ARTICLE

A session of resistance exercise increases vasodilation inintermittent claudication patientsAluísio Lima, Raphael Ritti-Dias, Cláudia Forjaz, Marilia Correia, Alessandra Miranda,Maria Brasileiro-Santos, Amilton Santos, Dario Sobral Filho, and Alexandre Silva

Abstract: No study has shown the effects of acute resistance exercise on vasodilatory capacity of patients with peripheral arterydisease. The aim of this study was to analyse the effects of a single session of resistance exercise on blood flow, reactivehyperemia, plasma nitrite, and plasma malondialdehyde in patients with peripheral artery disease. Fourteen peripheral arterydisease patients underwent, in a random order, 2 experimental sessions: control (rest for 30 min) and resistance exercise(8 exercises, 2 sets of 10 repetitions at an intensity of 5–7 in the OMNI Resistance Exercise Scale). Blood flow, reactive hyperemia,plasma nitrite, and malondialdehyde were measured before and 40 min after the interventions in both sessions. Data werecompared between sessions by analysis of covariance, using pre-intervention values as covariates. The increases in blood flow,reactive hyperemia, and log plasma nitrite were greater (p ≤ 0.05) after resistance exercise than the control session (3.2 ± 0.1 vs.2.7 ± 0.1 mL·100 mL−1 tissue·min−1, 8.0 ± 0.1 vs. 5.7 ± 0.1 AU, and 1.36 ± 0.01 vs. 1.26 ± 0.01 �mol/L, respectively). On the other hand,malondialdehyde was similar between sessions (p > 0.05). In peripheral arterial disease patients, a single session of resistanceexercise increases blood flow and reactive hyperemia, which seems to be mediated, in part, by increases in nitric oxide release.

Key words: peripheral artery disease, strength exercise, microvascular reactivity, oxidative stress.

Résumé : Il n’y a pas d’études sur les effets d’une séance d’exercices contre résistance sur la capacité vasodilatatrice de patientsaux prises avec une maladie artérielle périphérique. Cette étude se propose d’analyser les effets d’une seule séance d’exercicescontre résistance sur le débit sanguin, l’hyperémie réactive, le nitrite plasmatique et le malonaldéhyde chez des patients auxprises avec une maladie artérielle périphérique. Quatorze patients aux prises avec une maladie artérielle périphérique partici-pent aléatoirement a deux séances expérimentales : contrôle (repos de 30 min) ou exercices contre résistance (huit exercices,deux séries de dix répétitions a une intensité de 5–7 sur l’échelle OMNI des exercices contre résistance). On évalue le débitsanguin, l’hyperémie réactive, les concentrations plasmatiques de nitrite et de malonaldéhyde avant et 40 min aprèsl’intervention dans les deux séances. On compare les résultats au moyen de l’analyse de covariance en utilisant commecovariables les valeurs précédant l’intervention. Les augmentations du débit sanguin, de l’hyperémie réactive et du logarithmede la concentration plasmatique de nitrite sont supérieures (p ≤ 0,05) après les exercices contre résistance comparativement a laséance de contrôle (3,2 ± 0,1 vs 2,7 ± 0,1 mL·100 mL−1 de tissus·min−1, 8,0 ± 0,1 vs 5,7 ± 0,1 UA et 1,36 ± 0,01 vs 1,26 ± 0,01 �M,respectivement). Par contre, les concentrations de malonaldéhyde sont similaires d’une séance a l’autre (p > 0,05). Chez lespatients aux prises avec une maladie artérielle périphérique, une seule séance d’exercices contre résistance accroît le débitsanguin et l’hyperémie réactive qui, elle, semble médiée partiellement par l’augmentation de la libération d’oxyde nitrique.[Traduit par la Rédaction]

Mots-clés : maladie artérielle périphérique, exercice de force, réactivité microvasculaire, stress oxydatif.

