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medicina 52 (2016) 1927

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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

article info abstract

Article history: Oxidative stress is associated with the pathogenesis of hypertension. Decreased bioavail-
Received 29 November 2015 ability of nitric oxide (NO) is one of the mechanisms involved in the pathogenesis. It has been
Received in revised form suggested that physical exercise could be a potential non-pharmacological strategy in
15 January 2016 treatment of hypertension because of its benecial effects on oxidative stress and endothe-
Accepted 17 January 2016 lial function. The aim of this review is to investigate the effect of oxidative stress in relation
Available online 29 January 2016 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
Keywords: adverse effects in the correlation between oxidative stress and hypertension. Most of the
Oxidative stress previous studies found that aerobic exercise signicantly decreased blood pressure and
Hypertension oxidative stress in hypertensive subjects, but the intense aerobic exercise can also injure
Exercise endothelial cells. Isometric exercise decreases normally only systolic blood pressure. An
Redox state alternative exercise, Tai chi signicantly decreases blood pressure and oxidative stress in
Nitric oxide 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 interven-
tion 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/).

disease. Hypertension is dened as a chronic elevation of


1. Introduction
systolic blood pressure greater than 140 mm Hg and/or diastolic
blood pressure greater than 90 mm Hg, and is classied as
Hypertension is a major risk factor in the development of either essential (primary) or secondary hypertension [1].
cardiovascular diseases, including stroke and coronary artery 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/).
20 medicina 52 (2016) 1927

hypertension which is characterized by a lack of identiable reduction in endothelial NO synthase (eNOS), an uncoupling
trigger for blood pressure raise. The remaining 5% of the cases of eNOS enzymatic activity, scavenging of NO by ROS as well as
are categorized as secondary hypertension which is caused by the oxidation of the NO targets [20]. The calcium-calmodulin
various medical conditions, e.g. kidney disease and tumors [2]. It controlled eNOS activates by mechanical and chemical stimuli
is predicted that the prevalence of hypertension will increase by leading to an increase in endothelial cell calcium, e.g. shear
more than 50% during the next 30 years resulting in an stress, acetylcholine, endothelin, bradykinin and other, are
enormous disease burden for society [3]. In line with this known to stimulate NO production. NO then diffuses from
ongoing development, the effective treatment of hypertension endothelial cells into vascular smooth muscle cells where it
is becoming increasingly urgent. It is no longer sufcient to leads to relaxation and vasodilatation [7]. Through this
depend on pharmacological therapies, when a modest change mechanism NO is able to decrease total peripheral resistance
in lifestyle can be demonstrated to have a benecial effect. and lower blood pressure.
Previous studies suggested that redox imbalance might be ROS, the chemically reactive molecules containing oxygen
associated with pathogenesis of hypertension although it may can be generated in different ways. The nicotinamide adenine
not be the only cause of blood pressure elevation [47]. This dinucleotide phosphate oxidases (Nox) are the primary source
occurs due to imbalance between elevated reactive oxygen of ROS in the vascular wall and have been identied to play a
species (ROS) (e.g. superoxide, hydrogen peroxide and hydroxyl key role in the pathogenesis of hypertension [21]. Importantly,
radical) production and/or reduced antioxidant capacity at the Nox-dependent ROS production can be triggered by numerous
systemic level as well as the localized changes in the circulatory pro-contractile neurohumoral factors, e.g. angiotensin II,
regions [8]. ROS are known to play both physiological and endothelin-1 and norepinephrine [5]. Xanthine oxidase (XO)
pathophysiological roles in the body [5]. At the appropriate is another source for ROS in the vascular wall [22]. Further-
concentrations and sub-cellular localization ROS participate in more, functional uncoupling of eNOS resulting in the genera-
cellular signaling and phenotype regulation. Moreover, ROS are tion of ROS rather than protective NO [23] also occurs and this
known to modulate numerous pathways important for control pathway has been suggested to be important for hypertension
of systemic vascular resistance and blood pressure, including [24]. Finally, damage to the mitochondrial respiratory chain
decreased bioavailability of nitric oxide (NO), inammation, leads to dysfunction of the mitochondrial respiration increas-
imbalance in salt and water homeostasis, hyperactivity of the ing the mitochondrial ROS formation [25].
sympathetic nervous system (SNS) and disturbances of the Oxygen prematurely and incompletely reduced to super-
reninangiotensinaldosterone-system (RAAS) [6,9]. Interest- oxide radical (O2) is not particularly reactive by itself, but can
ingly, physical exercise has been suggested to be benecial in inactivate enzymes by acting primarily on the cysteine
hypertension by improving the redox state, particularly, in the containing proteins or can initiate lipid peroxidation into
vascular wall [10,11]. Physical exercise may therefore be of hydroperoxyl (HO2), which under normal physiological pH
potential importance for prevention or treatment of hyperten- exists in highly aggressive hydroxyl radical. Normally, the
sion or hypertension-associated pathologies besides conven- level of superoxide is kept low because it is detoxied by the
tional pharmacological treatment. enzyme superoxide dismutase (SOD) into H2O2 and eventually
This focused review provides an overview for the role of into water. A number of antioxidants including catalase,
redox imbalance in hypertension and its therapeutic modula- peroxidases, glutathione and thioredoxin protect cells from
tion by physical exercise. The focus is especially made on the the inappropriate elevation of ROS [26].
ROS-dependent reduction of NO bioavailability in hyperten- ROS may exert dual effects on signaling in vascular smooth
sive subjects and the effects of exercise on this endothelium- muscle cells. It may be detrimental as well as acting as
dependent pathway. endogenous signaling molecules. The interaction between
NO/cGMP and inositol trisphosphate (IP3) pathways has been
suggested in this regard [27]. Thus, IP3-induced intracellular
2. Redox state and NO bioavailability
calcium release from sarcoplasmic reticulum has been shown
to be facilitated by superoxide [28] and this might be mediated
Redox imbalance has been measured in hypertensive subjects via the decreased cross-inhibition of IP3 pathway by cGMP in
as an elevated level of oxidative stress [1216]. In this context vascular smooth muscle cells [27]. Under normal physiological
redox imbalance can be seen as outbalanced production/ conditions this might be used for well-tuned regulation of
accumulation of ROS [5]. Along with other pathways, ROS vascular resistance. However, if the level of superoxide is
decrease the bioavailability of NO [1]. Hypertension is known increased, the interaction with NO/cGMP dependent pathway
to be associated with endothelial dysfunction [17,18] and it will be imbalanced and this can be detected through the
might, therefore, be suggested that impairment in hyperten- decreased NO bioavailability leading to pathological vasocon-
sion endothelium-dependent vasodilation is the result of striction. The consequent reduction of tissue perfusion will
oxidative stress [6]. Alternatively, this redox imbalance can be result in a further increasing ROS production and thereby
the result of a reduction in antioxidant potential of NO, which coupling the process into a malignant cycle of the disease [29].
occurs secondary to the reduced production of NO. In any of
these scenarios, oxidative stress seems to play an important
3. Redox imbalance in hypertension
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 The importance of redox imbalance in the development of
involve a number of different mechanisms including a hypertension is clearly demonstrated in experimental animal
medicina 52 (2016) 1927 21

