IntechOpen

Home > Books > Novel Pathogenesis and Treatments for Cardiovascular Disease

Open access peer-reviewed chapter

Rat Electrocardiography and General Anesthesia

Written By

Pavol Svorc Jr and Pavol Svorc

Submitted: 31 March 2022 Reviewed: 13 April 2022 Published: 07 May 2022

DOI: 10.5772/intechopen.104928

Novel Pathogenesis and Treatments for Cardiovascular Disease IntechOpen
Novel Pathogenesis and Treatments for Cardiovascular Disease Edited by David Gaze

From the Edited Volume

Novel Pathogenesis and Treatments for Cardiovascular Disease

Edited by David C. Gaze

Book Details Order Print

Chapter metrics overview

185 Chapter Downloads

View Full Metrics
Advertisement

Abstract

General anesthesia is an established and well-known factor with a significant impact on cardiac parameters, which can be a problem in the final evaluation of changes in the individual electrophysiological myocardial parameters after various interventions. The present chapter provides a composite review of published data on electrocardiographic parameters (heart rate, PR interval, P wave duration, P wave amplitude, QRS complex, QT and QTc interval duration, and R wave and T wave amplitude) for in vivo rat experiments under general anesthesia from 130 articles, which were retrieved from a search of the Web of Science database, for articles published mainly between 2000 and 2021. ECG parameters reported as baseline or control values were summarized, and averages with ranges were calculated. It is important to be cautious in interpreting the results of such studies and discussions addressing the mechanisms underlying a given type of arrhythmia, it is important to acknowledge that initial ECG parameters may already be affected to some extent by general anesthesia as well as by sex and the time of day the experiments are performed. Although it is not an original research work, researchers working with rats in the laboratory, who routinely perform anesthesia, can use this as a reference to look into while analyzing their data.

Keywords

  • ECG parameters
  • general anesthesia
  • sex
  • chronobiology
  • rat

1. Introduction

In vivo experimental animal models are often used to elucidate or, at least clarify, specific mechanisms and/or to identify interrelationships between monitored functions that cannot be observed directly in humans. The results of such studies are often approximated to preclinical or clinical research and, can thus, have a significant scientific impact on a more detailed understanding of the monitored system.

A specific feature of in vivo experimental animal models is the fact that experiments are usually performed with the animals under general anesthesia, in which homeostatic regulatory mechanisms are not removed and the animal responds to various interventions. Undoubtedly, this also applies to experiments in which changes in electrocardiographic (ECG) parameters are monitored after various interventions or after the administration of specific agents to assess the basis of the origin and development of heart rhythm disorders. However, different anesthetics may have varying impacts on myocardial electrophysiology. Thus, the extent to which ECG parameters are altered from normal after anesthetic administration can become a confounder—if not a problem—even before assessing the effects of the intervention itself.

The second problem is that many published methodologies do not describe the synchronization of the animals to the light-dark (LD) cycle, mainly in studies based on rat models. The LD cycle is the strongest synchronizer for this type of laboratory animal, and it is known that all measurable cardiovascular parameters oscillate depending on the LD cycle. Moreover, even when this synchronization is described, the time of day at which the experiments are performed is often not reported. In common practice, experiments are performed during regular work hours (i.e., during the day); therefore, after synchronization of rats, for example, to the LD cycle (12 h: 12 h), these experiments are essentially being performed on “sleeping” animals during their naturally inactive period. The question then becomes, what are the oscillations of ECG parameter values during a 24-h period (i.e., spanning the light [inactive] and dark [active] period) in healthy, sexually mature rats?

Another possible problem in the correct evaluation of changes in myocardial electrophysiology in rats may be sex. Sex is not typically considered in in vivo cardiovascular and toxicological experiments involving rats, although this type of experimental model animal is commonly used to examine normal and pathological physiology. In the majority of experimental studies, only male rats are used; however, there is another sex (i.e., female) in which differences in the essence of functional systems and response(s) to the same interventions are different from males. The study of sex differences is also a driving force of development and, in many cases, the basis of health and medicine. However, there are opinions that the study of sex differences is ineffectual and does not merit extensive research [1]. One of the reasons why both sexes are not used in experiments is the simple fact that males and females are biologically different and these differences increase the range of variability. However, if sex differences are documented and accounted for in experimental studies, these must be respected. As such, future studies should address these questions and attempt to include females in experiments where possible.

This review aims to highlight the fact that there are differences in baseline or control values, which are, nevertheless, used as reference values in individual studies. However, they are impacted by the type of anesthesia used, and all the above-mentioned confounders/problems can significantly affect the correct interpretation of the results obtained.

Advertisement

2. Evaluation of ECG parameters

The methodologies of studies that performed in vivo rat cardiovascular or toxicological experiments were retrieved from a search of the Web of Science database for articles published mainly between 2000 and 2021; in total, 130 articles were retrieved. ECG parameters reported as baseline or control values were summarized and averages with ranges were calculated. Not all ECG parameters were described and evaluated in each study and, in some studies, two to three control values were reported. A relatively high number of studies described only changes in ECG parameters, in terms of lengthening and shortening, and these changes were directly indicated in graphs without reporting numerical baseline values.

Because each ECG parameter has diagnostic significance, we focused on commonly evaluated ECG parameters, including the following: heart rate (HR), atrial complex (PR interval, P wave duration, and P wave amplitude), and ventricular complexes (QRS complex, QT and QTc interval duration, and R wave and T wave amplitude).

Tables consider studies (although there were only one or two), which also suggest a possible sex difference with regard to the LD cycle on the monitored parameter. The figures show the ranges of the monitored parameter from at least three baseline or control values.

Advertisement

3. Prognostic significance of changes in HR in arrhythmogenesis

HR is an easily measurable parameter of cardiac activity, and alterations in HR can have a direct effect on the cardiovascular system. Caetano and Alves [2] reported that increased resting HR is an independent predictor of cardiovascular and overall mortality in the general population. Thus, the occurrence of arrhythmias is often associated with baseline HR, which has prognostic significance. In a review article titled “Arrhythmias and heart rate: Mechanisms and significance of a relationship”, Zaza et al. [3] describe, in detail, the mechanisms influencing arrhythmogenesis according to HR, in which the authors focused on several factors related mainly to electrical stability of the myocardium. HR also reflects autonomic balance, which also affects myocardial stability. The prognostic significance of the relationship between arrhythmias and HR may vary depending on the substrate present in a specific case and should be considered. In rats, electrical stability of the heart has been shown to be greatest at increased HRs in the dark (i.e., active) part of the regimen day, when myocardial vulnerability to ventricular arrhythmias decreases [4].

It has been found that tachycardia may provide greater electrical stability to the myocardium; however, if an abnormal substrate is present, it may trigger arrhythmia [5]. Severe bradycardia, in contrast, can trigger life-threatening arrhythmias, thus reflecting its destabilizing effect on repolarization. Zaza et al. [3] remained cautious, arguing that, from a mechanistic perspective in assessing the relationship between HR and arrhythmias, the question should be “what is the appropriate sinus rate for autonomic balance?” and not “what is the high (or low) heart rate?” Thus, it can be assumed that baseline HR in in vivo cardiovascular studies can significantly affect the results obtained during experimentation. The considerations mentioned above are also generally valid for rats. However, it is interesting that the effect of some interventions on HR is monitored and the impact of this change on myocardial electrophysiology is not further analyzed [6, 7, 8].

3.1 Telemetry and HR

To establish reference values for HR, as well as other ECG parameters, logically, the most suitable method is using telemetry studies, in which rats are not placed under general anesthesia and ECG can be recorded continuously throughout the day. Telemetry studies help to reveal very important information about fluctuations in myocardial electrophysiological parameters during the day. Currently, however, relatively few telemetry studies have analyzed ECG parameters in rats under in vivo conditions, and did not address circadian dependence and the dependence on sex.

Sex can also be a confounder. Nevertheless, several experimental rat studies [9] did not report any sex differences in heart repolarization, or that there is little clear evidence supporting sex differences in ventricular repolarizations per se, in which there is only a short estrous cycle lasting only 4 days [10]. Although no sex differences were found in the repolarization of isolated ventricular myocytes, they were 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, 14, 15, 16, 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 1). 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.

