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dOI 10.11603/IJMMR.2413-6077.2019.2.10902

GENDER-SpECIFIC DIFFERENCES OF CARDIAC VEGETATIVE CONTROL 
IN ADRENALINE-INDUCED NECROSIS AND LIGHT DEpRIVATION 

H.O. Bezkorovaina, I.M. Klishch, *M.R. Khara, V.Ye. Pelykh
I. HORBACHEVSKY TERNOPIL NATIONAL MEDICAL UNIVERSITY, TERNOPIL, UKRAINE

Background. Cardiovascular disease is the main cause of morbidity predominantly in males. Stress is one 
of the crucial factors, especially with light desynchronosis. 

Objective of the study was to assess gender-specific characteristics of cardiac vegetative control in myocardial 
necrosis in cases of light deprivation. 

Methods. Cardiac vegetative control in adrenaline-induced myocardial necrosis (AIMN) in a setting of light 
deprivation (LD) was assessed in 72 mature white rats of both sexes. The animals were divided into 2 groups: 
G1 – the animals kept under day/night cyclic balance (12 hours/12 hours); G2 – the animals kept at LD (illumination 
0.5-1 LX) for 10 days. On Day 11, AIMN caused by adrenaline (0.5 mg/kg) and heart rate variability (HRV) was 
assessed in 1 hour and 24 hours.

Results. The development of AIMN at LD in the ♂G2 led to HRV increase that was caused by augmentation 
of parasympathetic and reduction of sympathetic cardiac effects. In cases of AIMN, changes of CVC in the ♀G2 
were similar to the ♀G1. However, in 1 hour of AIMN, parasympathetic cardiac effects were more significant than 
in the ♀G1. While the ♀G2 AIMN animals experienced balanced sympathetic and parasympathetic actions, the 
predominance of the sympathetic component was evidenced in the ♀G1 AIMN animals. 

Conclusions. Light deprivation has different effects on baseline sympathetic/parasympathetic balance in 
males and females, i.e. increased parasympathetic control of heart rhythm in males and maintenance of 
sympathetic/ parasympathetic balance in females. 

KEY WORDS: myocardial necrosis; heart rhythm variability; light deprivation; gender.

*Corresponding author: Khara Mariya, MD, Ph.D., DSc, Profes-
sor of the Department of Pathophysiology, I. Horbachevsky 
Ternopil National Medical University, Ternopil, Ukraine.
E-mail: khara@tdmu.edu.ua

Introduction
According to the WHO data, cardiovascular 

disease is the most frequent cause of death in 
the European population; moreover, it has 
frequent severe sequelae, leads to disability 
and reduces the quality of life. Ukraine is on the 
list of countries in Eastern Europe, where 
coronary artery disease (CAD) mortality in 
people of 55-60 years of age is higher than that 
in French subjects 20 years senior [1]. The 
leading causes of increased mortality include 
ageing population and lifestyle factors, espe-
cially smoking and suffering from overweight 
[2]. Males are more frequently affected by 
coronary artery disease than females. This 
difference, however, is found in the middle-
aged persons. At menopause, the number of 
females in the population with coronary epi so-
des and myocardial infarction increases greatly. 
This might be associated with deficiency of 
oestrogens and their diminished cardiopro-
tective and vasoprotective activity [3]. 

Important risk factors of myocardial ne-
crosis include impaired circadian rhythms and 
functional disorders of the pineal gland [4, 5]. 
This is related to professional activity, sleep 
disorders and difficulty falling asleep [6, 7]. 
Similar to all other systems in the body, the 
cardiovascular system is controlled by the 
pineal gland. Its activity changes depending on 
the phase of the circadian cycle (light/darkness), 
as suggested by fluctuations in blood pressure 
and heart rhythm variability [5, 8]. However, the 
effects of melatonin synthesised by the pineal 
gland vary in males and females that is asso-
ciated not only with the ability of this hormone 
to regulate the synthesis of sex hormones [4, 
9, 10], but also to its capability to change the 
activity of sympathetic and parasympathetic 
components of the autonomic nervous system 
(ANS) [11, 12]. Murine experiments have de-
monstrated different ANS responses to mela-
tonin in males and females [11]. A higher basal 
tone of the parasympathetic component in 
female ANS contributes to a better cardio-
protective effect of melatonin when adrenaline-
induced myocardial necrosis is modelled in a 

International Journal of Medicine and Medical Research 
2019, Volume 5, Issue 2, p. 137-144
copyright © 2019, TNMU, All Rights Reserved

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setting of melatonin [13]. A similar trend was 
found in humans. Analysis of ANS status (as 
reported by a 24-hour monitoring of heart 
rhythm variability) suggests reduced parasym-
pathetic tone and increased sympathetic 
activity as predictors of fatal arrhythmias and 
sudden death in subjects with myocardial 
infarction [14]. The benefits of heart rhythm 
variability analysis and its diagnostic and 
prognostic value are beyond doubt. The use of 
this method allows assessment of cardiac 
vegetative control in a study of pathogenetic 
role of light desynchronosis as a contributor to 
myocardial necrosis. However, the available 
data do not provide a full understanding of the 
role of ANS in adaptation of heterosexual orga-
nisms to abnormal light conditions, including 
the development of cardiac disease under these 
conditions. 

