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Novel Pathogenesis and Treatments for Cardiovascular Disease
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associated with excitation and contraction [11]. Sex differences were not found in
APD90 between isolated ventricular myocytes, in external K+ currents, Ipk and Isus,
in internal rectification current IK1, or ICa [11, 12]. While less information is available from animal models, sex differences in the ionic basis of the effective refractory
period in the atria and atrioventricular node may also contribute to sex differences in
the incidence of atrial fibrillation and supraventricular tachycardias. Nevertheless,
the physiological significance of sex differences has yet to be fully determined; as
such, further studies are needed to clarify the basic mechanisms.
Baseline HR analysis from telemetry studies involving non-anesthetized rats,
in which a chronobiological approach was applied, indicates that there is a circadian rhythm in HR among rats, with a higher HR during the active (i.e., dark)
period of the regimen day and not only in males [13–17] but also in females
[15, 18]. If HR exhibits circadian fluctuations, then when it is evaluated, it can be
problematic.
The question is whether there are also sex differences in single-lighted periods.
Telemetry studies have revealed that among females, HR values are lower in both
light periods (Table ). The averaged results of baseline HR values indicate that sex
differences are exhibited in both the light and dark periods of the rat regimen day;
however, more experimental studies are needed to confirm these data. In female rats,
changes in HR depended on the LD cycle; however, LD differences were modified by
the anesthetic used [19, 20]. Although the adaptation of animals to the LD cycle was
described in the Methods sections, it is not clear from the methodologies whether the
values of the presented HRs were average values from the entire 24-h period, or the
current baseline value only from certain time intervals before the intervention itself
when the measurements were performed or recorded.
Anesthesia Not specified Light period Dark period
Female Male Female Male Female Male
Telemetry studies 460
432–488
(n=1)
Pentobarbital — 374
Thiopental — 349
Phenobarbital — 368
Nembutal — — — — — —
Ketamine/xylazine 331
304–257
(n=2)
Ketamine/medetomidine - 165
Ketamine/diazepam - 330
346
310–362
(n=16)
359–389
(n=22)
332–366
(n=13)
340–396
(n=1)
288
239–293
(n=18)
146–184
(n=1)
298–361
(n=2)
316
307–325
(n=2)
346
315–377
(n=1)
- — - —
- — - —
230
207–253
(n=1)
- — - —
- — - —
349
340–357
(n=5)
— 369
— 276
371
345–397
(n=2)
328–410
(n=1)
247–305
(n=1)
390
382–398
(n=5)
—
—
Rat Electrocardiography and General Anesthesia
DOI: http://dx.doi.org/10.5772/.104928
Anesthesia Not specified Light period Dark period
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Female Male Female Male Female Male
Ketamine/midazolam - 414
375–453
(n=1)
Urethane — 378
352–403
(n=14)
Isoflurane — 408
400–416
(n=5)
Desflurane — 441
429–453
(n=1)
Chloralose - 418
404–431
(n=2)
Tribromoethanol — 393
387–399
(n=1)
Ether — 366
343–388
(n=6)
Isolated heart — 368±14
354–382
(n=1)
Data presented as average heart rate (beats/min) (range); (n, number of baseline or control values from which heart rate
was evaluated). Not specified—the methodology did not specify the lighted period when the experiments were performed.
- — - —
— — — —
— — — —
— — — —
- - - -
— — — —
— — — —
— — — —
Table 1 .
Heart rate under individual types of anesthesia according to sex and light cycle (light [inactive]) versus dark
[active]).
. General anesthesia and HR
The question is what are the reference values for HR in the rat under normal circumstances? Based on the values reported in Table , is clear that HR varies depending on the type of general anesthesia, which can be problematic in evaluating changes
in HR after an intervention. Other factors, in addition to general anesthesia, that may
directly or indirectly affect the initial HR can be the methodology used to determine
HR, the time of day (or part of the rat regimen day) at which the experiments are
performed, or the fact that the majority of ECGs are evaluated only in male rats; as
such, there is little-to-no information about HR in females.