AnesthesiaNot specifiedLight periodDark period
FemaleMaleFemaleMaleFemaleMale
Telemetry studies460
432–488
(n = 1)		346
310–362
(n = 16)		316
307–325
(n = 2)		349
340–357
(n = 5)		371
345–397
(n = 2)		390
382–398
(n = 5)
Pentobarbital—374
359–389
(n = 22)		346
315–377
(n = 1)		—369
328–410
(n = 1)		—
Thiopental—349
332–366
(n = 13)		-—-—
Phenobarbital—368
340–396
(n = 1)		-—-—
Nembutal——————
Ketamine/xylazine331
304–257
(n = 2)		288
239–293
(n = 18)		230
207–253
(n = 1)		—276
247–305
(n = 1)		—
Ketamine/medetomidine-165
146–184
(n = 1)		-—-—
Ketamine/diazepam-330
298–361
(n = 2)		-—-—
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)		————

Table 1.

Heart rate under individual types of anesthesia according to sex and light cycle (light [inactive]) versus dark [active]).

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.

3.2 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 1, 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, 22, 23, 24, 25, 26, 27, 28, 29, 30, 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, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51], and urethane anesthesia (approximately 32 beats/min) [52, 53, 54, 55, 56, 57, 58, 59, 60]. In female rats under pentobarbital anesthesia, baseline HR values were reported in only one study, depending on the LD 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, 62, 63, 64, 65, 66, 67, 68, 69, 70, 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, 73, 74, 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, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 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, 100, 101, 102, 103, 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 1 and Figure 1, it is evident that for different types of general anesthesia, 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).

Advertisement

4. Prognostic significance of changes in the atrial complex in arrhythmogenesis

4.1 PR (PQ) interval

The PR (PQ) interval is measured from the beginning of the P wave to the beginning 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, 108, 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, 112, 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 2, Figure 2), 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/medetomidine [96], ketamine/diazepam [96], ketamine/midazolam, [97], anesthesia in isolated hearts [105, 115], and in tribromethal anesthesia [106, 116].

AnesthesiaNot specifiedLight periodDark period
FemaleMaleFemaleMaleFemaleMale
Telemetry Studies42.23 41.5–42.96
(n = 1)		49.26
47.51–50.88
(n = 10)		----
Pentobarbital—47.53
45.35–49.71
(n = 18)		44.16 36.46–51.86 (n = 1)—45.3
40.6–50
(n = 1)		—
Thiopental—48.35
46.52–50.18
(n = 6)		-—-—
Phenobarbital——————
Nembutal42
41–43
(n = 1)
Ketamine/Xylazine44
34–54
(n = 1)		44.77
41.02–45.42
(n = 13)		47
35.7–58.3
(n = 1)		—36.5
30.7–42.3
(n = 1)		—
Ketamine/Medetomidine-67.5
66.3–68.7
(n = 1)		-—-—
Ketamine/Diazepam-48.5
not reported
(n = 1)		-—-—
Ketamine/Midazolam-47
44–50
(n = 1)		-—-—
Urethane—48.99
45.03–52.95
(n = 9)		————
Isoflurane—48.05
46.52–49.63
(n = 6)		————
Desflurane—41.6
40.08–43.12
(n = 1)		————
Chloralose——————
Tribromethanol—52.6
50.4–54.8
(n = 2)		————
Ether—49.7
44.7–54.7
(n = 4)		————
Isolated Heart—44.5
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]).

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.

Figure 2.

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.

Duration of the PR (PQ) interval from telemetry studies [21, 23, 24, 25, 30, 117, 118, 119], inhalation (isoflurane) [72, 74, 75, 120, 121] pentobarbital [32, 34, 36, 37, 40, 43, 44, 45, 46, 47, 49, 122, 123, 124, 125, 126], thiopental [63, 64, 65, 68, 71], urethane [45, 52, 53, 56, 60, 128], and ether anesthesia [99, 100, 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, 128, 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. 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 (Table 2).

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].

4.2 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] 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 3). 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].

AnesthesiaP wave amplitude (mV)P wave duration (ms)
Telemetry studies—21.51 (19.84–23.18) n = 1
Pentobarbital0.39 (0.34–0.44) n = 216.15 (15.65–16.65) n = 2
Thiopental—14 (12.8–15.2) n = 1
Phenobarbital——
Nembutal0.29 (0.27–0.32) n = 1—
Ketamine/xylazine0.05 (0.03–0.07) n = 426.25 (24.25–28.25) n = 2
Ketamine/medetomidine0.08 (0.05–0.11) n = 132 (31–33) n = 1
Ketamine/diazepan0.09 (0.06–0.13) n = 2—
Ketamine/midazolam0.04 (0.013–0.067) n = 115 (13.5–16.5) n = 1
Isoflurane0.19 (0.17–0.21) n = 124.1 (23.1–25.1) n = 1
Desflurane—23.5 (22.6–24.4) n = 1
Chloralose——
Tribromethanol——
Ether—19.5 (17–22) n = 1
Urethane0.077 (0.074–0.080) n = 122.1 (18.7–25.5) n = 2
Isolated heart0.001 (0.00084–0.00116) n = 119.0 ± 0 n = 1

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.

Data presented as average (range); (n, number of baseline or control values in which the amplitude and duration of the P wave were evaluated).

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 (21.99 ms [range 17.38 ms–26.62 ms]) for females and 20.37 ms (range 18.84 ms–26.49 ms) in males [19]. However, to date, this is not statistically demonstrable for other types of anesthesia.

Advertisement

5. 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 wave is measured, with the total length corresponding to the duration of depolarization and repolarization of the ventricular muscle.

5.1 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 duration 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, 44, 45, 47, 48, 49, 50, 122, 124, 125, 126], thiopental [61, 62, 63, 64, 66, 67, 69], and Nembutal anesthesia [114]. Ketamine/xylazine [45, 78, 85, 87, 89, 90, 91, 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, 100, 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 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 4, Figure 3).

Anesthesia.Not specifiedLight periodDark period
FemaleMaleFemaleMaleFemaleMale
Telemetry studies—58.02
51.7–64.34
(n = 4)		----
Pentobarbital—68.85 65.56–69.26
(n = 19)		73.5
58.1–88.9 (n = 1)		—76.02
66.36–85.68 (n = 1)		—
Thiopental—64.75
54.03–67.52
(n = 8)		-—-—
Phenobarbital——————
Nembutal-62
60–63
(n = 1)		-—-—
Ketamine/xylazine87
79–95
(n = 1)		74.97
70.88–79.23
(n = 11)		89.9
73–106.8
(n = 1)		—91.7
82–101.4 (n = 1)		—
Ketamine/medetomidine-65
63.1–66.9
(n = 1)		-—-—
Ketamine/Diazepam-101.25
84.15–116.7
(n = 2)		-—-—
Ketamine/midazolam-78
69–87
(n = 1)		-—-—
Isoflurane—58.32
43.68–61.48
(n = 6)		————
Desflurane-69.0
67.72–0.28
(n = 1)		————
Chloralose-60.20
53.51–6.89
(n = 1)		————
Tribromethanol-36
33.5–38.5
(n = 1)		————
Ether—69.86
66.4–73.4
(n = 5)		————
Urethane—53.05
48.74–57.35
(n = 9)		————
Isolated heart—72.75
68,8–76.7
(n = 4)		————

Table 4.

QT interval duration (ms) under individual types of anesthesia with regard to sex and the cycle of light (inactive) and dark (active).

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.

Figure 3.

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.

5.2 QTc interval

In human cardiology, QTc interval assessment enables the comparison of QT values overtime at different HRs and improves the identification of patients at increased 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 use should be considered carefully in case of very low HR [143] . This fact is reflected in the data reported in Table 5 and Figure 4 of the average values of the QTc interval, where relatively large deviations under different types of anesthesia are evident.