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 Aim Measured parameters Results
[6] Casecontrol; controls vs. Vascular sources of Superoxide uorescent In hypertensive patients:
hypertensive patients oxidative stress, including detection with  vascular oxidative stress
COX-1, COX-2, and Nox dihydroethidium; enhanced;
Western blot COX-1 and  COX-2 and Nox
COX-2 expression in small upregulation in the vascular
arteries media
 endothelial dysfunction
through the reduction of NO
availability
[37] Double-blind randomized; Could the calcium Forearm blood ow; Lacidipine:
controls vs. essential antagonist (lacidipine) ROS measured by  restores NO bioavailability;
hypertensive patients increase antioxidant 2,7-dichloro-uorescin-  increases endothelium-
activity and restore NO diacetate oxidation; dependent vasodilation;
bioavailability? NO vasoconstriction to  decreased markers of
L-NMMA oxidative stress

Aerobic exercise
[38] Normotensive vs. mild Effect of 12 weeks aerobic Forearm blood ow Long-term exercise
hypertension patients exercise on endothelial response to acetylcholine improves vasorelaxation
function through an increase in NO
release in normotensive as
well as hypertensive
patients
[39] Casecontrol; aerobic Does the moderate- Urinary 8-OHdG Aerobic exercise improved
training (>12 months) vs. intensity exercise reduce measurements glycemic control and
sedentary controls oxidative stress in type 2 reduced oxidative stress in
diabetes patients with diabetes
[40] Walking exercise (12 weeks Short-term effects of Blood pressure and heart Systolic and diastolic blood
of 4050 min three times/ moderate intensity rate; pressures reduced by
week) of patients with exercise O2 consumption; exercise
metabolic syndrome Inammatory and
metabolic parameters
[41] 6 months of aerobic To determine whether the TAC in blood plasma; Aerobic exercise increases
exercise training; pre- p22phox subunit NOx in urine; antioxidant levels but
hypertensive and polymorphisms is 8-iso-GF2a in urine decrease in NO and increase
hypertensive subjects associated with the in oxidative stress
oxidative stress

