The Peptides

This article appeared in a journal published by Elsevier. The attached

copy is furnished to the author for internal non-commercial research

and education use, including for instruction at the authors institution

and sharing with colleagues.

Other uses, including reproduction and distribution, or selling or

licensing copies, or posting to personal, institutional or third party

websites are prohibited.

In most cases authors are permitted to post their version of the

article (e.g. in Word or Tex form) to their personal website or

institutional repository. Authors requiring further information

regarding Elsevier’s archiving and manuscript policies are

encouraged to visit:

http://www.elsevier.com/authorsrights

http://www.elsevier.com/authorsrights

Author's personal copy

Peptides 47 (2013) 85–93

Contents lists available at ScienceDirect

Peptides

j ourna l h o mepa ge: www.elsev ier .com/ locate /pept ides

The interface of hypothalamic–pituitary–adrenocortical axis andcirculating brain natriuretic peptide in prediction of cardiopulmonaryperformance during physical stress

Dejana Popovic a,∗, Bojana Popovicb, Bosiljka Plecas-Solarovic c, Vesna Pesic c,Vidan Markovicd, Stanimir Stojiljkovic e, Vladan Vukcevic a, Ivana Petrovic a,Marko Banovic a, Milan Petrovic a, Bosiljka Vujisic-Tesic a, Miodrag C. Ostojic a,Arsen Ristic a, Svetozar S. Damjanovicb

a Division of Cardiology, Faculty of Medicine, University of Belgrade, Visegradska 26, 11000 Belgrade, Serbiab Division of Endocrinology, Faculty of Medicine, University of Belgrade, Dr Subotica 13, 11000 Belgrade, Serbiac Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbiad Faculty of Technical Sciences, University of Novi Sad, Dositej Obradovic Square, 21000 Novi Sad, Serbiae Faculty of Sports and Physical Education, University of Belgrade, Blagoja Parovica 156, 11000 Belgrade, Serbia

a r t i c l e i n f o

Article history:

Received 8 April 2013

Received in revised form 8 July 2013

Accepted 8 July 2013

Available online 20 July 2013

Keywords:

Brain natriuretic peptide

Cortisol

Adrenocorticotropic hormone

Hypothalamic–pituitary–adrenocortical

axis

Cardiopulmonary test

Stress axis

a b s t r a c t

Brain natriuretic peptide (NT-pro-BNP) was implicated in the regulation of

hypothalamic–pituitary–adrenocortical (HPA) responses to psychological stressors. However, HPA

axis activation in different physical stress models and its interface with NT-pro-BNP in the prediction

of cardiopulmonary performance is unclear. Cardiopulmonary test on a treadmill was used to assess

cardiopulmonary parameters in 16 elite male wrestlers (W), 21 water polo player (WP) and 20 sedentary

age-matched subjects (C). Plasma levels of NT-pro-BNP, cortisol and adrenocorticotropic hormone (ACTH)

were measured using immunoassay sandwich technique, radioimmunoassay and radioimmunometric

techniques, respectively, 10 min before test (1), at beginning (2), at maximal effort (3), at 3rd min of

recovery (4). In all groups, NT-pro-BNP decreased between 1 and 2; increased from 2 to 3; and remained

unchanged until 4. ACTH increased from 1 to 4, whereas cortisol increased from 1 to 3 and stayed elevated

at 4. In all groups together, �NT-pro-BNP2/1 predicted peak oxygen consumption (B = 37.40, r = 0.38,

p = 0.007); cortisol at 3 predicted heart rate increase between 2 and 3 (r = −0.38,B = −0.06, p = 0.005);

cortisol at 2 predicted peak carbon-dioxide output (B = 2.27, r = 0.35, p < 0.001); �ACTH3/2 predicted

peak ventilatory equivalent for carbon-dioxide (B = 0.03, r = 0.33, p = 0.003). The relation of cortisol at 1

with NT-pro-BNP at 1 and 3 was demonstrated using logistic function in all the participants together (for

1/cortisol at 1 B = 63.40, 58.52; r = 0.41, 0.34; p = 0.003, 0.013, respectively). �NT-pro-BNP2/1 linearly

correlated with �ACTH4/3 in WP and W (r = −0.45, −0.48; p = 0.04, 0.04, respectively). These results

demonstrate for the first time that HPA axis and NT-pro-BNP interface in physical stress probably

contribute to integrative regulation of cardiopulmonary performance.

© 2013 Elsevier Inc. All rights reserved.

Abbreviations: ACTH, adrenocorticotropic hormone; BSA, body surface area;

BW, body weight; C, controls; CPET, cardiopulmonary exercise test; DBP, diastolic

arterial blood pressure; FFM, fat free mass; FM, fat mass; HR, heart rate; HPA,

hypothalamic–pituitary–adrenocortical; NT-pro-BNP, N-terminal fragment of brain

natriuretic peptide; SBP, systolic arterial blood pressure; peakVCO2, peak carbon-

dioxide output; peakVE/VCO2, peak ventilatory equivalent for carbon-dioxide;

peakVO2, peak oxygen consumption; W, wrestlers; WP, water polo players.∗ Corresponding author at: Division of Cardiology, Faculty of Medicine, University

of Belgrade, Veljka Dugosevica 27g, 11000 Belgrade, Serbia. Tel.: +381 64 3709684;

fax: +381 11 3615630.

E-mail address: [email protected] (D. Popovic).

1. Introduction

The endocrine system plays a key role in stress situation, includ-

ing physical activity, which is frequently used as a stress model

[19]. Hormones have been documented to have an important

role in chronic adaptation to physical stress [52]. Stress system

activation implies secretion of hypothalamic corticotropin releas-

ing hormone, which stimulates pituitary proopiomelanocortin

(POMC) secretion [102]. POMC is the precursor peptide of adreno-

corticotropin hormone (ACTH), which partially regulates cortisol

secretion from adrenal glands [20,56]. ACTH and cortisol, besides

epinephrine and norepinephrine, are the most important stress

hormones [1]. During acute stress, the circadian periodicity of

0196-9781/$ – see front matter © 2013 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.peptides.2013.07.009


86 D. Popovic et al. / Peptides 47 (2013) 85–93

ACTH secretion disappears [35], thus, circulating ACTH increases

in a few minutes and certain level of ACTH is a reliable measure of

acute stress, unlike the cortisol, which is more a measure of chronic

stress and has protective role [63,96]. However, the activation of

stress system exhibits marked variability [72], depending on age

[34], gender, race, genetic factors [11], nutrition [7], psychological

factors [54,83], type of stress and physical activity [2,17]. There

are numerous reports showing the relationship between physical

stress and hypothalamo–pituitary–adrenal (HPA) axis, which

deals mostly with the influence of physical activity to stress

hormones levels [2,17,19,21,44,67,98,101]. It was shown that

higher level of physical activity is associated with lower HPA

axis reactivity to psychosocial stress [61,80]. A growing body of

evidence suggest that remaining physically active is beneficial

for those undergoing chronic stress of another kind [50,77,81].

These relationships are likely mediated at least partially trough

repeated and prolonged activation of HPA axis [77]. On the other

hand, it was shown that greater diurnal decline of the HPA axis

is associated with better physical performance in later life [33].

