Download Intrinsic changes on automatism, conduction

J Appl Physiol
92: 225–229, 2002.
Intrinsic changes on automatism, conduction, and
refractoriness by exercise in isolated rabbit heart
L. SUCH,1 A. RODRIGUEZ,1 A. ALBEROLA,1 L. LOPEZ,1 R. RUIZ,1
L. ARTAL,1 I. PONS,1 M. L. PONS,1 C. GARCÍA,2 AND F. J. CHORRO3
Departments of 1Physiology, 2Physiotherapy, and 3Medicine,
University of Valencia, 46010 Valencia, Spain
Received 3 February 2000; accepted in final form 29 August 2001
HR (17). The concept of an increase in the parasympathetic activity by training is supported by the observations of increased acetylcholine levels in the myocardium of trained animals (2), as well as a greater gain of
baroreceptive mechanisms in trained animals (1). Conversely, several reports support the fact that electrophysiological training-induced modifications are the
result of intrinsic mechanisms. Indeed, Katona et al.
(10) and Lewis et al. (11) concluded that traininginduced bradycardia at rest is caused by a reduction in
the intrinsic cardiac rate and not the result of an
increase in parasympathetic tone. Finally, it has been
reported that, in some cases, the electrophysiological
changes produced by training are related to some heart
modifications, such as ventricular hypertrophy (3) or
myocardial damage (12, 15). The main objective of the
present study was to investigate in isolated rabbit
heart (Langendorff preparation), and thus not submitted to nervous and/or humoral influences, the effect of
exercise training on sinus chronotropism, sinus nodeatrial conduction, atrioventricular (A-V) node conduction and refractoriness, ventriculoatrial (V-A) retrograde conduction and refractoriness, and ventricular
refractoriness to analyze the intrinsic modifications of
these parameters.
MATERIALS AND METHODS
REGULARLY PERFORMED ENDURANCE exercise results in
changes in several cardiovascular variables at rest,
and especially significant are the changes on automatism and conduction. Several studies have assessed the
contribution of both the autonomic nervous system and
the intrinsic mechanisms on the myocardial changes
observed in trained humans and laboratory animals (1,
10). Some authors support the fact that the reduction
in heart rate (HR) at rest as a consequence of endurance training is the result of an increased vagal tone
(18, 19) and not because of a reduction in the intrinsic
Two groups of New Zealand rabbits were studied. Ten
rabbits (trained group) were trained on motor-driven treadmills, and eight rabbits (control group) were housed in the
animal quarters for 46 days. In the trained group, after
familiarization with treadmills during 4 days, rabbits were
submitted to a running program. They ran for 5 days/wk for
6 wk at 0.5 m/s. Each one of the training sessions was divided
into six periods of 4 min of running and 1 min of rest. The
correct realization of treadmill exercise was constantly supervised, and those animals that did not adequately run on
the treadmill, because they either stopped frequently or ran
irregularly, were excluded from the study. The number of
animals excluded for these reasons was two, and eight animals responded well to the treadmill protocol.
Preparation and perfusion. Sixteen isolated rabbit hearts
were studied. All of the procedures were performed in accor-
Address for reprint requests and other correspondence: L. Such,
Departamento de Fisiologı́a, Facultad de Medicina y Odontologı́a,
Av. Blasco Ibáñez, 17, 46010 Valencia, Spain (E-mail: Luis.Such
@uv.es).
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
physical training; heart electrophysiology
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Such, L., A. Rodriguez, A. Alberola, L. Lopez, R. Ruiz,
L. Artal, I. Pons, M. L. Pons, C. Garcı́a, and F. J. Chorro.
Intrinsic changes on automatism, conduction, and refractoriness by exercise in isolated rabbit heart. J Appl Physiol 92:
225–229, 2002.—We have studied the intrinsic modifications
on myocardial automatism, conduction, and refractoriness
produced by chronic exercise. Experiments were performed
on isolated rabbit hearts. Trained animals were submitted to
exercise on a treadmill. The parameters investigated were 1)
R-R interval, noncorrected and corrected sinus node recovery
time (SNRT) as automatism index; 2) sinoatrial conduction
time; 3) Wenckebach cycle length (WCL) and retrograde
WCL, as atrioventricular (A-V) and ventriculoatrial conduction index; and 4) effective and functional refractory periods
of left ventricle, A-V node, and ventriculoatrial retrograde
conduction system. Measurements were also performed on
coronary flow, weight of the hearts, and thiobarbituric acid
reagent substances and glutathione in myocardium, quadriceps femoris muscle, liver, and kidney, to analyze whether
these substances related to oxidative stress were modified by
training. The following parameters were larger (P ⬍ 0.05) in
trained vs. untrained animals: R-R interval (365 ⫾ 49 vs.