Isometric exercise
[42] Cohort study; bilateral/ Effect of IHG training on Forearm blood ow/FMD IHG training improved FMD
unilateral IHG training endothelial function and measured in both arms only in trained arm;
(four 2 min 3 times/week blood pressure Systolic blood pressure
for 8 weeks) signicantly reduced after
both bi- and unilateral IHG
training;
Diastolic blood pressure
remained unchanged
[43] Controlled prospective Effect of short-term Blood pressure Short-term exercise lowers
cohort study; hypertensive isometric exercise training measurements; systolic but not diastolic
individuals (training 3 in hypertensive individuals ROS measured by electron blood pressure in
times/week for 6 weeks) spin resonance hypertensive individuals;
spectroscopy in plasma Decrease in the exercise-
induced oxygen centered
radicals

Alternative exercise
[44] Casecontrol; non- Effect of alternative Antioxidant activity in Tai Chi exercise stimulates
hypertensive elderly (12 (Tai chi) exercise in elderly blood samples: GPx, SOD, endogenous antioxidant
months Tai chi vs. control) CAT, MDA; enzymes and reduced
Nutrient intake: FFQ oxidative stress markers.
Systolic blood pressure
lowered in Tai Chi subjects
22 medicina 52 (2016) 1927

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 diaminouorescein 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-20 -deoxyguanosine; CAT, catalase; COX, cyclooxygenase; eNOS, endothelial nitric
oxide synthase; HO, heme oxygenase; FFQ, food frequency questionnaire; FMD, ow-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 Redox imbalance evaluated as an elevated level of oxidative
less clear since many antioxidant trials have failed to show stress has been measured in both humans and experimental
benecial effects [32]. Nevertheless, it is appreciated that, in animals. Importantly, experimental animal studies clearly
patients with essential hypertension, blood pressure positive- demonstrate a well-documented association between high
ly correlates with biomarkers of oxidative stress and negative- blood pressure and oxidative stress [1,21,47]. Accordingly, pro-
ly correlates with the level of antioxidants [3336]. A number of hypertensive treatment of normotensive rats with angiotensin
epidemiological studies clearly indicate the relationship II is known to stimulate the production of ROS by Nox and raise
between hypertension, oxidative stress and exercise (Table 1). blood pressure [48]. A pharmacological improvement of
Oxidative stress has been measured experimentally in several mitochondrial respiratory chain dysfunctions has been shown
ways. It was indirectly evaluated noninvasively as an to produce an antihypertensive effect in hypertensive rats [49].
endothelial function using brachial artery ow-mediated Metabolic syndrome in hypertensive rats [50] is suggested to be
vasodilation [46]. Moreover, many biomarkers listed in Table 2 one of the reasons for the association between elevated blood
have been used to determine oxidative stress in various cell pressure and redox imbalance, ROS-mediated inactivation of
types, tissues, urine, blood, etc. [1]. 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
medicina 52 (2016) 1927 23