IntroductionPeripheral artery disease (PAD) is mainly caused by an athero-

sclerotic plaque that reduces blood flow and leads to a mismatchbetween oxygen delivery and demand to the lower limb muscles(Gardner and Montgomery 2008; Silvestro et al. 2003). PAD pa-tients also present endothelial dysfunction (Corrado et al. 2008;Shechter et al. 2009), decreased nitric oxide (NO) bioavailability(Arslan et al. 2010; Cannon 1998), and increased oxidative stress(Khawaja and Kullo 2009), which reduces endothelium-dependentvasodilatation (Allen et al. 2012). All these factors contribute to thewalking impairment and the high incidence of cardiovascularevents (e.g., myocardial infarction and stroke) observed in thesepatients (Weitz et al. 1996).

Walking and resistance training have been shown to be equallyefficient to improve walking capacity in PAD patients (Ritti-Diaset al. 2010). However, after a single session of walking exercise,limb blood flow (BF) and flow-mediated dilation (Andreozzi et al.2007; Silvestro et al. 2002) decrease, which suggests that walkingexercise acutely impairs vasodilatory function of PAD patients.Although the mechanisms underlying these responses are notcompletely understood, the repeated episodes of ischaemia dur-ing walking are known to increase inflammation and oxidativestress (Palmer-Kazen et al. 2009; Silvestro et al. 2002), which maydecrease endothelium-dependent vasodilation (Joannides et al.1995). In addition, these episodes of ischemia, inflammation, andoxidative stress may facilitate the atherogenic process, transiently

Received 19 August 2014. Accepted 11 September 2014.

A. Lima, R. Ritti-Dias, M. Correia, and A. Miranda. School of Physical Education, University of Pernambuco, Rua Arnóbio Marques, 310, Recife,Pernambuco 50.100-130, Brazil.C. Forjaz. Exercise Hemodynamic Laboratory, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.M. Brasileiro-Santos, A. Santos, and A. Silva. Department of Physical Education, University Federal of Paraíba, Paraíba, Brazil.D. Sobral Filho. Procape University Hospital, University of Pernambuco, Pernambuco, Brazil.Corresponding author: Raphael M. Ritti-Dias (e-mail: raphaelritti@gmail.com).

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increasing cardiovascular risk in individuals with cardiovasculardisease, and chronically favouring disease progression (Vallanceet al. 1997).

On the other hand, we have shown that resistance exercise isless painful than walking for PAD patients (Ritti-Dias et al. 2010),which suggests that less ischaemia occurs during the execution ofthis kind of exercise. Thus, it is plausible to suppose that resis-tance exercise may promote little oxidative stress in these pa-tients, resulting in an increase in NO bioavailability after exerciseand, consequently, in an increase in BF and reactive hyperemia(RH). However, to our knowledge this hypothesis has not beeninvestigated yet. Thus, the aim of this study was to analyze theeffects of a single session of resistance exercise on oxidative stress,postexercise BF, RH, and plasma nitrite in PAD patients.

Materials and methods

RecruitmentPatients with PAD and symptoms of claudication were recruited

from public hospitals and private vascular clinics. Patients weresubmitted to a medical history evaluation, performed a progres-sive treadmill exercise test until maximal claudication pain, andhad their ankle and arm systolic blood pressures measured tocalculate the ankle brachial index. Individuals were included inthe study if they (i) were aged between 50 and 80 years; (ii) pre-sented graded treadmill exercise test limited by claudication;(iii) presented ankle brachial index ≤ 0.90; (iv) had systolic bloodpressure < 160 mm Hg and diastolic blood pressure < 105 mm Hg;(v) presented no symptom of myocardial ischaemia during thetreadmill test; (vi) were not submitted to bypass surgery or angio-plasty in the last year; and (vii) and had not participated in reha-bilitation program in the last 6 months. The subjects wereexcluded if they had changed their medication during the study.Fourteen patients were eligible for the study.

