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902
Effects of -Adrenergic Receptor Stimulation
and Blockade on Rate-Dependent
Atrioventricular Nodal Properties
Mohsen Nayebpour, Mario Talajic, and Stanley Nattel
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Recent work has shown that alterations in the dynamic atrioventricular (AV) nodal response to changes
in heart rate can significantly modify AV nodal function. The present study was designed to evaluate the
nature and potential importance of sympathetic regulation of the rate-dependent properties of the AV
node. Selective stimulation protocols and mathematical formulations were used to independently quantify
AV nodal recovery, facilitation, and fatigue in 12 morphine-chloralose-anesthetized dogs. Vagal effects
were prevented by bilateral vagal transection and intravenous atropine, and the sinus node was crushed
to allow a broader range of pacing cycle lengths. In seven dogs with sympathetic nerves intact,
,B-adrenergic receptor blockade increased the recovery time constant (i-) for the conduction of
premature test beats from 47±2 (mean±SEM) msec (control) to 62±1 msec (p<0.001), whereas
to 38-t-1 msec (p<0.001). In addition, 3-blockade increased the maximum
isoproterenol decreased
amount of rate-dependent AV nodal fatigue from 7±1 msec (at a cycle length of 198±9 msec [control])
to 17±2 msec (p<0.001). In five dogs with decentralized stellate ganglia, ir, was decreased from 71±3
msec (control) to 57±4 msec and 48±2 msec (p<0.001 for each) by left stellate ganglion stimulation at
5 and 10 Hz, respectively. Maximum fatigue was similarly reduced from 16±1 msec (control) to 12±2
msec (p=NS) and 8±1 msec (p<0.01), respectively. Stellate ganglion stimulation, isoproterenol, and
13-blockade did not alter AV nodal facilitation. A mathematical model incorporating quantitative indexes
of AV nodal function accurately accounted for tachycardia-dependent increases in the atrial-His
activation interval, which were enhanced by S-adrenergic receptor blockade and reduced by isoproterenol.
Furthermore, this model showed that 1-adrenergic effects were increased by increasing heart rate, with
the majority of the rate-dependent action being due to changes in the time course of AV nodal recovery.
We conclude that 1-adrenergic receptor stimulation alters functional properties that govern the AV nodal
response to changes in heart rate. These changes in functional properties alter the ability of the AV node
to conduct impulses during tachycardia and, as such, could play a major role in the ability of sympathetic
stimulation to promote and 13-adrenergic receptor blockade to prevent the occurrence of AV nodal
reentrant arrhythmias. (Circulation Research 1992;70:902-911)
KEY WoRDs * atrioventricular node * arrhythmias, atrial * electrocardiogram * calcium
channels * sympathetic nervous system * isoproterenol
trioventricular (AV) nodal function determines
the occurrence and consequences of a wide
variety of cardiac arrhythmias. The likelihoods
of intranodal AV block, AV nodal reentrant tachycardia, and orthodromic tachycardia in association with an
accessory pathway, as well as the clinical consequences
of atrial fibrillation and flutter, are highly related to AV
nodal conduction and refractoriness.12 The ability of
A
From the Department of Medicine, Montreal Heart Institute;
the Departments of Pharmacology and Therapeutics and Medicine, McGill University; and the Department of Medicine, University of Montreal (Canada).
Supported by operating grants from the Medical Research
Council of Canada, the Quebec Heart Foundation, and the Fonds
de Recherche de l'Institut de Cardiologie de Montr6al. M.T. is a
Research Scholar of the Canadian Heart Foundation. S.N. is a
recipient of the Nordic-Fonds de la Recherche en Sante du
Quebec Research Scholarship.
Address for reprints: Stanley Nattel, MD, Montreal Heart
Institute, 5000 Belanger Street East, Montreal, Quebec H1T 1C8,
Canada.