redox state and NO availability have been shown to improve 2 (acetylcholine-induced) and endothelium-independent (sodi-
months after switching animals from prodiabetic to normal um nitroprusside induced) relaxations after the preconstriction
diet [50]. Several contributory factors can inuence oxidative with noradrenaline [6]. It was found that resistance arteries of
stress in hypertensive subjects. For example, a study of hypertensive subjects showed a signicant impairment of the
immobilizing stress in rats demonstrated that psychical stress endothelium-dependent relaxation compared with normoten-
can also lead to redox imbalance [51]. Redox imbalance was sive subjects due to overexpression of cyclooxygenase-2 (COX-2)
also shown in association with chronic mild stress in rats [52]. and Nox. Since both these enzymes are sources for generating
It has been found that arterial eNOS and NO decreased by ROS (Figure), an elevation of oxidative stress was suggested to be
psychical stress leading to reduced acetylcholine-induced responsible for the reduced availability of NO [6].
relaxation [52,53], and that this was associated with an
increase in plasma malondialdehyde (MDA) suggesting ele-
4. Redox state and physical exercise
vated oxidative stress (Table 2).
Experimental results from animal studies have received
substantial support from the clinical studies in hypertensive The hypothesis about the importance of redox imbalance for
patients where redox state was evaluated [6,37]. An associa- hypertension pathology suggests that oxidative stress may be
tion between oxidative stress and essential hypertension in a possible target and focus for therapeutic intervention in the
humans was identied [5]. The importance of redox imbalance treatment of hypertension. A number of different therapeutic
in hypertension has also been demonstrated in many strategies including physical exercise have been suggested
population-based studies where reduced level of antioxidant [4,5]. The benecial effects of exercise in hypertensive subjects
protection was correlated to high blood pressure [14,54,55]. are thought to be mediated by an improvement of the redox
Direct measurements in vascular smooth muscle cells derived state [57]. Since hypertension is known to be associated with
from resistance arteries of hypertensive patients demonstrat- endothelial dysfunction an early feature of vascular diseases
ed the elevated level of ROS at rest and after angiotensin II in humans lifestyle modications, including exercise, are
stimulation in comparison with normotensive controls [56]. In expected to prevent cardiovascular complications and appear
the study by Taddei and coauthors, it is assumed that essential to be an effective nonpharmacological therapy for prevention
hypertension is associated with impaired endothelium-de- and control of hypertension [11].
pendent vasodilation caused by ROS-induced NO breakdown. It has been shown that exercise improves endothelial
It was suggested that, since calcium antagonists can improve function in animal experimental models of hypertension and
endothelial function, the potential benecial effect can relate in patients with essential hypertension (Table 3). In normo-
to restoration of NO availability caused by antioxidant activity tensive humans exercise is also shown to have a benecial
[37]. Accordingly, they have found that the calcium channel effect on cardiovascular control and particularly for endothe-
blocker lacidipine increases endothelium-dependent vasodila- lial function [38]. Although the mechanisms underlying the
tion by restoring NO availability possibly via antioxidant activity antihypertensive effects of exercise have not yet been fully
(Table 1). Thus, the reduction of ROS by lacidipine was suggested claried, it has been suggested that the improvement of
to have a benecial mechanism mainly because it might endothelium-dependent relaxation, endothelial adaptation, is
prevent the formation of the peroxynitrite anion (ONOO) mainly mediated by a signicant increase in vascular NO
(Figure). In the follow up study resistance arteries from patient production and/or decrease in NO scavenging by ROS [57,58].
biopsies were studied in vitro for endothelium-dependent 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 proinammatory
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 prole changes and
Figure A schematic interaction of endothelial nitric oxide humoral factors, e.g. insulin [for review see: 59]. Moreover,
(NO) and reactive oxygen species (ROS). active muscles suggested releasing several cytokines and
cGMP, cyclic guanosine monophosphate; sGC, soluble other peptides, termed myokines, and exerting anti-inam-
guanylate cyclase; eNOS, endothelial NO synthase; SOD, matory action [62] which in turn increases NO bioavailability
superoxide dismutase; NAD(P)H, nicotinamide adenine via decrease of ROS production [57]. In general, the phenome-
dinucleotide (phosphate) hydrogen, ONOOS, peroxynitrite non of endothelial adaptation supports the systemic effect of
anion. exercise on redox state of the whole body suggesting it
24 medicina 52 (2016) 1927

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


Subject Analyzed tissue Benet Training program Reference
Rats Aorta "eNOS Treadmill run for 2 or 6 weeks at 50% VO2max: [45]
"NO  2 h/d (endurance training, moderate volume)
 3 h/d (intense training high volume)
Rats Coronary/mesenteric #O2 Treadmill run: [11]
arteries "SOD expression 1 h/day 5 days/week for 12 weeks at 55%65% VO2max
"NO
"NOS expression
Humans Forearm artery #BP (systolic and diastolic) Aerobic exercise: [38]
#Norepinephrine 30-min walking 57 times/week for 12 weeks
"NO
Humans Plasma # O2 Aerobic exercise: [39]
"Glycemic control min. 30 min 3 days/week for 12 months at 50% VO2max
Humans Plasma "Antioxidant capacity Aerobic exercise: [41]
#Urinary NO 1 h/day 3 days/week for 6 months at 60%70% VO2max
"Oxidative stress
Humans Plasma #DNA damage Tai Chi: [44]
#HR 1 h twice a week for 12 months
#Systolic BP
Humans Brachial artery #BA FMD in trained arm IHG contractions: [42]
#Systolic BP 4  2 min 3 times/week for 8 weeks at 30% VO2max
Humans Brachial artery/plasma #ROS IET: [43]
"Antioxidants 10 min/day 3 days/week for 6 weeks at 50% MVC
#Systolic BP
BA FMD, brachial artery ow-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.