The regulatory mechanisms for the complex relation of physical

stress and HPA axis, together with the differential responses of

HPA axis to different type of stress, are predicted to be at the

adrenal level and stress regulatory brain areas [5,22]. This theory

is supported by morphological and biochemical changes in adrenal

cortex and medulla due to exercise [8]. However, biological effects

of stress hormones are still not completely elucidated, although

their role in complex interrelation of endocrine, metabolic,

immune, neurological and cardiovascular system in stress situa-

tions is based on assumption [95]. To achieve complex regulatory

role, HPA axis interacts with hypothalamo–pituitary–thyroid

axis, hypothalamo–pituitary–gonad axis,

hypothalamo–pituitary–growth hormone axis [48,60], brain

serotonergic, noradrenergic and dopaminergic systems [72] and

renin–angiotensin–aldosterone system [9,31]. In addition, puta-

tive role of several peptides in these complex regulations and

interaction is under investigation. For example, physical activity

elicits region specific changes in CART expression in the adrenal

gland and stress regulatory brain areas, thereby indicating that

CART fragments may have a role in the regulation of the HPA and

sympatho–adrenal axis activity during physical stress [5]. Cardiac

hormone BNP was first identified in the adrenal medulla of rats

as an aldosterone secretion inhibitory factor [68], but there are

number of reports showing the regulatory effects of BNP on ACTH

and cortisol secretion in several mammal species [40,66,75]. Fur-

thermore, in humans NT-pro-BNP is implicated in the regulation of

HPA responses to psychological stressors [4], suggesting interreac-

tion of these hormonal systems in adaptation to stress. However,

the pathways of HPA axis activation are different in physical and

emotional stress, leaving the relation of NT-pro-BNP and HPA axis

during physical stress unclear [43]. Furthermore, as NT-pro-BNP is

well known marker of global cardiac function, and has predictive

value for cardiopulmonary parameters, which we have partially

shown in our recent paper [74], it is possible that HPA axis in

coordination with NT-pro-BNP take a part in the regulation of

cardiopulmonary function during stress. Therefore, the aim of this

study was to further elucidate the HPA axis activation during acute

physical stress in different chronic physical stress models and its

interface with NT-pro-BNP, as well as their predictive value for

cardiopulmonary performance.

2. Materials and methods

2.1. Participants

Participants in this study were 57 male subjects matched

for age (21 elite water-polo players, 16 elite wrestlers and 20

sedentary subjects). Athletes have trained intensively for more than

10 years and all have been successfully competitive at the interna-

tional level for the past 5 years. Most of water polo players were

the members of the national team and all of wrestlers won medals

at the international level. Both groups of athletes performed com-

bined strength and endurance training protocols. Wrestlers were

in a period of preparations for the international competition at the

time they were examined. They had 9 h of wrestling a week, 4 h of

power training in the gym so as to improve the explosive strength

and 4 h of high intensity running a week (4 km per training, at heart

rate 85–100% of maximal). Water polo players were also in a period

of preparations for the competition. They trained 12 h a week in the

pool, with at least 2 km of swimming per each training, and three

additional hours a week in the gym where they performed both

power and endurance exercises. Control subjects were not engaged

in sporting activities other than at recreational level (lesser then 2 h

a week for the last 10 years). Also, a detailed personal and family

history of illness were obtained from all participants, and there-

after they embarked on physical examination, blood tests and ECG

recording. Though some of them had limb injuries in their personal

history, they declared any diseases and risk factors (hypertrophic

cardiomyopathy, hypertension, arrhythmias, diabetes, renal dis-

eases, cardiac and other infections, smoking, anabolic steroids

usage, etc.), which were the exclusion criteria because of the influ-

ence on myocardial function and total functional capacity of the

body. There was no record of any chest pain and loss of concious-

ness. Thus, physical examination and blood tests showed that all

of them were healthy and normotensive. ECG was physiological.

In addition, there was no family history of hypertrophic cardiomy-

opathy and sudden cardiac death. The participants underwent the

study after they have been given an informed consent and finally,

the study was approved by the Local Ethical Committee.

2.2. Anthropometry

Body weight, fat mass (FM) and fat free mass (FFM) were

obtained by bioelectrical impedance analysis using Tanita weight

(phase sensitive multi-frequency analyzer Data Input GmbH 2000,

using software Nutri 3). Body surface area (BSA) was calculated

according to the DuBois and DuBois formula [23].

2.3. Ergospirometry

All the athletes underwent a progressive continuous cardiopul-

monary exercise test on treadmill based on breath by breath

method to assess peak oxygen consumption (peakVO2), as the

measure of the functional capacity, peak carbon-dioxide output

(peakVCO2), maximal heart rate (HRmax) and peak ventilatory

equivalent for carbon-dioxide (peakVE/VCO2), which was obtained

as the ratio of peak minute ventilation (peakVE) and peakVCO2. The

protocol involved 3 min rest, 2 min at speed 6 km/h and 2% inclina-

tion, 2 min at speed 9 km/h and 2% inclination, with an increase of

inclination for 2% every 2 min after, until the criteria for maximal

test were reached, and 3 min recovery. The protocol was made by

pretesting nine randomly chosen subjects to optimize the duration

of the test (8–12 min) as recommended. The testing of all subjects

was performed at the same time of the day [39,103].

2.4. Blood analysis

Examiners were free of food and drink (except water) at least

3 h before collecting blood samples. In order to avoid hormonal

stimulation by needle punctuation, all blood samples were taken

from braunii which was placed into the patient’s brachial vein

before the test. Blood was taken in four phases of the test as

follows: 20 ml at rest, 10 min before CPET (phase 1); 20 ml at


D. Popovic et al. / Peptides 47 (2013) 85–93 87

Table 1

Peak values of cardiopulmonary parameters.

Parameter C (n = 20) WP (n = 21) W (n = 16) WP vs. W (pa) WP vs. C (pa) W vs. C (pa)

�HR 3/2 99 ± 11 108 ± 11 98 ± 12 0.009 0.015 ns

PeakVCO2 4026.9 ± 507.42 5299.76 ± 433.86 5372.71 ± 530.72 ns <0.001 <0.001

PeakVE/VCO2 30.58 ± 3.69 28.47 ± 3.39 28.55 ± 1.78 ns ns ns

Resuts are presented as mean ± SD. C, controls; W, wrestlers; WP, water polo players; �HR 3/2, the increase in HR from phase 2 to phase 3 (bpm); peakVCO2, peak

carbon-dixide output (ml/min); peak VE/VCO2, peak ventilatory equivalent for carbon-dioxidea Adjusted for BSA, FM and FFM.

the beginning of CPET (phase 2); 20 ml at the maximal effort

(phase 3) and 20 ml at the 3rd min of recovery (phase 4). Samples

were centrifuged on 4000 Hz and kept at −80 ◦C. NT-pro-BNP was

measured in all samples using immunoassay sandwich technique

(pro-BNP II, Cobas, Roche, Burgess Hill, England, with lower sensi-

tivity limit 5 pg/ml). ACTH was measured by immunoradiometric

method (ELSA-ACTH, CIS BioInternational, Gif-Sur-Yvette Cedex,

France with lower sensitivity limit 2 ng/l). Cortisol was measured

by radioimmunoassay (CORT-CT2, CIS BioInternational, Gif-Sur-

Yvette Cedex, France, with lower sensitivity limit 4.6 nmol/l). The

intra- and interassay coefficient of variation was lesser than 10%

for all assays.

2.5. Statistics

The results were expressed by classic descriptive parameters

like mean and standard deviation for parametric variables, and

median for not normally distributed variables. In order to apply

parametric analytical methods, the analysis of distribution of the

observed variables was performed by Kolmogorov–Smirnov test.

The differences between the groups were tested by analysis of vari-

ance (ANOVA): post hoc multiple group comparisons were assessed

with Bonferroni’s method and LSD method. Kruskal Wallis non-

parametric ANOVA followed by the Man Whitney test was used for

the variables that deviated from normal distribution. Correlations

between variables were performed by Pearson’s correlation test

and Spearman’s rank correlation test. Multiple regression analysis

was used to adjust for body surface area, fat free mass, fat mass and

heart rate when examining the differences between the groups for

Doppler measurements and cavity dimensions. The difference was

considered significant when a p value was lesser than 0.05, and is

highly significant when a p value was lesser than 0.01. SPSS soft-

ware (SPSS version 10.0, SPSS Inc., Chicago, IL, USA) was used for

statistical analysis.

3. Results

The participants were similar in age (C 21.35 ± 2.08 vs. WP

21.45 ± 3.47 vs. W 23.25 ± 3.53, p > 0.05). Athletes had higher BSA

(C 1.97 ± 0.10 m2, WP 2.12 ± 0.09 m2, W 2.13 ± 0.27 m2; WP vs.

