 3). In untreated hypertensive patients, aerobic exercise for 12 weeks significantly increased forearm blood flow response to acetylcholine and lowered blood pressure through the acetylcholine-stimulated NO release [38]. The acetylcholine-stimulated NO release was also augmented by long-term aerobic exercise in the normotensive subjects [38]. In general, the effect of exercise is most notable in subject populations with preexisting cardiovascular risk factors or diseases [59]. Similarly, an exercise intervention in patients with metabolic syndrome showed significant reductions in systolic and diastolic blood pressures [40]. This is in line with findings that the urinary marker of oxidative stress, 8-OHdG level (Table 2) decreases in patients with type 2 diabetes as a result of 12-month program of aerobic training [39]. Interestingly, aerobic exercise was shown to have most of the beneficial results in lowering systolic blood pressure, although diastolic blood pressure was also affecte [38,40].

Taken together these studies indicate that aerobic physical exercise effectively lowers blood pressure and improves endothelium-dependent vasodilation in patients with essential hypertension through the increased bioavailability of NO in the vascular wall. These findings suggest that regular aerobic exercise is beneficial for maintenance of the resistance to oxidative stress and should be considered as an essential part of patient treatment.

6. Isometric exercise

An isometric or static contraction is a form of resistance exercise which is defined as a sustained muscle contraction (i.e. increase in tension) with no change in length of the involved muscle group. Resistance exercise has not been evaluated to the same extent as aerobic exercise in relation to redox imbalance. Two studies examining the effect of isometric exercise in hypertension are of interest in this regard [42,43]. The first demonstrated that isometric handgrip training (IHG) improves endothelial-dependent vasodilation [42]. Of interest, the improvement only occurred locally in the trained limbs. The second study examined the effect of isometric exercise in hypertensive patients and showed that systolic but not diastolic blood pressure was significantly lowered by training [43] (Table 3). Importantly, the markers of oxidative stress were affected by isometric exercise and a major decrease in exercise-induced oxygen radicals was reported [43].

7. Alternative training

Tai chi is a gentle exercise program that is a part of traditional Chinese medicine. Derived from the martial arts, Tai chi is composed of slow, deliberate movements, meditation, and deep breathing, which should enhance physical health and emotional wellbeing. Accordingly, Tai chi exercise was found associated with similar physiological and biochemical improvements seen with other forms of physical training [44]. Tai chi exercise was found to decrease systolic bloodpressurebutithad no effect on diastolic blood pressure in middle-age adults. Similar to the results associated with other forms of physical training [43], an enhanced level of antioxidant protection has been suggested as the mechanism underlying the decrease in ROS which, in turn, lowers blood pressure [44]. This was suggested to be a result of a mild training-associated induction of oxidative stress leading to stimulation of antioxidant defenses.

Importantly, this latter study did not include hypertensive patients [44] and, therefore, may not necessarily be the representative exercise intervention for hypertensive patients. Moreover, the individuals that performed Tai chi were not sedentary and a sedentary lifestyle is known to be a risk factor of hypertension [66]. Furthermore, the lowered blood pressure in the Tai chi training group was only compared to blood pressure in this group before the training program started, and not to the sedentary group. Tai chi is focusing on mind and body which could also be a reason for the beneficial effects of this training linked to the well-known association between stress and hypertension [51,66,68].

8. Conflicting results

Although most of the studies reviewed here (Table 1) found that moderate aerobic exercise and isometric training had beneficial effects, conflicting results have also been shown. The study by Sun and coauthors [45] have demonstrated the beneficial effects of acute and chronic aerobic training.

However, the effect of high-volume intense training in this study resulted in mild hypertension with significant impairment in the endothelium-dependent vasodilation. Another study of aerobic exercise with participants in a relatively large population (94 participants) found an increase in oxidative stress marker (8-iso-PGF2a) 6 months after of aerobic exercise [41]. This was also associated with a decrease in urinary NO metabolites though antioxidant levels was increased. This result conflicts with the results showing the beneficial effects of aerobic exercise [39].