AnesthesiaQTc interval (ms)QRS complex (ms)R wave amplitude (mV)T wave amplitude (mV)
Telemetry studies87.02
(81.79–92.31)
n = 5		26.08
(25.68–29.52)
n = 5		—0.139
(0.118–0.16)
n = 1
Pentobarbital203.77
(196.2–211.5)
n = 7		25.4
(23.68–27.13)
n = 19		0.56
(0.54–0.58)
n = 4		0.08
(0.07–0.9)
n = 2
Thiopental110.23
(100.5–120)
n = 7		22.76
(21.12–24.47)
n = 8		1.8
(1.76–1.84)
n = 1		—
Phenobarbital71.6
(69.36–73.84)
n = 1		55
(45–65)
n = 1		-—
Nembutal-20
(19–21
n = 1		1.06
(0.99–1.12)
n = 1		0.37
(0.34–0.41)
n = 1
Ketamine/xylazine143.76
(138.97–148.55)
n = 8		23.9
(22.16–25.64)
n = 12		0.49
(0.41–0.57)
n = 5		0.09
(0.06–0.11)
n = 5
Ketamine/medetomidine-27.5
(22.5–32.5)
n = 1		-—
Ketamine/diazepam-18.5
(13.25–23.75)
n = 2		-—
Ketamine/midazolam-18
(16.8–19.2)
n = 1		-0.07
(0.034–0.106)
n = 1
Isoflurane58.32
(43.68–61.48)
n = 4		18.3
(16.75–19.85)
n = 4		1.7
1.5–1.9
n = 1		0.11
(0.09–0.13)
n = 1
Desflurane184.7
(181.32–188.08)
n = 1		28.8
(25.22–32.38)
n = 1		——
Chloralose-66
(55.7–76.3)
n = 1		——
Tribromethanol90.5
(85.5–95.5)
n = 1		26.2
(25.3–27.1)
n = 2		——
Ether153
(151–155)
n = 1		22.15
(18.8–25.5)
n = 2		——
Urethane165.5
(158.6–180.5)
n = 3		18.41
(17.39–20.5)
n = 15		0.65
(0.64–0.66)
n = 2		0.337
(0.335–0.337)
n = 1
Isolated heart83.43
(52.65–114.2)
n = 2		32.5
(31.4–33.6)
n = 2		1.61
(not specified)
n = 2		1.42
(0.95–1.89)
n = 1

Table 5.

QTc interval, QRS complex duration, R and T wave amplitude, regardless of the synchronization of the animals to the light and dark cycle under individual types of anesthesia.

Data presented as average (range) n, number of experimental studies in which ventricular parameters were evaluated.

Figure 4.

Distribution of ranges of QTc interval from telemetry studies and under different types of general anesthesia in male rat males without taking into account the light periods of the rat regimen day when the experiments were performed. Only QTc interval ranges from at least three studies where QTc interval has been evaluated are shown in the figure. Telemetry studies (n = 5), pentobarbital anesthesia (n = 7), thiopental anesthesia (n = 7), ketamine/xylazine anesthesia (n = 8), urethane anesthesia (n = 3), isoflurane anesthesia (n = 4). n, number of baseline or control values from which duration of QTc interval was evaluated.

When comparing the duration of the QTc interval with the mean value from telemetry studies [26, 30, 31, 117, 118], significant prolongation occurred under pentobarbital [32, 38, 41, 42, 43, 47, 51] ketamine/xylazine [87, 90, 91, 92, 129, 136, 152, 153], and urethane [52, 57, 60] anesthesia, with moderate prolongation under thiopental [31, 62, 63, 66, 68, 71] anesthesia. The shortened QTc interval duration compared with the mean value from telemetry studies was under isoflurane anesthesia [72, 74, 75, 121].

The problem is the comparison between the sexes and to evaluate the effect of the LD cycle, for which insufficient experimental data are available. LD differences were found in females under ketamine/xylazine anesthesia (light 174.5 ± 34.8 ms vs. dark 202.1 ms) [19], unlike pentobarbital anesthesia, where there were no significant differences (light 197.7 ± 40.9 ms vs. dark 190.7 ± 26.6 ms) [20]. Unfortunately, this dependence has not been tested with other types of general anesthesia. The age effect of rats was demonstrated under rather unconventional tribromoethanol anesthesia by da Silva et al. [106], where the duration of the QTc interval was two times longer in older rats (117 ± 4 ms vs. 64 ± 6 ms) than in young rats at relatively the same HR (young, 381 ± 1 beats/min. vs. old, 405 ± 11 beats/min).

5.3 QRS complex

In some cases, it is also important to evaluate other parameters related to the electrophysiology of the ventricles. For example, the QRS complex indicates depolarization of the right and left ventricles and the contraction of the large ventricular muscles. Any conduction abnormality lasts longer and causes “extended” QRS complexes. The duration, amplitude, and morphology of the QRS complex are useful in the diagnosis of cardiac arrhythmias, conduction abnormalities, ventricular hypertrophy, myocardial infarction, electrolyte disturbances, and other disease states. High-frequency analysis of the QRS complex may be useful for detecting coronary artery disease during a stress test. Evaluation of the amplitude of the R wave as well as the P wave in experimental work on rats also proved to be important. They are informative and changes can help to determine the tendency of the myocardium to arrhythmias.

When comparing the average value of QRS complex duration from telemetry studies [21, 31, 117, 118, 119] to barbiturate anesthesia—under pentobarbital [32, 34, 37, 40, 42, 44, 45, 46, 47, 48, 49, 51, 122, 124, 125, 126, 154], thiopental [31, 61, 63, 64, 68, 69, 71], and Nembutal [114] anesthesia—the average value of the QRS complex duration was somewhat shorter and the ranges did not differ significantly.

Ketamine/xylazine [45, 78, 79, 84, 85, 89, 91, 92, 128, 129, 152], ketamine/diazepam [96, 98], and ketamine/midazolam [97] as well as ether [100, 101] and urethane anesthesia [45, 53, 55, 56, 57, 58, 60, 135, 137, 138] shortened the duration of the QRS complex compared to the value(s) from telemetry studies. The longer duration was under phenobarbital [95], ketamine/medetomidine [96], desflurane [72], chloralose [77] anesthesia, and in isolated hearts [105, 115] (Figure 5). Of course, such comparisons can be misleading because the values were reported in only one study. Similar to previously described ECG parameters, all experiments were performed on males without specifying the adaptation of the animals to the LD cycle, and there was no study addressing sex 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 5, Figure 5).

Figure 5.

Distribution of ranges of QRS complex 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 QRS complex ranges from at least three studies where QRS complex has been evaluated are shown in the figure. Telemetry studies (n = 5), pentobarbital anesthesia (n = 19), thiopental anesthesia (n = 8), ketamine/xylazine anesthesia (n = 12), urethane anesthesia (n = 15), isoflurane anesthesia (n = 4). n, number of baseline or control values from which duration of QT interval was evaluated.

Advertisement

6. Conclusions

In the discussion sections of many published in vivo studies, the results obtained are compared with previously published findings. Although changes in ECG parameters are often described, the type of anesthesia used in the experiments is not taken into account. Moreover, in acute in vivo experiments, the time of day the experiments are performed, and the adaptation of the animals to the LD cycle, and/or sex, are not taken into account whatsoever. This approach is self-evident and logical because the experiments are mostly performed only on males and during the workday, often without regard for chronobiological principles.

However, if changes in ECG parameters are considered to be important indicators of arrhythmogenesis, such comparisons may be misleading and must not be immediately regarded to indicate a difference in myocardial electrical stability. We should be more careful in interpreting results and, in discussing the mechanisms underlying a given type of arrhythmia, acknowledge that initial ECG parameters may already be affected to some extent by the anesthesia used and by regular daytime experimentation. The data presented in the tables clearly demonstrate the differences in baseline or control values with different types of anesthesia and whether the baseline or control value is “normal” or already altered by anesthesia should be taken into account. For example, a change in the evaluated ECG parameter after an intervention may not necessarily indicate a possible electrophysiological substrate for the development of an arrhythmia, it can only be “adjusted to a normal value” because we do not know the reference value.

