Headache Medicine 2020, 11(1):14-21 ISSN 2178-7468, e-ISSN 2763-6178
14
ASAA
DOI: 10.48208/HeadacheMed.2020.5
Headache Medicine
© Copyright 2020
Original
Plasma ACE activity after aerobic exercise training is related to
sleep in migraine patients: A secondary, per protocol analysis
Atividade da ECA após treinamento físico aeróbio é correlacionada com sono em pacientes com migrânea:
uma análise secundária por protocolo
Arão Belitardo Oliveira
1,2
Bruna Visniauskas
3
Jair Ribeiro Chagas
4
Mario Peres
2,5
1
Universidade Federal de São Paulo, Neurologia e Neurocirurgia, São Paulo, São Paulo, Brazil.
2
Hospital Israelita Alber Einstein, Instituto do Cerebro,
São Paulo, São Paulo, Brazil.
3
Tulane University School of Medicine, Department of Physiology, New Orleans, Louisiana, Estados Unidos.
4
Universi-
dade Federal de São Paulo, Biologia Molecular, São Paulo, São Paulo, Brazil.
5
Universidade de São Paulo, Instituto de Psiquiatria, São Paulo, São
Paulo, Brazil.
Abstract
Angiotensin converting enzyme-1 (ACE) has been implicated in sleep regulation and nociception. In a
secondary, per-protocol analysis, we investigated the effect of a 12-week aerobic exercise program on
plasma ACE activity (primary outcome variable), migraine clinical outcomes, and psychometric scores be-
tween migraine and control, non-headache participants. Fifty-nine participants (migraine: n=31 and control:
n=28) gave signed consent form and were per-protocol analyzed. At baseline, there were no differences
between groups for ACE activity. After the intervention period, the ACE activity increased in the migraine
exercise group compared to control waitlist group [mean difference (95% CI) = 33.8 nM.min
–1
.mg
–1
(1.0,
66.5), p = 0.02]. Among patients, the migraine exercise group showed greater numeric reduction in the
number of sleep deprivation-triggered attacks compared to migraine waitlist group (-21 vs -8, respectively),
and lower insomnia scores [mean difference (95% CI) = -0.625 (-996, -254), p = 0.001]. There was an
inverse correlation between BECK-II insomnia domain scores and ACE activity (r = -0.53, p = 0.035). This
study suggests that aerobic exercise training increases plasma ACE activity with possible implication on
sleep regulation in migraine patients.
Resumo
A enzima conversora de angiotensina-1 (ECA) está implicada na regulação do sono e nocicepção. Em uma
análise secundária por protocolo, objetivamos investigar o efeito de um programa de exercícios aeróbicos
de 12 semanas na atividade da ECA plasmática (variável de resposta primária), variáveis clínicas e escores
psicométricos entre participantes com migrânea e controle sem nenhum tipo de cefaleia. Cinquenta e nove
participantes (enxaqueca: n = 31 e controle: n = 28) assinaram o termo de consentimento e foram anali-
sados por protocolo. No período basal, não houve diferenças entre os grupos para a atividade da ECA.
Após o período de intervenção, a atividade da ECA aumentou no grupo de exercícios com migrânea em
comparação ao grupo de lista de espera de controle [diferença média (IC95%) = 33,8 nM.min – 1.mg – 1
(1,0, 66,5), p = 0,02]. Entre os pacientes, o grupo exercício mostrou maior redução numérica no número
de ataques desencadeados por privação do sono em comparação com o grupo controle (-21 vs -8, respec-
tivamente) e menores escores médios do domínio de insônia BECK-II [diferença média (95% CI) = -0,625
(-996, -254), p = 0,001]. Houve uma correlação inversa entre os escores de insônia e a atividade da ECA
(r = -0,53, p = 0,035). Este estudo sugere que o exercício aeróbico regular aumenta a atividade da ECA
no plasma com possível implicação na regulação do sono em pacientes com migrânea.
Arão Belitardo Oliveira
araoliva@gmail.com
Received: March 12, 2020.
Accepted: March 23, 2020.
Edited by:
Marcelo Moraes Valença
Keywords:
Physical Activity
Exercise Therapy
Angiotensin-Converting Enzyme
Chronic Pain
Headaches Disorders
Migraine
Sleep
Palavras-chave:
Atividade Física
Terapia por Exercício
Enzima conversora da angiotensina
Dor crônica
Cefaleias
Migrânea
Sono
15
Oliveira AB et al.
Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis
Introduction
A
erobic exercise training exerts prophylactic effects on migrai-
ne
1,2
, and also promotes anxiolytic effects
2
in this population.
In spite of ample theoretical explanations for the preventive effects
of exercise for migraine, the mechanisms underlying the therapeutic
effects of aerobic exercise are still elusive.
Angiotensin-I-converting enzyme (ACE), a key protease of the renin
angiotensin system (RAS), has been implicated in migraine patho-
physiology by mechanisms still not understood
3–5
. ACE cleavages
angiotensin-I into angiotensin-II (AngII), a potent vasoconstrictor
which also orchestrates several physiological adjustments and
adaptations in response to acute and chronic physical exercise
6,7
.
The RAS is operative in stress sensitivity
8
and sleep regulation
9
,
which are associated with migraine triggers
10
, and pain perception
11
.
Thus, it is plausible to hypothesize the participation of this signaling
system in the clinical response to regular aerobic exercise and the
mechanisms related to common migraine triggers such as stress
and sleep deprivation.
Considering the participation of ACE in other pathological states
such as hypertension, heart failure, diabetes, and chronic kidney
disease, and the health-related effects of aerobic exercise training
counterpointing an exaggerated RAS tone observed in these con-
ditions
6,7
, we hypothesized that migraine patients would exhibit
higher plasma ACE activity and that aerobic exercise training would
reduce plasma ACE activity in this population. Secondarily, we
hypothesized that there would be correlations between changes in
ACE and clinical outcomes, as well as with migrainerelated triggers
and psychometric variables associated with ACE physiology.
Therefore, we compared plasma ACE activity between patients with
migraine and healthy, nonheadache individuals, and investigate
the inuence of aerobic exercise training on this protease activity.
We further exploited possible correlations between exercise training-
induced changes in ACE activity, psychometric scores (i.e., stress,
sleep, etc.) and clinical outcomes (e.g., days with headaches and
migraine triggers). These data were preliminary presented at the
5th European Headache and Migraine Trust International Congress,
held in Glasgow in September 2016.
Methods
Study Design
This is secondary, per-protocol analysis of a randomized controlled
trial aimed at testing the effect of a 12-week aerobic exercise
program on clinical outcomes
2
. We analysed the plasma ACE
activities, clinical outcomes and psychometric scores, as well as
tested the correlations between these variables. Participants were
randomly assigned to receive intervention with aerobic exercise
training (exercise groups) or enter a waitlist (waitlist groups). Simple
randomization (1:1) was performed using an online number
generation software.
Study’s protocol was composed by 7 clinical visits scheduled every
4 weeks, including the screening, neurological examination, and
delivery of headache diaries (Visit 0), and revaluations for checking
the headache diagnosis and diaries (visits 1-6). The baseline
period was set as the 4-week period between visits 0 and 1.
Blood sampling and psychometric interview were scheduled in the
samevisit, between visits 1 and 2, and were followed by the 12-
week intervention period. The last 4 weeks of the intervention period
(between visits 5-6) was set as “post-intervention” period for clinical
analyses. Test-retest visits for blood collection and psychometric
interviews were scheduled in the same order. All women were at
the follicular phase of the menstrual cycle at the blood sampling
visit. Retest visits for blood sampling were performed between 2-5
days after the last exercise session, or 48h after the last exercise
session within the same phase of the menstrual cycle as undertaken
at baseline. For all test-retest visits, participants were instructed to
breakfast regularly, but to abstain from coffee. All patients were
within the interictal period during all test-retest measurements.
The study’s protocol complied with the 1964 Helsinki declaration
on human research and was approved by the UNIFESP`s Research
Ethical Committee, registered under #081511, and all participants
gave written informed consent. This study was also registered in
the National Institute of Health (www.ClinicalTrials.gov) under
#NCT01972607.
Participants
We recruited patients from the Headache Unit of Hospital São
Paulo and a headache tertiary clinic, and healthy individuals
from the local community through printed and electronic media
advertisements between March 2012 and March 2015. Participants
were screened and evaluated by a neurologist. In this analysis, we
added 9 participants to the primary analysis sample, 7 chronic
migraine patients and 2 healthy controls.
Inclusion criteria were: individuals of both sex, aged between 18
and 65 years, non-headache individuals (dened as controls), and
patients with episodic and chronic migraine with/without aura,
according to the 2
nd
version of the International Classication
of Headache Disorders
12
. Patients should not be under any
prophylactic treatment for migraine (except for using abortive
medication during attacks) or taking any other prescribed drug or
dietary supplement. Participants should be physically inactive (≤1
day/week of leisuretime physical activity the previous 12 months).