The objective of the study was to assess 
gender­specific characteristics of cardiac vege­
tative control in adrenaline-induced myocardial 
necrosis in rats in cases of light deprivation.

Methods
The experiments were conducted according 

to ethical guidelines approved by the European 
Convention for the Protection of Vertebrate 
Animals Used for Experimental and Other 
Scientific Purposes (Strasbourg, 1986), reso­
lution of the First National Congress on Bio-
ethics (Kyiv, 2001) and the Order of the Ministry 
of Health of Ukraine No. 690, dated September 
23, 2009. The tests were performed on 72 non-
linear male and female white rats (body weight: 
220­270 g; age: 5­5.5 months). The rats were 
provided with a standard laboratory pellet diet 
and water and were housed in plastic cages at 
constant ambient temperature and humidity. 
The rats of the control group (group 1, 18♂, 
18♀) were kept under a natural day/night cycle 
(light 12 hours, 500 LX/night 12 hours, 0.5-1 LX). 
The rats of the experimental group (group 2, 
18♂, 18♀) were kept in permanent darkness 
(0.5-1 LX) for 10 days. Necrosis of myocardium 
was modelled by administration of adrenaline 
(intramuscular, 0.5 mg/kg of body weight) on 
day 11. In 1 and 24 hours after adrenaline 
administration, EKG was captured (2 standard 
leads) using a Cardiolab-CE computer-based 
complex (Kharkiv, Ukraine). The durations of 
1000 consecutive cardiac R-R intervals accurate 
to 0.001 second were assessed. In order to 
evaluate the regulatory activity of sympathetic 
and parasympathetic ANS components on the 
heart rhythm, the following parameters were 

registereg: Mo (sec) = mode, i.e. the most 
frequently captured duration of the R­R interval; 
AMo (%) = the amplitude of mode, i.e. the 
percentage of cardiac intervals meeting the Mo 
value; ∆X (sec) = the difference between the 
largest and the smallest R­R value; HSI (abs. 
value) = heart strain index reflecting the degree 
of centralisation of heart rhythm control, this 
parameter is obtained from the following 
expression: HSI=AMo/(2·∆X·Mo); VBI (abs. 
value) = vegetative balance index reflecting the 
ratio between the activities of the sympathetic 
and parasympathetic nervous system, this 
parameter is obtained from the following 
expression: VBI=AMo/∆X; VRI (abs. value) = 
vegetative rhythm index reflecting the activity 
of the autonomic circuit of heart rhythm 
control, this parameter is obtained from the 
following expression: VRI =1/Mo·∆X, and IARP 
(abs. value) = index of adequate regulation 
processes reflecting the balance between the 
activity of the sympathetic component of the 
autonomic nervous system and the predominant 
functional level of the sinus node. By matching 
against heart rhythm (HR), this parameter 
allows judgment on excessive or insufficient 
centralisation of heart rhythm control; this 
parameter is obtained from the following 
expression: IARP=AMo/Mo. 

Statistical analysis of the results was 
performed using parametric method of varia-
tion statistics based on established normal 
distribution of data in the rows compared, with 
n=6 in each of the rows. The following para-
meters were determined by the arithmetic 
mean (M), standard deviation (ō) and Student’s 
t-test (t). The difference between the arithmetic 
means was statistically significant at t value not 
less than 2.228 (p≤0.05). Microsoft Excel XP 
(BioStat Pro 6.7.1.0) software (US) was used for 
calculations. 

Results
The results attained in the animals of the 

control group (Group 1), which were under 
c o n   d i t i o n s  o f  b a l a n c e d  l i g h t / d a r k n e s s 
(12 hours/12 hours), are presented in Table 1. 

The development of adrenaline-induced 
myo cardial necrosis within 1 hour after adre-
naline administration was found to cause a 
significant increase in HR (by 12.5% in the ♂, 
by 13% in the ♀, p<0.05). This process was 
accompanied by a predictable reduction in Mo 
values (by 12% in the ♂, by 13% in the ♀). AMo 
values were increased in the ♂ (by 87%, p<0.05) 
and the ♀ animals by (34%, p<0.05). The ΔX 

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values significantly decreased in the animals of 
either sex (by 97% in the ♂, by 67% in the ♀, 
p<0.05). HSI, which is an integral parameter, 
increased in the animals of either sex (a 3.7-fold 
increase in the ♂, a 2.4-fold increase in the ♀, 
p<0.05). Such changes reflected the increased 
role of the sympathetic ANS component and 
the reduced influence of the parasympathetic 
component in heart rhythm control. These 
findings were confirmed by increases in VBI (a 
3.3-fold increase in the ♂, a 2.1-fold increase in 
the ♀, p<0.05), VRI (a 2.0-fold increase in the 
♂, a 1.8-fold increase in the ♀, p<0.05) and IARP 
(a 2.1-fold increase in the ♂, a 1.5-fold increase 
in the ♀, p<0.05).