Similarly, sex and time of day the experiments are performed can be a problem because it is not possible to determine sex differences as well as changes during the active and nonactive period of rat regimen day because there are no studies that have directly addressed this aspect. Telemetry studies that would reveal changes in ECG parameters in circadian dependence, to describe reference values and, possibly, sex differences, could help to facilitate interpretation of the results obtained. However, it is highly speculative to consider the values from the cited telemetry studies as reference values (although the ECG is measured from nonanesthetized rats) because the methodologies do not report whether the indicated baseline value is the 24 h average (mesor) or is the current value measured immediately before the intervention. Most likely, they are baseline values before the experimental intervention and this only applies to male rats, whereas the lighted (light or dark) period when the experiment is performed is not reported, although an adaptation of animals to the LD cycle is described.

Thus, the question “Which anesthetic is the most suitable anesthetic in in vivo rat cardiological experiments so that the initial electrophysiology of the heart is not significantly affected” is relatively difficult to address for several reasons. First, we do not currently have specified sex-related reference values for rats. Second, because there are circadian variations in the measurable parameters of the cardiovascular system, there are also changes in individual ECG parameters, depending on the light cycle (inactive period) and dark (active period). Finally, the effects of anesthetics at the level of ion channels are not described in detail because the entire electrophysiology of the myocardium depends on ionic currents and the overall metabolism of minerals.

As such, when evaluating changes in ECG parameters in rats, these possible variations should also be taken into account. The correct assessment of changes, in turn, depends on knowledge of the reference values according to sex and on the time of day the experiments or measurements are performed. Although rat ECG parameters are only analyzed in this study, these can be of basis to further researches and studies that may involve humans in the future.

Advertisement

Acknowledgments

This work was supported by a VEGA grant: 1/0008/20.

Advertisement

Conflict of interest statement

The authors declare that there is no conflict of interest.