Evaluation of HR in telemetry studies involving male rats [21–31] reported a mean
HR of 347 beats/min, with a range of 303 beats/min up to 362 beats/min without
taking into account the evaluation methodologies and the time of day the experiments
were performed.
If we consider that the average HR value with the range reported in telemetry
studies involving male rats is our desired reference value, then a slightly increased
average HR in pentobarbital (approximately 28 beats/min.) [32–51], and urethane
anesthesia (approximately 32 beats/min) [52–60]. In female rats under pentobarbital
anesthesia, baseline HR values were reported in only one study, depending on the LD
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cycle [20]. Even with pentobarbital anesthesia, although nonsignificant, there were
LD differences. In female Wistar rats, pentobarbital probably only modifies circadian
rhythms, but does not disturb them. Thiopental anesthesia [31, 61–71] did not alter
HR from the mean HR reported in telemetry studies.
A significant tachycardic effect was found under isoflurane (approximately 62
beats/min) [72–75], desflurane (approximately 95 beats/min) [72], and chloralose
(approximately 72 beats/min) [76, 77] anesthesia in male rats.
Under ketamine/xylazine anesthesia [45, 78–92], HR was drastically reduced in
males and reduced values were also recorded in females [93, 94]. In females have
been preserved significant LD differences [19].
The effect of phenobarbital [95], ketamine/medetomidine [96], ketamine/midazolam [97], and ketamine/diazepam [96, 98] on anesthesia could not be assessed as
valid because there was only one study.
Although ether is no longer used to induce general anesthesia, some works used
this type of light anesthesia needed to perform ECG recordings [99–104]. However,
ether anesthesia had virtually no effect on HR. One study describing HR in isolated rat
hearts did not reveal any significant deviation, in terms of tachycardia or bradycardia
[105]. Interesting differences were also found between young and old rats under tribromoethanol anesthesia, where higher values prevailed in older rats (405±11 beats/
min vs. 381±1 beats/min) [106]. Unfortunately, these comparisons are only from
males and without a description of the adaptation of the animals to the LD cycle.
From Table and Figure , it is evident that for different types of general anes-
thesia, baseline or control HR values can differ significantly compared to the mean
baseline HR from telemetry studies, which can logically be considered as a reference
value. There is very little information about HR in females and almost none of the
studies took circadian fluctuations into account.
Figure 1.
Distribution of average values and ranges of heart rate (HR) from telemetry studies and under different types
of general anesthesia in rat males without taking into account the light periods of the rat regimen day when
the experiments were performed. Only HR ranges from at least three studies where HR has been evaluated are
shown in the figure. Telemetry studies (n=16), pentobarbital anesthesia (n=22), thiopental anesthesia (n=13),
ketamine/xylazine anesthesia (n=18), isoflurane anesthesia (n=5), ether anesthesia (n=6), urethane anesthesia
(n=14). (n—number of baseline or control values from which heart rate [HR] was evaluated).
Rat Electrocardiography and General Anesthesia
DOI: http://dx.doi.org/10.5772/.104928
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. Prognostic significance of changes in the atrial complex in
arrhythmogenesis
. PR (PQ
) interval
The PR (PQ ) interval is measured from the beginning of the P wave to the begin
ning of the QRS complex. This interval reflects the time that the electrical impulse
passes from the SA node through the AV node. The PR interval provides information
about the time required for the transmission of the electrical impulse from the atria
through the AV node, His bundle, Tawar’s branches, and Purkinje fibers to the start of
ventricular muscle depolarization [107–109].
A prolonged PQ interval reflects a longer time of transmission of the impulse from
the atrium to the ventricles in disorders of the conductive system of the AV node [110,
111]. A shortened PQ interval means that the impulse was transmitted to the ventricular conductive system earlier than normal; thus, it is likely that it passes around the AV
node through abnormal connections of the conductive system [111–113]. The duration of the PR interval is a crucial marker in the diagnosis of atrioventricular blocks.