C p = 0.006, W vs. C p = 0.005, WP vs. W p > 0.05) and FFM (C

67.92 ± 5.75 kg, WP 73.91 ± 5.37 kg, W 77.77 ± 8.71 kg; WP vs. C

p = 0.015, W vs. C p < 0.001, WP vs. W p > 0.05). FM was higher

in water polo players than in wrestlers (WP 14.10 ± 4.94 kg vs.

W 9.25 ± 6.48 kg, p = 0.021), and are not different between the

control population (C 10.14 ± 4.31 kg) and both groups of ath-

letes (p > 0.05). HR at rest was higher in control population

than in both groups of athletes, which had similar values (C

77 ± 11 bpm, WP 63 ± 10 bpm, W 67 ± 13 bpm; WP vs. C p < 0.001,

W vs. C p = 0.017, WP vs. W p > 0.05). There was no difference in

Fig. 1. Plasma levels of NT-pro-BNP in water polo players, wrestlers and controls in four phases of CPET (10′ before the test-phase 1, at beginning of the test-phase 2, at

maximal effort-phase 3, at 3rd min of recovery-phase 4). The results are expressed as median values. P values delineate significant differences among groups at corresponding

phase. Figure adapted from our published paper [74].



HRmax among groups (C 194 ± 10 bpm vs. WP 192 ± 9 bpm vs. W

189 ± 10 bpm, p > 0.05). The increase of HR in maximal effort was

higher in water polo athletes than in other two groups, which

had similar increase, as seen in Table 1. PeakVO2 was higher

in wrestlers then in controls (C 3918.70 ± 415.08 ml/min vs. W

4568.50 ± 687.24 ml/min, p < 0.001) and the highest in water polo

players (WP 5205.67 ± 384.52 ml/min; WP vs. C p < 0.001, WP vs.

W p < 0.001). PeakVCO2 was higher in athletes than in the control

population, and peakVE/VCO2 was similar in all groups (Table 1).

We observed significant changes of similar pattern during the

test in plasma level of NT-pro-BNP in both, controls and athletes

(Fig. 1). Plasma level of NT-pro-BNP significantly decreased from

phase 1 to phase 2, in anticipation of the stress (p = 0.002); increased

from phase 2 to phase 3, during maximal effort (p < 0.001) and

remained unchanged from phase 3 to phase 4, in recovery period

(p > 0.05). Plasma level of NT-pro-BNP was significantly higher in

controls compared to wrestlers in all phases of the test (C vs. W at

rest p = 0.017, at the beginning p = 0.013, at maximal effort p = 0.011

and after recovery p = 0.006); water polo athletes had similar values

as wrestlers and controls in all phases of the test (p > 0.05). Besides,

the changes in NT-pro-BNP plasma level between the phases of

experiment in controls, wrestlers and water polo players were sim-

ilar (p > 0.05), indicating a similar response.

In both controls and athletes circulating ACTH significantly

increased between the phases of the test (p < 0.001; phase 1 vs.

phase 2 p = 0.008; phase 2 vs. phase 3 p < 0.001; phase 3 vs. phase

4 p < 0.001; Fig. 2a). Plasma ACTH was not different among groups

at any particular phase of the test (p > 0.05).

Besides, the changes in ACTH plasma level between the phases

of experiment in controls, wrestlers and water polo players were

similar (p > 0.05), indicating a similar response (Fig 2b).

We observed significant changes of circulating cortisol during

the test in both controls and athletes (p < 0.001) as seen in Fig. 3a.

Circulating cortisol increased from phase 1 to phase 2 (p < 0.001)

and from phase 2 to phase 3 (p < 0.001), while there was no change

in circulating cortisol from phase 3 to phase 4 (p > 0.05). Circulating

cortisol was higher in wrestlers than in control population in the

first three phases of the test (p = 0.002, 0.001, and 0.022, respec-

tively), and similar in the phase 4 (p > 0.05). Water polo athletes

had similar cortisol levels as wrestlers and controls in all phases

(p > 0.05), except in phase 2, when they had higher value of circu-

lating cortisol than controls (p = 0.022).

The change of cortisol from phases 1 to 2, and 3 to 4 was not

different between the groups. Between phases 2 and 3 significant

difference in cortisol response was shown between the wrestlers

and control population (p < 0.05), while water polo athletes had

similar response as two other groups. (Fig. 3b)

3.1. Correlations of cardiopulmonary variables and hormones

In all three groups together, we observed significant correlations

of hormonal variables and cardiopulmonary parameters. NT-pro-

BNP at rest significantly correlated with HRmax (r = −0.32, p = 0.02).

The increase of heart rate from phase 2 to phase 3 (�HR 3/2) cor-

related with cortisol level in phases 1, 2, 3, and 4 (r = −0.34, −0.29,

−0.38, and −0.36; p = 0.011, 0.033, 0.005, and 0.007, respectively).

The change of NT-pro-BNP from phase 1 to phase 2 (�NT-pro-

BNP 2/1) correlated with peakVO2 (r = 0.40, p = 0.003). PeakVCO2

correlated with the plasma level of cortisol in phase 2 (r = 0.38,

p = 0.004) and with NT-pro-BNP plasma level in phases 1, 3 and

4 (r = −0.30, −0.29, and −0.28; p = 0.03, 0.043, and 0.038, respec-

tively). The change of ACTH from phase 2 to phase 3 (�ACTH 3/2)

correlated with peakVE/VCO2 (r = 0.35, p = 0.009).

The multiple regression analysis, which includes hormonal and

anthropometric variables, in all three groups together demon-

strated that: the best independent predictor of HR max was

Fig. 2. (a) Circulating levels of ACTH in water polo players, wrestlers and controls

in four phases of CPET (10′ before the test-phase 1, at the beginning of the test-

phase 2, at maximal effort-phase 3, at 3rd min of recovery-phase 4). The results are

expressed as median values. P values delineate statistical differences among groups

at corresponding phase. (b) The changes of ACTH in water polo players, wrestlers

and controls during CPET (from phase 1 to phase 2; from phase 2 to phase 3; and

from phase 3 to phase 4). The results are expressed as mean ± 2SD.

NT-pro-BNP at rest (B = −0.22, r = −0.32, p = 0.02) and of �HR

3/2 was cortisol in phase 3 (r = −0.38, B = −0.06, p = 0.005); the

best independent predictor of peakVO2 was �NT-pro-BNP 2/1

(B = 36.01, r = 0.37, p = 0.001) and of peakVCO2 was cortisol in

phase 2 (r = 0.41, B = 2.65, p = 0.002); peakVE/VCO2 was predicted

by �ACTH 3/2 (B = 0.03, r = 0.33, p = 0.003).

3.2. Correlations of hormones

In all three groups together plasma cortisol at rest inversely

correlated with the increase of cortisol in maximal effort and

was its predictor (for 1/cortisol = 0.30, B = 2228.25, p = 0.03;

y = 22.55 + 2228.25/x).

Although there was no linear correlation of NT-pro-BNP at rest

and NT-pro-BNP max with cortisol in all three groups together,

regression S curve showed a significant relation of NT-pro-BNP

at rest and cortisol at rest (for 1/cortisol B = 63.40, = 0.41,

p = 0.003; according to equation y = 2.83 + 1/(1 + e−63.4x)) as can be

seen in Fig. 4, as well as NT-pro-BNPmax and cortisol at rest

(for 1/cortisol B = 58.52, = 0.34, p = 0.013; according to equation

y = 3.04 + 1/(1 + e−58.52x)), as can be seen also in Fig. 5.



Fig. 3. (a) Circulating levels of cortisol in water polo players, wrestlers and controls

in four phases of CPET (10′ before the test-phase 1, at the beginning of the test-

phase 2, at maximal effort-phase 3, at 3rd min of recovery-phase 4). The results are

expressed as median values. P values delineate statistical differences among groups

at corresponding phase. (b) The change of cortisol in water polo players, wrestlers

and controls during CPET (from phase 1 to phase 2; from phase 2 to phase 3; and

from phase 3 to phase 4). The results are expressed as mean ± 2SD.

