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Volume 4 | Issue 2 | 1 of 6
Anesth Pain Res, 2020
Sex Differences in HRV Under General Anesthesia in Rat Model
1Department of Physiology, Medical Faculty Safarik’s University,
Kosice, Slovak Republic.
2Laboratory of Research Bio-models, Medical Faculty Safarik’s
University, Kosice, Slovak Republic.
3Department of Physiology and Pathophysiology, Medical Faculty
Ostrava University, Ostrava, Czech Republic.
*Correspondence:
Pavol Svorc, Assoc. Prof., Dr., PhD., Department of Physiology,
Medical Faculty, Safarik’s University, Tr. SNP 1, 04001 Kosice,
Slovak Republic, Tel: 00421907177340.
Received: 07 July 2020; Accepted: 04 August 2020
Pavol Švorc1,3, Darina Petrášová2 and Pavol ŠvorcJr3
Anesthesia & Pain Research
ABSTRACT
Background: It is known that general anesthesia weakens autonomic function and baroreex control. Intravenous
anesthetics may have different qualitative and quantitative effects on the peripheral autonomic nervous system
(ANS) and, can thus, alter the activity of sympathetic or parasympathetic divisions of the ANS. Presently, there are
relatively little data regarding sex differences in ANS activity or sex differences in ANS activities during anesthesia.
The primary goal of the present study was to assess sex differences in ANS activity in dependence on the light-dark
(LD) cycle in healthy, sexually mature, spontaneously breathing zoletil-anesthetized rats.
Methods: Experiments were performed using zoletil-anesthetized (30 mg/kg [intraperitoneal]) female and
male Wistar rats after a four-week adaptation to an LD cycle (12h:12h). The animals were divided into four
experimental groups according to sex and light period (n=20). Heart rate variability (HRV) was evaluated 20 min
after administration of anesthesia.
Results: Sympathetic and baroreceptor activity were decreased, parasympathetic activity was increased in both
sexes and in both lighted periods. LD differences were preserved mainly in the HF component; thus, circadian
rhythm in parasympathetic activity probably persists in both sexes. Taking into account sex differences, HRV was
signicantly lower in females versus males in the light period. In the dark period, females exhibited higher HRV
than males. Taking into account LD differences, in females, HRV was lower in the light versus the dark period,
unlike males, in which HRV was higher in the dark versus light period of the rat regimen day.
Conclusions: It is concluded that the sex differences exist in rat ANS activity, persist in general anesthesia and
depend on the LD cycle, what can be also related to its regulatory effect on the cardiovascular system. Future
studies should address this issue and try to include females into the experiment if it is possible.
ISSN 2639-846XResearch Article
Citation: Pavol Švorc, Darina Petrášová, Pavol ŠvorcJr. Sex Dierences in HRV Under General Anesthesia in Rat Model. Anesth Pain
Res. 2020; 4(2): 1-4.
Keywords
General anesthesia, Sex differences, Chronobiology, Heart rate
variability, Rat.
Introduction
Small, periodic uctuations in heart rate are well known to
physicians and scientic investigators. Because these uctuations
are caused by varying activity of the ANS, an examination of heart
rate variability (HRV) is needed to obtain information about the
functional status of the ANS.
HRV analysis, which supports the evaluation of successive RR
intervals using electrocardiographic methods, has been used as
a powerful tool in the evaluation of autonomic cardiac control
[1]. For example, in humans, reduced HRV is associated with
an increased risk for ventricular arrhythmia and has been shown
to be an independent prognostic mortality factor in patients
with cardiac disease(s) [2,3]. On the other hand, some studies
demonstrated that in rats, HRV spectral performance analysis is
an ineffective method of detecting heart-related autonomic control
disorders in some experimental models of myocardial infarction or
diabetic neuropathy [4-6]. However, approaches that are based on
electrocardiographic recordings in an anesthetic state are not ideal
nor valid for HRV analysis due to signicant heart rate uctuations
Volume 4 | Issue 2 | 2 of 6Anesth Pain Res, 2020
associated with impaired autonomic modulation of the heart [7,8].