However, it appears that the PR interval in rats also appears to be dependent on the
type of anesthesia, and we have practically no information about sex differences and
changes dependent on the LD cycle.
Although mean values of the duration of the PR (PQ ) interval were comparable
among the different types of anesthesia and did not exhibit significant differences
(Table , Figure ), the shortest duration was found with nembutal anesthesia [114].
With this type of anesthesia, there is a problem with the validity of this value because
it is from only one study. The situation is similar with desflurane [72], ketamine/
Anesthesia Not specified Light period Dark period
Female Male Female Male Female Male
Telemetry Studies 42.23
41.5–42.96
(n=1)
Pentobarbital — 47.5 3
Thiopental — 48.35
Phenobarbital — — — — — —
Nembutal 42
Ketamine/Xylazine 44
34–54
(n=1)
49.26
47.51–50.88
(n=10)
45.35–49.71
(n=18)
46.52–
50.18
(n=6)
41–43
(n=1)
44.77
41.02–
45.42
(n=13)
- - - -
44.16 36.46–
51.86 (n=1)
- — - —
47
35.7–58.3
(n=1)
— 45.3
40.6–50
(n=1)
— 36.5
30.7–
42.3
(n=1)
—
—
-
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Anesthesia Not specified Light period Dark period
Female Male Female Male Female Male
Ketamine/
Medetomidine
Ketamine/
Diazepam
Ketamine/
Midazolam
Urethane — 48.99
Isoflurane — 48.05
Desflurane — 41.6
Chloralose — — — — — —
Tribromethanol — 52.6
Ether — 49.7
Isolated Heart — 44.5
Data are presented as the average value of PR (PQ ) interval duration (ms) (range); (n, number of baseline or control
values from which heart rate was evaluated). Not specified - the methodology did not specify the lighted period when
the experiments were performed.
- 6 7.5
66.3–68.7
(n=1)
- 48.5
not
reported
(n=1)
- 47
44–50
(n=1)
45.03–
52.95
(n=9)
46.52–
49.6 3
(n=6)
40.08–
43.12
(n=1)
50.4–54.8
(n=2)
44.7–54.7
(n=4)
41.8–47.2
(n=2)
- — - —
- — - —
- — - —
— — — —
— — — —
— — — —
— — — —
— — — —
- - — —
Table 2 .
Duration of PR (PQ ) interval duration under individual types of anesthesia according to sex and light cycle
(light [inactive]) versus dark [active]).
medetomidine [96], ketamine/diazepam [96], ketamine/midazolam, [97], anesthesia
in isolated hearts [105, 115], and in tribromethal anesthesia [106, 116].
Duration of the PR (PQ) interval from telemetry studies [21, 23–25, 30, 117–119],
inhalation (isoflurane) [72, 74, 75, 120, 121] pentobarbital [32, 34, 36, 37, 40, 43–47,
49, 122–126], thiopental [63–65, 68, 71], urethane [45, 52, 53, 56, 60, 128], and ether
anesthesia [99–101, 104] did not differ significantly from one another. The shortened
duration of the PR (PQ) interval was under ketamine/xylazine anesthesia [45, 78, 79,
84, 85, 89, 91, 92, 127–129]. The duration of the PQ (PR) interval in isolated hearts
[105, 115] did not differ significantly from the duration with other types of anesthesia.
Rat Electrocardiography and General Anesthesia
DOI: http://dx.doi.org/10.5772/.104928
Figure 2.
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Distribution of average values and ranges of PR (PQ ) interval duration from telemetry studies and under
different types of general anesthesia in male rats without taking into account the light periods of the rat regimen
day when the experiments were performed. Only PR (PQ) interval ranges from at least three studies where PR
(PQ ) interval was evaluated and is shown in the figure. Telemetry studies (n=10), pentobarbital anesthesia
(n=18), thiopental anesthesia (n=6), ketamine/xylazine anesthesia (n=13), isoflurane anesthesia (n=6), ether
anesthesia (n=4), urethane anesthesia (n=9). n, number of baseline or control values from which duration of
PR (PQ ) interval was evaluated.