In water polo athletes NT-pro-BNP at rest and maximal effort

linearly correlated with cortisol at rest (r = −0.56, −0.48; p = 0.009,

0.03, respectively). However, the relation of NT-pro-BNP at rest

and maximal effort with cortisol at rest in water polo athletes can

120.00

100.00

80.00

60.00

40.00

20.00

0.00

800.00600.00400.00200.000.00

Cortisol rest (nmol/l)

S

Observed

n=57for 1/cortisol beta=0.41, p=0.003y= 2.83 + 1/(1+e

-63.4x)

All three groups together

NT

-pro

-BN

P r

est

(pg

/ml)

Fig. 4. Relation of NT-pro-BNP at rest and cortisol at rest in all three groups together.

140.00

120.00

100.00

80.00

60.00

40.00

20.00

0.00

800.00600.00400.00200.000.00

Cortisol rest (nmol/l)

S

Observed

All three groups together

n=57for 1/cortisol B=58.52, beta=0.34, p=0.013y= 3.04 + 1/(1+e

-58.52x)

NT

-pro

-BN

P m

ax (p

g/m

l)

Fig. 5. Relation of NT-pro-BNPmax and cortisol at rest in all three groups together.

be best presented with exponential curves (B = −0.003, = −0.61,

p = 0.003 according to equation y = 54.05 + e−0.003x; B = −0.003,

ˇ = −0.54, p = 0.012 according to equation y = 55.75 + e−0.003x,

respectively). Other groups showed no linear correlations of NT-

pro-BNP at rest and maximal effort with cortisol at rest.

�NT-pro-BNP 2/1 linearly correlates with �ACTH 4/3 in all

groups (Fig. 6a–c), but reached statistical significance only in water

polo athletes and wrestlers. In addition, different direction of cor-

relation in athletes and controls was also observed.

4. Discussion

Stress condition increases metabolic demands and the intensity

of hormonal activity [52,59,95], and consequently chronic exposure

to stress influences cardiopulmonary performance [13,14,71]. It is

known that long-term activation of stress system may even lead

to lethal outcome [72]. On the other hand, the adaptive changes in

athletes, as stress models, go in the direction of the whole body‘s

improvement ability [13,71], but these changes are different in

different sport disciplines and levels of fitness, depending on the

ratio of strength and endurance component in training [71,85,89].

Thus, the adaptation to stress condition is different in various stress

models, either physiological or pathological [71,85,89,99,100], and

hormonal regulatory factors are considered to be key determinants

in this process [52,59,95]. Distinguishing physiological from patho-

logical plasma levels of stress hormones is very hard with only few

animal studies dealing with this problem [96]. Therefore, the prob-

lem is more complicated as a result of physiological variability of

stress system activation [72].

In this study, as expected, control population and two different

chronic stress models, water polo athletes and wrestlers, showed

different cardiopulmonary adaptive changes [13,71]. Athletes had

higher peak VO2, which is a representative of the functional capac-

ity. The increase of the functional capacity in controls and two

groups of athletes was achieved due to different adaptive changes

of heart and lungs. In that direction, even when all groups had sim-

ilar maximal heart rate, the increase in heart rate in maximal effort

was the highest in water polo athletes. Athletes had higher maximal

carbon-dioxide output too, which serves as a measure of anaero-

bic metabolism intensity [39,103], and is the ventilatory stimulant

needed for maintaining ventilatory efficiency at certain level that

are necessary for maximal effort. Thus, the differences in cardiopul-

monary parameters between study groups are adaptive response

to metabolic demands with hormonal regulatory role as crucial

[52,59,95].

The response to physical stress implies neurohormonal sig-

nals from nervous, endocrine and immune system, which lead to



10.00

5.00

0.00

-5.00

-10.00

-15.00

-20.00

250.00200.00150.00100.0050.000.00-50.00

Linear

Observed

controls

(a)

(b)

(c)

n=20r= 0.41, p=0.07

Δ ACTH 4/3 (ng/l)

Δ p

ro-B

NP

2/1

(p

g/m

l)

10.00

5.00

0.00

-5.00

-10.00

300.00200.00100.000.00

Linear

Observed

water polo athletes

n=21

r= -0.45, p=0.04

Δ ACTH 4/3 (ng/l)

Δ p

ro-B

NP

2/1

(p

g/m

l)

10.00

0.00

-10.00

-20.00

300.00200.00100.000.00

Linear

Observed

wrestlers

n=13r= -0.58, p=0.04

Δ ACTH 4/3 (ng/l)

Δ p

ro-B

NP

2/1

(p

g/m

l)

Fig. 6. (a) Correlation of the NT-pro-BNP change in anticipation of the test and ACTH

change in recovery phase in controls. (b) Correlation of the NT-pro-BNP change in

anticipation of the test and ACTH change in recovery phase in water polo athletes. (c)

Correlation of the NT-pro-BNP change in anticipation of the test and ACTH change

in recovery phase in wrestlers.

morphofunctional changes in the organ systems [18,95]. HPA axis

activity was the first to be responsible for adaptation to stress, but

it is important to realize that there are complex interactions of

hormonal systems in between [4,31,48,60,72,76].

Previous studies have documented the increase in plasma ACTH

level during acute physical stress, followed by unchanged cortisol

[24,55,104]. This was explained by a reduction in the sensitivity of

HPA axis at pituitary level to negative feedback of cortisol but not

with decreased responsiveness of adrenal gland to ACTH stimula-

tion, which might be a protective mechanism against prolonged

increased cortisol levels [27]. However, some studies have shown

the increase of both ACTH and cortisol during dynamic and static

physical stress, even in anticipation of the test [92], depending on

its intensity and duration [28,49], and the results from our study

are consistent with these findings.

Due to repeated HPA axis activation, chronic physical stress may

alter basal levels of HPA hormones [10,38,58]. Static training of high

intensity increases resting cortisol, whereas static training of low

intensity and long duration decreases resting cortisol [3,32]. Inten-

sive aerobic training increases resting levels of both ACTH [41] and

cortisol [10,87]. On the other hand, some studies have shown the

increase in basal cortisol level with unchanged ACTH in athletes

[84,86], and our results are in agreement with this finding. Thus,

wrestlers had the highest basal level of cortisol, probably due to a

higher static component in training.

Furthermore, chronic physical stress may alter the sensitiv-

ity of HPA-axis [25,26,45]. There are literature data showing no

changes in HPA axis activation in both trained and untrained

individuals [37,51]. Nevertheless, others have demonstrated that

only few weeks of training decreased responsiveness of HPA axis

[41,42] and that according to them HPA axis activation is depen-

dent on duration, type and intensity of training [10,17,41]. This

was explained as a protective mechanism in condition of repeated

stress in order to keep the reserves of the body from exhaustion

[59]. In that direction, decreased response of ACTH in physical

stress was shown in endurance athletes [59], but static training,

on the contrary, may increase cortisol response [32,64]. However,

the data about HPA axis activation in different athletic population

are confusing. In this study, the response of ACTH to acute phys-

ical stress was similar, regardless of the chronic physical stress

adaptive models. For the same plasma level of ACTH the response

of cortisol was different among groups. This finding suggests

that in different stress adaptive models there might be different

sensitivity of adrenal glands to ACTH stimulation with possible

diverse involvement of other regulatory mechanisms, like auton-

omy of adrenal gland or sympathetic control [56]. The response of

cortisol at maximal effort was attenuated in wrestlers in compari-

son to controls, probably because of their higher cortisol plasma

levels in wrestlers at rest, which is supported by the inverse

correlation of cortisol at rest and cortisol increase in maximal

effort.

Intensive hormonal activity during stress acts for customiza-

tion of cardiopulmonary abilities in condition of increased demands

[13,14,71]. It is known that HPA axis has complex role in the reg-

ulation of carbohydrate, lipid and protein metabolism as well as

energy homeostasis [12], and also in the regulation of body fluids

and body composition, which are related directly to cardiac func-

tion [78,79,95]. Previous studies have shown that cardiovascular

effects of ACTH and cortisol are mostly directed to the regulation of

blood pressure and heart rate [78,79,95]. In this study, we found

that maximal cortisol level predicted heart rate increase during

stress. Furthermore, the increase of cortisol in anticipation of the

stress predicted maximal carbon-dioxide output, probably because

of its regulatory role in carbohydrate metabolism, which is favored

in maximal effort and also related to an increased carbon-dioxide

production. As carbon-dioxide is the main ventilatory stimulant,

this might be the mechanism of ventilatory regulation medi-

ated by cortisol. Additionally, the increase of ACTH during stress

predicted maximal ventilatory efficiency, which reflects ventila-

tory adaptation to metabolic demands, probably throughout the



sensitivity of central hypercapnic receptors [105]. Thus, HPA axis

has proven predictive value for cardiopulmonary performance,

which suggests possible regulatory role.