This study was approved by the Joint Committee on Ethics ofHuman Research of the University (process no. 269/10). Each pa-tient was informed of the risks and benefits involved in the study,and signed a written informed consent for participation.

Pre-experimental proceduresPrior to the experiments, patients underwent a familiarization

session designed to standardize resistance exercises. In this ses-sion, they performed the following exercises: bench press, leg press,seated row, knee extension, frontal rise, knee curl, arm curl, andhip abduction. In each exercise, they executed 2 sets of 10 repeti-tions with the minimum load allowed by the machines.

Afterwards, the patients underwent sessions to identify theload and the movement velocity that would be used in the exper-imental sessions. In these sessions, the load corresponding to arate of perceived exertion between 5 and 7 on the OMNI resistanceexercise scale (OMNI-RES) was determined for each resistance ex-ercise, as previously described (Gearhart et al. 2001). Once theworkload was determined in 1 session, it had to be confirmed in asubsequent session. This procedure was repeated until the correctload was established and confirmed for all the exercises.

Experimental sessionsAll patients underwent 2 experimental sessions conducted in a

random order: control (C) and resistance exercise (R). Each sessionwas initiated between 0800 and 1000 h, and an interval of at least3 days was kept between them. Before the experimental sessions,patients were instructed to have a light meal in the morning andto keep similar meals before both sessions. They were also in-structed to avoid exercise practice (48 h before the experiments),alcohol ingestion (48 h before the experiments), caffeine inges-tion (24 h before the experiments), and smoking (on the day of theexperiments). Figure 1 presents the design of the experimentalsession.

In each experimental session, patients rested in the supine po-sition for 40 min (pre-intervention) in a temperature-controlledlaboratory (21 to 23 °C). During this period, blood was collected fordetermining malondialdehyde (MDA) and plasma nitrite levels.After this, blood pressure, and subsequently, BF and RH weremeasured in the leg with the lower ankle brachial index to eval-uate the postexercise effect on the leg affected by the PAD. Then,patients went to the exercise room, where they rested in the C ses-sion or exercised in the R session. Patients were blinded to whichsession they were going to perform until the beginning of theexercise. In the R session, patients performed 2 sets of 10 repeti-tions of the aforementioned 8 resistance exercises with a work-load of 5–7 in the OMNI-RES scale. Intervals of 2 min wereinterspersed between the sets and the exercises. This exerciseprotocol was chosen because it is in accordance to guidelines forpatients with cardiovascular diseases (Thompson et al. 2013). Inthe C session, patients remained resting at the exercise machinesfor 30 min. After the interventions, the patients returned to thelaboratory, where they remained resting in the supine positionfor 40 min. Blood samples, blood pressure, BF, and RH were reas-sessed in this post-intervention period.

Measurements

Plasma nitriteBlood samples (4 mL) were collected in tubes containing

EDTA, homogenised by inversion, and then were centrifuged at1500 r·min−1 for 15 min. Thereafter, the plasma was separated,placed in Eppendorf tubes, and kept at −80 °C until analysis.Plasma nitrite analysis was based on the use of the Griess reagent,which was prepared using equal parts of 5% phosphoric acid,0.1% N-1-naphthylenediamine, 1% sulphanilamide in 5% phosphoricacid, and distilled water. To perform the assay, 100 �L of the super-natant of the homogenate at 10% was added to potassium phos-phate buffer in 100 �L of Griess reagent. For a blank, 100 �L of thereagent was added to 100 �L of buffer, and to obtain a standardcurve, a dilution series (100, 50, 25, 12.5, 6.25, 3.12, and 1.56 �mol/L)of nitrite was performed. Every assay was read at 560 nm absor-bance.