It has also been shown that IHG training only lowered blood pressure in the trained limb [42] suggesting that the enhanced systemic endothelial-dependent vasodilation is not the mechanism responsible for post-IHG training reduction of blood pressure in hypertensive patients. It should be noted that isometric exercise training involves markedly smaller time commitment (8-10 min/session) compared with the aerobic exercise programs (>30 min/session). In the study by Higashi and coauthors [38] blood pressure was reduced after aerobic exercise but there was no significant correlation between this exercise-induced reduction in blood pressure and the increase in acetylcholine-induced forearm response to after exercise. This suggests that other than endothelium-dependent mechanisms might be involved including cardiac and neuronal functions. Moreover, the aerobic exercise augmented endothelium-dependent vasodilation but did not alter blood pressure in normotensive subjects. This suggests that the reduction in blood pressure may not be directly associated with the improved response of forearm vasculature to acetylcholine and the increase in NO release [38].

The range of different and sometimes conflicting results could be due to variations in intensity, duration, and the type of exercise. The available data on redox imbalance in humans are still limited with only one marker of oxidative stress often being measured. This is, at least in part, because redox imbalance is primarily confined to the kidney, the heart and the brain, and is therefore difficult to access in living humans [69]. For this reason, most of the clinical results are obtained from urine and blood samples. As such, they are not necessarily reflective of a complete redox state in the body.

In addition, most of the clinical studies are based on small populations and this affects integrity of the results, while some of the samples are not representative since they deal with populations that are restricted territorially, e.g. the study of Japanese people from a particular area [38]. Altogether, this may compromise the validity of clinical experimental results. Animal studies overcome these obstacles, but the clarity of their results cannot always be easy applied to humans. It is therefore clear, that further studies are needed to determine the exact mechanisms involved in the effects of exercise in humans.

9. Concluding remarks

The available experimental results indicate that physical exercise has a beneficial effect on redox state and hypertension. However, it is clinically important to select the appropriate intensity, duration, frequency and type of exercise. This is not simply because inappropriate exercise will be ineffective but also because it can be pathogenic, leading to

endothelial dysfunction and cardiac injury. This point is [13 especially important for extreme sport athletes or elderly patients that are of greater vulnerability to mechanical injury. For elderly patients exercise should be carefully selected and it can be suggested, that Tai chi may be a suitable form of exercise and that it may provide the beneficial effect on blood pressure. Isometric training has shown some effectiveness [15 and is as well time-efficient, but it needs further study. Finally, aerobic exercise of moderate intensity has been shown to have the best results in reducing blood pressure.

Conflict of interest [17

The authors have no any conflict of interest.

REFERENCES

[1] Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, et al. Hypertension: physiology and [20 pathophysiology. Compr Physiol 2012;2:2393-442.

[2] Behrens G, Leitzmann MF. The association between

physical activity and renal cancer: systematic review and [21

meta-analysis. Br J Cancer 2013;108:798-811.

[3] Bauer UE, Briss PA, Goodman RA, Bowman BA. Prevention

of chronic disease in the 21st century: elimination of the [22

leading preventable causes of premature death and disability in the USA. Lancet 2014;384:45-52.

[4] Montezano AC, Touyz RM. Oxidative stress, Noxs, and [23 hypertension: experimental evidence and clinical controversies. Ann Med 2012;44(Suppl. 1):S2-16. http://dx. doi.org/10.3109/07853890.2011.653393

[5] Montezano AC, Dulak-Lis M, Tsiropoulou S, Harvey A, Briones AM, Touyz RM. Oxidative stress human [24 hypertension: vascular mechanisms, biomarkers, and novel therapies. Can J Cardiol 2015;31:631-41.

[6] Virdis A, Bacca A, Colucci R, Duranti E, Fornai M, Materazzi [25 G, et al. Endothelial dysfunction in small arteries of

essential hypertensive patients: role of cyclooxygenase-2 in oxidative stress generation. Hypertension 2013;62:337-44. [26

[7] Vanhoutte PM, Shimokawa H, Tang EH, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol

(Oxf) 2009;196:193-222. [27

[8] Higashi Y, Maruhashi T, Noma K, Kihara Y. Oxidative stress and endothelial dysfunction: clinical evidence and

therapeutic implications. Trends Cardiovasc Med 2014;24 [28

(4):165-9.