On the other hand, NT-pro-BNP hormone secreted in cardiac

chambers as response to wall stress [93], is marker of the global

cardiac function, and widely explored for different diagnostic pur-

poses, with lacking specificity and predicted, but unclear regulatory

role in cardiopulmonary adaptation [97].

In this study, all stress models showed an increase in NT-pro-

BNP during stress and similar response. However, the literature

data about the dynamics of NT-pro-BNP during physical stress

are controversial. Some studies showed that there are no sig-

nificant changes of this hormone during physical stress [91,94],

while others showed an increase in plasma levels [29,46,53,62],

not only during dynamic but also during static load [16], which

is in accordance with our results. The increase of NT-pro-BNP

can be explained by the fact that exercise might generate transi-

tory ischemia, increase of wall stress and diastolic dysfunction [6],

which are stimuli for the NT-pro-BNP secretion [36,47], in order

to obtain further necessary regulation of cardiac function in stress

condition. Besides, the response of NT-pro-BNP during physical

activity is lesser in athletes with physiological hypertrophy than in

patients with pathological hypertrophy [106], thereby suggesting

different adaptative response to stress. Studies also showed altered

mean values of BNP at rest in athletes, either decreased [6,15,30,57],

or increased [69], and significant negative correlation was found

with training duration [70]. In our study, wrestlers had lower mean

values of NT-pro-BNP than control group in all phases, unlike the

cortisol. This finding suggests that BNP acts differently in different

stress adaptive models, which reflects different cardiopulmonary

status.

Some authors showed no correlation of maximal BNP level and

exercise capacity in healthy individuals [53], whereas others found

relation of BNP increase with exercise and better exercise capacity

[65]. It was also shown that in heart failure patients oxygen uptake

correlates with BNP [88]. The increase in BNP levels in postcardiac

surgery patients is associated with reduced exercise capacity [82].

Our results revealed that the functional capacity is strongly pre-

dicted by the change of plasma NT-pro-BNP in anticipation of the

test thereby suggesting that cardiac hormonal response may be a

key element in reaching peak oxygen consumption. This finding

is consistent with the prediction of the maximal heart rate with

resting NT-pro-BNP level, which suggests possible involvement of

NT-pro-BNP in the regulation of the heart rate response, partic-

ularly in athletes with better cardiac efficiency, as supported by

previous experimental findings [65,90].

Summarizing the observations from this study, it is noticeable

that HPA axis and NT-pro-BNP have mutually enriching predictive

value for cardiopulmonary performance in healthy participants

subjected to an acute physical stress. Furthermore, the intere-

lation of HPA axis and NT-pro-BNP was shown. Previously, it

was demonstrated that NT-pro-BNP has been implicated in the

HPA responses to psychological stressors, and the correlation of

NT-pro-BNP and HPA axis parameters was negative [4]. To our

knowledge, this is the first study to report the interface of HPA axis

and peripheral natriuretic peptide system during physical stress.

Moreover, the study proves their mutual interreaction, apparently

suggesting complex mechanisms that exist under HPA axis. How-

ever, untrained heart was related to higher NT-pro-BNP levels

and lower cortisol at rest. The relation of NT-pro-BNP at rest and

maximal effort and cortisol at rest, which is the most compelling

in athletes with the highest cardiac wall stress [73], suggests

that NT-pro-BNP, which reflects the functional status of cardiac

chambers, may be a reliable biomarker of chronic physical stress.

In addition, the correlation of NT-pro-BNP change in anticipation of

the stress and HPA axis recovery, which is different in athletes and

controls, deepens possible integrative role of these two systems

in the regulation of stress reaction and adaptation. However,

further investigation should be warranted to elucidate to a certain

extent obviously intricate integrative regulatory mechanisms

of peripheral natriuretic peptide system and stress axis in the

coordination of cardiopulmonary adaptation to stress condition.

5. Conclusion

Plasma level of NT-pro-BNP both at rest and during stress tend

to be lower in athletes than in untrained subjects, unlike corti-

sol which tends to be higher, differently in two groups of athletes

examined as a chronic physical stress adaptation models, while

circulating ACTH remains similar. The increase in ACTH and NT-

pro-BNP during stress is of the same pattern in both athletes and

controls, however cortisol increase is attenuated in athletes with

higher static component in training, probably because of an already

higher basal cortisol plasma level. NT-pro-BNP has a predictive

value for HRmax and total functional capacity of the body, while

cortisol during stress has predictive value for heart rate increase

and maximal carbon-dioxide output. Additionally, ACTH increase

during stress predicts maximal ventilatory efficiency. Even more,

the interreaction of HPA axis and NT-pro-BNP in physical stress was

shown. Thus, stress hormones and peripheral natriuretic peptide

system interface during physical stress showing noticeable, mutu-

ally enriching, predictive value for cardiopulmonary performance.

This finding suggests their possible integrative regulatory role in

cardiopulmonary adaptation to stress condition.

Limitation of the study

Our data are preliminary and further investigations of this topic

in different population groups and on a higher number of partici-

pants are needed.

Disclosures

The authors have nothing to disclose.

Acknowledgements

We thank the subjects who participated in this study. This

research was supported by the Clinical Center of Serbia Belgrade,

Faculty of Medicine University of Belgrade, Faculty of Pharmacy

University of Belgrade and Ministry of Education, Science and Tech-

nological Development (Project No 175036).

References

[1] Adams HA, Hampelmann G. The endocrine stress reaction in anaestesiaand surgery-origine and significance. Anaesthesiol Intensivmed NotfallmedSchmerzther 1991;26(6):294–305.

[2] Ahtiainen JP, Pakarinen A, Kraemer WJ, Häkkinen K. Acute hormonalresponses and recovery to forced vs. maximum repetitions multiple resis-tance exercises. International Journal of Sports Medicine 2003;24(6):410–41.

[3] Alen M, Pakarinen A, Hakkinen K, Komi PV. Responses of serumandrogenic–anabolic and catabolic hormones to prolonged strength training.International Journal of Sports Medicine 1988;9:299–333.

[4] Amir O, Sagiv M, Eynon N, Yamin C, Rogowski O, Gerzy Y, et al. The responseof circulation brain natriuretic peptide to academic stress in college students.Stress 2010;13(1):83–90.

[5] Balkan B, Keser A, Gozen O, Koylu EO, Dagci T, Kuhar MJ, et al. Forced swimstress elicits region-specific changes in CART expression in the stress axis andstress regulatory brain areas. Brain Research 2012;1432:56–65.

[6] Banfi G, D‘Eril GM, Barassi A, Lippi G. N-terminal proB-type natriuretic peptide(NT-proBNP) concentrations in elite rugby players at rest and after active andpassive recovery following strenuous training sessions. Clinical Chemistryand Laboratory Medicine 2008;46(2):247–9.

[7] Barbadoro P, Annino I, Ponzio E, Romanelli RM, D’Errico MM, Prospero E, et al.Fish oil supplementation reduces cortisol basal levels and perceived stress: a



randomized, placebo-controlled trial in abstinent alcoholics. Molecular Nutri-tion & Food Research 2013, doi: 10.1002/mnfr.201200676. [Epub ahead ofprint].

[8] Bartalucci A, Ferrucci M, Fulceri F, Lazzeri G, Lenzi P, Toti L, et al. High-intensityexercise training produces morphological and biochemical changes in adrenalgland of mice. Histology and Histopathology 2012;27(6):753–69.