Exclusion criteria were: starting any non-pharmacological or
pharmacological treatment during the study period, or presenting
any other disease such as cardiovascular, pulmonary, metabolic,
musculoskeletal, rheumatic, or neurological disorder, including
another primary or secondary headache; smoking, alcohol, or drug
abuse, and disagreement to continue the protocol.
Intervention
All exercise sessions were supervised by experienced exercise
16
Oliveira AB et al.
Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis
physiologists. The 12- week program of aerobic exercise training
was conducted at the Center for Studies in Psychobiology and
Exercise, São Paulo, Brazil. It comprised 40-minute sessions of
walking or jogging on treadmill, performed 3 times per week
at treadmill speed (m.min
-1
), heart rate, and rate of perceived
effort corresponding to the ventilatory threshold. The ventilatory
threshold was determined during maximal cardiopulmonary
exercise test as described in a previous study
2
.
Headache Diary
The headache diary retrieved data on days with migraines,
migraine frequency, number of acute medication used, and
commonly reported migraine attack triggers: stress/irritability,
oversleep, sleep deprivation, alcohol, fasting, odorants and
photic stimuli, foods, menstruation, fatigue, weather, neck/back
pain, or nonidentiable.
Psychometric Questionnaire
Participants lled the psychometric questionnaires at the
Psychobiology Department before the blood collection.
Depression scores were assessed by Beck Depression Inventory-II
(BECK-II). Beck-II questionnaire has been validated and translated
into Brazilian Portuguese.
ACE Activity Assays
Blood samples were collected between 8:00AM and 10:00AM
at the Psychobiology Department after questionnaire lling,
by venepuncture of the antecubital vein in cooled heparinized
vacutainers (BD Vacutainer®, Franking Lakes, NY, USA). Samples
were immediately centrifuged for 10 minutes at a 3,400g at 4°C.
Plasma was separated, aliquoted in 2 mL vials, and stored at
-80°C until analysis. All samples were analysed within 6 months
after blood collection.
ACE activity was determined spectrouorimetrically using
uorescence resonance energy transfer (FRET) peptides. The
FRET peptides Abz-FRK(Dnp)P-OH (Aminotech Pesquisa e
Desenvolvimento, Brazil) was used, as described by Carmona et
al 2006
13
. Briey, ACE activity assays were performed in a Tris-
HCl 100 mM pH 7.0 buffer containing NaCl 100 mM and ZnCl2
10 mM. Lisinopril (Sigma, USA) was used as ACE inhibitor to
ensure substrate specicity. The reactions were continuously
followed in a Gemini XS uorimeter (Molecular Devices Company,
Sunnyvale, CA, USA) that measured the uorescence at lex =
320nm and lem = 420 nm (Abz group) and lex = 360 nm and
lem =440 nm.
All measurements were performed in duplicate and proteases
activity values were reported as nanomolar of substrate
hydrolyzed per minute per milligram of protein (nM.min
–1
.mg
–1
).
Outcome Variables
The primary outcome variable was ACE activity. Secondary
outcome variables were changes in days with headaches,
migraine frequency, psychometric scores, and attacks trigger factors.
Statistical Analysis
Between- and within-groups comparisons (4 groups x 2 times) for
ACE activity, anthropometric variables, and psychometric scores
were performed by repeated-measure ANOVA with Bonferroni’s
post hoc corrections for multiple pairwise comparisons. Comparisons
between migraine groups (2 groups x 2 time points) for clinical
variables were performed by repeated-measure ANOVA with
Bonferroni’s adjustments for multiple pairwise comparisons.
Differences between pre-post intervention values (delta values)
for proteases activity were calculated by univariate ANOVA with
Bonferroni’s corrections for pairwise comparisons.
For the trigger factors analyses, we performed descriptive statistics
of the trigger’s prevalence in the patients’ sample. Correlations
were calculated by Pearson’s correlation coefcients or Spearman’s
correlation coefcients, depending on variables distribution features.
The SPSS software (IBM SPSS Statistics for Windows, Version 20.0.
Armonk, NY) was used for statistical analyses. A p < 0.05 was
accepted as statistically signicant.