In 24 hours after adrenaline administration 
(i.e. the peak of focal necrosis), the type of ANS 
response to development of the abnormal 
process changed somewhat. In the ♂ animals, 
the findings of HR, Mo, ΔX, VBI and VRI 
recovered to the control levels, AMo decreased 
(by 35%, p<0.05), while IARP were above control 
values (by 43%, p<0.05). In the ♀ rats, HR was 
higher (by 10%, p<0.05) and Mo was lower (by 
10%, p<0.05). The following parameters were 
higher than the respective control values: AMo 
(by 38%, p<0.05), HSI (by 78%, p<0.05), VBI (by 
61%, p<0.05), VRI (by 45%, p<0.05) and IARP (by 
34%, p<0.05). 

Gender­specific analysis showed Mo in the 
Group 1 lower in the ♂ than in the ♀ (by 8%, 

p<0.05). In 1 hour of necrotic process develop-
ment, Mo was lower than in the ♀ (7%, p<0.05), 
AMo was higher (by 31%, p<0.05) and IARP was 
also higher (by 40%, p<0.05). In 24 hours after 
adrenaline administration, the ΔX in the ♂ was 
higher than in the ♀ (by 45%, p<0.05) and HSI, 
VBI and VRI were lower (by 37%, 41% and 45%, 
p<0.05, respectively), reflecting gender­specific 
differences of cardiac adjustment mechanisms 
in cases of ANS-mediated damage.

Analysis of parameters in the animals of the 
experimental group (Group 2) that were kept 
in permanent darkness for 10 days (light 
deprivation) showed that in 1 hour of myocardial 
necrosis development, ♂ animals had lower HR 
(by 9%, p<0.05), higher Mo (by 9%, p<0.05) and 
lower ΔX (by 23%, p<0.05) (Table 2). As for other 
parameters, no significant changes were evi­
denced. When the ♀ animals were exposed to 
identical conditions, HR increased (by 6%, 
p<0.05), while Mo and ΔX decreased (by 6% and 
29%, respectively, p<0.05). Under these con-
ditions, the increase in HSI, VBI and VBI were 
quite predictable (by 65%, 55% and 40%, respec-
tively, p<0.05). IARP values did not change.

In 24 hours after adrenaline administration, 
the ♂ HR was lower than in the controls (by 16%, 
p<0.05), Mo was higher (by 16%, p<0.05) and 
IARP was lower (by 34%, p<0.05). In the ♀ at 
this phase of myocardial necrosis, HR was 
higher (by 6%, p<0.05), Mo was lower (by 6%, 

Table 1. Parameters of heart rhythm variability in the rats developing adrenaline-induced 
myocardial necrosis under the intact day/night cycle (12 hours/12 hours), M±ō

Parameter Gender Controls(n=6)
1 h post-adrenaline

(n=6)
24 h post-adrenaline

(n=6)
HR ♂ 472±21# 531±17* 491±29

♀ 438±19# 496±27* 481±12*
Mo (sec) ♂ 0.127±0.006# 0.113±0.002*# 0.122±0.007

♀ 0.137±0.006 # 0.121±0.007*# 0.125±0.003*
AMo (%) ♂ 31.7±3.8 59.2±5.8# 43.7±7.5*

♀ 33.8±4.5 45.2±5.0*# 41.2±3.1*
ΔX (sec·10-2) ♂ 0.65±0.22 0.35±0.08* 0.58±0.04#

♀ 0.55±0.14 0.33±0.05* 0.40±0.06*#
HSI (abs. value) ♂ 21621±9813 79493±23420* 30953±6342#

♀ 23875±7223 57384±10855* 42514±9872*#
VBI (abs. value) ♂ 5425±2245 17873±4936* 7527±1391#

♀ 6578±2211 13783±2142* 10598±2484*#
VRI (abs. value) ♂ 1333±470 2716±935* 1418±190#

♀ 1419±442 2537±419* 2051±347*#
IARP (abs. value) ♂ 0.250±0.040 0.525±0.058*# 0.358±0.061*

♀ 0.247±0.038 0.375±0.056*# 0.330±0.024*
Note: * – a statistically significant (p≤0.05) differences relative to the controls, # – relative to the animals of the opposite sex.



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p<0.05), HSI and VBI were higher (by 70%, 62%, 
p<0.05), and AMo, ΔX, VRI and IARP did not 
differ from the respective baseline values in this 
group. 