[9] Manrique C, Lastra G, Gardner M, Sowers JR. The renin [29 angiotensin aldosterone system in hypertension: roles of insulin resistance and oxidative stress. Med Clin North Am [30 2009;93:569-82.

[10] Millar PJ, McGowan CL, Cornelissen VA, Araujo CG, Swaine

IL. Evidence for the role of isometric exercise training in [31

reducing blood pressure: potential mechanisms and future directions. Sports Med 2014;44:345-56. [32

[11] Roque FR, Briones AM, Garcia-Redondo AB, Galan M, Martinez-Revelles S, Avendano MS, et al. Aerobic exercise [33 reduces oxidative stress and improves vascular changes of

small mesenteric and coronary arteries in hypertension. Br J Pharmacol 2013;168:686-703.

[12] Hendre AS, Shariff AK, Patil SR, Durgawale PP, Sontakke AV, [34] Suryakar AN. Evaluation of oxidative stress and anti-

oxidant status in essential hypertension. J Indian Med Assoc 2013;111:377-81.

Patil SB, Kodliwadmath MV, Kodliwadmath SM. Role of lipid peroxidation and enzymatic antioxidants in pregnancy-induced hypertension. Clin Exp Obstet Gynecol 2007;34:239-41.

Rodrigo R, Prat H, Passalacqua W, Araya J, Guichard C, Bachler JP. Relationship between oxidative stress and essential hypertension. Hypertens Res 2007;30:1159-67. Chan SH, Chan JY. Brain stem NOS and ROS in neural mechanisms of hypertension. Antioxid Redox Signal 2014;20:146-63.

Choi BH, Kang KS, Kwak MK. Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules 2014;19:12727-59.

Cheng ZJ, Vaskonen T, Tikkanen I, Nurminen K, Ruskoaho H, Vapaatalo H, et al. Endothelial dysfunction and saltsensitive hypertension in spontaneously diabetic Goto-Kakizaki rats. Hypertension 2001;37:433-9. Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Tiberio G, et al. Endothelial dysfunction in hypertension is independent from the etiology and from vascular structure. Hypertension 1998;31:335-41.

Munzel T, Sinning C, Post F, Warnholtz A, Schulz E. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann Med 2008;40:180-96. Risbano MG, Gladwin MT. Therapeutics targeting of dysregulated redox equilibrium and endothelial dysfunction. Handb Exp Pharmacol 2013;218:315-49. Majzunova M, Dovinova I, Barancik M, Chan JY. Redox signaling in pathophysiology of hypertension. J Biomed Sci 2013;20:69.

Anderson TJ. Nitric oxide, atherosclerosis and the clinical relevance of endothelial dysfunction. Heart Fail Rev 2003;8:71-86.

Zweier JL, Chen CA, Druhan LJ. S-glutathionylation reshapes our understanding of endothelial nitric oxide synthase uncoupling and nitric oxide/reactive oxygen species-mediated signaling. Antioxid Redox Signal 2011;14:1769-75.

Roe ND, Ren J. Nitric oxide synthase uncoupling: a therapeutic target in cardiovascular diseases. Vasc Pharmacol 2012;57:168-72.

Radi R, Cassina A, Hodara R, Quijano C, Castro L. Peroxynitrite reactions and formation in mitochondria. Free Radic Biol Med 2002;33:1451-64. Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011;15:1583-606.

Wu L, Girouard H, de CJ. Involvement of the cyclic GMP pathway in the superoxide-induced IP3 formation in vascular smooth muscle cells. J Hypertens 2000;18:1057-64. Suzuki YJ, Forman HJ, Sevanian A. Oxidants as stimulators of signal transduction. Free Radic Biol Med 1997;22:269-85. Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med 2005;26:33-65. Dikalov SI, Ungvari Z. Role of mitochondrial oxidative stress in hypertension. Am J Physiol Heart Circ Physiol 2013;305: H1417-2.