For a given ECG parameter, it was difficult to determine sex differences, as well as
differences dependent on the LD cycle because there was only one study (Tabl e ).
The P wave represents the depolarization of the atria. Atrial depolarization
spreads from the SA node toward the AV node, and the right to the left atrium. In
humans, but also in rats, the physiological sinus rhythm is characterized by the same
P wave orientation as the R wave and its occurrence before each QRS complex in all
cardiac cycles. P wave duration has been evaluated in Wistar rats, for which prolongation after myocardial infarction may be associated with increased sensitivity to
supraventricular arrhythmias [130].
Other parameters of atrial complex evaluation include amplitude and polarity
(either negative or positive, although it can also be so flat that it is indistinguishable
from the isoelectric line). If the P wave is unusually high, it may reflect enlargement
of the atria. Typically, an enlarged right atrium exhibits a high, spiked P wave, while
an enlarged left atrium is reflected by a bifidic P wave on ECG. The absence of a P
wave or its altered shape is present in various cardiac arrhythmias, the most common
of which is atrial [131, 132]. Although the analysis of P wave duration and shape in
humans provides clinically important information, there is a lack of experimental
data from rats to draw definitive conclusions about sex-related changes and circadian
rhythm in P wave amplitude and duration [45].
. P wave duration and amplitude
The duration and amplitude of the P wave, despite their important prognostic
significance, have only been sporadically evaluated in in vivo experiments involving
rats. The average amplitudes of the P wave were essentially the same at all types of
anesthesia (i.e., in studies where the given parameter was evaluated). Only one telemetry study [118] evaluated P wave duration, and if it is considered as a reference value,
only in males, prolonged duration was under ketamine/xylazine anesthesia [84, 89]
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Anesthesia P wave amplitude (mV) P wave duration (ms)
Telemetry studies — 21.51 (19.84–23.18) n=1
Pentobarbital 0.39 (0.34–0.44) n=2 16.15 (15.65–16.65) n=2
Thiopental — 14 (12.8–15.2) n=1
Phenobarbital — —
Nembutal 0.29 (0.27–0.32) n=1 —
Ketamine/xylazine 0.05 (0.03–0.07) n=4 26.25 (24.25–28.25) n=2
Ketamine/medetomidine 0.08 (0.05–0.11) n=1 32 (31–33) n=1
Ketamine/diazepan 0.09 (0.06–0.13) n=2 —
Ketamine/midazolam 0.04 (0.013–0.067) n=1 15 (13.5–16.5) n=1
Isoflurane 0.19 (0.17–0.21) n=1 24.1 (23.1–25.1) n=1
Desflurane — 23.5 (22.6–24.4) n=1
Chloralose — —
Tribromethanol — —
Ether — 19.5 (17–22) n=1
Urethane 0.077 (0.074–0.080) n=1 22.1 (18.7–25.5) n=2
Isolated heart 0.001 (0.00084–0.00116) n=1 19.0±0 n=1
Data presented as average (range); (n, number of baseline or control values in which the amplitude and duration of the
P wave were evaluated).
Table 3.
P wave amplitude and duration, regardless of synchronization of the male rats to the light and dark cycle under
individual types of anesthesia.
and ketamine/medetomidine [96]. Shorter durations were under pentobarbital [46,
126] and thiopental [64] anesthesia. Approximately the same duration of the P wave
was under the other types of anesthesia (Table ). The amplitude of the P wave was
the smallest in all combinations with ketamine (ketamine/xylazine) [82, 84, 89],
ketamine/medetomidine [96], ketamine/diazepam [96, 98], ketamine/midazolam
[97] and urethane [133], and isolated hearts [115].