Results
Fifty-eight participants were randomized, concluded the study,
and were per protocol- analyzed. Participants characteristics’ are
reported in Table 1. For days with migraine and migraine attacks
frequency, there were no statistically signicant differences between
migraine groups at baseline (Table 1). There was a signicant group
vs time interaction [F(1,29) = 8.921, p = 0.006, η2 = 0.56] for
days with migraine. Migraine exercise group showed a signicant
reduction in days with headaches [mean difference (95% CI) = -5.0
(-8.5, -1.4); p = 0.007], without signicant changes observed in the
migraine waitlist group [mean difference (95% CI) = 2.2 (-1.2, 5.7);
p = 0.19)]. No signicant group vs time interaction was observed for
migraine attacks frequency [F(1, 29) =1.389, p = 0.248, η2 = 0.06].
For plasma ACE activity, repeated-measure ANOVA’s pairwise
comparisons showed no differences between groups at baseline
(Figure 1), while there was a group vs time interaction [F(3, 54)
= 3.324, p = 0.026, η2 = 0.42]. Bonferroni-adjusted pairwise
comparisons showed increased ACE activity in migraine exercise
group compared to control waitlist group after the intervention
period [mean difference (95% CI) = 33.8 nM.min
–1
.mg
–1
(1.0, 66.5),
p = 0.02]. One-way ANOVA univariate test using the delta values
expressed as percentage change from baseline showed signicant
between-group effects [F(3, 54) = 3.223, p = 0.03, η2 = 0.41], with
ACE activity in migraine exercise group [mean difference (95% CI) =
47.3 % (21.3 %, 75.5 %)] signicantly higher than the control waitlist
group [mean difference (95% CI) = -9.1% (-41.1 %, 19.3 %)]; p =
0.039] (Figure 1). There were no correlations between ACE activity
and days with migraine, neither at baseline (r = -0.83, p = 0.657)
nor for changes after the intervention period (r = -0.156, p = 0.409).
p < 0.001, η2 = 0.27]. Bonferroni-adjusted pairwise comparisons
17
Oliveira AB et al.
Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis
Figure 1. Plasma angiotensin-converting enzyme activity at baseline and percentage change after intervention. Data are expressed as mean±SE. *: p <
0.05, compared with control waitlist
Table 1. Participants anthropometric and clinical characteristics. Data are expressed as mean±SD
Groups
Control Waitlist Control Exercise Migraine Waitlist Migraine Exercise
Age (yrs) 35.3±9.5 34.4±11.5 36.2±10.2 39.8±13.5
BMI (kg/cm
2
) 26.2±3.4 25.6±3.6 26.4±5.4 27.2±4.1
Sex
Female 11 11 12 12
Male 4 4 3 3
Diagnosis
MwoA - - 7 5
MwA - - 4 8
CM - - 4 3
Time with Disease (yrs) - - 15.9±8.9 18.5±11.9
Days with Headaches (/month) - - 9.0±5.9 12.3±8.0
Acute Medication (/month) - - 7.4±6.3 9.4±9.9
SBP (mmHg) 112.5±2.8 114±2.5 110±2.7 115.6±2.5
DBP (mmHg) 74.1±1.7 75±1.5 69.6±1.6 72.6±1.5
VO
2Peak
34.0±7.5 33.0±6.8 31.5±6.7 31.5±6.7
MwoA: Migraine without aura; MwA: Migraine with aura; CM: Chronic migraine; SBP: Sitolic Blood Pressure; DBP: Diatolic Blood Pressure; VO
2Peak
: Peak
Oxygen Uptake (Measure of cardiorespiratory tness).
showed that the migraine waitlist group had higher baseline BECK-
II total score than the control waitlist [mean difference (95% CI) =
11.9 (4.6, 19.1); p < 0.001], control exercise [mean difference (95%
CI) = 12.5 (5.7, 19.3); p < 0.001], and migraine exercise [mean
difference (95% CI) = 7.0 (.56, 13.6); p = 0.027] groups (Figure
2). For the BECK-II insomnia domain, repeated-measure ANOVA
showed a main effect of time [F(1, 58) = 9.444, p = 0.003, η2 =
0.17].
Bonferroni-adjusted pairwise comparisons showed that the migraine
exercise group had higher baseline BECK-II insomnia score than the
control exercise group [mean difference (95% CI) = 0.409 (0.007,
0.901); p < 0.001], and was the only group with signicant changes
after intervention period [mean difference (95% CI) = -0.625 (-996,
-254), p = 0.001] (Figure 2). No signicant main effects of time
or group, neither interaction was observed for BECK-II irritability
domain.
18
Oliveira AB et al.
Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis
Because triggers prevalence varied both within and between
subjects over the study period, we only conducted a descriptive
analysis of triggers. The most common triggers were stress/
irritability, sleep deprivation, and fasting (Figure 3). The migraine
exercise group showed a greater numeric reduction than migraine
waitlist group for sleep-deprivation (-21 vs -8 attacks, respectively)
and stress/irritability triggers (-20 vs -13, respectively) (Figure 3). In
order to explore the relation of major triggers in this sample with
ACE activity, we compute the correlations of BECK-II subdomains
as potential triggers correlates, that is, the BECK-II insomnia
domain for sleep deprivation trigger, and the irritability domain
for stress/irritability trigger. There was an inverse correlation
between changes (delta values) in BECKII insomnia domain
scores and ACE activity (r = -0.53, p = 0.035), while there was no
correlation between ACE activity and BECK-II irritability domain
scores (r= 0.022, p = 0.883).
Discussion
This study aimed at measuring the effect of a 12- week supervised
moderate aerobic exercise training on plasma ACE activity and
whether there would be any correlations with clinical outcomes.
To the best of our knowledge, this is the rst study to report a
stimulatory effect of regular aerobic exercise on plasma ACE
activity in migraine patients (nearly 50% increase), and a
correlation between plasma ACE activity and sleep quality
scores. Contrary to our hypothesis, we found no baseline ACE
activity differences between migraine and control groups.
Clinical studies have found elevated circulating ACE activity in
migraine patients in the interictal period
3
and increased plasma
AngII and aldosterone in patients experiencing salt-induced
migraine attacks
14
. At molecular level, an immunocytochemical
investigation has uncovered the presence of an angiotensinergic
system in the trigeminal ganglia of humans and rats
5
, suggesting
a role for this signaling system in migraine pathophysiology. At
genetic level, a meta-analysis found no association between ACE
I/D polymorphism and migraine, albeit in the Turkish population
ACE II polymorphism – which is characterized by lower ACE
expression than DD polymorphism - was associated with reduced
risk for migraine
4
. Furthermore, ACE inhibitors or AngII receptor
antagonists are common prophylactic drugs prescribed for migraine
15,16
.
As such, we expected that migraine patients would exhibit higher
baseline ACE activity that could be reversed by aerobic exercise
training with clinical implications, as observed in other pathological
conditions such as hypertension
17
, heart failure
18
, or chronic kidney
disease
6,18
, wherein there is a noticeable exaggerated RAS
activity. Our results indicate that the relationship between ACE
and migraine and its response to exercise is not as simplistic as
hypothesized. Possible explanations to our data may lie in the
etiological mechanisms of migraine, ACE response to exercise, and
the complex, less known ACE actions on pain and sleep physiology.
The response of ACE or AngII to exercise vary in the population,
with studies showing increase, decrease or no change following
either acute or chronic exercise
6,7
. Increased resting, interictal ACE
activity in migraine reported in a previous study was interpreted as
a compensatory mechanism over vasoactive/algogenic molecules
involved in migraine pathophysiology such as nitric oxide (NO) and
calcitonin gene-related peptide (CGRP)
3
. In fact, there are evidences
corroborating this hypothesis, showing an inhibitory effect of ACE on
NO
19
and CGRP
20
production. A recent study showed an abnormal
cardiovascular response following the administration of the NO
donor nitroglycerin in migraine patients, suggesting heightened
sensitivity to NO in this population
21
. Moreover, aerobic exercise
is one of the more effective natural inducers of NO release - which
in turn has been also credited as the cause of exerciseprovoked
migraine attacks
22
. Thus, theoretically, this higher ACE activity
response to exercise training found here could represent a migraine-
specic compensatory mechanism to counteract exercise-induced
exaggerated NO actions in migraine patients.
The RAS system has been implicated in pain
11,23,24
and sleep
25
physiology. Preclinical and clinical studies suggest a dual action of
the RAS in pain perception, partly depending on whether its actions
are mediated by angiotensin type-1 (AT1) or type-2 (AT2) receptors
11
.
Figure 2. Beck II inventory scores (total and insomnia domain) at baseline and after intervention. Data are expressed as mean±SE. *: p < 0.05, compared
with migraine exercise group; **: p < 0.001, compared with control exercise and control waitlist groups; #: p < 0.001, compared with control exercise
group; †: p < 0.01, compared with baseline.
19
Oliveira AB et al.
Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis
It seems that through AT1 receptors, ACE-AngII can promote
algogenic effects in several models of neuropathic and nociceptive
pain by activating downstream signaling cascades culminating in
pro-inammatory cytokines upregulation, such as interleukin-6
(IL-6) and tumor necrosis factor-α (TNF-α)
11
. As pro-inammatory
cytokines are associated with migraine
26
, this could be a putative
mechanism through which ACE activity inhibitors or AT1 receptors
antagonists are efcacious for migraine prophylaxis
11,16
.
On the other hand, mounting evidence have suggested opposite
effects of ACE-AngII on pain through AT2 receptors-dependent
and -independent mechanisms centrally and in the periphery
11
.
As reviewed by Bali et al.
11
, microinjections of AnII administered
in the ventrolateral periachedutal gray matter (PAG) attenuates
nociception in pain paradigms such as tail ick test and incision
allodynia; intracerebroventricular administration of AngII promotes
increases of tail ick and thermoalgesic stimuli latencies in rats;
spontaneous hypertensive rats, which exhibit high RAS tone, have
decreased pain sensitivity, while peripheral administration of AnII
in normal rats decrease pain sensitivity. A higher RAS tone seems
to mediate higher pain tolerance in hypertensive patients, as
enalapril and losartan were shown to induce a lower dental pain
tolerance in these patients
24
.
The mechanisms by which ACE-AngII exerts hypoalgesic effects is
believed to involve its stimulatory action of AngII on β-endorphin
release, the participation of ACE in kinins degradation such
as the potent algogenic mediators bradykinin and substace
P (besides NO and CGRP aforementioned), and the formation
of other peptides derived from AngII with centrally-mediated
antinociceptive actions
11,23
.
The correlation between improved insomnia score and changes
in ACE activity following exercise training may involve also the
interaction between physical exercise and RAS in sleep regulation.
Regular aerobic exercise has been associated with improved
sleep
27
, and is considered a synchronizer of human circadian
rhythms, partly by modulating melatonin secretion
28,29
. The RAS
is believed to exerts stimulatory effects on melatonin production
9
.
Angiotensin, ACE, AngII, and AT1 receptors are present in the
pineal gland of rats, and pineal gland forms AngII at a higher rate
than other brain areas. Furthermore, oral administration of losartan,
an AT1 antagonist, reduces by 35% the melatonin secretion,
while pineal gland cultures treated with this drug yielded a 67.6%
reduction in melatonin secretion in rats
25
. Conversely, reduction in
ACE specic activity and mRNA relative levels was observed in
the hypothalamus and brainstem of rats under the paradoxal sleep
deprivation paradigm
30
.
Considering the prominent role of melatonin in migraine
pathophysiology
31
, and its modulation by the RAS
9
, along with
the inuence of physical exercise on both hormonal signaling
systems
6,7,28,29
, it is admissible to speculate on a possible causal
relation with regard the signicant inverse correlation between
BECK II insomnia score and plasma ACE activity in migraine patients
following aerobic exercise training.
At this point, it is worth mentioning some aspects of ACE biochemistry
in the body that should be considered when interpreting the data
here. ACE et al. can be found in either plasma soluble or membrane
bound forms, with tissue-specic production
30
. As underscored
by Visniauskas et al.
30
, as a cytoplasmatic membrane anchored
enzyme, ACE turnover may vary in tissues and suffer inuence of
other peptidases, as well as its catalytic effects may be dissociated
from AngII formation. Agreeably, the antihypertensive effects of
ACE inhibition have long been seen to fail to correlate with plasma
ACE inhibition
32
. Moreover, aerobic exercise can stimulate ACE-
independent AngII production
33
. Nonetheless, our data cannot be
extrapolated to assume that plasma ACE reect the actions of ACE-
AngII on pain and sleep processes in the brain.
The limitations of this study are as follows: this is a post hoc analysis
from a clinical trial, therefore, the primary outcome in this analysis
was not the original primary outcome. This per-protocol analysis
also included 7 chronic migraine patients excluded from primary
analysis. Also, the ndings here cannot be generalized to the
whole migraine population, as the data are underpowered, and
the sample´s clinical characteristics are different regarding exercise-
trigger attacks. For example, the fact that migraine participants
showed no exercisetrigger attack, which is commonly observed
Figure 3.Prevalence of triggers (%) and changes in the number of trigger-related attacks for sleep and stress/irritability (numeric changes from group's sum).
20
Oliveira AB et al.
Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis
in this population
10
, and voluntarily sought for exercise as a
therapeutic option for migraine may constitute selection biases.