Gender­specific analysis showed that HR 
and IARP in the control group was higher in the 
♂ than in the ♀ (by 18%, 37%, p<0.05); the Mo 
values were lower (by 18%, p<0.05). There were 
no differences between the animals in terms of 
other parameters. In 1 hour of myocardial 
necrosis, ΔX in the ♂ was higher than in the ♀ 
(by 27%, p<0.05); HSI, VBI and IARP were lower 
(by 38%, 40% and 10%, p<0.05). In 24 hours of 
myocardial necrosis, ΔX ♂ was significantly 
higher (by 50%, p<0.05), and HSI, VBI and VRI 
were lower (in 2.1 times, 2.0 times and 1.7-times, 
respectively, p<0.05).

In terms of ANS responses, effects of light 
deprivation in development of myocardial 
necrosis have shown that staying in darkness 
for 10 days had different influences on vegeta­
tive control of heart rhythm in male and female 
animals. In ♂, HR increased by 8.5% (p<0.05), 
Mo decreased by 85% (p<0.05). Other parame-
ters remained unchanged and were not statis-
tically different from those in animals of Group 1. 
In the ♀ cohort, light deprivation did not cause 
any changes in investigational para meters. 

Under conditions of a necrotic process (1 
and 24 hours after administration of adrenaline), 
HR ♂ was lower than the respective values in 

Group 1 (13% and 11%, respectively, p<0.05); in 
the meantime, Mo was higher (13% and 11%, 
respectively, p<0.05), AMo was lower (73% and 
32%, respectively, p<0.05) and ΔX was higher 
(63% and 29%, respectively p<0.05). All integral 
parameters were significantly lower than 
comparative ones; in part, this was true of HSI 
(in 3.3 times and 1.9 times, p<0.05), VBI (in 2.9 
times and 1.7 times, p<0.05), VRI (in 1.9times 
and 1.4times, p<0.05) and IARP (in 2.0 times and 
1.5 times, p<0.05). The differences between 
Group 1 and Group 2 in the females in 1 hour 
after adrenaline administration were for HR (by 
7% lower, p<0.05), Mo (by 7% higher, p<0.05) 
and ΔX (36% higher, p<0.05); the values of HSI, 
VBI and VRI were lower (in1.7 times, 1.6 times 
and 1.4 times, respectively, p<0.05). In 24 hours 
after adrenaline administration, no significant 
differences were evidenced regarding the 
parameters.

Discussion 
Analysis of heart rhythm variability is per-

formed by a non-invasive method of functional 
diagnostics, which is used not only in a clinical 
setting, but also in experimental studies. It 
allows assessing of cardioregulatory ANS 
activity, determining the balance between 
activities of sympathetic and parasympathetic 
components as they affect the heart rhythm, 
making a conclusion about the predominant 

Table 2. Parameters of heart rhythm variability in the rats with developing adrenaline-induced 
myocardial necrosis in cases of light deprivation, (M±ō)

Parameter Gender Controls (n=6)
1 hours post-adrenaline

(n=6)
24 hours post-adrenaline 

(n=6)
HR ♂ 512±14^# 469±21*^ 443±29*^

♀ 435±11# 463±11*^ 461±22*
Mo (sec) ♂ 0.117±0.003^# 0.128±0.006*^ 0.136±0.009*^

♀ 0.138±0.003# 0.130±0.003*^ 0.130±0.006*
AMo (%) ♂ 38.3±7.8^ 34.3±3.7^ 33.0±2.7^ 

♀ 32.7±4.4 38.3±5.2 40.5±11.6
ΔX (sec·10-2) ♂ 0.70±0.13 0.57±0.08*^# 0.75±0.08^#

♀ 0.58±0.04 0.45±0.08*^# 0.50±0.14#
HSI (abs. value) ♂ 24730±9622 24464±6557^# 16398±2345^#

♀ 20535±3552 33835±7738*^# 34836±17417*#
VBI (abs. value) ♂ 5672±2123 6223±1446^# 4458±846^#

♀ 5642±939 8732±1891*^# 9118±4656*#
VRI (abs. value) ♂ 1257±234 1405±244^ 996±118^#

♀ 1256±90  1762±299*^ 1657±517#
IARP (abs. value) ♂ 0.326±0.060# 0.268±0.039^# 0.243±0.010*^

♀ 0.238±0.036# 0.296±0.043# 0.309±0.078
Note: * – statistically significant (p≤0.05) differences relative to the controls, ^ – relative to the findings in the group 1 animals 
during the same observation period, # – relative to the animals of the opposite sex.