Advertisement

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

  1. 1. Fields RD. Vive la Différence. Scientific American. 2014;311(3):14
  2. 2. Caetano J, Alves JD. Heart rate and cardiovascular protection. European Journal of Internal Medicine. 2015;26(4):217-222
  3. 3. Zaza A, Ronchi C, Malfatto G. Arrhythmias and heart rate: Mechanisms and significance of a relationship. Arrhythmia & Electrophysiology Review. 2018;7(4):232-237
  4. 4. Svorc P, Tomori Z, Bracokova I, Marossy A. Effect of pentobarbital and ketamine/xylazine anaesthesia on the electrical stability of the heart and heart rate in rat hypoventilation/reoxygenation model. Biologia. 2003;58(3):379-386
  5. 5. Priori SG, Chen SR. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circulation Research. 2011;108:871-883
  6. 6. Haxxox JP. Effect of temperature on the heart rate, electrocardiogram and certain myocardial oxidations of the rat. Circulation Research. 1958;6:771-778
  7. 7. Baldwin A, Wagers C, Schwartz GE. Reiki improves heart rate homeostasis in laboratory rats. The Journal of Alternative and Complementary Medicine. 2008;14(4):417-422
  8. 8. Heisser A. Effect of exercise and L-citrulline on heart rate in rats. Cantaurus. 2020;28:5-7
  9. 9. James AF, Choisy SCM, Hancox JC. Recent advances in understanding sex differences in cardiac repolarization. Progress in Biophysics and Molecular Biology. 2007;94(3):265-319
  10. 10. Harkness JE, Wagner JE. In Book: The Biology and Medicine of Rabbits and Rodents. Philadelphia: Lea & Febiger; 1977
  11. 11. Leblanc N, Chartier D, Gosselin H, Rouleau JL. Age and gender differences in excitation-contraction coupling of the rat ventricle. Journal of Physiology (London). 1998;511(Pt 2):533-548
  12. 12. Philp KL, Coker SJ, Hussain M, Hart G. Actions of 17b-oestradiol on the current-voltage relationship for the L-type calcium current (ICa) in ventricular myocytes isolated from male and female rats. Journal of Physiology (London). 2002;544P:57P-58P
  13. 13. Hashimoto M, Kuwahara M, Tsubone H, Sugano S. Diurnal variation of autonomic nervous activity in the rat - investigation by power spectral analysis of heart rate variability. Journal of Electrocardiology. 1999;32(2):167-171
  14. 14. Hashimoto M, Harada T, Ishikawa T, Obata M, Shibutani Y. Investigation on diabetic autonomic neuropathy assessed by power spectral analysis of heart rate variability in WBN/Kob rats. Journal of Electrocardiology. 2001;34(3):243-250
  15. 15. Koresh O, Kaplan Z, Zohar J, Matar MA, Geva AB, Cohen H. Distinctive cardiac autonomic dysfunction following stress exposure in both sexes in an animal model of PTSD. Behavioural Brain Research. 2016;308:128-142
  16. 16. Molcan L, Teplan M, Vesela A, Zeman M. The long-term effects of phase advance shifts of photoperiod on cardiovascular parameters as measured by radiotelemetry in rats. Physiological Measurement. 2013;34:1623-1632
  17. 17. Molcan L, Vesela A, Zeman M. Repeated phase shifts in the lighting regimen change the blood pressure response to norepinephrine stimulation in rats. Physiological Research. 2014;63(5):567-575
  18. 18. Schlatter J, Zbinden G. Heart rate- and ECG-recording in the rat by biotelemetry. In: Chambers CM, Chambers PL, editors. New Toxicology for Old. Archives of Toxicology (Supplement) 5. Berlin: Heidelberg, Springer; 1982
  19. 19. Svorc P, Svorc P Jr, Novakova M, Bacova I, Jurasova Z, Marossy A. Ketamine/xylazine anaesthesia in the chronobiological studies. Biological Rhythm Research. 2014;45(4):633-642
  20. 20. SvorcJr. P, Svorc P, Bacova I, Gresova S. Pentobarbital anaesthesia in the chronobiological studies. Biological Rhythm Research 2015;46(3):445-452.
  21. 21. Farmer JB, Levy GP. A simple method for recording the electrocardiogram and heart rate from conscious animals. British Journal of Pharmacology and Chemotherapy. 1968;32:193-200
  22. 22. Sgoifo A, De Boer SF, Buwalda B, Korte-Bouws G, Tuma J, Bohus B, et al. Vulnerability to arrhythmias during social stress in rats with different sympathovagal balance. American Journal of Physiology. Heart and Circulatory Physiology. 1998;275(2):460-466
  23. 23. Nijsen MJMA, Croiset G, Diamant M, Stam R, Delsing D, de Wied D, et al. Conditioned fear-induced tachycardia in the rat; vagal involvement. European Journal of Pharmacology. 1998;350(2-3):211-222
  24. 24. Nijsen MJMA, Croiset G, Stam R, Bruijnzeel A, Diamant M, de Wied D. The role of the CRH type 1 receptor in autonomic responses to corticotropin-releasing hormone in the rat. Neuropsychopharmacology. 2000;22(4):388-399
  25. 25. Nijsen MJMA, Croiset G, Diamant M, De Wied D, Wiegant VM. CRH signalling in the bed nucleus of the stria terminalis is involved in stress-induced cardiac vagal activation in conscious rats. Neuropsychopharmacology. 2001;24(1):1-10
  26. 26. Baillard C, Mansier P, Ennezat PV, Mangin L, Medigue C, Swynghedauw B, et al. Converting enzyme inhibition normalizes QT interval in spontaneously hypertensive rats. Hypertension. 2000;36:350-354
  27. 27. Towa S, Kuwahara M, Tsubone H. Characteristics of autonomic nervous function in Zucker-fatty rats: Investigation by power spectral analysis of heart rate variability. Experimental Animals. 2004;53(2):137-144
  28. 28. Pereira-Junior PP, Marocolo M, Rodrigues FP, Medei E, Nascimento JHM. Noninvasive method for electrocardiogram recording in conscious rats: Feasibility for heart rate variability analysis. Anais Academia Brasileria de Ciências. 2010;82(2):431-437
  29. 29. Koizumi S, Minamisawa S, Sasaguri K, Onozuka M, Sato S, Ono Y. Chewing reduces sympathetic nervous response to stress and prevents poststress arrhythmias in rats. American Journal of Physiology-Heart and Circulatory Physiology. 2011;301(4):H1551-H1558
  30. 30. Carll AP, Hazari MS, Perez CM, Krantz QT, King CJ, Winsett DW, et al. Whole and particle-free diesel exhausts differentially affect cardiac electrophysiology, blood pressure, and autonomic balance in heart failure-prone rats. Toxicological Sciences. 2012;128(2):490-499
  31. 31. Kumar P, Srivastava P, Gupta A, Bajpai M. Noninvasive recording of electrocardiogram in conscious rat: A new device. Indian Journal of Pharmacology. 2017;49(1):116-118
  32. 32. Lessard Y, Vernhet L, Mainguy A. Relationships between transmembrane action potential changes and simultaneous changes in electrocardiograms of rats after a one-month aortic pressure overload. Physiological Research. 1997;46(4):257-269
  33. 33. Miki K, Kosho A, Hayashida Y. Method for continuous measurements of renal sympathetic nerve activity and cardiovascular function during exercise in rats. Experimental Physiology. 2002;87(1):33-39
  34. 34. Sugiyama A, Takahara A, Honsho S, Nakamura Y, Hashimoto K. A simple in vivo atrial fibrillation model of rat induced by transesophageal atrial burst pacing. Journal of Pharmacological Sciences. 2005;98:315-318
  35. 35. Rivero DHRF, Sassaki C, Lorenzi-Filho G, Saldiva PHN. PM2.5 induces acute electrocardiographic alterations in healthy rats. Environmental Research. 2005;99(2):262-266
  36. 36. Yokokawa M, Ohnishi S, Ishibashi-Ueda H, Obata H, Otani K, Miyahara Y, et al. Transplantation of mesenchymal stem cells improves atrioventricular conduction in a rat model of complete atrioventricular block. Cell Transplantation. 2008;17(10-11):1145-1155
  37. 37. Kumar R, Kela A, Tayal G. Effect of acute stress on rat ECG. The Internet Journal of Pharmacology. 2009;8(1)
  38. 38. Imani A, Faghihi M, Keshavarz DM, Karimian SM, Niaraki SS. Effect of different doses of noradrenaline against ischemia-induced ventricular arrhythmias in rat heart in vivo. Indian Pacing Electrophysiology Journal. 2009;9(1):35-44
  39. 39. Chang YT, Wann SR, Wu PL, Hsieh KH, Lin CC, Huang MS, et al. Influence of age on heart rate variability during therapeutic hypothermia in a rat model. Resuscitation. 2011;82(10):1350-1354
  40. 40. Howarth FC, Jacobson M, Shafiullah M, Ljubisavljevic M, Adeghate E. Heart rate, body temperature and physical activity are variously affected during insulin treatment in alloxan-induced type 1 diabetic rat. Physiological Research. 2011;60(1):65-73
  41. 41. Liu B, Li S, Su Y, Xiong MT, Xu YW. Comparative study of the protective effects of terfenadine and amiodarone on barium chloride/aconitine-induced ventricular arrhythmias in rats: A potential role of terfenadine. Molecular Medicine Reports. 2014;10(6):3217-3226