In addition, anesthesia may contribute an important additional risk
for animal mortality under some pathological conditions such as
myocardial infarction and diabetes mellitus [9-11].
General anesthesia weakens autonomic function and baroreex
control. This side effect should be avoided as much as possible
because it limits the ability of the subject to respond to physiological
challenges during surgery (e.g., arterial pressure and decreases
in chamber inotropy) [12]. Therefore, any research intervention
that could affect aspects of the ANS and its impact on internal
organs should take into account the anesthetic used. Intravenous
anesthetics may have different qualitative and quantitative
effects on the peripheral ANS and, can thus, alter the activity of
sympathetic or parasympathetic divisions of the ANS.
Presently, however, there are relatively little data regarding sex
differences in ANS activity or sex differences in ANS activities
during anesthesia. During resting conditions, male rats exhibit a
signicantly higher heart rate and lower HRV parameters than
female rats. This state is not only during the active, but also during
the inactive, phase of the daily rat cycle [13].
These data support the concept that sex-based variations should
also be taken into account given that females in human and animal
studies use different mechanisms of cardiovascular regulation
[14]. Although these data suggest that if there are sex differences
in individual cardiovascular parameters, they are predominantly
regulated by the ANS. Logically, therefore, if sex differences
exist in cardiovascular activities, sex differences in the circadian
oscillations of individual divisions of the ANS must also exist in
parallel. However, supportive evidence of HRV changes in rats
during a 24h period is lacking.
Zoletil anesthesia is used by veterinarians mainly for pets and
wildlife animals but is not commonly used in experiments. It has
been reported that this type of anesthesia is an appropriate anesthesia
since it does not affect vital functions. The unanswered question is
whether there are sex differences also in the dependence on the
time of day at this type of anesthesia and whether the choice of
this type of anesthesia is suitable for experiments with a rat model.
Accordingly, the primary goal of the present study was to assess
whether sex differences exist in ANS activity, measured according
to HRV in dependence on the light-dark (LD) cycle (a parallel
to circadian rhythm) in healthy, sexually mature, spontaneously
breathing zoletil-anesthetized rats.
Animals
The present study conformed to the Guide for the Care and Use
of Laboratory Animals published by the United States National
Institutes of Health (publication number 85-23, revised 1996).
The study protocol was approved by the Ethics Committee of the
Medical Faculty of Safarik University (Kosice, Slovak Republic)
(permission number 2/05 and permission number ŠVPS SR: Ro-
4234/15-221).
The experiments were performed using albino Wistar rats
(weight, 340 ± 40 g, three to four months of age) acquired from a
breeding and vendor company (VELAZ, Koleč, Czech Republic,
certicate number 70029/2013-MZE-17214), with the veterinary
registration number CZ 21760118. The animals were quarantined
for 2 weeks in the Laboratory of Research Biomodels of Medical
Faculty Safarik’s University in Košice (ofcial number SK UCH
08018) and adapted to an LD cycle (12h light:12h dark [intensity
of articial illumination 80 Lux]; 40% to 60% humidity; cage
temperature, 24°C; two animals/plastic cage for four weeks. The
rats were fed a standard, pelleted diet, with ad libitum access to
food and water. Animal handling was performed by professional
staff of the menagerie.
Anesthesia (Zoletil, 30 mg/kg, Virbac, France) in prescribed
doses based on the weight of the animal was administered by
intraperitoneal injection in the adaptation room. After testing
the effect of anesthesia (loss of uprighting reexes, reaction to
painful stimulus), the animals were transferred to the operating
room where they were xed to an experimental table on which the
subcutaneous electrodes used record ECG and HRV were applied.
Again, the depth of anesthesia was assessed, depending on whether
the painful stimulus caused noticeable motor movements (minimal
limb movement, muscle tension change), or cardiovascular
responses, such as change in heart rate or onset of heart rhythm
disorders.