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component, and assessing the stress upon 
regulatory systems as part of adjustment to 
adverse influences [15]. Analysis of histograms 
reflecting the distribution of RR intervals (va­
riational pulsography) was used in the study. 
Assessment of the results involved use of a 
cybernetic double-circuit model for heart 
rhythm regulation as suggested by R.M. Bayev-
sky: the central circuit (cerebral cortex, higher 
autonomic centres and the cardiovascular 
centre) and the autonomic circuit (sinus node, 
lungs and the respiratory centre) [16]. The 
patterns of changes in experimental findings 
with time allowed drawing a conclusion that 
significant difference in ANS effects on the 
heart rhythm occurred between male and 
female animals. In males, development of 
adrenaline-induced myocardial necrosis under 
normal day/night balance was accompanied by 
an increased impact of sympathetic ANS com-
ponent, as evidenced by increased levels of HSI, 
VBI, VRI and IARP. A more significant increase 
in test parameters in 1 hour of the experiment 
was predictable due to a presence of hyper-
catecholaminemia caused by administration of 
adrenaline. The effects of adrenaline were not 
limited to the sinus node, but also extended to 
myocardial contractility. This was also true 
regarding its metabolite, adrenochrome [17]. 
The amount of adrenochrome increased 
significantly under our experiment as a result 
of catabolism and an active part of myocardial 
damage through stimulation of free radical 
processes [18]. Under the circumstances, ANS 
response to hypercatecholaminemia-induced 
oxidative stress was also a matter of discussion. 
This was confirmed by ipsidirectional but less 
significant changes in ANS responses in the 
females. In this model, the severity of myocardial 
damage was substantially lower in the females 
[19]. In this case, the increase in AMo reflected 
strengthening of the central circuit of heart 
rhythm regulation, and the decrease in ΔX 
reflected the reduced involvement of the 
autonomic circuit, i.e. the role of the vagus 
nerve. This data is consistent with the literature 
on using a model with adrenaline-induced 
myocardial necrosis. It was established that not 
only hypercatecholaminemia, but also sex 
hormones were crucial in the capacity of ANS 
to develop other adaptive effects [20, 21]. In 24 
hours after adrenaline administration, the 
primary effects of adrenaline diminished 
according to the pattern described. In the 
males, all of the parameters were normal again, 
which was proved by a recovery of the baseline 

balance between ANS components. In the 
females, all pulsographic parameters demons-
trated retention of increased sympathetic 
activity, which was the principal difference 
between the males and females. 

The males of Group 2 responded to a 10-day 
stay in darkness with increased HR and with an 
accordingly reduced Mo. This reflected the state 
of stress and the increased involvement of 
humoral adaptive mechanisms, which were 
implemented by the adrenal glands [22]. The 
maintenance of regulatory balance under such 
conditions was attained at the expense of 
reduced activity of the central regulatory circuit, 
as confirmed by a reduction in AMo. Therefore, 
adjustment of the males in Group 2 to per-
manent darkness caused a moderate activation 
of sympathetic cardiac effects. In such a 
situation, myocardial necrosis developed under 
activation of the parasympathetic component 
and predominance of the latter in heart rhythm 
control. This was confirmed by higher (compare 
to the Group 1 animals) ΔX values and by lower 
values of HSI, VRI, VBI and IARP. Lower AMo 
values have demonstrated that the predo mi-
nance of parasympathetic ANS component was 
also facilitated by the reduced activity of 
sympathetic ANS component. 

A 10-day stay of the Group 2 females under 
conditions of permanent darkness did not 
cause any functional changes in the ANS, as 
confirmed by the absence of significant dif­
ferences in all parameters in the Group 1 and 
Group 2 females. In 1 hour after administration 
of adrenaline, HR increased and Mo decreased 
in the females of Group 2, which reflected an 
increase in adrenergic effects of ANS in the 
heart, with the effects implemented through 
the humoral channel (mainly the adrenal 
glands). The reduction in ΔX suggested a de­
crease in vagal cardiac effects. As a natural 
result, HSI, VBI and VRI values increased. The 
constancy of IARP reflected a preserved balance 
between the central and the autonomic circuits 
of heart rhythm control. In 24 hours after ad-
renaline administration, HR was still in creased, 
and Mo was lower than in the controls of this 
group. To a greater degree than in the controls, 
the HSI and VBI values demonstrated a pred-
ominance of sympathetic ANS effects in heart 
rhythm control, but the stability of IARP 
suggested a preserved balance between the 
activities of the central and the autonomic 
control circuits. It is important that under 
developing myocardial necrosis, the changes 
of parameters with time were similar to those 



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in the Group 1, although less significant. In 
particular, Mo was higher in the Group 2 
females compare to those of Group 1, which 
suggested a less active involvement of adrenal 
glands under the simulated conditions [22]. In 
this case, there was no involvement of the 
central control circuit, as confirmed by the ab­
sence of significant AMo changes. This de-
monstrated a lack of response of cerebral 
cortex to hyperadrenalinemia. Despite the 
increases in HSI, VBI and VRI values in 1 hour 
of myocardial necrosis (which reflected a phase 
of hyperadrenalinemia), these values were 
significantly lower than in the Group 1 females. 
To a degree greater than in the Group 1 
animals, the ΔX value reflected a more active 
involvement of parasympathetic mechanisms 
in cardiac adjustment to damage, which main-
tained a stable IARP and preserved a baseline 
balance between central and autonomic control 
circuits, unlike the Group 1 females, where the 
control balance shifted towards predominance 
of sympathetic ANS activity. 