Received November 28, 1990; accepted December 10, 1991.
the AV node to respond to an atrial input with a
propagated response is, in turn, related in a complex
fashion to the activation history of the AV node.3-13
A number of discrete properties can be identified that
relate activation history to AV nodal conduction. The
conduction of extrasystolic impulses through the AV
node is slowed increasingly as their prematurity increases.3-10,12-21 This phenomenon, AV nodal recovery,
has a time constant in the range of 50-100 msec.8,12,'8-21
On the other hand, an abrupt and sustained increase in
atrial activation frequency results in a gradual slowing of
AV nodal conduction, called "fatigue," requiring minutes to reach steady state.48,122-25 Single premature
AV nodal activations (A2) shift the relation between His
bundle-atrial activation time (HA interval) and atrialHis activation time (AH interval) of a subsequent A3
beat to the left on the recovery time axis.4,16,18 This shift
decreases the conduction time of premature activations
for a given recovery interval and has been called AV
nodal "facilitation." The properties of recovery, fatigue,
and facilitation can be characterized independently
using specific stimulation protocols.13,18,24
Nayebpour et al
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The degree of sympathetic stimulation is an important regulator of AV nodal function. ,B-Adrenergic
stimulation, via direct activation of the sympathetic
innervation of the heart26-28 or by the exogenous administration of adrenergic agonists,8'29,30 accelerates AV
nodal conduction. Changes in sympathetic input play an
important role in baroreflex control of AV conduction.31,32 The autonomic adjustments to upright posture
facilitate the induction of sustained AV nodal reentrant
tachycardia,33 and in some patients with AV nodal
reentrant tachycardia, programmed stimulation fails to
induce the tachycardia unless isoproterenol is infused.34-36 ,-Blockade slows AV nodal conduction37
and can prevent the induction3839 and clinical occurrence39-41 of AV nodal reentry. The sympathetic nervous system thus plays an important role in regulating
AV nodal function and determining the occurrence and
manifestations of supraventricular arrhythmias.
The dependence of AV nodal function on heart rate
and autonomic tone are well known, but the interactions
between the latter two are poorly understood. We have
recently shown that changes in the AV nodal response
to heart rate change are a potentially important mechanism of vagal action.42 Wallick et a128 showed that heart
rate influences the effect of sympathetic nerve stimulation on AV nodal conduction in dogs, and Prystowsky
and Page43 have provided evidence for a similar interaction in humans. We have developed mathematical
approaches to the quantification of individual AV nodal
properties44 and have shown that these approaches can
account for both the rate-dependent changes in AV
nodal conduction time44 and the rate-dependent effects
of the vagus nerve on AV conduction.42 The present
study was designed to assess the possibility that sympathetic stimulation alters AV nodal conduction by changing the ways in which the AV node adapts to changes in
heart rate. Specific goals were 1) to evaluate whether
,B-adrenergic receptor stimulation or blockade alter AV
nodal recovery, facilitation, or fatigue and 2) to determine the extent to which changes in these rate-dependent properties account for alterations in AV nodal
conduction as a function of heart rate.
Materials and Methods
General Methods
Mongrel dogs of either sex were anesthetized with
morphine (2 mg/kg) and a-chloralose (100 mg/kg i.v.).
Catheters were inserted into both femoral veins and
arteries and were kept patent with heparinized saline
solution (0.9%). Dogs were ventilated via an endotracheal tube using an animal respirator (Harvard Apparatus, South Natick, Mass.). Tidal volume and respiratory rate were adjusted to ensure adequate oxygenation
(Sao2290%) and physiological arterial pH (7.35-7.45).
A thoracotomy was performed through the fourth right
intercostal space, and intrathoracic temperature was
maintained at 37-38°C by a homeothermic heating
blanket.
Bipolar Teflon-coated stainless-steel electrodes were
inserted into the lateral right atrium, right atrial appendage, and high lateral right ventricle. A bipolar
electrode was inserted epicardially to record a His
bundle electrogram.45
J3-Adrenergic Effects on Rate Dependence of AV Node
903
The electrodes in the atrial appendage and right
ventricle were used to record atrial and ventricular
electrograms. The lateral right atrial electrode was used
to apply 4-msec square-wave pulses at twice diastolic
threshold, with timing controlled by a programmable
stimulator (Digital Cardiovascular Instruments Inc.,
Berkeley, Calif.). Electrogram signals were filtered (30500 Hz) and amplified (Bloom Instruments Ltd., Flying
Hills, Pa.), with the amplified output led into a paper
recorder and/or a sensing circuit of the stimulator. A
Statham P23 1D transducer (Statham Medical Instruments, Los Angeles, Calif.), electrophysiological amplifiers, and a Mingograf T-16 paper recorder (SiemensElema, Ltd., Toronto) were used to record blood
pressure; electrocardiographic leads II and aVR; atrial,
His bundle, and ventricular electrograms; and stimulus
artifacts. Recordings were obtained at a paper speed of
200 mm/sec (measurement accuracy, ±2.5 msec).