MDAThe rate of lipid lipoperoxidation was estimated by determina-

tion of MDA using the thiobarbituric acid test. An aliquot of250 �L of plasma was withdrawn and put into a water bath at 37 °Cfor 1 h. Then, 400 �L of 35% perchloric acid was added and themixture was centrifuged at 14 000 r·min−1 for 20 min at 4 °C.The supernatant was removed, placed in contact with 400 �Lof 0.6% thiobarbituric acid, and the mixture was incubated at100 °C for 1 h. After cooling, the absorbance of the supernatantwas read at 532 nm. A standard curve was generated using1,1,3,3-tetramethoxypropane. The results are expressed as nmolMDA·mg−1 protein.

Blood pressureBlood pressure was measured beat-by-beat by Finometer (Finapres

Medical Systems, Netherlands) throughout the experiments andthe variables were calibrated at baseline using the Return to Flowcalibration system.

Muscle blood flowBF was measured by venous occlusion plethysmography

(Hokanson, EC6, USA), as previously described (Wilkinson andWebb 2001). The measurements were taken in the leg with thelowest ankle brachial index while the patients were in the supineposition. A cuff was placed around the ankle and inflated to240 mm Hg to interrupt circulation to the feet. A second cuff wasplaced above the knee and was inflated to subdiastolic blood pres-sure (40–60 mm Hg) for 10 s every 20 s. This procedure allowsarterial blood inflow but interrupts venous withdraw. A mercury

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sensor was placed in the largest circumference of the leg to registerthe increase in leg circumference due to arterial blood influx.The slope of the increase in leg circumference was used to assessBF. Nine measurements were taken and the mean value was con-sidered for analysis.

Reactive hyperemiaThe RH was assessed 10 min after BF measurement. Proximal to

the site of measurement, the cuff placed above the knee wasinflated to 200 mm Hg and this occlusion was maintained for3 min. Afterwards, the cuff was deflated and BF was measured for3 min, as already described. RH was defined as the area under thecurve of BF measured after ischaemia.

Statistical analysesThe sample size was calculated based on data from a pilot study

that showed a difference in BF of 1.03 ± 0.60 mL·100 mL−1 tissue·min−1

between the resistance exercise and control interventions. Consid-ering a power of 80% and an alpha error of 5%, a minimum size of11 subjects was required for this study.

The Gaussian distribution and the homogeneity of variance ofthe data were analyzed, respectively, by Shapiro−Wilk and Levenetests. The log transformation was effective in normalizing thevariables that did not present a normal distribution.

Comparisons between pre-intervention values observed in theC and R sessions as well as comparisons between pre- and post-intervention values in each session were performed by pairedt test. As pre-intervention values differed between the sessions,comparison between post-intervention values was performed byanalysis of covariance (ANCOVA), using pre-intervention values ascovariate. p ≤ 0.05 was accepted as significant. The data are pre-sented as means ± SE.

ResultsThe characteristics of the PAD patients are shown in Table 1.

They were mostly elderly, female, and hypertensive. Furthermore,86.7% of them were receiving anti-hypertensive medication, and53.3% were receiving peripheral vasodilator.

Eight participants began the study by performing the C sessionand 6 started with the R session. In the R session, the loads corre-sponding to a rate of perceived exertion of 5–7 on OMNI-RES were15.8 ± 1.8 kg for bench press, 32.6 ± 7.4 kg for 45° leg press, 23.2 ±3.0 kg for seated row, 13.2 ± 3.0 kg for knee extension, 6.4 ± 0.7 kgfor frontal rise, 19.8 ± 3.8 kg for knee curl, 8.4 ± 1.0 kg for elbowcurl, and 24.0 ± 2.3 kg for hip abduction.

Pre-intervention systolic and diastolic blood pressure, RH, andplasma MDA were similar in both sessions (p > 0.05). However,despite randomization, pre-intervention BF tended to be higher(p = 0.06) and log plasma nitrite was higher (p = 0.01) in the C ses-sion than in the R session.

In comparison with pre-intervention values, systolic and dia-stolic blood pressure increased similarly after the C and R sessions(C, 132 ± 4 vs. 139 ± 5 mm Hg; R, 132 ± 2 vs. 135 ± 3 mm Hg; p < 0.05).