The extent to which these values are valid cannot yet be assessed because there
are an insufficient number of studies; this problem also affects sex and the LD effect
on the amplitude and duration of the P wave. There is an indication, however, that
there may be sex differences in the duration of the P wave under ketamine/xylazine
anesthesia (21.99ms [range 17.38ms–26.62ms]) for females and 20.37ms (range
18.84ms–26.49ms) in males [19]. However, to date, this is not statistically demonstrable for other types of anesthesia.
. Prognostic significance of changes in the ventricular complex in
arrhythmogenesis
Evaluation of the parameters of the ventricular complex (QT interval, QTc
interval, QRS complex, R, and T wave amplitudes) is undoubtedly important because
it provides information about the course of depolarization and repolarization of the
ventricles. The distance from the beginning of the QRS complex to the end of the T
Rat Electrocardiography and General Anesthesia
DOI: http://dx.doi.org/10.5772/.104928
wave is measured, with the total length corresponding to the duration of depolariza-
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tion and repolarization of the ventricular muscle.
. QT interval
In rats, the determination of the QT interval is more complicated because the
T wave is not clearly separated from the QRS complex. Therefore, it is necessary
to develop a method for analyzing repolarization time in nonanesthetized rats.
However, the importance of QT interval dispersion is a complex matter involving
at least two different phenomena—namely, prolongation of the average action
potential duration and myocardial heterogeneity [26]. Based on the evaluation
of the QT, as well as the QTc interval in rat experimental models, cardioprotection was also assessed after stimulation of vitamin D receptors and the effect of
isoprenaline [42], the effect of doxorubicin [134] and L-glutamine in diabetic rats
[135], saffron on atrial and ventricular conduction velocity [64], or the effect of
preconditioning at different doses of noradrenaline on ischemia-induced ventricular arrhythmias.
The mentioned examples confirm the informative value of changes in the dura
tion of the QT interval in the evaluation of the severity of disorders in the dispersion
of ventricular refractory periods and their impact on the onset and development of
ventricular arrhythmias. If we consider the values from telemetry studies, in terms of
reference value and range [21, 26, 117, 118], QT interval prolongation was measured
with virtually every type of barbiturate anesthesia; as such, under pentobarbital
[32, 34, 37, 38, 40, 41, 43–45, 47–50, 122, 124–126], thiopental [61–64, 66, 67, 69],
and Nembutal anesthesia [114]. Ketamine/xylazine [45, 78, 85, 87, 89–92, 129,
136], ketamine/medetomidine [96], ketamine/diazepam [96, 98], and ketamine/
midazolam [97], anesthesia had the greatest effect on QT interval prolongation. A
moderate prolongation was also found under chloralose anesthesia [77] and similar
prolongations under ether anesthesia [99–101, 103, 104]. The shorter QT interval
duration was under urethane [45, 52, 55, 56, 60, 135, 137, 138] and tribromoethanol
[106] anesthesia compared with telemetry studies. Isoflurane [72, 74, 75, 120, 121]
and desflurane anesthesia [72] did not affect QT interval duration. There were virtually no significant changes in QT interval duration in working with isolated hearts
[105, 115, 139, 140]. All experiments were performed on males without specifying the
adaptation of the animals to the LD cycle and there were no studies investigating sex
Anesthesia. Not specified Light period Dark period
Telemetry studies — 58.02
Pentobarbital — 68.85
Thiopental — 64.75
Phenobarbital — — — — — —
Female Male Female Male Female Male
- - - -
51.7–64.34
(n=4)
—
65.56–69.26
(n=19)
54.03–67.52
(n=8)
73.5
58.1–88.9
(n=1)
- — - —
— 76.02
66.36–85.68
(n=1)
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Anesthesia. Not specified Light period Dark period
Female Male Female Male Female Male
Nembutal - 62
Ketamine/xylazine 87
Ketamine/
medetomidine
Ketamine/Diazepam - 101.25
Ketamine/midazolam - 78
Isoflurane — 58.32
Desflurane - 69.0
Chloralose - 60.20
Tribromethanol - 36
Ether — 69.86
Urethane — 53.05
Isolated heart — 72.75
Data presented as average (range); (n, number of baseline or control values from which QT interval was evaluated). Not
specified—in the methodology does not specify the lighted period when the experiments were performed.