The sinus node was crushed19 to allow for a wide
range of pacing rates. The vagus nerves were isolated in
the neck, ligated, and divided. Atropine was given as an
initial intravenous bolus of 1 mg, followed by 0.5 mg
every 2 hours to produce sustained muscarinic receptor
blockade.46
Measurement of Electrophysiological Variables
Wenckebach cycle length was determined by decreasing atrial pacing cycle length by 10 msec every 10 beats
until second-degree AV block occurred. The effective
refractory period of the AV node and atrial effective
refractory period were measured with the extrastimulus
technique. The effective refractory period of the AV
node was defined as the longest atrial (A1A2) interval
failing to result in a His bundle deflection, and the atrial
effective refractory period was defined as the longest
(S1S2) interval failing to result in a propagated atrial
response.
AV conduction was assessed from the His bundle
electrogram, with the AH interval measured from the
peak after the most rapid deflection in the atrial electrogram of the His bundle electrode to the peak after
the most rapid deflection of the His bundle electrogram.
The HV interval was the time from bundle of His
depolarization to the onset of ventricular activation in
the His signal. The HA interval was the time from the
peak after the most rapid deflection in the His electrogram to the peak in the next atrial electrogram in the
His recording.
Quantitative Assessment of Functional
Rate-Dependent Properties of the AV Node
Specific stimulation protocols and analysis techniques
were used as previously described4244 to quantify selected functional AV nodal properties before and after
interventions altering the level of cardiac 13-adrenergic
receptor stimulation. A brief summary of these protocols and techniques is given below.
AV nodal recovery. The atrium was paced at a basic
cycle length (S1S1) of 500 msec, and a single premature
or delayed stimulus (S2) was introduced after every 15
basic stimuli. The relation between the A2H2 (AV nodal
conduction time of the test impulse) and the H1A2
interval was established and fitted to a single exponential function.
904
Circulation Research Vol 70, No 5 May 1992
TABLE 1. Effects of Isoproterenol and ,-Adrenergic Receptor Blockade
Blood pressure (mm Hg)
Diastolic
Systolic
WBCL (msec)
136±7
89±5
132+6
57±5
167±8.8
Control
142±10
69±5t
122±5
146±10*
47±3t
Isoproterenol
161±10*
103±7t
73±6t
242±15t
92±6t
,(-Blockade
atrial
effective
refractory period; AH, AH
Values are mean±SEM. WBCL, Wenckebach cycle length; AERP,
interval. All measurements other than WBCL were obtained at a basic cycle length of 500 msec.
*p<0.01, tp<0.05, and tp<0.001 compared with control.
AERP (msec)
Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017
AV nodal facilitation. The atrium was paced at a
constant basic cycle length of 500 msec. A premature
atrial impulse (S2) was introduced to produce a selected
A1A2 facilitation cycle after every 15 basic stimuli. A test
impulse (S3) was then applied after each S2, and the AV
nodal response to S3 was monitored to generate an
H2A3-A3H3 recovery curve. The latter curve was studied
at seven values of (A1A2) facilitation cycle length (FCL)
between 500 msec and 20 msec greater than the refractory period of the AV conduction system.
Each H2A3-A3H3 recovery curve was fitted by a
monoexponential model, and the H2A3 value at which
the A3H3 interval is 125 msec (to be referred to as the
"HA125') was calculated for each curve. The HA125 is an
index of the position of the curve on the horizontal axis.
Changes in HA125 reflect the magnitude of parallel
leftward shift resulting from facilitation and are an
exponential function of FCL.42
AV nodal fatigue. A sensing and pacing circuit was
used to sense ventricular activation and to pace the right
atrium with a given VA delay. Since the HV interval was
constant, this caused a tachycardia with a constant HA
interval. Tachycardia was initiated abruptly and maintained for 5 minutes, with the atrial cycle length before
tachycardia set at 500 msec by using an activationinhibited demand pacemaker at a rate of 120 beats per
minute. After 5 minutes of tachycardia, the sense-pace
circuit was closed, and 5 minutes at the baseline cycle
length (500 msec) was allowed for recovery before
initiating tachycardia with a different HA interval.