Materials and Methods
The effect of the light period on the monitored parameters was
examined after adaptation to an LD cycle, with the light period
from 06:00 h to 18:00 h. The effect of the dark period was monitored
after adaptation to the inverse setting of the LD cycle (i.e., with
the light period from 18:00 h to 06:00 h). Animals were divided
randomly into four experimental groups (n = 20 each) according
to sex and light conditions: group 1: female (light period); group
2: female (dark period); group 3: male (light period); and group 4:
male (dark period). In in vivo experiments, at least 20 animals are
valid sample for statistical processing.
HRV was analyzed using the ID Instruments computer system for
biopotential recording from an average of 220 heart cycles, 20
min after administration of anesthesia at 09:00 and 12:00h using
separate animals. In analyzing HRV parameters, the focus was on
the evaluation of RR interval duration, spectral power at very-low
frequency (VLF 0.003 Hz – 0.04 Hz), low-frequency (LF 0.04
Hz – 0.15 Hz) and high-frequency (HF 0.15 Hz – 0.4 Hz), total
spectral power of HRV and the LF/HF ratio. Upon completion of
the measurement, the animals were transferred to the menagerie.
Data are expressed as mean ± standard deviation (SD). Data were
analyzed using GraphPad InStat (GraphPad, San Diego, CA, USA).
The Tukey-Kramer test was used to identify signicant differences
between the groups, and p < 0.05 was considered to be statistically
signicant. The experiments were conducted throughout the year
and the results were averaged independently of the season and,
in females, independently of estral cycle. Animals included in
Volume 4 | Issue 2 | 3 of 6Anesth Pain Res, 2020
statistical analysis was 20/20 and no animal was excluded from the
statistical analysis. Before and after administration of the anesthetic
as well as during the measurement, there were no adverse events
or unexpected changes in the HRV or ECG parameters, although
considerable variability has been observed.
Results
RR interval
The duration of the RR interval corresponds to increased heart
rate in both sexes in both lighted periods of the regimen day. In
females, LD differences were not observed in the duration of the
RR interval (light 142.30 ± 25.19 ms vs. dark 134.97 ± 9.09 ms),
in contrast to males, in which a signicantly (p < 0.001) longer RR
interval was recorded during the light part of the day (light 145.05
± 8.51 ms vs. dark 124.68 ± 5.14 ms). Sex differences were found
only in the dark (i.e., active) part of the day (Figure 1).
Figure 1: Duration of RR intervals under general zoletil anesthesia 20
min after zoletil administration in male and female Wistar rats in the
light and dark parts of the regimen day. Hollow bars represent the light
and the solid bars represent the dark part of the rat regimen day. ***p
<0.001 statistically signicant sex differences; ###p <0.001 statistically
signicant light-dark differences in the same sex.
HRV analysis
Despite the large variation in HRV spectral powers under
zoletil anesthesia, in terms of sex differences, parasympathetic
activity dominated in both sexes and in both light periods with
nonsignicant higher sympathetic (VLF), baroreceptor (LF)
activities and signicant (p < 0.001) parasympathetic (HF) activity
in females (Tables 1 and 2).
VLF
(ms²) LF (ms²) HF (ms²)
Total spectral
power of HRV
(ms2)
LF/HF
Female, L 0.232 ±
0.264
0.160 ±
0.223
1.765 ±
2.281 0.778 ± 0.54 0.34 ±
0.386
Female, D 0.189 ±
0.239
0.089 ±
0.157
0.903 ±
0.730 1.219 ± 0.97 0.113 ±
0.170
Male, L 0.167 ±
0.192
0.062 ±
0.048
1.156 ±
0.873 1.495 ± 1.08 0.105 ±
0.132
Male - D 0.049 ±
0.024
0.059 ±
0.106
0.155 ±
0.093 0.3 ± 0.16 0.284 ±
0.198
Table 1: Heart rate variability parameters in the light (L) and dark (D)
periods.
Data presented as mean ± standard deviation. VLF, very-low frequency;
LF, low frequency; HF, high frequency.