The development of necrotic process in the 
myocardium of the Group 2 males was accom-
panied by activation of cholinergic mechanisms 
of cardiac control, which was more significant 
than in the females. This proved that the males 
and females employed different mechanisms 
of adjustment to adverse effects of adrenaline 
under light deprivation. These differences may 
be associated with different levels of melatonin 
synthesis by the pineal gland under conditions 
of permanent darkness [9, 23]. The females 
synthesises more melatonin at night-time [10] 
and their melatonin synthesis during sleep 
peaked sooner than in the males [24]. Consi-
dering that all animals in the experiment were 
under identical conditions, higher melatonin 
levels in the females could be asserted. Howe-
ver, a clearer understanding of the significance 
of endogenous melatonin within a framework 
of adaptive responses with ANS involvement in 
modelling of adrenaline-induced myocardial 

necrosis might yield the results attained in 
modelling of cardiac disease under permanent 
lighting, which was the prospect of the research. 
In summary, it should be noted that the 
attained data have proved that the males and 
females have different ANS responses to 
developing adrenaline-induced myocardial 
necrosis under light deprivation that suggests 
the necessity to specify the gender of animals 
in the conclusions and the incorrectness of 
extrapolating the established patterns to 
animals of other sex.

Conclusions
A 10-day light deprivation activates the 

heart rhythm impact of the sympathetic 
component of ANS in the male rats and does 
not alter the baseline balance of sympathetic 
and parasympathetic components of ANS in the 
females. The development of adrenaline-
induced myocardial necrosis under 10-day light 
deprivation is characterised by a higher 
(compared today/night cycle) involvement of 
the parasympathetic ANS component in heart 
rhythm control in the males and by development 
of bradycardia. In the females, light deprivation 
facilitates the maintenance of sympathetic/
parasympathetic balance in cases of adrenaline-
induced myocardial necrosis. This differs from 
the females under the day-night cycle, where 
an increase in the sympathetic component of 
the ANS was evidenced in cases of developing 
myocardial necrosis. 

Funding
This research received no external funding.
Conflict of Interests
The authors declare no conflict of interest.
Authors Contributions 
Bezkorovaina H.O. – conceptualization, for-

mal analysis, investigation, methodology, vi-
sualization, writing – original draft; Klishch I.M. – 
conceptualization, supervision, resources; 
Khara M.R. – formal analysis, investigation, 
methodology; Pelykh V.Ye. – investigation.

статеВа ВідмінністЬ ВегетатиВноЇ регуляціЇ серця ЩуріВ при 
адреналін-індукоВаному некрозі на тлі сВітлоВоЇ деприВаціЇ

Г.О. Безкоровайна, І.М. Кліщ, М.Р. Хара, В.Є. Пелих
ТЕРНОПІЛЬСЬКИЙ НАЦІОНАЛЬНИЙ МЕДИЧНИЙ УНІВЕРСИТЕТ ІМЕНІ І.Я. ГОРБАЧЕВСЬКОГО,  

ТЕРНОПІЛЬ, УКРАЇНА

Bступ. Серцево-судинні захворювання є головною причиною захворюваності у світі. У когорті 
хворих на ішемічну хворобу серця переважають чоловіки. Серед факторів ризику головним залишається 
стрес, в тому ж числі на ґрунті світлового десинхронозу. 

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Мета дослідження. Вивчити гендерні особливості вегетативної регуляції серця при адреналін-
індукованому некрозі міокарда в щурів на тлі світлової деривації. 

Методи дослідження. У 72 білих статевозрілих самців і самиць щурів досліджували варіабельність 
серцевого ритму (ВСР) при адреналін-індукованому некрозі міокарда (АНМ) на тлі світлової депривації 
(СД). Тварин поділили на 2 групи: Г1 – тварини були в умовах циклу день/ніч (12 год/12 год); та Г2 – щури 
перебували 10 днів в умовах світлової депривації (СД). На 11-й день моделювали АНМ (адреналін в/м, 
0.5 мг/кг) і ВСР вивчали через 1 та 24 год.

Результати. Розвиток АНМ у ♂Г1 і ♀Г1 викликав зменшення варіабельності серцевого ритму (ВСР), 
посилення симпатичних впливів на серце, що було суттєвішим в ♂. СД викликала посилення симпатичних 
впливів на серце в ♂Г2. Розвиток АНМ в ♂Г2 викликав суттєве збільшення ВСР та значне зменшення 
ЧСС. Це було результатом посилення парасимпатичних впливів на серце та зменшення симпатичних. 
У ♀Г2 в умовах АНМ динаміка показників ВСР була аналогічною до такої в ♀Г1. Проте, на 1 год АНМ 
активність парасимпатичних впливів на серце була більшою, ніж в ♀Г1. Якщо в ♀Г2 в умовах АНМ 
зберігався баланс між активністю симпатичної та парасимпатичної ланок, то в ♀Г1 в умовах АНМ 
переважала активність симпатичної ланки. 