signicance for nonexercising vascular beds [63,64]. Overall, mechanical and functional properties of coronary arteries
two large groups of exercise are usually distinguished: aerobic and resistance arteries in hypertensive rats [11]. This benet
and resistance training. Aerobic exercise includes a broad appears to be mainly due to similar mechanisms, i.e. the
spectrum of training performed at moderate level of intensity increased expression of eNOS, the elevated NO bioavailability
for extended period and involves or improves oxygen and the reduced levels of superoxide.
consumption to sufciently meet energy demands during These results have received support from the patient
exercise [65]. One of the common forms for resistance training studies (Table 3). In untreated hypertensive patients, aerobic
is isometric exercise where high-intensity, short-duration exercise for 12 weeks signicantly increased forearm blood
muscle contractions are mechanically opposed. Over the past ow response to acetylcholine and lowered blood pressure
two decades the effects of different forms of exercise in both through the acetylcholine-stimulated NO release [38]. The
animal models and humans have been intensively studied. An acetylcholine-stimulated NO release was also augmented by
overview of the subjects, tissue, programs and benets in the long-term aerobic exercise in the normotensive subjects
redox state achieved by the exercise interventions are [38]. In general, the effect of exercise is most notable in
provided in Table 3. subject populations with preexisting cardiovascular risk
factors or diseases [59]. Similarly, an exercise intervention in
patients with metabolic syndrome showed signicant
5. Aerobic exercise
reductions in systolic and diastolic blood pressures [40].
This is in line with ndings that the urinary marker of
Aerobic exercise has been shown to be effective in a signicant oxidative stress, 8-OHdG level (Table 2) decreases in patients
reduction of ROS and in a decrease of the occurrence of ROS- with type 2 diabetes as a result of 12-month program of
associated diseases, including hypertension [11]. It has been aerobic training [39]. Interestingly, aerobic exercise was
suggested that aerobic exercise enhances the adaptation to shown to have most of the benecial results in lowering
oxidative stress by increasing level of antioxidants [66]. systolic blood pressure, although diastolic blood pressure
Accordingly, improved eNOS phosphorylation and increased was also affected [38,40].
antioxidant enzyme expression have been observed in Taken together these studies indicate that aerobic physical
diabetic mice after aerobic exercise [67]. Moreover, rats exercise effectively lowers blood pressure and improves
subjected to acute and chronic aerobic training demonstrated endothelium-dependent vasodilation in patients with essen-
an increased blood ow and augmented sheer stress induced tial hypertension through the increased bioavailability of NO
endothelium-dependent vasodilation [45]. This was associat- in the vascular wall. These ndings suggest that regular
ed with an upregulation of eNOS leading to the greater aerobic exercise is benecial for maintenance of the resistance
bioavailability of NO. Furthermore, it has been shown that 12 to oxidative stress and should be considered as an essential
weeks of moderate aerobic treadmill running improved part of patient treatment.
medicina 52 (2016) 1927 25