Period Heart rate variabilty parameter
VLF (ms²) LF (ms²) HF (ms²) LF/HF
Female vs. male -light p < 0.001 p < 0.09 p < 0.27 p < 0.05
Female vs. male -dark p < 0.01 p < 0.51 p < 0.001 p < 0.01
Light vs. dark - female p < 0.644 p < 0.29 p < 0.012 p < 0.05
Light vs. dark - male p < 0.06 p < 0.9 p < 0.001 p < 0.01
Table 2: Comparison of sex differences and LD differences in individual
heart rate variability parameters.
Data presented as p value. Bolded values indicate statistically signicant
differences. VLF, very-low frequency; LF, low frequency; HF, high
frequency.
Signicant sex differences in dependence on the LD cycle were
recorded in total spectral power of HRV. In the light period in
females, it was signicantly lower than in males, and vice versa
in males in the dark period of the regimen day (Figure 2). The
opposite tendency was found in the LF/HF ratio, with dominance
of parasympathetic activity in both light periods of the day (Figure
3).
Figure 2: Total spectral power of heart rate variability (HRV) in female
and male Wistar rats in the light and dark period of the regimen day. Hollow
bars represent the light and solid bars represent the dark period of the
regimen day. *p < 0.05; ***p < 0.001 statistically signicant differences
between sexes in both light periods of the rat regimen day; ###p < 0.001
statistically signicant light-dark differences in the same sex.
Figure 3: Low frequency (LF)/high frequency (HF) ratio in female and
in male Wistar rats in the light and in the dark periods of the regimen
day. Hollow bars represent the light and the solid bars represent the dark
period of the rat regimen day. *p < 0.05; **p < 0.01 statistically signicant
differences between the sexes in both light periods of the rat regimen day,
##p < 0.01 statistically signicant light-dark differences in the same sex.
Discussion
The limitations of the study were not whereas it was evaluation
of the current status in ANS activity in healthy animals under
anesthesia. The imprecisions in presentation of the results are
Volume 4 | Issue 2 | 4 of 6Anesth Pain Res, 2020
primarily associated with relatively large variability of the
measured parameters of HRV.
In rats, sympathetic activity dominates their normal life cycle
[6,15]. Zoletil anesthesia increases parasympathetic activity in
both sexes. Similar results have been reported in previous studies.
Administration of the anesthetic agent tribromoethanol in male
Wistar rats [16], ketamine hydrochloride and diazepam in albino
Wistar rats [17], and ketamine/xylazine and pentobarbital in
females [18] resulted in predominant parasympathetic activity.
However, our results indicate that precisely dening changes in
HRV is difcult due to signicant variability which, therefore,
makes it difcult to attribute sex differences. Thus, we agree with
the opinion mentioned in the introduction that approaches based
on ECG recording under general anesthesia are not fully valid for
HRV analysis.
Although there is signicant variation of HRV in Wistar rats, some
parameters point to sex differences also in dependence on the
LD cycle. If we consider the duration of RR intervals (adequate
to heart rate) 20 min after zoletil administration, signicant sex
differences were found only in the dark (i.e., active) part of the day,
with signicantly shorter RR intervals (higher heart rate) in males.
During the light period of the rat regimen day, sex differences in
the duration of RR intervals were not detected. On the other hand,
signicant LD differences were maintained in males; however, they
were eliminated in females. Our results, therefore, indicate that
in zoletil-anesthetized rats, LD differences were maintained only
in males but not in females. Considering the results of telemetric
studies by Molcan et al. [19,20], heart rate exhibits a signicant
circadian rhythm in non-anesthetized rats, in which the heart rate
in the dark period uctuates from 347 beats/min to 363 beats/min,
and from 309 beats/min to 321 beats/min in the light period. Thus,
it appears that although zoletil exerts a tachycardic effect, it can
eliminate―or, at least modify―circadian rhythm of heart rate, but
only in females.