Fatigue was studied at a total of seven HA intervals in
each experiment.
Experimental Protocol
AV nodal recovery, fatigue, and facilitation were
characterized under control conditions as described
above. Steady-state values for the AH interval were
determined at various cycle lengths, with 5 minutes of
pacing at each cycle length used to ensure steady-state
conditions. Wenckebach cycle length was measured
before and after each experimental protocol to confirm
the stability of each preparation. Isoproterenol was then
infused via an infusion pump (model 848, EDCO Scientific Inc., Chapel Hill, N.C.). The rate of isoproterenol infusion was selected to produce a 20-30-msec
decrease in the Wenckebach cycle length, and the
infusion rate was then kept constant in a given dog.
Three dogs received an infusion of 2 ,g/min, and four
others received an infusion of 5 ,ug/min. Thirty minutes
after the onset of isoproterenol infusion, the measurements obtained under control conditions were repeated.
Isoproterenol was then discontinued, and 20 minutes
were allowed for a return to baseline. When the Wencke-
AH (msec)
bach cycle length had returned to control values, we
administered 0.5 mg/kg nadolol, which we have shown
causes sustained fl-blockade for over 2 hours. Twenty
minutes later, all measurements were repeated.
To compare the effects of endogenous sympathetic
nerve stimulation with those of exogenous ,B-adrenergic
receptor activation and blockade, an additional series of
experiments was performed. The left stellate ganglion
was decentralized by cutting its connections with the
thoracic sympathetic chain and rami communicantes,
and outflow from the right stellate ganglion was prevented by cutting both ansae. An insulated bipolar
electrode (Dastre Electrode, Ealing Scientific Ltd., St.
Laurent, Canada) was attached (anodal pole proximal)
to the dorsal and ventral ansae, and stimulation was
applied via an SD 9F stimulator (Grass Instrument Co.,
Quincy, Mass.). Square-wave stimuli of 2-msec duration, 6-10-V intensity, and 5- or 10-Hz frequency were
used. AV nodal functional properties were studied in
the absence of sympathetic nerve stimulation, and the
measurements were repeated during continuous nerve
stimulation, first at 5-Hz and then at 10-Hz frequency.
Finally, nadolol (0.5 mg/kg i.v.) was given, and the
measurements were repeated. Experimental protocols
were approved by the animal care committee of the
Montreal Heart Institute.
Data Analysis
Results are reported as mean±SEM. Comparisons
between multiple groups were made by two-way analysis
of variance with Scheffe contrasts.47 Comparisons between two groups of experimental data only were made
with Student's t test. Two-tailed tests were used, and a
value of p=0.05 was taken to indicate statistical significance. Nonlinear curve fitting was performed with
Marquardt's technique on an IBM AT-compatible
computer. The effects of exogenous ,B-adrenergic receptor stimulation with isoproterenol were evaluated in
seven dogs, and the effects of sympathetic nerve stimulation were assessed in five dogs.
Results
General Effects of /B-Adrenergic Receptor Stimulation
and Blockade
Isoproterenol accelerated AV nodal conduction and
decreased the Wenckebach cycle length (Table 1).
,B-Adrenergic receptor blockade had the opposite effects. The effective refractory period of the AV node
was not measurable because it was exceeded by the
atrial effective refractory period. Isoproterenol reduced
diastolic pressure and tended to increase systolic pres-
sure, whereas fl-blockade significantly reduced both
Nayebpour et al
j3-Adrenergic Effects on Rate Dependence of AV Node
CONTROL
180140
100
905
0 A1A2 =500 1
a A1A2 =400
,, A1A2 =250
A1A2 =180
~~~~~V
_
. em
60.