286 ⫾ 60 ms), WCL (177 ⫾ 20 vs. 146 ⫾ 32 ms), and
functional refractory period of the left ventricle (172 ⫾ 27 vs.
141 ⫾ 5 ms). Corrected SNRT was not different between
groups despite the larger noncorrected SNRT obtained in
trained animals. Thus training depresses sinus chronotropism, A-V nodal conduction, and increases ventricular refractoriness by intrinsic mechanisms, which do not involve
changes in myocardial mass and/or coronary flow.
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TRAINING AND CARDIAC INTRINSIC ELECTROPHYSIOLOGY
J Appl Physiol • VOL
of 30-s duration were used to calculate the SNRT (the first
train at a frequency 10% above the spontaneous HR), and in
each stimulation period the train frequency was increased by
40 beats/min. Several trains were used until the maximum
frequency with auricular capture was reached. The pause
between two consecutive trains was 30 s. 2) Atrial stimulation with a short train of eight stimuli at a rate slightly
higher than spontaneous HR (Narula test) was used to determine SACT. 3) Pacing with fixed-rate trains of 30-s duration (stimuli of 2-ms duration and twice diastolic threshold)
at increasing rates (10-beat/min increments) was used to
calculate the WCL. 4) Atrial extrastimulus test was used
with basic trains of 10 beats at a cycle length of 250 ms,
which was a frequency slightly higher than the spontaneous
frequency in the control group, and the pause between trains
was 1 s. This basic cycle length was maintained in the
trained group, and the extrastimulus was delivered with
5-ms decrements of the coupling interval, from a 250-ms
coupling interval to determine the AVNERP, and A-V node
functional refractory period. The left ventricle was stimulated in a random sequence, and the protocol was continued.
5) Pacing with fixed-rate trains of 30-s duration (stimuli of
2-ms duration and twice diastolic threshold) at increasing
rates (10-beat/min increments) was used to calculate RWCL.
6) Ventricular extrastimulus test, using the same technique
as in atrial extrastimulus test, was used to determine ventricular and V-A retrograde conduction refractoriness. Spontaneous HR was measured in all cases, immediately before
the electrophysiological study.
Measurements were also performed on thiobarbituric acid
reagent substances (TBARS) and GSH, in myocardium,
quadriceps femoris muscle, liver, and kidney, to analyze
whether these substances that are related to the oxidative
stress were modified by our training method. Immediately
after the animals were killed, biopsies (between 800 and
1,000 mg) were taken from the quadriceps femoris muscle,
liver, and kidney. At the end of the electrophysiological
measurements, an additional biopsy of the myocardium was
taken to analyze the substances mentioned above. Tissue
samples were immediately placed in liquid nitrogen and
manually powdered with a mortar. Part of this powder was
homogenized in cold 6% perchloric acid containing 1 mM
EDTA, and GSH was determined with 1-dichloro-2,4-dinitrobenzene as substrate and glutathione S-transferase, according to Brigelius et al. (5). Another part of the powder was
homogenized with cold 1.15% KCl and afterwards was mixed
with an aqueous solution of phosphoric and thiobarbituric
acids and boiled. After extraction with butanol, measurements were made by a spectrophotometric method according
to Uchiyama and Mishara (23).
Coronary flow was measured directly by collection during
1 min. Measurements were performed before to start the
electrophysiological protocol and also at the end of this period. The hearts were weighed at the end of the experiments.
Table 1. Parameters of chronotropism and conduction
R-R
SNRT
CSNRT
SACT
WCL
RWCL
Control 286⫾60 460⫾36 174⫾68 25⫾15 146⫾20 179⫾25
n
8
8
8
8
7
8
Trained 365⫾49* 554⫾66* 189⫾45 31⫾22 177⫾32* 205⫾32
n
8
8
8
7
8
7
Values are means ⫾ SD in ms; n ⫽ no. of experiments. R-R,
R-wave to R-wave; SNRT, sinus node recovery time; CSNRT, corrected SNRT; SACT, sinoatrial conduction time; WCL, Wenckebach
cycle length; RWCL, retrograde WCL. * P ⬍ 0.05 vs. control.
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dance with the agreements of the European Convention of
Strasbourg of March 18, 1986 (Instrument of Ratification of
8/2/89, Official State Bulletin of 10/25/90). After heparinization, the animals were killed by cervical dislocation, and,
after midsternal thoracotomy, the heart was quickly removed
and immersed in cold Tyrode solution for further preparation. The aorta was cannulated and connected to a Langendorff system to provide the heart with warmed and oxygenated Tyrode solution containing (in mM) 130 NaCl, 4.7 KCl,
2.2 CaCl2, 0.6 MgCl2, 1.2 NaH2PO4, 24.2 NaHCO3, and 12
glucose. The pH was maintained at 7.4 by equilibration with
a mixture of 95% O2 and 5% CO2. The temperature was
constant throughout the experiment (37°C), and perfusion
pressure was maintained at 50 mmHg.