However, the effect of high-volume intense training in this


6. Isometric exercise
study resulted in mild hypertension with signicant im-
pairment in the endothelium-dependent vasodilation. Anoth-
An isometric or static contraction is a form of resistance er study of aerobic exercise with participants in a relatively
exercise which is dened as a sustained muscle contraction large population (94 participants) found an increase in
(i.e. increase in tension) with no change in length of the involved oxidative stress marker (8-iso-PGF2a) 6 months after of aerobic
muscle group. Resistance exercise has not been evaluated to the exercise [41]. This was also associated with a decrease in
same extent as aerobic exercise in relation to redox imbalance. urinary NO metabolites though antioxidant levels was
Two studies examining the effect of isometric exercise in increased. This result conicts with the results showing the
hypertension are of interest in this regard [42,43]. The rst benecial effects of aerobic exercise [39].
demonstrated that isometric handgrip training (IHG) improves It has also been shown that IHG training only lowered blood
endothelial-dependent vasodilation [42]. Of interest, the im- pressure in the trained limb [42] suggesting that the enhanced
provement only occurred locally in the trained limbs. The systemic endothelial-dependent vasodilation is not the
second study examined the effect of isometric exercise in mechanism responsible for post-IHG training reduction of
hypertensive patients and showed that systolic but not diastolic blood pressure in hypertensive patients. It should be noted
blood pressure was signicantly lowered by training [43] that isometric exercise training involves markedly smaller
(Table 3). Importantly, the markers of oxidative stress were time commitment (810 min/session) compared with the
affected by isometric exercise and a major decrease in exercise- aerobic exercise programs (30 min/session). In the study by
induced oxygen radicals was reported [43]. Higashi and coauthors [38] blood pressure was reduced after
aerobic exercise but there was no signicant correlation
between this exercise-induced reduction in blood pressure
7. Alternative training
and the increase in acetylcholine-induced forearm response to
after exercise. This suggests that other than endothelium-
Tai chi is a gentle exercise program that is a part of traditional dependent mechanisms might be involved including cardiac
Chinese medicine. Derived from the martial arts, Tai chi is and neuronal functions. Moreover, the aerobic exercise
composed of slow, deliberate movements, meditation, and deep augmented endothelium-dependent vasodilation but did not
breathing, which should enhance physical health and emo- alter blood pressure in normotensive subjects. This suggests
tional wellbeing. Accordingly, Tai chi exercise was found that the reduction in blood pressure may not be directly
associated with similar physiological and biochemical improve- associated with the improved response of forearm vasculature
ments seen with other forms of physical training [44]. Tai chi to acetylcholine and the increase in NO release [38].
exercise was found to decrease systolic blood pressure but it had The range of different and sometimes conicting results
no effect on diastolic blood pressure in middle-age adults. could be due to variations in intensity, duration, and the type
Similar to the results associated with other forms of physical of exercise. The available data on redox imbalance in humans
training [43], an enhanced level of antioxidant protection has are still limited with only one marker of oxidative stress often
been suggested as the mechanism underlying the decrease in being measured. This is, at least in part, because redox
ROS which, in turn, lowers blood pressure [44]. This was imbalance is primarily conned to the kidney, the heart and
suggested to be a result of a mild training-associated induction the brain, and is therefore difcult to access in living humans
of oxidative stress leading to stimulation of antioxidant [69]. For this reason, most of the clinical results are obtained
defenses. from urine and blood samples. As such, they are not
Importantly, this latter study did not include hypertensive necessarily reective of a complete redox state in the body.
patients [44] and, therefore, may not necessarily be the In addition, most of the clinical studies are based on small
representative exercise intervention for hypertensive patients. populations and this affects integrity of the results, while some
Moreover, the individuals that performed Tai chi were not of the samples are not representative since they deal with
sedentary and a sedentary lifestyle is known to be a risk factor populations that are restricted territorially, e.g. the study of
of hypertension [66]. Furthermore, the lowered blood pressure Japanese people from a particular area [38]. Altogether, this may
in the Tai chi training group was only compared to blood compromise the validity of clinical experimental results. Animal
pressure in this group before the training program started, and studies overcome these obstacles, but the clarity of their results
not to the sedentary group. Tai chi is focusing on mind and cannot always be easy applied to humans. It is therefore clear,
body which could also be a reason for the benecial effects of that further studies are needed to determine the exact
this training linked to the well-known association between mechanisms involved in the effects of exercise in humans.
stress and hypertension [51,66,68].

9. Concluding remarks
8. Conicting results
The available experimental results indicate that physical
Although most of the studies reviewed here (Table 1) found exercise has a benecial effect on redox state and hyperten-
that moderate aerobic exercise and isometric training had sion. However, it is clinically important to select the
benecial effects, conicting results have also been shown. appropriate intensity, duration, frequency and type of exer-
The study by Sun and coauthors [45] have demonstrated the cise. This is not simply because inappropriate exercise will be
benecial effects of acute and chronic aerobic training. ineffective but also because it can be pathogenic, leading to
26 medicina 52 (2016) 1927

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[14] Rodrigo R, Prat H, Passalacqua W, Araya J, Guichard C,
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Conict of interest
H, Vapaatalo H, et al. Endothelial dysfunction and salt-
sensitive hypertension in spontaneously diabetic Goto-
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