[9] Berardelli R, Karamouzis I, Marinazzo E, Prats E, Picu A, Giordano R, et al.Effect of acute and prolonged mineralocorticoid receptor blockade on spon-taneous and stimulated hypothalamic–pituitary–adrenal axis in humans.European Journal of Endocrinology/European Federation of Endocrine Soci-eties 2010;162(6):1067–74.

[10] Buyukuazi G, Karamizrak SO, Islegen C. Effects of continuous and intervalrunning training on serum growth and cortisol hormones in junior malebasketball players. Acta Physiologica Hungarica 2003;90(1):69–79.

[11] Charmandari E, Kino T, Chrousos GP. Primary generalized familial and spo-radic glucocorticoid resistance (chrousos syndrome) and hypersensitivity.Endocrine Development 2013;24:67–85.

[12] Coker RH, Krishna MG, Brooks Lacy D, Bracy DP, Wasserman DH. Role ofhepatic �- and �-adrenergic receptor stimulation on hepatic glucose produc-tion during heavy exercise. American Journal of Physiology 1997;273:E831–8.

[13] D’Andrea A, Limongelly G, Caso P, Sarubbu B, Della Pietra A, Brancaccio P, et al.Association between left ventricular structure and cardiac performance dur-ing effort in two morphological forms of athlete’s heart. International Journalof Cardiology 2002;86(2/3):177–84.

[14] D’Andrea A, Caso P, Scarafile R, Salerno G, De Corato G, Mita C, et al. Biven-tricular myocardial adaptation to different training protocols in competitivemaster athletes. International Journal of Cardiology 2007;115:342–9.

[15] Daniels LB, Allison MA, Clopton P, Redwine L, Siecke N, Taylor K, et al. Use ofnatriuretic peptides in pre-participation screening of college athletes. Inter-national Journal of Cardiology 2008;124(3):411–4.

[16] Date H, Imamura T, Onitsuka H, Maeno M, Watanabe R, Nishihira K, et al. Dif-ferential increase in natriuretic peptides in elite dynamic and static athletes.Circulation Journal 2003;67:691–6.

[17] de Diego Acosta AM, Garcia JC, Fernandez-Pastor VJ, Perán S, Ruiz M,Guirado F. Influence of fitness on the integrated neuroendocrine responseto aerobic exercise until exhaustion. Journal of Physiology and Biochemistry2001;57(4):313–20.

[18] de Graaf-Roelfsema E, Keizer HA, van Breda E, Wijnberg ID, van der Kolk JH.Hormonal responses to acute exercise: training and overtraining. A reviewwith emphasis on the horse. Veterinary Quarterly 2007;29(3):82–101.

[19] De Vries WR, Bernards NT, de Rooij MH, Koppeshaar HP. Dynamic exercisediscloses different time-related responses in stress hormones. PsychosomaticMedicine 2000;62:866–72.

[20] Dickmeis T. Glucocorticoids and the circadian clock. Journal of Endocrinology2009;200:3–22.

[21] Di Luigi L, Guidetti L, Baldari C, Romanelli F. Heredity and pituitary responseto exercise-related stress in trained men. International Journal of SportsMedicine 2003;24(8):551–8.

[22] Droste SK, Chandramohan Y, Hill LE, Linthorst AC, Reul JM. Voluntary exerciseimpacts on the rat hypothalamic–pituitary–adrenocortical axis mainly at theadrenal level. Neuroendocrinology 2007;86(1):26–37.

[23] DuBois D, DuBois EF. Clinical calorimetry. A formula 17: to estimate theapproximate surface area if height and weight be known. Archives of InternalMedicine 1916;17:863–71.

[24] Duclos M, Corcuff JB, Rashedi M, Fougère V, Manier G. Trained versusuntrained men: different immediate post-exercise reponses of pituitaryadrenal axis. A preliminary study. European Journal of Applied Physiology1997;75:343–50.

[25] Duclos M, Corcuff JB, Arsac L, Moreau-Gaudry F, Rashedi M, Roger P, et al. Cor-ticotroph axis sensitivity after exercise in endurance-trained athletes. ClinicalEndocrinology 1998;48:493–501.

[26] Duclos M, Corcuff JB, Pehourcq F, Tabarin A. Decreased pituitary sensitivity toglucocorticoids in endurance-trained man. European Journal of Endocrinol-ogy/European Federation of Endocrine Societies 2001;144:363–8.

[27] Duclos M, Gouarne C, Bonnemaison D. Acute and chronic effects of exer-cise on tissue sensitivity to glucocorticoides. Journal of Applied Physiology2003;94:869–75.

[28] Farell PA, Garthwaite TL, Gustafson AB. Plasma adrenocorticotripin and cor-tisol responses to submaximal and exhaustive exercise. Journal of AppliedPhysiology 1983;55(5):1441–4.

[29] Foote RS, Pearlman JD, Siegel AH, Yeo KT. Detection of exercise-inducedishaemia by changes in B-type natriuretic peptides. Journal of the AmericanCollege of Cardiology 2004;44:1980–7.

[30] Frassl W, Kowoll R, Katz N, Speth M, Stangl A, Brechtel L, et al. Cardiacmarkers (BNP, NT-pro-BNP, Troponin I, Troponin T, in female amateur run-ners before and up until three days after a marathon. Clinical Laboratory2008;54(3/4):81–7.

[31] Freel EM, Ingram M, Wallacet AM, White A, Fraser R, Davies E, et al. Effectof variation in CYP11B1 and CYP11B2 on corticosteroid phenotype andhypothalamic–pituitary–adrenal axis activity in hypertensive and normoten-sive subjects. Clinical Endocrinology 2008;68:700–6.

[32] Fry AC, Kraemer WJ, Stone MH, Warren BJ, Fleck SJ, Kearney JT, et al. Endocrineresponses to overreaching before and after 1 year of weightlifting. CanadianJournal of Applied Physiology 1994;19:400–10.

[33] Gardner MP, Lightman S, Sayer AA, Cooper C, Cooper R, Deeg D, et al. Hal-cyon Study Team; Dysregulation of the hypothalamic pituitary adrenal (HPA)

axis and physical performance at older ages: an individual participant meta-analysis. Psychoneuroendocrinology 2013;38(1):40–9.

[34] Garrido P. Aging and stress: past hypotheses, present approaches and per-spectives. Aging and Disease 2011;2(1):80–99.

[35] Georgopoulos NA, Rottstein L, Tsekouras A, Theodoropoulou A, Koukkou E,Mylonas P, et al. Abolished circadian rhythm of salivary cortisol in elite artisticgymnasts. Steroids 2011;76(4):353–7.

[36] Goetze JP, Christoffersen C, Perko M, Arendrup H, Rehfeld JF, Kastrup J,et al. Increased cardiac BNP expression associated with myocardial ischemia.FASEB Journal 2003;17:1105–7.

[37] Goldfarb AH, Hatfield BD, Potts J, Armstrong D. B-endorphin time courseresponse to intensity of exercise: effect of training status. International Jour-nal of Sports Medicine 1991;12(3):264–8.

[38] Gouarné C, Groussard C, Gratas-Delamarche A, Delamarche P, Duclos M.Overnight urinary cortisol and cortisone add new insights into adapta-tion to training. Medicine and Science in Sports and Exercise 2005;37(7):1157–67.

[39] Guazzi M, Adams V, Conraads V, Halle M, Mezzani A, Vanhees L, et al.EACPR/AHA Scientific Statement. Clinical recommendations for cardiopul-monary exercise testing data assessment in specific patient populations.Circulation 2012;126(18):2261–74.

[40] Guild SB, Cramb G. Characterisation of the effects of natriuretic peptides uponACTH secretion from the mouse pituitary. Molecular and Cellular Endocrinol-ogy 1989;152(1/2):11–9.

[41] Heitkamp HC, Schmid K, Scheib K. �-Endorphin and adrenocorticotrophinafter incremental exercise and marathon running-female responses. Euro-pean Journal of Applied Physiology 1993;66(3):269–74.

[42] Heitkamp HC, Schultz H, Rocker K, Dickhuth HH. Endurance training infemales: changes in �-endorphin and ACTH. International Journal of SportsMedicine 1998;19(4):260–4.