Such elimination or modication of LD differences in heart
rate in females may also be partly explained by perhaps greater
sensitivity of females to acidosis, hypoxia, and hypercapnia under
general anesthesia [21]. Previous studies have described the effect
of hypoxia on the modulation of daily rhythmicity [22-26]. The
fact that hypoxia modies circadian oscillations of important
variables, such as body temperature and metabolism, can lead to
the expectation that the rhythms of many functions are interrupted
by hypoxia on the basis of their relationship with the primary
variables. Such a hypoxic relationship probably contributes to a
greater parasympathetic effect(s) on the heart [27]. Additionally,
the effect of anesthetics can contribute to the loss or modication
of rhythmicity. For example, in female rats under pentobarbital
anesthesia, parasympathetic activity increases and sympathetic
and baroreex activity decreases; however, LD differences in heart
rate are eliminated. In ketamine/xylazine anesthesia, a preference
toward parasympathetic activity was increased and sympathetic
and baroreex activity was depressed, resulting in signicant
bradycardia but with maintenance of LD differences [18].
The question remains that if on the one hand, there is clearly proven
increased parasympathetic activity and, on the other, increased
heart rate. This paradox has been described by several authors
[28-32], who assumed that stimulation of the vagal nerve releases
catecholamines, which in turn can affect heart activity. This is
also probably the case with zoletil anesthesia, which may have
a similar effect on the release of catecholamines through higher
parasympathetic activity, and is particularly evident in males in
both light periods of the regimen day.
The LF to HF ratio (i.e., LF/HF) can be used to quantify the
changing relationship between sympathetic and parasympathetic
nerve activities (i.e., sympathetic-vagal balance) [33-35]. The exact
interpretation of the LF/HF ratio also depends on the assumption
that physiological interventions always cause mutual changes in
parasympathetic and sympathetic activity.
Our results demonstrate that the LF/HF ratio depends on the light
periods of the regimen day. In females in the light period, the LF/HF
ratio was signicantly higher and, in the dark period, signicantly
lower than in males. These conclusions, however, should be
interpreted with caution. In the article by Billman [36], addressing
the meaning of HRV examination, evaluation of the LF/HF ratio was
questioned. The LF component of HRV does not provide a cardiac
sympathetic response index, but rather reects a complex and not
readily recognizable mixture of sympathetic, parasympathetic and
other unidentied factors with parasympathetic factors, which
represent the largest part of variability in this frequency range. As
a result, it is difcult to recognize the physiological basis for LF/
HF. In addition, a relatively large amount of data suggests that the
spectral power of the HF component cannot be attributed solely to
changes in cardiac vagal efferentation, further compromising the
accurate interpretation of the LF/HF ratio [36].
In in vivo experiments, homeostatic regulatory mechanisms are
not eliminated. It means that the obtained results are a reection a
direct but signicantly intravariable response of the animals to the
administration of the anesthetic. At evaluation of HRV in in vivo
conditions, replacement and reduction of animals is not possible,
but knowledge about the sex differences during anesthesia in the
dependence on LD cycle in ANS activity may improve the quality
of the experiment design. We do not have any data about sex
differences and we do not have any data about changes of ANS
activity depending on the LD cycle under general anesthesia.
Further research is needed to assess the responses of other
species, because the effect of zoletil is practically not described in
experimental practice.
Conclusion
Based on our results, we conclude that under zoletil anesthesia,
sympathetic (VLF) and baroreceptor (LF) activity were decreased,
and parasympathetic (HF) activity was increased in both sexes and
in both light periods. LD differences were preserved mainly in the
HF component; thus, circadian rhythm in parasympathetic activity
probably also persists in both sexes.
Volume 4 | Issue 2 | 5 of 6Anesth Pain Res, 2020
Taking into account sex differences based on total spectral power
of HRV, our results suggest that HRV, in the light period of the rat
regimen day, was signicantly lower in females versus males. In
the dark period, females exhibited higher HRV than males. Taking
into account LD differences, in females, HRV was lower in the
light versus the dark period, unlike males, in which HRV was
higher in the dark versus light period of the rat regimen day.
Acknowledgment
This work was supported by VEGA [grant number 1/0423/11].
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