BF (3.5 ± 0.4 vs. 2.9 ± 0.3 mL·100 mL−1 tissue·min−1; p = 0.01),RH (7.7 ± 0.9 vs. 6.2 ± 0.7 AU; p = 0.02), and MDA (5.0 ± 0.4 vs. 4.3 ±0.3 �mol·L−1; p = 0.03) decreased after the intervention in theC session, while log plasma nitrite did not change (1.25 ± 0.05 vs.1.31 ± 0.06 �mol·L−1; p = 0.12). In the R session, in comparison withpre-intervention, BF (3.0 ± 0.3 vs. 3.1 ± 0.3 mL·100 mL−1 tissue·min−1;p = 0.64) and MDA (5.1 ± 0.4 vs. 5.0 ± 0.3 �mol·L−1; p = 0.64) did notchange, while RH (6.3 ± 0.6 vs. 7.6 ± 0.5 AU; p = 0.01) and log plasmanitrite (1.14 ± 0.05 vs. 1.30 ± 0.08 �mol·L−1; p = 0.01) increased afterthe intervention. The individual values of each variable are shownin Fig. 2.

Comparison of sessions with ANCOVA showed that exerciseincreased BF, RH, and log plasma nitrite and there was no changein MDA (Fig. 3).

DiscussionThe main findings of this study were that in PAD patients, a

single session of resistance exercise increased BF and RH, suggest-ing improvement of the microvascular reactivity after its execution;

Fig. 1. Design of the experimental session. BF, blood flow; BP, blood pressure; RH, reactive hyperemia.

Table 1. Physical and functional characteristics of the patients (n = 14).

Values

Male/female 5/9Age (y) 64.7±2.6Weight (kg) 62.2±5.2Height (m) 1.57±0.02Body mass index (kg·m−2) 25.5±2.0Ankle brachial index 0.57±0.02

Cardiovascular risk factorsHypertension (%) 85.7Diabetes (%) 35.7Current smokers (%) 7.2

Anti-hypertensive medicationNon-medicated (%) 13.3Inhibitors of angiotensin-converting enzyme (%) 40.0Angiotensin receptor antagonist (%) 6.7Calcium channel blocker and diuretics (%) 6.7Inhibitors of angiotensin-converting enzyme and

diuretic (%)13.3

Angiotensin receptor antagonist and diuretics (%) 6.7Angiotensin receptor antagonist, calcium channel

blocker, and diuretics (%)13.3

Peripheral vasodilatadorNon-medicated (%) 46.7Cilostazol (%) 53.3

Note: Values are means ± SE.

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moreover, these responses were accompanied by an increase inplasma nitrite, without any change in MDA.

In the present study, BF decreased and remained below baselinefor a long time after the C session in which the patients stayed inthe supine position. This response may seem odd at first, but it isin accordance with the increase in BP observed in this studythroughout time and also in accordance to other study with PADpatients that reported an increase in systemic vascular resistanceand in BP throughout supine rest conducted in the morning(Cucato et al. 2014). The mechanisms responsible for the decreasein BF and RH in the C session are not clear and are not related toa decrease in NO or to an increase in oxidative stress, since plasmanitrite did not change in this session and MDA decreased. Never-theless, it may be linked to the circadian variation of physiologicalvariables, since sessions were conducted in the morning, whenvasoconstrictive mechanisms, such as sympathetic activity andrenin-angiotensin systems, were increasing (Cugini and Lucia 2004;Grassi et al. 2010).