In conclusion, this study found a stimulatory effect of regular
aerobic exercise on plasma ACE activity in migraine patients,
which was inversely correlate with improved insomnia scores.
Further studies should explore the participation of the RAS, and
the relation of other ACE-derived peptides following exercise in
migraine patients in a larger cohort. Clinical aspects of migraine
such as trigger prole and its relationship with these molecules
could also provide insights for the participation of RAS in multiple
behavioral and homeostatic features of migraine.
Aknowlegements:
The authors appreciate the whole staff of the
Center for Studies in Psychobiology and Exercise for their support
in scheduling and conducting the exercise sessions and testing
References
1. Peres M, Mercante J, Belitardo de Oliveira A. Non-Pharma-
cological Treatment for Primary Headaches Prevention and
Lifestyle Changes in a Low-Income Community of Brazil: A
Randomized Clinical Trial. Headache: The Journal of Head
and Face Pain. 2019;59(1):86–96.
2. Oliveira AB, Ribeiro RT, Mello MT, Tuk S, Peres MFP. Anan-
damide Is Related to Clinical and Cardiorespiratory Benets
of Aerobic Exercise Training in Migraine Patients: A Rando-
mized Controlled Clinical Trial. Cannabis and Cannabinoid
Research. 2019;4(4):275–84.
3. Fusayasu E, Kowa H, Takeshima T, Nakaso K, Nakashima
K. Increased plasma substance P and CGRP levels, and high
ACE activity in migraineurs during headache-free periods.
Pain. 2007;128(3):209–14.
4. Wan D, Wang C, Zhang X, Tang W, Chen M, Dong Z, et al.
Association between angiotensin- converting enzyme inser-
tion/deletion polymorphism and migraine: a meta-analysis.
International Journal of Neuroscience. 2016;126(5):393–9.
5. Imboden A, Patil J, Nussberger J, Nicoud F, Hess B, Ahmed
N, et al. Endogenous angiotensinergic system in neurons of
rat and human trigeminal ganglia. Regul Pept. 2009;154(1–
3):23–31.
6. Goessler K, Polito M, Cornelissen V. Effect of exercise training
on the renin-angiotensin- aldosterone system in healthy indivi-
duals: a systematic review and meta-analysis. Hypertension
research : ofcial journal of the Japanese Society of Hyper-
tension. 2016;39(3):119–26.
7. Rush J, Aultman C. Vascular biology of angiotensin and the
impact of physical activity. Appl Physiol Nutr Metab [Internet].
2008;33(1):162–72.
8. Müller H, Kröger J, Jöhren O, Szymczak S, Bader M, Domi-
niak P, et al. Stress sensitivity is increased in transgenic rats
with low brain angiotensinogen. Journal of Endocrinology.
2010;204(1):85–92.
9. Campos LA, Cipolla-neto J, Amaral FG, Michelini LC, Bader
M, Baltatu OC. The Angiotensin- Melatonin Axis. International
Journal of Hypertension. 2013;2013:1–7.
10. Pellegrino ABW, Davis-Martin RE, Houle TT, Turner DP, Smither-
man TA. Perceived triggers of primary headache disorders: A
meta-analysis. Cephalalgia. 2017;38(6):1188–98.
11. Bali A, Singh N, Jaggi A. Renin-angiotensin system in pain:
existing in a double life? J Renin Angiotensin Aldosterone Syst.
2014;15(4):329–40.
12. Headache Classication Sub-Committee of the International
Headache Society. The International Classication of Headache
Disorders. Cephalagia, 2004, 24:9-160.
13. Carmona A, Schwager S, Juliano M, Juliano L, Sturrock E. A
continuous uorescence resonance energy transfer angiotensin
I-converting enzyme assay. Nature Protocols. 2006;1(4):1971–6.
14. Brainard J. Angiotensin and Aldosterone Elevation in Saltindu-
ced Migraine. Headache: The Journal of Head and Face Pain.
1981;21(5):222–6.
15. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C,
Ashman E. Evidence-based guideline update: pharmacologic
treatment for episodic migraine prevention in adults: report of
the Quality Standards Subcommittee of the American Academy
of Neurology and the American Headache Society. Neurology
[Internet]. 2012;78(17):1337–45.
16. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic
Treatment of Migraine With an Angiotensin II Receptor Blocker.
JAMA. 2003 Jan 1;289(1):65–9.
17. Ghiadoni L, Taddei S, Virdis A. Hypertension and Endothelial
Dysfunction: Therapeutic Approach. Current Vascular Pharma-
cology. 2011;10(1):42–60.