79–95
(n=1)
- 65
60–63
(n=1)
74.97
70.88–79.23
(n=11)
63.1–66.9
(n=1)
84.15–116.7
(n=2)
69–87
(n=1)
43.68–61.48
(n=6)
67.72–0.28
(n=1)
53.51–6.89
(n=1)
33.5–38.5
(n=1)
66.4–73.4
(n=5)
48.74–57.35
(n=9)
68,8–76.7
(n=4)
- — - —
89.9
73–106.8
(n=1)
- — - —
- — - —
- — - —
— — — —
— — — —
— — — —
— — — —
— — — —
— — — —
— — — —
— 91.7
82–101.4 (n=1)
—
Table 4 .
QT interval duration (ms) under individual types of anesthesia with regard to sex and the cycle of light (inactive)
and dark (active).
differences. Similarly, it was not possible to determine the circadian fluctuation in the
duration of the QT interval or the dependence on the LD cycle (Table , Figure ).
. QTc interval
In human cardiology, QTc interval assessment enables the comparison of QT val-
ues overtime at different HRs and improves the identification of patients at increased
Rat Electrocardiography and General Anesthesia
DOI: http://dx.doi.org/10.5772/.104928
Figure 3.
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Distribution of ranges of QT intervals from telemetry studies and under different types of general anesthesia
in male rats without taking into account the light periods of the rat regimen day when the experiments were
performed. Only QT interval ranges from at least three studies in which QT interval was evaluated are shown in
the figure. Telemetry studies (n=4), pentobarbital anesthesia (n=19), thiopental anesthesia (n=8), ketamine/
xylazine anesthesia (n=11), isoflurane anesthesia (n=6), ether anesthesia (n=5), urethane anesthesia (n=9),
isolated heart (n=4). n, number of baseline or control values from which duration of the QT interval was
evaluated.
risk for arrhythmias. Prolonged QTc is caused by premature action potentials during
the late phases of depolarization. This increases the risk for ventricular arrhythmias,
including fatal ventricular fibrillation [141]. These changes make it difficult to compare QT intervals measured at different HRs. To account for this and, thus, improve
the reliability of QT measurements, the QT interval can be corrected for HR (QTc)
using various mathematical formulae, a process that modern ECG recorders often
perform automatically. The duration of the QTc interval is a key and critical factor in
assessing changes in repolarization with regard to drug safety and cardiac disorders.
There was only one study that reported changes in the duration of the QTc interval
depending on commonly used drugs, especially when used in combination with other
substances that affect their metabolism [142, 143]. Possible changes in QTc interval
depending on sex and age have also been described in humans. Higher rates of
prolonged QTc are observed in women, older patients, with high systolic blood pressure or HR, and low body height [144]. It was found that the rate of QT/RR hysteresis
decreases with increasing age, while the duration of the individually corrected QTc
interval increases with increasing age. In contrast to longer QTc intervals, the rate of
QT/RR hysteresis was faster in women [145]. There are many causes of prolonged QT
intervals, and acquired causes are more common than genetic causes [146].
Changes in the QTc interval have also been described in rats, where, for example,
induction of ischemia shortened the QTc interval and led to ventricular arrhythmias.
Administration of low doses of noradrenaline prevented shortening of the QTc
interval during ischemia but could not significantly reduce the severity and incidence
of arrhythmias [38]. However, in the experimental field, determination of QTc
interval is somewhat more complicated because HR values are extremely variable
among different species [147]. In rats, there is a lack of a validated approach to QT
interval correction [143] and, despite some efforts [148, 149], there is no validated
and widely used method for such QTc interval adjustment. Thus, most researchers in
experimental cardiology, pharmacology, and toxicology must use formulas designed
for other species, without commenting on their accuracy in rats [26, 150, 151], and its
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