Four bipolar surface electrodes (silver wire Teflon coated,
with an interelectrode distance of 1 mm) were positioned as
follows: two on the right atrium and two on the left ventricle
for pacing and recording. The right atrium was opened to
place one bipolar electrode on the septal leaflet of the tricuspid valve for His bundle electrogram recording, as well as low
right atrial activity and high-ventricular septal depolarization. After amplification, the electrograms were recorded by a
four-channel Mingograph 34 polygraph (Siemens-Elema,
Solna, Sweden). Electrical stimuli were delivered by a Grass
S-88 stimulator (Grass Instruments, Quincy, MA) fitted to
two SIU 5 stimulus isolation units. The recordings were
made at 100 mm/s, with a measurement precision of 1 ms. In
previous studies, our laboratory checked the reproducibility
of the measurements (16, 17).
Measurements and calculations. The procedure in the experiments with trained (trained group) and nontrained rabbits (control group) was the same. The parameters studied
and their definitions were as follows: 1) R-R interval: the
interval between two successive ventricle electrograms during basal sinus rhythm; 2) sinus node recovery time (SNRT):
the A1-A2 cycle length after atrial pacing (A1 represents the
last beat of an atrial pacing train, and A2 the first spontaneous beat after pacing); 3) corrected SNRT (CSNRT): SNRT ⫺
basal sinus cycle length; 4) sinoatrial conduction time (SACT):
0.5 ⫻ (return cycle length ⫺ basal sinus cycle length); 5)
Wenckebach cycle length (WCL): the maximum cycle length
of atrial pacing that produces A-V Wenckebach block; 6)
retrograde WCL (RWCL): the maximum cycle length of ventricular pacing that impedes a 1:1 V-A conduction; 7) ventricular effective refractory period: the maximum ventricular
extrastimulus coupling interval without ventricular capture
(S1-S2 interval; S1 and S2 represent the stimulus artifacts of
the last beat of the basic train and the extrastimulus, respectively); 8) ventricular functional refractory period: the minimum interval between the ventricle electrogram produced by
the last basic ventricular train stimulus and that triggered
by the extrastimulus; 9) A-V node effective refractory period
(AVNERP): the maximum atrial electrogram coupling interval, produced by the extrastimulus, without His bundle capture; 10) A-V node functional refractory period (AVNFRP):
the minimum interval between the His electrogram produced
by the last basic atrial train stimulus and that triggered by
the extrastimulus; 11) effective refractory period of the V-A
retrograde conduction: the maximum ventricular electrogram coupling interval, produced by the extrastimulus, without atrial capture; 12) functional refractory period of the V-A
retrograde conduction: the minimum interval between the
atrial electrogram produced by the last basic ventricular
train stimulus and that triggered by the ventricular extrastimulus.
The right atrium was stimulated in a random sequence
according to the following protocol. 1) Fixed-frequency trains
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TRAINING AND CARDIAC INTRINSIC ELECTROPHYSIOLOGY
Table 2. A-V nodal, V-A retrograde conduction, and ventricular refractoriness
Control
n
Trained
n
AVNERP
AVNFRP
VARCERP
VARCFRP
VERP
VFRP
110 ⫾ 19
5
116 ⫾ 26
5
152 ⫾ 18
8
157 ⫾ 23
8
146 ⫾ 30
5
175 ⫾ 16
5
177 ⫾ 14
7
186 ⫾ 26
6
129 ⫾ 30
5
153 ⫾ 27
5
141 ⫾ 5
5
172 ⫾ 27*
5
Values are means ⫾ SD in ms; n ⫽ no. of experiments. AVNERP, atrioventricular (A-V) node effective refractory period; AVNFRP, A-V
node functional refractory period; VARCERP, ventriculoatrial (V-A) retrograde conduction effective refractory period; VARCFRP, V-A
retrograde conduction functional refractory period; VERP, ventricular effective refractory period; VFRP, ventricular functional refractory
period. * P ⬍ 0.05 vs. control.
Heart weights were similar in trained and control
rabbits (12.1 ⫾ 1.9 and 11.8 ⫾ 1.9 g, respectively).
RESULTS
DISCUSSION
Sinus chronotropism and sinoatrial conduction. The
R-R interval was 28% larger in the trained vs. control
group, and SNRT was 20% larger in the trained group
vs. control group (Table 1). No differences were observed in CSNRT and SACT between the two groups of
animals.
A-V and V-A conduction. WCL was 21% larger in the
trained group with respect to the control group (Table 1).