[43] Herman JP, Cullinan WE. Neurocircuitry of stress: central control ofthe hypothalamo–pituitary–adrenocortical axis. Trends in Neurosciences1997;20(2):78–84.

[44] Hill EE, Zack E, Battaglini C, Viru M, Viru A, Hackney AC. Exercise and circulat-ing cortisol levels: the intensity threshold effect. Journal of EndocrinologicalInvestigation 2008;31(7):587–91.

[45] Hu Y, Liao HB, Guo DH, Guo DH, Rahman K. A bioactive compaund from Poly-gala tenuifolia regulates efficiency of chronic stress on HPA-axis. Pharmazie2009;64(9):605–8.

[46] Huang WS, Lee MS, Perng HW, Yang SP, Kuo SW, Chang HD. Circulatingbrain natriuretic peptide values in healthy men before and after exercise.Metabolism: Clinical and Experimental 2002;51(11):1423–6.

[47] Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, et al. B-type natri-uretic peptide strongly reflects diastolic wall stress in patients with chronicheart failure; comparison between systolic and diastolic heart failure. Journalof the American College of Cardiology 2006;47:742–8.

[48] Johnson EO, Kamilaris TC, Calogero AE, Gold PW, Chrousos GP.Experimentally-induced hyperthyroidism is associated with acti-vation of the rat hypothalamic–pituitary–adrenal axis. EuropeanJournal of Endocrinology/European Federation of Endocrine Societies2005;153(1):177–85.

[49] Kjaer M, Bangsbo J, Lortie G, Galbo H. Hormonal response to exercise inhumans: influence of hypoxia and physical training. American Journal ofPhysiology 1988;254:R197–203.

[50] Kobasa SC, Maddi SR, Puccetti MC. Personality and exercise as buffersin the stress–illness relationship. Journal of Behavioral Medicine1982;5(4):391–404.

[51] Kraemer RR, Blair S, Kraemer GR, Castracane VD. Effects of treadmill run-ning on plasma �-endorphin, corticotrophin and cortisol levels in male andfemale10K runners. European Journal of Applied Physiology and OccupationalPhysiology 1989;58:845–51.

[52] Kraemer WJ, Fleck SJ, Maresh CM, Ratamess NA, Gordon SE, Goetz KL, et al.Acute hormonal responses to a single bout of heavy resistance exercise intrained power lifters and untrained males. Canadian Journal of Applied Phys-iology 1999;24:524–37.

[53] Krupicka J, Janota T, Kasalova Z, Hradec J. Effect of short term maximal exer-cise on BNP plasma levels in healthy individuals. Physiological Research2010;59(4):625–8.

[54] Laurent HK, Neiderhiser JM, Natsuaki MN, Shaw DS, Fisher PA, Reiss D, et al.Stress system development from age 4.5 to 6: family environment predic-tors and adjustment implications of HPA activity stability versus change.Developmental Psychobiology 2013, doi: 10.1002/dev.21103. [Epub ahead ofprint].

[55] Lehmann M, Knizia K, Gastmann U, Petersen KG, Khalaf AN, Bauer S, et al. Influ-ence of 6-weak, 6 days per weak, training on pituitary function in recreationalathletes. British Journal of Sports Medicine 1993;27:186–92.

[56] Lightman SL. The neuroendocrinology of stress: a never ending story. Journalof Neuroendocrinology 2008;20:880–4.

[57] Löwbeer C, Seeberger A, Gustafsson SA, Bouvier F, Hulting J. Serum cardiactroponin T: troponin I, plasma BNP and left ventricular mass index in profes-sional football players. Journal of Science and Medicine in Sport 2007;10(5):291–6.

[58] Luger A, Deuster PA, Kyle SB, Gallucci WT, Montgomery LC, Gold PW,et al. Acute HPA responses to the stress of tredmill exercise. Physio-logic adaptations to physical training. New England Journal of Medicine1987;316:1309–15.



[59] Luger A, Deuster PA, Gold PW, Loriaux DL, Chrousos GP. Hormonal responsesto the stress of exercise. Advances in Experimental Medicine and Biology1993;245:273–80.

[60] Maghnie M, Uga E, Temporini F, Di Iorgi N, Secco A, Tinelli C, et al. Eval-uation of adrenal function in patients with growth hormone deficiencyand hypothalamic–pituitary disorders: comparison between insulin-inducedhypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests.European Journal of Endocrinology/European Federation of Endocrine Soci-eties 2005;152(5):735–41.

[61] Martikainen S, Pesonen AK, Lahti J, Heinonen K, Feldt K, Pyhälä R,et al. Higher levels of physical activity are associated with lowerhypothalamic–pituitary–adrenocortical axis reactivity to psychosocialstress in children. Journal of Clinical Endocrinology and Metabolism2013;98(4):E619–27.

[62] McNairy M, Gardetto N, Clopton P, Garcia A, Krishnaswamy P, Kazanegra R,et al. Stability of B-type natriuretic peptide levels during exercise in patientswith congestive heart failure: implications for outpatient monitoring withB-type natriuretic peptide. American Heart Journal 2002;143:406–11.

[63] Michalaki M, Margeli T, Tsekouras A, Gogos CH, Vagenakis AG, KyriazopoulouV. Hypothalamic–pituitary–adrenal axis response to the severity of illnessin non-critically ill patients: does relative corticosteroid insufficiency exist?European Journal of Endocrinology/European Federation of Endocrine Soci-eties 2010;162(2):341–7.

[64] Minetto MA, Lanfranco F, Baldi M, Termine A, Kuipers H, Ghigo E, et al.Corticotroph axis sensitivity after exercise: comparison between elite ath-letes and sedentary subjects. Journal of Endocrinological Investigation2007;30(3):215–23.

[65] Mottram PM, Haluska BA, Marwick TH. Response of B-type natriuretic peptideto exercise in hypertensive patients with suspected diastolic heart failure:correlation with cardiac function, hemodynamics and workload. AmericanHeart Journal 2004;148(2):365–70.

[66] Nawata H, Ohashi M, Haji M, Takayanagi R, Higuchi K, Fujio N, et al. Atrialand brain natriuretic peptide in adrenal steroidogenesis. Journal of SteroidBiochemistry and Molecular Biology 1991;40(1/3):367–79.

[67] Niess AM, Fehrenbach E, Strobel G, Roecker K, Schneider EM, Buergler J, et al.Evaluation of stress responses to interval training at low and moderate alti-tudes. Medicine and Science in Sports and Exercise 2003;35:263–9.

[68] Nguyen TT, Lazure C, Babinski K, Chretien M, Ong H, De Lean A. Aldosteronesecretion inhibitory factor: a novel neuropeptide in bovine chromaffin cells.Endocrinology 1989;124(3):1591–3.

[69] Ohba H, Takada H, Musha H, Nagashima J, Mori N, Awaya T, et al. Effectsof prolonged strenous exercise on plasma levels of atrial natriuretic pep-tide and brain natriuretic peptide in healthy men. American Heart Journal2001;141:751–8.

[70] Pagourelias ED, Giannoglou D, Kouidi E, Efthimiadis GK, Zorou P, Tzioma-los K, et al. Brain natriuretic peptide and the athlete’s heart: a pilot study.International Journal of Clinical Practice 2010;64(4):511–7.

[71] Pluim BM, Zwinderman AH, van der Laarse A, van der Wall E. The ath-lete’s heart. A meta-analysis of cardiac structure and function. Circulation2000;101(3):336–44.

[72] Pompili M, Serafini G, Innamorati M, Möller-Leimkühler AM, GiupponiG, Girardi P, et al. The hypothalamic–pituitary–adrenal axis and sero-tonin abnormalities: a selective overview for the implications of suicideprevention. European Archives of Psychiatry and Clinical Neuroscience2010;260(8):583–600.

[73] Popovic D, Ostojic MC, Petrovic M, Vujisic-Tesic B, Popovic B, Nedeljkovic I,et al. Assessment of the left ventricular chamber stiffness in athletes. Echocar-diography 2011;28(3):276–87.