Araujo M, Wilcox CS. Oxidative stress in hypertension: role of the kidney. Antioxid Redox Signal 2014;20:74-101. Schiffrin EL. Antioxidants in hypertension and cardiovascular disease. Mol Interv 2010;10:354-62. Ahmad A, Singhal U, Hossain MM, Islam N, Rizvi I. The role of the endogenous antioxidant enzymes and malondialdehyde in essential hypertension. J Clin Diagn Res 2013;7:987-90.

Holowatz LA, Kenney WL. Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans. Am J Physiol Heart Circ Physiol 2007;293:H1090-6.

[35] Carrizzo A, Puca A, Damato A, Marino M, Franco E, Pompeo F, et al. Resveratrol improves vascular function in patients with hypertension and dyslipidemia by modulating NO metabolism. Hypertension 2013;62:359-66.

[36] 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;36:226-32.

[37] Eslami S, Sahebkar A. Glutathione-S-transferase M1 T1 null genotypes are associated with hypertension risk: a systematic review and meta-analysis of 12 studies. Curr Hypertens Rep 2014;16:432.

[38] Rafiq A, Aslam K, Malik R, Afroze D. C242T polymorphism of the NADPH oxidase p22. PHOX gene and its association with endothelial dysfunction in asymptomatic individuals with essential systemic hypertension. Mol Med Rep 2014;9:1857-62.

[39] Touyz RM, Yao G, Schiffrin EL. c-Src induces phosphorylation and translocation of p47phox: role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003;23:981-7.

[40] Roque FR, Hernanz R, Salaices M, Briones AM. Exercise training and cardiometabolic diseases: focus on the vascular system. Curr Hypertens Rep 2013;15:204-14.

[41] Higashi Y, Sasaki S, Kurisu S, Yoshimizu A, Sasaki N, Matsuura H, et al. Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide. Circulation 1999;100:1194-202.

[42] 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;102:87-96.

[43] Padilla J, Simmons GH, Bender SB, Arce-Esquivel AA, Whyte JJ, Laughlin MH. Vascular effects of exercise: endothelial adaptations beyond active muscle beds. Physiology (Bethesda) 2011;26:132-45.

[44] Lash JM. Exercise training enhances adrenergic constriction and dilation in the rat spinotrapezius muscle. J Appl Physiol (1985) 1998;85:168-74.

[45] Faulx MD, Wright AT, Hoit BD. Detection of endothelial dysfunction with brachial artery ultrasound scanning. Am Heart J 2003;145:943-51.

[46] Clarkson P, Montgomery HE, Mullen MJ, Donald AE, Powe AJ, Bull T, et al. Exercise training enhances endothelial function in young men. J Am Coll Cardiol 1999;33:1379-85.

[47] Pedersen BK. The diseasome of physical inactivity - and the role of myokines in muscle - fat cross talk. J Physiol 2009;587:5559-68.

[48] Mayhan WG, Arrick DM, Patel KP, Sun H. Exercise training normalizes impaired NOS-dependent responses of cerebral arterioles in type 1 diabetic rats. Am J Physiol Heart Circ Physiol 2011;300:H1013-20.

[49] Mayhan WG, Arrick DM, Sun H, Patel KP. Exercise training restores impaired dilator responses of cerebral arterioles during chronic exposure to nicotine. J Appl Physiol (1985) 2010;109:1109-14.

[50] Siti HN, Kamisah Y, Kamsiah J. The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vasc Pharmacol 2015.

[51] Mandic S, Myers J, Selig SE, Levinger I. Resistance versus aerobic exercise training in chronic heart failure. Curr Heart Fail Rep 2012;9:57-64.

[52] Huang CJ, Webb HE, Zourdos MC, Acevedo EO. Cardiovascular reactivity, stress, and physical activity. Front Physiol 2013;4:314.

[53] Lee S, Park Y, Zhang C. Exercise training prevents coronary endothelial dysfunction in type 2 diabetic mice. Am J Biomed Sci 2011;3:241-52.