Висновки. Світлова депривація посилює симпатичні впливи на ритм серця в самців щурів і не 
змінює вихідного балансу активності симпатичної та парасимпатичної ланок в самиць. Розвиток 
адреналін-індукованого некрозу міокарда на тлі світлової депривації характеризується більшою, ніж 
за збереженого балансу день/ніч, активністю парасимпатичної ланки в регуляції ритму серця самців 
та викликає розвиток брадикардії. У самиць світлова депривація сприяє підтриманню балансу між 
активністю симпатичної та парасимпатичної ланок в умовах адреналін-індукованого некрозу міокарда, 
на відміну від самиць, що перебували в умовах зміни циклу день/ніч і демонстрували посилення 
активності симпатичної ланки АНС при розвитку некрозу міокарда. 

KЛЮЧОВІ СЛОВА: некроз міокарда; варіабельність серцевого ритму; світлова депривація, 
стать

Відомості про авторів 
Безкоровайна Галина Олександрівна – лікар, здобувач кафедри патологічної фізіології 

Тернопільського національного медичного університету імені І.Я Горбачевського.
Кліщ Іван Миколайович – доктор біологічних наук, професор кафедри функціональної і 

лабораторної діагностики Тернопільського національного медичного університету імені І.Я 
Горбачевського. 

Хара Марія Романівна – доктор медичних наук, професор кафедри патологічної фізіології 
Тернопільського національного медичного університету імені І.Я Горбачевськогою 

Пелих Володимир Євгенович – кандидат медичних наук, доцент кафедри патологічної фізіології 
Тернопільського національного медичного університету імені І.Я Горбачевськогою

Information about the authors 
Bezkorovaina H.O. – MD, Ph.D. Student, I. Horbachevsky Ternopil National Medical University, Ternopil, 

Ukraine. e­mail: 111ya111@ukr.net.
Klishch I.M. – MD, Ph.D., DSc, Professor, Functional and Clinical diagnostics Department, I. Horbachevsky 

Ternopil National Medical University, Ternopil, Ukraine. 
ORCID 0000­0001­6226­4296, e­mail: klishch@tdmu.edu.ua. 
Khara M.R. – MD, Ph.D., DSc, Professor, Pathophysiology Department, I. Horbachevsky Ternopil National 

Medical University, Ternopil, Ukraine. 
ORCID 0000­0002­6028­9876, e­mail: khara@tdmu.edu.ua
Pelykh V.Ye. – MD, PhD, Associate Professor of Pathophysiology Department, I. Horbachevsky Ternopil 

National Medical University, Ternopil, Ukraine. 
ORCID 0000­0003­3468­858X, e­mail: pelykh_ve@tdmu.edu.ua

References
1. Townsend N, Wilson L, Bhatnagar P, Wickra-

masinghe K, Rayner M, Nichols M. Cardiovascular 
disease in Europe: epidemiological update 2016. 
European Heart Journal. 2016 Aug 14;37(42):3232­45.

2. Roth GA, Forouzanfar MH, Moran AE, Barber R, 
Nguyen G, Feigin VL, Naghavi M, Mensah GA, Murray 
CJ. Demographic and epidemiologic drivers of global 

cardiovascular mortality. New England Journal of 
Medicine. 2015 Apr 2;372(14):1333­41. 

doi: 10.1056/NEJMoa1406656
3. EUGenMed, Cardiovascular Clinical Study 

Group, Regitz-Zagrosek V, Oertelt-Prigione S, 
Prescott E, Franconi F, Gerdts E, Foryst-Ludwig A, 
Maas AH, Kautzky-Willer A, Knappe-Wegner D. 



144

B
io

m
e

d
ic

a
l

 S
c

ie
n

c
e

S

iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2

Gender in cardiovascular diseases: impact on clinical 
manifestations, management, and outcomes. Euro-
pean Heart Journal. 2015 Nov 3;37(1):24­34.

doi: 10.1093/eurheartj/ehv598
4. Pyle WG, Martino TA. Circadian rhythms 

influence cardiovascular disease differently in males 
and females: role of sex and gender. Current Opinion 
in Physiology. 2018 Oct 1;5:30­7. 

doi:10.1016/j.cophys.2018.05.003
5. Reitz CJ, Martino TA. Disruption of circadian 

rhythms and sleep on critical illness and the impact 
on cardiovascular events. Current pharmaceutical 
design. 2015 Jul 1;21(24):3505­11.

6. Ariznavarreta C, Cardinali DP, Villanúa MA, 
Granados B, Martín M, Chiesa JJ, Golombek DA, and 
Tresguerres JA. Circadian rhythms in airline pilots 
submitted to long­haul transmeridian flights. Avia­
tion, Space, and Environmental Medicine. 2002;73(5): 
445­455. PMID: 12014603

7. Wulff K, Dijk DJ, Middleton B, Foster RG. Sleep 
and circadian rhythm disruption in schizophrenia. 
British Journal of Psychiatry.2012;200(4):308­16. 

doi: 10.1192/bjp.bp.111.096321
8. Molcan L, Sutovska H, Okuliarova M, Senko T, 

Krskova L, Zeman M. Dim light at night attenuates 
circadian rhythms in the cardiovascular system and 
suppresses melatonin in rats. Life Sci. 2019;231:116568. 

doi: 10.1016/j.lfs.2019.116568
9. Pandi-Perumal SR, Srinivasan V,  Maestroni GJM, 

Cardinali DP, Poeggeler B, Hardeland R. Melatonin. 
Nature’s most versatile biological signal? FEBS 
Journal. 2006;273(13):2813­38.