[74] Popovic D, Ostojic MC, Popovic B, Petrovic M, Vujisic-Tesic B, Kocijancic A,et al. Brain natriuretic peptide predicts forced vital capacity of the lungs, oxy-gen pulse and peak oxygen consumption in physiological condition. Peptides2013;43C:32–9.

[75] Portzionato A, Macchi V, Rucinski V, Malendowicz LK, De Caro R. Natriureticpeptides in the regulation of the hypothalamic–pituitary–adrenal axis. Inter-national Review of Cell & Molecular Biology 2010;280:1–39.

[76] Prpic-Krizevac I, Canecki-Varzic S, Bilic-Curcic I. Hyperactivity of thehypothalamic–pituitary–adrenal axis in patients with type 2 diabetes andrelations with insulin resistance and chronic complications. Wiener KlinischeWochenschrift 2012;124(11/12):403–11.

[77] Puterman E, O’Donovan A, Adler NE, Tomiyama AJ, Kemeny M, WolkowitzOM, et al. Physical activity moderates effects of stressor-induced ruminationon cortisol reactivity. Psychosomatic Medicine 2011;73(7):604–11.

[78] Raastad T, Bjoro T, Hallen J. Hormonal responses to high and moderate-intensity strength exercise. European Journal of Applied Physiology2000;82(2):121–8.

[79] Raastad T, Glomsheller T, Bjoro T, Hallén J. Changes in human skeletal musclecontractility and hormone status during two weeks of heavy strength training.European Journal of Applied Physiology 2001;84(1/2):54–63.

[80] Rimmele U, Zellweger BC, Marti B, Seiler R, Mohiyeddini C, Ehlert U, HeinrichsM. Trained men show lower cortisol, heart rate and psychological responses topsychosocial stress compared with untrained men. Psychoneuroendocrinol-ogy 2007;32(6):627–35.

[81] Roth D, Holmes D. Influence of physical fitness in determining the impactof stressful life events on physical and psychologic health. PsychosomaticMedicine 1985;47(2):164–73.

[82] Salustri A, Cerquetani E, Piccoli M, Pastena G, Amici E, La Carrubba S,et al. B-type natriuretic peptide levels predict functional capacity in post-cardiac surgery patients. Journal of Cardiovascular Medicine (Hagerstown)2011;12(3):167–72.

[83] Schmid B, Buchmann AF, Trautmann-Villalba P, Blomeyer D, Zimmer-mann US, Schmidt MH, et al. Maternal stimulation in infancy predictshypothalamic–pituitary–adrenal axis reactivity in young men. Journal of Neu-ral Transmission 2013 [Epub ahead of print].

[84] Schwarz L, Kindermann W. �-Endorphin, adrenocorticotropic hormone, cor-tizol and catecholamines during aerobic and anaerobic exercise. EuropeanJournal of Applied Physiology 1990;61(3/4):165–71.

[85] Sharma S. Athlete’s heart – effect of age, sex, ethnicity and sporting discipline.Exp Physiol 2003;88(5):665–9.

[86] Silverman HG, Mazzeo RS. Hormonal responses to maximal and submax-imal exercise in trained and untrained man of various ages. Journals ofGerontology Series A, Biological Sciences and Medical Sciences 1996;51(1):B30–7.

[87] Skoluda N, Dettenborn L, Stalder T, Kirschbaum C. Elevated hair cor-tisol concentrations in endurance athletes. Psychoneuroendocrinology2012;37(5):611–7.

[88] Smart NA, Meyer T, Butterfield JA, Faddy SC, Passino C, Malfatto G, et al. Indi-vidual patient meta-analysis of exercise training effects on systemic brainnatriuretic peptide expression in heart failure. European Journal of PreventiveCardiology 2012;19(3):428–35.

[89] Spirito P, Pelliccia A, Proschan M, Granata M, Spataro A, Bellone P,et al. Morphology of the athletes heart assessed by echocardiography in947 elite athletes representing 27 sports. American Journal of Cardiology1994;74:802–6.

[90] Springer J, Azer J, Hua R, Robbins C, Adamczyk A, McBoyle S, et al. The natri-uretic peptides BNP and CNP increase heart rate and electrical conductionby stimulating ionic currents in the sinoatrial node and atrial myocardiumfollowing activation of guanil cyclase-linked natriuretic peptide receptors.Journal of Molecular and Cellular Cardiology 2012;52(5):1122–34.

[91] Steele IC, McDowel G, Moore A, Campbell NP, Shaw C, Buchanan KD, et al.Responses of atrial natriuretic peptide and brain natriuretic peptide to exer-cise in patients with chronic heart failure and control subjects. EuropeanJournal of Clinical Investigation 1997;27:270–6.

[92] Suay F, Salvador A, Gonzalez-Bono E, Sanchís C, Martínez M, Martínez-SanchisS, et al. Effects of competition and its outcome on serum testosterone, cortisoland prolactin. Psychoneuroendocrinology 1999;24:551–66.

[93] Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide inporcine brain. Nature 1988;332:78–81.

[94] Tanaka M, Ishizuka Y, Ishiyama Y, Kato J, Kida O, Kitamura K, et al. Exercise-induced secretion of brain natriuretic peptide in essential hypertension andnormal subjects. Hypertension Research 1995;18:159–66.

[95] Teschemacher H. Proopiomelanocortin What role does this ACTH andendorphin precursor play in stress adaptation? Internistische Praxis2003;43:605–15.

[96] Tripp KM, Verstegen JP, Deutsch CJ, Bonde RK, de Wit M, Manire CA, et al.Evaluation of adrenocortical function in Florida manatees (Trichechus manatuslatirostris). Zoo Biology 2011;30(1):17–31.

[97] Troughton RW, Prior DL, Pereira JJ, Martin M, Fogarty A, Morehead A, et al.Plasma B-type natriuretic peptide levels in systolic heart failure. Journal ofthe American College of Cardiology 2004;43:416–22.

[98] VanBruggen MD, Hackney AC, McMurray RG, Ondrak KS. The relationshipbetween serum and salivary cortisol levels in response to different intensi-ties of exercise. International Journal of Sports Physiology and Performance2011;6(3):396–407.

[99] van Reedt Dortland AK, Vreeburg SA, Giltay EJ, Licht CM, Vogelzangs N,van Veen T, et al. The impact of stress systems and lifestyle on dysli-pidemia and obesity in anxiety and depression. Psychoneuroendocrinology2013;38(2):209–18.

[100] Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG.Differentiation between pathologic and physiologic left ventricular hyper-trophy by tissue Doppler assessment of long axis function in patients withhypertrophic cardiomyopathy or systemic hypertension and in athletes.American Journal of Cardiology 2001;88:53–8.

[101] Wang J, Zhao D, Li J, Wang G, Hu L, Shao J, et al. The impact of water-floatingand high-intensity exercise on rat’s HPA axis and interleukins concentrations.Acta Physiologica Hungarica 2012;99(3):261–70.

[102] Weiser MJ, Osterlund C, Spencer RL. Inhibitory effects of corticosterone in thehypothalamic paraventricular nucleus (PVN) on stress-induced adrenocorti-cotrophic hormone secretion and gene expression in the PVN and anteriorpituitary. Journal of Neuroendocrinology 2011;23(12):1231–40.

[103] Weisman IM, Beck KC, Casaburi R, Cotes JE, Crapo RO, Dempsey JA, et al.ATS/ACCP statement on cardiopulmonary exercise testing. American Journalof Respiratory and Critical Care Medicine 2003;167:211–77.

[104] Wittert GA, Livesey JH, Espiner EA, Donald RA. Adaptation of the hypothala-mopituitary adrenal axis to chronic exercise stress in humans. Medicine andScience in Sports and Exercise 1996;28:1015–9.

[105] Wolk R, Johnson BD, Somers VK. Leptin and the ventilatory reponse toexercise in heart failure. Journal of the American College of Cardiology2003;42(9):1644–9.

[106] Yamazaki H, Senju Y, Kinoshita N, Katsukawa F, Onishi S. Plasma brain natri-uretic peptide in athletes. American Journal of Cardiology 2000;85:1393–4.

The Peptides

Documents