18. Haack K, Zucker I. Central Mechanisms for Exercise Training-
Induced Reduction in Sympatho- Excitation in Chronic Heart
Failure. Autonomic Neuroscience [Internet]. 2015;0:44–50.
19. Ancion A, Tridetti J, Nguyen Trung M-L, Oury C, Lancellot-
ti P. A Review of the Role of Bradykinin and Nitric Oxide in
the Cardioprotective Action of Angiotensin-Converting Enzy-
me Inhibitors: Focus on Perindopril. Cardiology and Therapy.
2019;8(2):179–91.
20. Krämer HH, Schmidt K, Leis S, Schmelz M, Sommer C, Birklein
F. Angiotensin converting enzyme has an inhibitory role in CGRP
metabolism in human skin. Peptides. 2006;27(4):917– 20.
21. van Oosterhout WPJ, Schoonman GG, Saal DP, Thijs RD, Ferrari
MD, van Dijk JG. Abnormal cardiovascular response to nitrogly-
cerin in migraine. Cephalalgia [Internet]. 2019;0(0):1–12.
22. Hindiyeh NA, Krusz JC, Cowan RP. Does Exercise Make Mi-
graines Worse and Tension Type Headaches Better? Curr Pain
Headache Rep. 2013;17:380.
23. Pelegrini-da-Silva A, Rosa E, Guethe LM, Juliano MA, Prado WA,
Martins AR. Angiotensin III modulates the nociceptive control
mediated by the periaqueductal gray matter. Neuroscience
[Internet]. 2009;164(3):1263–73.
24. Guasti L, Zanotta D, Diolisi A, Garganico D, Simoni C, Gaudio
G, et al. Changes in pain perception during treatment with angio-
tensin converting enzyme-inhibitors and angiotensin II type 1 re-
ceptor blockade. Journal of Hypertension. 2002;20(3):485–91.
25. Baltatu O, Afeche SC, José dos Santos SH, Campos LA, Barbosa
R, Michelini LC, et al. Locally synthesized angiotensin modulates
pineal melatonin generation. Journal of neurochemistry [Internet].
2002 Jan;80(2):328–34.
26. Oliveira AB, Bachi ALL, Ribeiro RT, Mello MT, Tuk S, Peres MFP.
Unbalanced plasma TNF-α and IL-12/IL-10 prole in women with
migraine is associated with psychological and physiological
outcomes. Journal of Neuroimmunology. 2017;313:138–44.
27. Rubio-Arias JÁ, Marín-Cascales E, Ramos-Campo DJ, Hernan-
dez A v., Pérez-López FR. Effect of exercise on sleep quality
and insomnia in middle-aged women: A systematic review
and meta- analysis of randomized controlled trials. Maturitas.
2017;100:49–56.
28. Knight J a, Thompson S, Raboud JM, Hoffman BR. Light andexer-
cise and melatonin production in women. American journal of
epidemi o l o g y. 20 05;162(11):1114 –22.
29. Buxton OM, Lee CW, L’Hermite-Baleriaux M, Turek FW, van
Cauter E. Exercise elicits phase shifts and acute alterations of
melatonin that vary with circadian phase. American journal of
21
Oliveira AB et al.
Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis
physiology Regulatory, integrative and comparative physiology
[Internet]. 2003 Mar [cited 2014 Mar 19];284(3):R714-24.
30. Visniauskas B, Oliveira V, Carmona A, D’Almeida V, de Melo
R, Tuk S, et al. Angiotensin I- converting enzyme (ACE) acti-
vity and expression in rat central nervous system after sleep
deprivation. Biol Chem. 2011;392(6):547–53.
31. Peres MF, Valença MM, Amaral FG, Cipolla-Neto J. Current
understanding of pineal gland structure and function in hea-
dache. Cephalalgia. 2019;0(0):1–10.
32. Waeber B, Nussberger J, Juillerat L, Brunner HR. Angiotensin
converting enzyme inhibition: discrepancy between antihyper-
tensive effect and suppression of enzyme activity. Journal of
Cardiovascular Pharmacology. 1989;14(Suppl 4):S53-9.
33. Aldigier JC, Huang H, Dalmay F, Lartigue M, Baussant T, Chas-
sain, A. P., Leroux-Robert C, et al. Angiotensin-Converting Enzy-
me Inhibition Does Not Supress PLasma Angiotensin II Increase
During Exercise in Humans. Journal of Cardiovascular Pharma-
cology. 1993;21:289–95.