  42. 42. Abbod AM, Elshal MF. VDR stimulation improves outcome of isoprenaline-induced myocardial infarction in rats via down-regulation of cardiac inos gene expression. Biomedical Research. 2015;36(4):755-764
  43. 43. Ahmad A, Sattar MZ, Rathore HA, Khan SA, Lazhari MA, Hashmi F, et al. Impact of isoprenaline and caffeine on development of left ventricular hypertrophy and renal hemodynamic in Wistar Kyoto rats. Acta Poloniae Pharmaceutica. 2015;72(5):1015-1026
  44. 44. Pugsley MK, Hayes ES, Wang WQ , Walker MJA. Ventricular arrhythmia incidence in the rat is reduced by naloxone. Pharmacological Research. 2015;97:64-69
  45. 45. Konopelski P, Ufnal M. Electrocardiography in rats: A comparison to human. Physiological Research. 2016;65(5):717-725
  46. 46. Comerma-Steffensen SG, Carvacho I, Hedegaard ER, Simonsen U. Small and intermediate calcium-activated potassium channel openers improve rat endothelial and erectile function. Frontiers in Pharmacology. 2017;8:660
  47. 47. Pezolato VA, Mascarin AL, Ferreira RB, Dias R, Silva CA. Acompanhamento eletrocardiográfico no desenvolvimento de ratos Wistar. Arquivo Brasileiro de Medicina Veterinaria e Zootecnia. 2017;69(01):39-47
  48. 48. Wang S, Cheng ZY, Chen XJ, Xue HZ. Ulinastatin protects rats with myocardial infarction by activating Nrf2/NOS pathway. European Review for Medical and Pharmacological Sciences. 2018;22(24):8990-8998
  49. 49. Chen XY, Guo HC, Li Q , Zhang Y, Liu HL, Zhang XF, et al. Protective effect of berberine on aconite-induced myocardial injury and the associated mechanisms. Molecular Medicine Reports. 2018;18(5):4468-4476
  50. 50. Huang XW, Pan MD, Du PH, Wang LX. Arginase-2 protects myocardial ischemia-reperfusion injury via NF-kappa B/TNF-alpha pathway. European Review for Medical and Pharmacological Sciences. 2018;22(19):6529-6537
  51. 51. Abdulsalam TM, Hasanin AH, Mohamed RH, Badawy AELS. Angiotensin receptor-neprilysin inhibitior (thiorphan/irbesartan) decreased ischemia-reperfusion induced ventricular arrhythmias in rat; in vivo study. European Journal of Pharmacology. 2020;882:173295
  52. 52. Lin MT, Liu HH, Yang YL. Involvement of interleukin-1 receptor mechanisms in development of arterial hypotension in rat heatstroke. American Journal of Physiology. Heart and Circulatory Physiology. 1997;273(4):H2072-H2077
  53. 53. Buschmann G, Schumacher W, Budden R, Kühl UG. Evaluation of the effect of dopamine and other catecholamines on the electrocardiogram and blood pressure of rats by means of on-line biosignal processing. Journal of Cardiovascular Pharmacology. 1980;2:777-795
  54. 54. Chaswal M, Das S, Prasad J, Katyal A, Fahim M. Chemical sympathectomy restores baroreceptor-heart rate reflex and heart rate variability in rats with chronic nitric oxide deficiency. Physiological Research. 2015;64(4):459-466
  55. 55. Aydin B, Hocaoglu N, Micili SC, Ergur BU, Kalkan S. Effects of 2-hydroxypropyl-beta-cyclodextrin on cardiovascular signs of amitriptyline poisoning in a rat model. Cardiovascular Toxicology. 2016;16(4):374-380
  56. 56. Emeka PM, Al-Ahmed A. Effect of metformin on ECG, HR and BP of rats administered with cardiotoxic agent doxorubicin. International Journal of Basic & Clinical Pharmacology. 2017;6(5):1054-1059
  57. 57. Younis NS, Al Ahmed A, Al Mulhim N, AlGarni AA, Madu EP. Exenatide attenuation of cardiac rhythm abnormalities and blood pressure changes induced by doxorubicin in rats. International Journal of Pharmacology. 2017;13(8):1098-1102
  58. 58. Sharma S, Khan V, Najmi AK, Alam O, Haque SE. Prophylactic treatment with icariin prevents isoproterenol-induced myocardial oxidative stress via nuclear factor-like 2 activation. Pharmacognsy Magazine. 2018;14(suupl. S, 55):S227-S236
  59. 59. Bozdogan O, Bozcaarmutlu A, Kaya ST, Sapmaz C, Ozarslan TO, Eksioglu D, et al. Decreasing myocardial estrogen receptors and antioxidant activity may be responsible for increasing ischemia- and reperfusion-induced ventricular arrhythmia in older female rats. Life Sciences. 2021;271:119190
  60. 60. Lin C-C, Hsu K-H, Shih C-P, Chang G-J. Hemodynamic and electromechanical effects of paraquat in rat heart. PLoS One. 2021;16(4):e0234591
  61. 61. Kralova E, Mokran T, Murin J, Stankovicova T. Electrocardiography in two models of isoproterenol-induced left ventricular remodeling. Physiological Research. 2008;57(suppl 2):583-589
  62. 62. Kralova E, Racanska E, Vicenova A, Boselova I, Malik I, Stankovicova T. Pharmacological evaluation of the effects of phenylcarbamic acid derivatives on cardiovascular functions in rats. Acta Pharmaceutica. 2018;68(4):507-515
  63. 63. Maciel NR, Reis PG, Kato KC, Vidal AT, Guimaraes HN, Frezard F, et al. Reduced cardiovascular alterations of tartar emetic administered in long-circulating liposomes in rats. Toxicology Letters. 2010;199(3):234-238
  64. 64. Joukar S. Electrocardiogram alterations following one-week consumption of Crocus sativus L. (saffron). EXCLI Journal. 2012;11:480-486
  65. 65. Joukar S, Ghorbani-Shahrbabaki S, Hajali V, Sheibani V, Naghsh N. Susceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation. Sleep Medicine. 2013;14(12):1277-1282
  66. 66. Klimas J, Vaja V, Vercinska M, Kyselovic J, Krenek P. Discrepant regulation of QT (QTc) interval duration by calcium channel blockade and angiotensin converting enzyme inhibition in experimental hypertension. Basic & Clinical Pharmacology & Toxicology. 2012;111(4):279-288
  67. 67. Elsherbiny NM, Salama MF, Said E, El-Sherbiny M, Al-Gayyar MMH. Crocin protects against doxorubicin-induced myocardial toxicity in rats through down-regulation of inflammatory and apoptic pathways. Chemico-Biological Interactions. 2016;247:39-48
  68. 68. Raji-Amirhasani A, Joukar S, Naderi-Boldaji V, Bejeshk MA. Mild exercise along with limb blood-flow restriction modulates the electrocardiogram, angiotensin, and apelin receptors of the heart in aging rats. Iranian Journal of Basic Medical Sciences. 2018;21(6):558-563
  69. 69. Rahmanifard M, Vessal M, Noorafshan A, Karbalay-Doust S, Naseh M. The protective effects of coenzyme Q10 and lisinopril against doxorubicin-induced cardiotoxicity in rats: A stereological and electrocardiogram study. Cardiovascular Toxicology. 2021;21(11):936-946
  70. 70. El-Marasy SA, El-Awdan SA, Hassan A, Abdallah HMI. Cardioprotective effect of thymol against adrenaline-induced myocardial injury in rats. Heliyon. 2020;6(7):e04431
  71. 71. Haydari S, Nazari A, Moghimian M, Sedighi M, Ghaderpour S. Cardioprotective activity of ethanolic extract of Echinophora cinerea against aluminum phosphide poisoning in rats. Journal of Food Biochemistry. 2020;44:e13300
  72. 72. Ozturk A, Altug ME. Effects of repeated application of isoflurane and desflurane on electrocardiogram, anaesthesia induction, and recovery characteristics in rats. Bulletin-Veterinary Institute in Pulawy. 2007;51(4):635-640
  73. 73. Rey M, Weber E, Hess PD. Simultaneous pulmonary and systemic blood pressure and ECG interval measurement in conscious, freely moving rats. Journal of the American Association for Laboratory Animal Science. 2012;51(2):231-238
  74. 74. Jiang M, Murias JM, Chrones T, Sims SM, Lui E, Noble EG. American ginseng acutely regulates contractile function of rat heart. Frontiers in Pharmacology. 2014;5:43
  75. 75. Imoto K, Hirakawa M, Okada M, Yamawaki H. Canstatin modulates L-type calcium channel activity in rat ventricular cardiomyocytes. Biochemical and Biophysical Research Communications. 2018;499(4):954-959
  76. 76. Kruger C, Landerer V, Zugck C, Ehmke H, Kubler W, Haass M. The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction. Cardiovascular Research. 2000;45(4):900-912
  77. 77. Dai GF, Wang ZJY. Octreotide protects doxorubicin-induced cardiac toxicity via regulating oxidative stress. European Review for Medical and Pharmacological Sciences. 2018;22(18):6139-6148
  78. 78. Mao PR, Jamali F. Methoxyflurane anesthesia augments the chronotropic and dromotropic effects of verapamil. Journal of Pharmacy & Pharmaceutical Sciences. 1999;2(1):30-35
  79. 79. Regan CP, Cresswell HK, Zhang R, Lynch JJ. Novel method to assess cardiac electrophysiology in the rat: Characterization of standard ion channel blockers. Journal of Cardiovascular Pharmacology. 2005;46(1):68-75
  80. 80. Trindade DC, Trindade RC, Marassi MP, Martins OPPR, Costa-E-Sousa RH, Mattos EC, et al. Role of renin-angiotensin system in development of heart failure induced by myocardial infarction in rats. Anais da Academia Brasileira de Ciências. 2007;79(2):251-259