Opposite to what was observed in the C session, after low-intensity resistance exercise, BF did not change and RH increased,which show the effects of resistance exercise in increasing bothpostexercise BF and RH in PAD patients. This is in agreement witha previous study conducted with healthy individuals (Collier et al.2010; Willoughby et al. 2011). The novelty of the present study wasto show that similar responses were observed in PAD patients,who are known to have reduced BF, RH, and increased oxidativestress at rest (Gokce et al. 2003; Silvestro et al. 2003). The mecha-nisms underlying the vascular effects of resistance exercise maybe related to the effect of exercise in increasing NO productionand bioavailability, since plasma nitrite, a stable precursor of NO(Lei et al. 2013), was increased after resistance exercise. The me-chanical contraction of the muscles around the vessels duringresistance exercise may produce a partial occlusion of BF, increas-ing shear stress and consequently stimulating NO release (Grzelaket al. 2010; Hutcheson and Griffith 1991; Pyke et al. 2008). In addi-tion, it has been shown that shear stress also mediates the release

Fig. 2. Individual responses of blood flow (BF) (A), reactive hyperemia (RH) (B), log plasma nitrite (C), and malondialdehyde (MDA)(D) measured before (pre) and after (post) the interventions in the control and resistance exercise sessions in 14 patients with intermittentclaudication. *, Significantly different from pre-intervention period (paired t test).

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of other endothelium-dependent dilators (Koller et al. 1995; Martinet al. 1996).

In regards to oxidative stress, resistance exercise did not lead toa change in MDA in PAD patients, which differs from the resultsobtained in previous studies in healthy subjects (Cardoso et al.2012; Rahimi 2011). The differences in results may be attributed toexercise intensity, since this study employed low-intensity resis-tance exercise (�55% of 1-repetition maximum (1RM)), whileprevious studies used greater intensities (�70% of 1RM). A lowerintensity may produce a better balance between oxidative andanti-oxidative pathways (Nikolaidis et al. 2007; Paschalis et al.2007; Vincent et al. 2004).

The clinical relevance of the findings is that a single session ofresistance exercise increased BF, RH, and plasma nitrite and didnot increase oxidative stress, suggesting strongly that this kindof exercise improves microvascular reactivity of these patients.Since reduced BF and increased oxidative stress are markers ofmorbidity and mortality (Weitz et al. 1996), this mode of exercisemay provide benefits for these patients if these responses arereproduced after chronic training.

In the present study, a postexercise increase in vasodilatorycapacity was observed with an exercise protocol that includedwhole-body stimuli. Exercise effects on BF and RH seem to besystemically mediated, since a previous study with healthy sub-jects and chronic heart failure patients showed an increase in BFand RH measured in the forearm after resistance leg exercise(Guindani et al. 2012). In addition, in healthy subjects, BF alsoincreased after exercise performed with the muscles where BFwas measured (Guindani et al. 2012; Willoughby et al. 2011). How-ever, as patients with PAD presented BF and RH impairment dur-ing exercise with affected limb, responses should be different inthese patients if only lower-limb exercises were employed, whichshould be tested in the future.

This study has limitations that should be considered. PAD pa-tients with different characteristics and taking different med-ications were included. These factors may have influenced theresponses. However, differences in comorbidities and treatmentrepresent the reality of PAD patients in clinical practice. Thus, theinclusion of heterogenic patients increased the applicability of

the results. However, these differences might be responsible forthe differences found in pre-intervention parameters between thesessions, and to minimize any possible influence an ANCOVA anal-ysis was performed. In addition, some patients were receivingvasodilators and others not. Thus, whether responses are differ-ent in patients with and without vasodilators should be tested inthe future. The control condition was conducted at rest, thusfuture studies may compare responses to resistance and walkingexercise, which may bring insights about exercise recommenda-tion for these patients.

In conclusion, in PAD patients, a single session of resistanceexercise increases BF and RH, probably mediated, in part, by in-creased NO production and maintenance of oxidative stress. Thisresult supports that resistance exercise acutely improves vasodi-lation in PAD patients.

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Fig. 3. Blood flow (BF) (A), reactive hyperemia (RH) (B), log plasma nitrite (C), and malondialdehyde (MDA) (D) covariated responses calculated afterthe control and resistance exercise sessions in 14 patients.*, Significantly different from the control session (ANCOVA). Values are means ± SE.

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