[54] Sun MW, Zhong MF, Gu J, Qian FL, Gu JZ, Chen H. Effects of different levels of exercise volume on endothelium-dependent vasodilation: roles of nitric oxide synthase and heme oxygenase. Hypertens Res 2008;31:805-16.

[55] Colombo CM, de Macedo RM, Fernandes-Silva MM, Caporal AM, Stinghen AE, Costantini CR, et al. Short-term effects of moderate intensity physical activity in patients with metabolic syndrome. Einstein (Sao Paulo) 2013;11:324-30.

[56] Nojima H, Watanabe H, Yamane K, Kitahara Y, Sekikawa K, Yamamoto H, et al. Effect of aerobic exercise training on oxidative stress in patients with type 2 diabetes mellitus. Metabolism 2008;57:170-6.

[57] Peters PG, Alessio HM, Hagerman AE, Ashton T, Nagy S, Wiley RL. Short-term isometric exercise reduces systolic blood pressure in hypertensive adults: possible role of reactive oxygen species. Int J Cardiol 2006;110:199-205.

[58] McGowan CL, Visocchi A, Faulkner M, Verduyn R, Rakobowchuk M, Levy AS, et al. Isometric handgrip training improves local flow-mediated dilation in medicated hypertensives. Eur J Appl Physiol 2007;99:227-34.

[59] Goon JA, Aini AH, Musalmah M, Anum MY, Nazaimoon WM, Ngah WZ. Effect of Tai Chi exercise on DNA damage, antioxidant enzymes, and oxidative stress in middle-age adults. J Phys Act Health 2009;6:43-54.

[60] Bouzinova EV, Wiborg O, Aalkjaer C, Matchkov VV. The role of peripheral vascular resistance for the association between major depression and cardiovascular disease. J Cardiovasc Pharmacol 2014;65:299-307.

[61] Taddei S, Virdis A, Ghiadoni L, Magagna A, Pasini AF, Garbin U, et al. Effect of calcium antagonist or beta blockade treatment on nitric oxide-dependent vasodilation and oxidative stress in essential hypertensive patients. J Hypertens 2001;19:1379-86.

[62] Sumbalova Z, Kucharska J, Kristek F. Losartan improved respiratory function and coenzyme Q content in brain mitochondria of young spontaneously hypertensive rats. Cell Mol Neurobiol 2010;30:751-8.

[63] Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part II: Animal and human studies. Circulation 2003;108:2034-40.

[64] Matchkov VV, Kravtsova VV, Wiborg O, Aalkjaer C, Bouzinova EV. Chronic selective serotonin reuptake inhibition modulates endothelial dysfunction and oxidative state in rat chronic mild stress model of depression. Am J Physiol 2015;309:R814-23.

[65] Chung IM, Kim YM, Yoo MH, Shin MK, Kim CK, Suh SH. Immobilization stress induces endothelial dysfunction by oxidative stress via the activation of the angiotensin II/its type I receptor pathway. Atherosclerosis 2010;213:109-14.

[66] Bouzinova EV, Norregaard R, Boedtkjer DM, Razgovorova IA, Moeller AM, Kudryavtseva O, et al. Association between endothelial dysfunction and depression-like symptoms in chronic mild stress model of depression. Psychosom Med 2014;76:268-76.

[67] Feairheller DL, Brown MD, Park JY, Brinkley TE, Basu S, Hagberg JM, et al. Exercise training, NADPH oxidase p22phox gene polymorphisms, and hypertension. Med Sci Sports Exerc 2009;41:1421-8.

[68] Roberts CK, Barnard RJ, Sindhu RK, Jurczak M, Ehdaie A, Vaziri ND. Oxidative stress and dysregulation of NAD(P)H oxidase and antioxidant enzymes in diet-induced metabolic syndrome. Metabolism 2006;55:928-34.

[69] Vaziri ND, Rodriguez-Iturbe B. Mechanisms of disease: oxidative stress and inflammation in the pathogenesis of hypertension. Nat Clin Pract Nephrol 2006;2:582-93.