  81. 81. Yenisehirli A, Naseri E. Omeprazole, lansoprazole and pantoprazole had no effect on blood pressure and electrocardiogram of anesthetized rat. Pharmacological Research. 2008;58(1):65-71
  82. 82. Parasuraman S, Raveendran R, Selvaraj RJ. Effects of cleistanthins a and B on blood pressure and electrocardiogram in Wistar rats. Zeitschrift für Naturforschung C. 2011;66(11-12):581-587
  83. 83. Kannan M, Quine SD. Ellagic acid ameliorates isoproterenol induced oxidative stress: Evidence from electrocardiological, biochemical and histological study. European Journal of Pharmacology. 2011;659(1):45-52
  84. 84. Mutiso SK, Rono DK, Bukachi F. Relationship between anthropometric measures and early electrocardiographic changes in obese rats. BMC Research Notes. 2014;7:931
  85. 85. Selcuk EB, Sungu M, Parlakpinar H, Ermis N, Taslidere E, Vard N, et al. Evaluation of the cardiovascular effects of varenicline in rats. Drug Design, Development and Therapy. 2015;9:5705-5717
  86. 86. Binu P, Priya N, Abhilash S, Vineetha RC, Nair RH. Studies on curative efficacy of monoterpene eugenol on anti- leukemic drug arsenic trioxide induced cardiotoxicity. Biomedicine & Pharmacotherapy. 2017;91:559-566
  87. 87. Bora S, Erdogan MA, Yigitturk G, Erbas O, Parlak I. The effects of lipid emulsion, magnesium sulphate and metoprolol in amitriptyline-induced cardiovascular toxicity in rats. Cardiovascular Toxicology. 2018;18(6):547-556
  88. 88. Pişkin Ö, Ayoğlu H. Effects of remifentanil pretreatment on bupivacaine cardiotoxicity in rats. Cardiovascular Toxicology. 2018;18(1):56-62
  89. 89. Arini PD, Liberczuk S, Mendieta JG, Santa María M, Bertrán GC. Electrocardiogram delineation in a Wistar rat experimental model. Computational and Mathematical Methods in Medicine. 2018;2018(3):1-10
  90. 90. Ramezani-Aliakbari F, Badavi M, Dianat M, Mard SA, Ahangarpour A. The effects of trimetazidine on QT-interval prolongation and cardiac hypertrophy in diabetic rats. Arquivos Brasileiros de Cardiologia. 2019;112(2):173-178
  91. 91. Sohrabi F, Dianat M, Badavi M, Radan M, Mard SA. Does gallic acid improve cardiac function by attenuation of oxidative stress and inflammation in an elastase-induced lung injury? Iranian Journal of Basic Medical Sciences. 2020;23:1130-1138
  92. 92. Boarescu PM, Boarescu I, Bulboacă AE, Bocsan IC, Pop RM, Gheban D, et al. Multi-organ protective effects of curcumin nanoparticles on drug-induced acute myocardial infarction in rats with type 1 diabetes mellitus. Applied Sciences. 2021;11:5497
  93. 93. Miranda A, Costa-e-Sousa RH, Werneck-de-Castro JP, Mattos EC, Olivares EL, Ribeiro VP, et al. Time course of echocardiographic and electrocardiographic parameters in myocardial infarct in rats. Anais da Academia Brasileira de Ciências. 2007;79:639-648
  94. 94. Ketabchi F, Sepehrinezhad A, Dehghanian A. The relationship between liver dysfunction, electrocardiographic abnormalities and metabolism in rat. Journal of Clinical and Experimental Cardiology. 2018;9(10):1000610
  95. 95. Kumar P, Verma S, Singh S, Tiwari S, Khan MY. Effect of Aloe vera (Aloe barbadensis) gel extract on repolarization state of myocardium in albino rat. African Journal of Pharmacy and Pharmacology. 2010;4(12):885-889
  96. 96. Barrasa JLM, Rodriguez NS, Rodriguez-Perez JC, Hidalgo AC, Garcia AT, Camarillo JAI, et al. Electrocardiographic changes in rats undergoing thoracic surgery under combined parenteral anesthesia. Lab Animal. 2008;37(10):469-174
  97. 97. Sedmera D, Neckar J, Benes J Jr, Pospisilova J, Petrak J, Sedlacek K, et al. Changes in myocardial composition and conduction properties in rat heart failure model induced by chronic volume overload. Frontiers in Physiology. 2016;7:367
  98. 98. Yadav RK, Rawat JK, Gautam S, Singh M, Kumar M, Ansari MN, Roy S, Saeedan AS, Kaithwas G. Antidiabetic activity of mefloquine via GLP-1 receptor modulation against STZ-NA-induced diabetes in albino wistar rats. 3 Biotech 2018;8(5), 1-10
  99. 99. Normann SJ, Priest RE, Benditt EP. Electrocardiogram in the normal rat and its alteration with experimental coronary occlusion. Circulation Research. 1961;9:282-287
  100. 100. Fraser RS, Harley C, Wiley T. Electrocardiogram in the normal rat. Journal of Applied Physiology. 1967;23(3):401-402
  101. 101. Kela AK, Reddy IP, Thombre DB. E.C.G. findings in normal rats and after administration isoproterenol. Indian Journal of Physiology and Pharmacology. 1980;24(2):84-90
  102. 102. Krandycheva VV, Kharin SN, Shmakov DN. P-wave body surface potential distribution in rats. Journal of Electrocardiology. 2006;39(1):88-92
  103. 103. Upaganlawar AA, Balaraman R. Cardioprotective effects of co-administration of pomegranate extract and vitamin E on electrocardiographic, biochemical and apoptotic changes in isoproterenol induced myocardial infarction in rats. Pharmacologia. 2015;6(5):178-185
  104. 104. Farag NE, El-Kherbetawy MK, Ismail HM, Abdelrady AM, Toraih EA, Abdelbasset WK, et al. Differential effect of three macrolide antibiotics on cardiac pathology and electrophysiology in a myocardial infarction rat model: Influence on sodium Nav1.5 channel expression. Pharmaceuticals. 2021;14:597-603
  105. 105. Taskin E, Kindap EK, Ozdogan K, Aycan MBY, Dursun N. Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II. Cytotechnology. 2016;68(1):33-43
  106. 106. Da Silva VJD, Neto EF, Salgado HC, Junior RF. Chronic converting enzyme inhibition normalizes QT interval in aging rats. Brazilian Journal of Medical and Biological Research. 2002;35(9):1025-1031
  107. 107. Walsh EP, Alexander ME, Cecchin F. Chapter 12 - electrocardiography and introduction to electrophysiologic techniques. In: Nadas’ Pediatric Cardiology. 2nd ed. Amsterdam: Elsevier Inc; 2006. pp. 145-181
  108. 108. Surawicz B, Knilans TK. Normal electrocardiogram. PR interval. In: Chou’s Electrocardiography in Clinical Practice. 6th ed. Amsterdam: Elsevier Inc; 2008
  109. 109. Richig JW, Sleeper MM. PR (PQ), QRS, QT, and other issues. In: Electrocardiography of Laboratory Animals. 2nd ed. London, UK: Academic Press, Elsevier Inc; 2019
  110. 110. Mauer DE, Naegeli B, Straumann E, Bertel O, Frielingsdorf J. Quality of life and exercise capacity in patients with prolonged PQ interval and dual chamber pacemakers: A randomized comparison of permanent ventricular stimulation vs intrinsic AV conduction. EP Europace. 2003;5(4):411-417
  111. 111. Portnov A. PQ interval extension. Diseases of the heart and blood vessels (cardiology). PQ interval extension: symptoms, diagnosis, treatment (iliveok.com). 2021.
  112. 112. Lown B, Ganong WF, Levine SA. The syndrome of short P-R interval normal QRS complex and paroxysmal rapid heart action. Circulation. 1952;5:693-706
  113. 113. Zada M, Lo Q , Trivedi SJ, Harapoz M, Boyd AC, Devine K, et al. Electrocardiographic characteristics and their correlation with echocardiographic alterations in fabry disease. Journal of Cardiovascular Development and Disease. 2022;9(1):11
  114. 114. Shumilova TE, Shereshkov VI, Yanvareva IN, Nozdrachev AD. Peculiarities of myocardial electrogenesis in laboratory rats under conditions of acute nitrite intoxication. Journal of Evolutionary Biochemistry and Phys. 2010;46(2):179-188
  115. 115. Sadeghi N, Saadatfard S, Dianat M, Abedi H, Dehghani K. Combination effects of gallic acid and cyclosporine a during ischemia/ reperfusion on rat electrocardiogram parameters and arrhythmia. Physiology and Pharmacology. 2021;25:162-170
  116. 116. Damasceno DD, Lima MP, Motta DF, Ferreira AJ, Quintão-Junior JF, Drummond-Junior LR, et al. Cardiovascular and eletrocardiographic parameters after tonin administration in Wistar rats. Regulatory Peptides. 2013;181:30-36
  117. 117. Gohma H, Kuramoto T, Kuwamura M, Okajima R, Tanimoto N, Yamasaki K, et al. WTC deafness Kyoto (dfk): A rat model for extensive investigations of Kcnq1 functions. Physiological Genomics. 2006;24:198-206
  118. 118. Mamalyga ML. Heart rate regulation at different levels of convulsive readiness. Bulletin of Experimental Biology and Medicine. 2013;155(4):425-428
  119. 119. Adeyemi O, Parker N, Pointon A, Rolf M. A pharmacological characterization of electrocardiogram PR and QRS intervals in conscious telemetered rats. Journal of Pharmacological and Toxicological Methods. 2020;102:106679