10. Gunn PJ, Middleton B, DaviesSK, Revell VL, 
Skene DJ. Sex differences in the circadian profiles of 
melatonin and cortisol in plasma and urine matrices 
under constant routine conditions. Chronobiol. Int. 
2016;33(1):39–50.

doi: 10.3109/07420528.2015.1112396
11. Khara MR, Shkumbatiuk OV. Sex aspects of 

melatonin involvement in the regulation of heart 
rhythm in adrenaline damage. Clinical and Experi-
mental Pathology. 2013; 46(4):126­129. [in Ukrainian]

12. Lin WL, Chen HR, Lo LW, Lai CT, Yamada S, 
Liu SH, Chou YH, Chen SA, Fu YC, Kuo TB. Sleep-
related changes in cardiovascular autonomic 
regulation in left coronary artery ligation rats: Neural 
mechanism facilitating arrhythmia after myocardial 
infarction. International Journal of Cardiology. 2016 
Dec 15;225:65­72.

doi: 10.1016/j.ijcard.2016.09.121 
13. Khara MR, Shkumbatiuk OV. Sex differences 

in metabolic changes in the myocardium in the 
development of a necrotic process against melatonin. 

Actual problems of transport medicine. 2014;36(2, 
p­II):47­52. [in Ukrainian]

14. Kolettis TM, Kontonika M, Lekkas P, Vlahos AP, 
Baltogiannis GG, Gatzoulis KA, Chrousos GP. Auto-
nomic responses during acute myocardial infarction 
in the rat model: implications for arrhythmogenesis. 
J Basic Clin Physiol Pharmacol. 2018;29(4):339­45. 

doi: 10.1515/jbcpp­2017­0202
15. Baevsky RM., Ivanov GG., Chireikin LV. Ana-

lysis of heart rhythm variability when using various 
electrocardiographic systems (guidelines) // Bulletin 
of Arrhythmology. 2001;24:65–87. [in Russian].

16. Buoy MZ, Taratukhin EO. Possibilities of the 
method of heart rhythm variability. Russian Journal 
of Cardiology. 2011;6(92):69­75. [in Russian]

17. Thandroyen FT, Opie LH. Catecholamine-
induced myocardial cell damage: Catecholamines or 
adrenochrome. J Mol Cell Cardiol. 1985;17(4):349­359.

18. Ahmed SS, Strobel HW, Napoli KL, Grevel J. 
Adrenochrome reaction implicates oxygen radicals 
in metabolism of cyclosporine A and FK-506 in rat 
and human liver microsomes. J Pharmacol Experim 
Therap. 1993;265(3):1047­54.

19. Khara MR, Bodnar YaYa, Fayfura VV. Features 
of structural changes in the heart of animals of dif-
ferent sex in the modelling of adrenaline myocardio-
dystrophy // Rus Morphol Statements. 2000;1(2):289­
290. [in Ukrainian]

20. Khara MR. Influence of trasicor on cholinergic 
reactions of heart of animals of different sex with 
adrenaline myocardiodystrophy. Galician Medical 
Bulletin. 2004;11(1):110­2. [in Ukrainian]

21. Khara MR. The modulating effect of carba-
cholin and castration on the cholinergic regulation 
of cardiac rhythm different sex rats in conditions of 
adrenaline myocardial damage. Bull Ukrain Dent 
Acad. 2003;3(2):13­5. [in Ukrainian]

22. Anishchenko TG, Igosheva IB. Sex differences 
of stress reactivity in awake and anesthetized rats 
under surgical stress. Bull Experim Biol Med. 1992; 
113(1):26­8. [in Russian]

23. Talaei SA, Sheibani V, Salami M. Light depri-
vation improves melatonin related suppression of 
hippocampal plasticity. Hippocampus. 2010;20(3): 
447-55. 

doi: 10.1002/hipo.20650
24. Cain SW, Dennison CF, Zeitzer JM, Guzik AM, 

Khalsa SB, Santhi N, Schoen MW, Czeisler CA, Duffy JF. 
Sex differences in phase angle of entrainment and 
melatonin amplitude in humans. J Biol Rhythms. 
2010;25(4):288­96. 

doi: 10.1177/0748730410374943

Received 05 September 2019; revised 13 October 2019; 
accepted 23 October 2019.

This is open access article distributed under the Creative Com-
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distribution, and reproduction in any medium, provided the 
original work is properly cited.

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