Ventricular, A-V nodal, and V-A retrograde conduction system refractoriness. The functional refractory
period of the left ventricle was 20% larger in trained
animals vs. controls. No significant differences were
observed in the remaining parameters of refractoriness
between trained and untrained animals (Table 2).
AVNERP was not measured in three cases because, in
these animals, the atrial effective refractory period was
reached before the A-V node refractory period took
place. Ventricular refractoriness was only measured in
five experiments because the extrastimulus artifacts or
the electrograms were not adequately identified in
three cases.
GSH and TBARS content. No significant differences
in GSH and TBARS content were observed between
groups (Table 3).
Coronary flow and heart weights. Coronary flow was
not different between groups when it was normalized
with respect to HR and thus expressed in milliliters
per minute per gram per heartbeat (0.021 ⫾ 0.06 vs.
0.021 ⫾ 0.005 ml 䡠 min⫺1 䡠 g⫺1 䡠 heartbeat⫺1), despite the
differences when it was expressed in milliliters per
minute per gram (3.1 ⫾ 0.9 in trained group vs. 4.4 ⫾
1.3 ml 䡠 min⫺1 䡠 g⫺1 in control animals).
We have investigated the effects of physical training
on the electrophysiological properties of the heart by
using an isolated rabbit heart preparation. With respect to the experimental preparation used, two main
points should be considered. First, it has been reported
that the rabbit model is ideal for examining the effects
of exercise training, and, by using the proper intensity,
duration, and frequency of exercise, the rabbit obtains
a documented cardiovascular training effect rather
easily (8). Second, the isolated heart preparation used
is not a “working heart,” and the differences between
groups are not due to differences in cardiac work.
Our results demonstrate that physical training produces electrophysiological modifications in the isolated
rabbit heart. These changes take place not only on the
chronotropism but also on conduction. Modifications on
refractoriness were not statistically significant, except
for the changes observed in ventricular functional refractory period. It has been previously reported that
training increases parasympathetic activity (1, 7, 18,
19). Other studies show that electrophysiological training-induced modifications are the result of intrinsic
mechanisms (10, 11).
In our study, the chronotropic-negative effect of
training is shown by the decrease in HR. CSNRT did
not change, despite the increase in noncorrected
SNRT, and this, therefore, does not imply prolongation
in this parameter. The increase in noncorrected SNRT
is probably due to a decrease in HR. The changes
observed in the intrinsic HR are in accordance with
previous experimental studies performed in rats (13)
and dogs (14). However, other studies in isolated
Table 3. GSH and TBARS in different tissues
Heart
Control
n
Trained
n
Muscle
Liver
Kidney
TBARS
GSH
TBARS
GSH
TBARS
GSH
TBARS
GSH
54 ⫾ 7
7
61 ⫾ 24
6
1.2 ⫾ 0.2
7
0.9 ⫾ 0.2
6
18 ⫾ 6
7
19 ⫾ 12
6
0.9 ⫾ 0.2
6
0.9 ⫾ 0.2
6
32 ⫾ 17
7
37 ⫾ 14
6
8.4 ⫾ 1.1
7
7.3 ⫾ 0.8
6
53 ⫾ 19
7
75 ⫾ 39
6
1.2 ⫾ 0.3
7
0.9 ⫾ 0.4
6
Values are means ⫾ SD; n ⫽ no. of experiments. GSH values are in ␮mol/g. Thiobarbituric acid reagent substance (TBARS) values are
expressed as optical density at 535 nm (OD535) minus optical density at 520 nm (OD520).
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Data analysis. Student’s unpaired t-test was used to perform comparisons between the two groups. Statistical significance was accepted when P ⬍ 0.05.
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J Appl Physiol • VOL
and exerts deleterious effects on tissues (4, 6, 9). Thus
measurements were performed in this study to assess
whether the training program used produced modifications in lipid peroxidation (TBARS) and in the GSH
content in several tissues. We did not find any modification of TBARS and GSH content by training, which is
in agreement with other studies showing that neither
long-term physical training nor acute exhaustive exercise affected lipid peroxidation (24). Similarly, others
did not find modifications by training of the antioxidant enzymatic activity in several tissues (21). Thus
lipid peroxidation does not appear to be involved in the
electrophysiological modifications mentioned above.
Finally, it seems that the electrophysiological modifications by training are not related to coronary flow
changes, because this was not modified in trained animals, despite the decrease in nonnormalized coronary
flow, which is an indirect effect closely related to the
decrease in HR.
In conclusion, we demonstrate in the present study
that training endurance in rabbits produces a depression on sinoatrial node automatism and A-V node conduction and some modifications on ventricular refractoriness by means of intrinsic mechanisms. These
mechanisms do not seem to be related to heart hypertrophy, lipid peroxidation, and/or coronary flow modifications.
The authors express sincere thanks to Dr. Lluch for valuable
review and advice on the manuscript.
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