  120. 120. Hamdy DA, Brocks DR. Experimental hyperlipidemia causes an increase in the electrocardiographic changes associated with amiodarone. Journal of Cardiovascular Pharmacology. 2009;53:1-8
  121. 121. Patel JP, Brocks DR. Effect of experimental hyperlipidaemia on the electrocardiographic effects of repeated doses of halofantrine in rats. British Journal of Pharmacology. 2010;161(6):1427-1440
  122. 122. Machidal K, Dol K, Kaburaki M, Sugano S. Electrocardiographical findings of WBN/Kob rats. Laboratory Animals. 1990;24(3):288-291
  123. 123. Van Buren T, Schiereck P, De Ruiter GJW, Gispen WH, De Wildt DJ. Vagal efferent control of electrical properties of the heart in experimental diabetes. Acta Diabetologica. 1998;35(1):19-25
  124. 124. Lee JK, Nishiyama A, Kambe F, Seo H, Takeuchi S, Kamiya K, et al. Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy. American Journal of Physiology. Heart and Circulatory Physiology. 1999;277(5):H1725-H1731
  125. 125. Barrett TD, Hayes ES, Yong SL, Zolotoy AB, Abraham S, Walker MJA. Ischaemia selectivity confers efficacy for suppression of ischaemia-induced arrhythmias in rats. European Journal of Pharmacology. 2000;398(3):365-374
  126. 126. Ghelfi E, Ramos-Rhoden C, Wellenius GA, Lawrence J, Gonzalez-Flecha B. Cardiac oxidative stress and electrophysiological changes in rats exposed to concentrated ambient particles are mediated by TRP-dependent pulmonary reflexes. Toxicological Sciences. 2008;102(2):328-336
  127. 127. Regan CP, Stump GL, Wallace AA, Anderson KD, McIntyre CJ, Liverton NJ, et al. In vivo cardiac electrophysiologic and antiarrhythmic effects of an isoquinoline IKur blocker, ISQ-1, in rat, dog, and nonhuman primate. Journal of Cardiovascular Pharmacology. 2007;49(4):236-245
  128. 128. Medeiros DM, Shiry LJ, McCune SA. Marginal copper intakes over a protracted period in genetically and nongenetically susceptible heart disease rats disturb electrocardiograms and enhance lipid deposition. Nutrition Research. 2005;25(7):663-372
  129. 129. Medei E, Lima-Leopoldo AP, Pereira-Junior PP, Leopoldo AS, Campos DHS, Raimundo JM, et al. Could a high-fat diet rich in unsaturated fatty acids impair the cardiovascular system? The Canadian Journal of Cardiology. 2010;26(10):542-548
  130. 130. Milliez P, Deangelis N, Rucker-Martin C, Leenhardt A, Vicaut E, Robidel E, et al. Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction. European Heart Journal. 2005;26(20):2193-2199
  131. 131. Haugan K, Lam HR, Knudsen CB, Petersen JS. Atrial fibrillation in rats induced by rapid transesophageal atrial pacing during brief episodes of asphyxia: A new in vivo model. Journal of Cardiovascular Pharmacology. 2004;44(1):125-135
  132. 132. Nattel S, Shiroshita-Takeshita A, Brundel BJ, Rivard L. Mechanisms of atrial fibrillation: Lessons from animal models. Progress in Cardiovascular Diseases. 2005;48:9-28
  133. 133. Gupta C, Omanwar S, Bubber P, Saidullah B. ECG alterations precedes cardiac hypertrophy in rat model of diabetes. Open Access Journal of Toxicology. 2018;2(5)
  134. 134. Shamala S, Krishna KL. Cardioprotective activity of fruit extracts of momordica dioca roxb on doxorubicin induced toxicity on rats. Science International. 2013;1(12):392-400
  135. 135. Badole SL, Jangam GB, Chaudhari SM, Ghule AE, Zanwar AA. L-glutamine supplementation prevents the development of experimental diabetic cardiomyopathy in streptozotocin-nicotinamide induced diabetic rats. PLoS One. 2014;9(3):e92697
  136. 136. Cagiltay E, Pouwels S, Erbas O, Taskiran D, Tas SK, Aslan I. The prophylactic effects of metoprolol, diltiazem, and pilocarpine on hypoglycemia induced prolongation of QT interval. Cureus. 2021;13(3):e14058
  137. 137. Jain PG, Mahajan UB, Shinde SD, Surana SJ. Cardioprotective role of FA against isoproterenol induced cardiac toxicity. Molecular Biology Reports. 2018;45(5):1357-1365
  138. 138. Sultan F, Kaur R, Mir AH, Maqbool I, Lonare M, Singh D, et al. Rosuvastatin and retinoic acid may act as pleiotropic agents’ against β-adrenergic agonist-induced acute myocardial injury through modulation of multiple signalling pathways. Chemico-Biological Interactions. 2020;318:108970
  139. 139. Gogelein H, Ruetten H, Albus U, Englert HC, Busch AE. Effects of the cardioselective K-ATP channel blocker HMR 1098 on cardiac function in isolated perfused working rat hearts and in anesthetized rats during ischemia and reperfusion. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2001;364(1):33-41
  140. 140. Di Filippo C, D'Amico M, Marfella R, Berrino L, Giugliano D, Rossi F. Endothelin-1 receptor antagonists reduce cardiac electrical instability induced by high glucose in rats. Naunyn-Schmiedeberg's Archives of Pharmacology. 2002;366(3):193-197
  141. 141. Panoulas VF, Toms TE, Douglas KMJ, Sandoo A, Metsios GS, Stavropoulos-Kalinoglou A, et al. Prolonged QTc interval predicts all-cause mortality in patients with rheumatoid arthritis: An association driven by high inflammatory burden. Rheumatology. 2014;53(1):131-137
  142. 142. Jayasinghe R, Kovoor P. Drugs and the QTc interval. Australian Prescriber. 2002;25:63-65
  143. 143. Kmecova J, Klimas J. Heart rate correction of the QT duration in rats. European Journal of Pharmacology. 2010;641(2-3):187-192
  144. 144. Rossing P, Breum L, Major-Pedersen A, Sato A, Winding H, Pietersen A, et al. Prolonged QTc interval predicts mortality in patients with type 1 diabetes mellitus. Diabetic Medicine. 2001;18(3):199-205
  145. 145. Andršová I, Hnatkova K, Šišáková M, Toman O, Smetana P, Huster KM, et al. Sex and rate change differences in QT/RR hysteresis in healthy subjects. Frontiers in Physiology. 2022;12:2473
  146. 146. Van Noord C, Eijgelsjeim M, Stricker BHC. Drug- and non-drug-associated QT interval prolongation. British Journal of Clinical Pharmacology. 2010;70(1):16-23
  147. 147. Hayes E, Pugsley MK, Penz WP, Adaikan G, Walker MJ. Relationship between QaT and RR intervals in rats, Guinea pigs, rabbits, and primates. Journal of Pharmacological and Toxicological Methods. 1994;32:201-207
  148. 148. Tavakoli S, Hajrasouliha AR, Jabehdar-Maralani P, Ebrahimi F, Solhpour A, Sadeghipour H, et al. Reduced susceptibility to epinephrine-induced arrhythmias in cirrhotic rats: The roles of nitric oxide and endogenous opioid peptides. Journal of Hepatology. 2007;46:432-439
  149. 149. Volk T, Nguyen TH, Schultz JH, Faulhaber J, Ehmke H. Regional alterations of repolarizing K+ currents among the left ventricular free wall of rats with ascending aortic stenosis. The Journal of Physiology. 2001;530:443-455
  150. 150. Allon N, Rabinovitz I, Manistersky E, Weissman BA, Grauer E. Acute and long-lasting cardiac changes following a single whole-body exposure to sarin vapor in rats. Toxicological Sciences. 2005;87:385-390
  151. 151. Howden R, Hanlon PR, Petranka JG, Kleeberger S, Bucher J, Dunnick J, et al. Ephedrine plus caffeine causes age-dependent cardiovascular responses in Fischer 344 rats. American Journal of Physiology Heart and Circulatory Physiology. 2005;288:H2219-H2224
  152. 152. Lamb CM, Hazari MS, Haykal-Coates N, Carll AP, Krantz QT, King C, et al. Divergent electrocardiographic responses to whole and particle-free diesel exhaust inhalation in spontaneously hypertensive rats. Toxicological Sciences. 2012;125(2):558-568
  153. 153. Nwokocha C, Palacios J, Simirgiotis MJ, Thomas J, Nwokocha M, Young L, et al. Aqueous extract from leaf of Artocarpus altilis provides cardio-protection from isoproterenol induced myocardial damage in rats: Negative chronotropic and inotropic effects. Journal of Ethnopharmacology. 2017;203:163-170
  154. 154. Mohammed HS, Hosny EN, Khadrawy YA, Magdy M, Attia YS, Sayed OA, et al. Protective effect of curcumin nanoparticles against cardiotoxicity induced by doxorubicin in rat. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1866;2020(5):165665

Written By

Pavol Svorc Jr and Pavol Svorc

Submitted: 31 March 2022 Reviewed: 13 April 2022 Published: 07 May 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All
Chapter 3 G Protein-Coupled Receptor Regulation in Cardiovas...

By Asma S. Alonazi, Anfal F. Bin Dayel, Tahani K. Als...

164 downloads

Chapter 4 Gut Microbial Metabolite Trimethylamine-N-Oxide an...

By Shubham Barik, Aritra Mukherjee, Angelina Job Kola...

98 downloads

Chapter 5 Obesity and Cardiovascular Risk

By Pedro Felipe Parra Velasco

130 downloads