'
.w
IL
_
180--
ISOPROTEEO
E
(I
to
1 2 3
CONTROL
1
2
3
1
#-BLOCKED
C
ISO
2 3
re)
100--
60
20
a
Pl-Blocked
180--
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FIGURE 1. Bar graph showing Wenckebach cycle length
(WBCL) at the beginning (1), middle (2), and end (3) of
electrophysiological study protocols under control, isoproterenol (ISO), and ,B-blocked conditions. C represents the value
after discontinuation of isoproterenol and before nadolol
administration. Results are mean+±SEM. **p<0.0J and
***p<0.00I compared with WBCL under control conditions.
systolic and diastolic pressure. The stability of the
preparation is indicated by the consistent values of the
Wenckebach cycle length obtained at the beginning,
midpoint, and end of each experimental protocol (Figure 1).
Changes in AV Nodal Recovery
Typical recovery curves under control conditions, in
the presence of isoproterenol, and after nadolol are
shown in Figure 2. (3-Adrenergic receptor blockade
resulted in a slower time course of recovery, whereas
isoproterenol slightly accelerated recovery. The mean
time constant for all recovery curves averaged 47+2
msec under control conditions, compared with 62+1
msec (p<0.001) after (3-blockade and 38±1 msec
(p<0.001) in the presence of isoproterenol.
AVNodal Facilitation
A premature AV nodal activation resulted in a leftward shift of the AV nodal recovery curve for a
200
1
o~~CONTROL
z
160()
<m
ISOPROTERENOL
r=62
01
Pl-BLOCKED
E
801
'< 40-
H1A2
msec
FIGURE 2. Recovery curves from a representative experishowing relation between atrioventricular conduction
time (AH interval) and recovery time (IIA interval). The best
exponential curve fits are shown by the solid lines. The time
constants (rs) for each curve are indicated by arrows.
ment
100
20 o
-
1 oo
200
300
coo
500
H2A3 (msec)
FIGURE 3. Recovery curves for a test atrial beat (A3)
preceded by a variety of A1A2 (facilitation) cycle lengths in a
representative experiment. As the A1A2 decreased, the atrioventricular nodal recovery curve of the A3 beat shifted
progressively to the left. The solid lines are best-fit exponentials to the raw data shown.
subsequent beat (Figure 3). The magnitude of the
leftward shift for a given coupling interval was similar
under all three conditions. To analyze changes in facilitation, each AV recovery curve was fitted to the
equation
(1)
AHHA=AH +A. exp(-HA/Trec)
where AHHA is the AH interval at a given HA interval,
AHl is the AH interval after full recovery, A is a constant,
and rrec is a recovery time constant. The magnitude of the
leftward shift of the recovery curve was quantified by
calculating the HA125 from Equation 1.
The HA125 decreased with decreased FCL under all
three conditions (Figure 4). HAl25 was greater in the
presence of P3-blockade, indicating that lesser degrees of
prematurity were needed to attain an AH of 125 msec
than under control conditions. Isoproterenol produced
changes in HA125 qualitatively opposite to those resulting from ,3-blockade. However, the differences between
HA125 under control compared with isoproterenol conditions were small and not statistically significant. Isoproterenol accelerated basal AV nodal conduction, as
shown by AHl, whereas P-blockade had the opposite
effect.
Decreases in HA125 produced by a premature beat at
any FCL relative to the value at the basic cycle length of
500 msec (AHA) are an index of the magnitude of the
facilitating effect at that FCL.42,4448 This index of facilitation was not altered by 83-adrenergic stimulation or
blockade (Figure 5). Changes in the HA interval can be
fitted to an equation of the form
AHA=K. exp(-FCL B)
(2)
where K is a constant equal to the (theoretical) change
in the HA interval at an FCL of 0 and B is a rate
906
Circulation Research Vol 70, No 5 May 1992
zuu
0
S
0
.
150¢*-.i .4 4
E
in
C4
-
FIGURE 4. Values of the HA interval corresponding to an AH value of 125 msec (HA125), the AH
interval after full recovery (AH.), and the recovery
time constant (re,c) as a function of A1A2 (facilitation) cycle length (FCL). Results were obtained by
fitting recovery data (of the type shown in Figure 3)
at each FCL for an A3 test beat to the equation
AHHA =AH. +A * exp(-HA/ r,e), where AHHA is the
AH intervalfor a given HA recovery time; AHl, is the
AH interval afterfull recovery, and A is a constant.
HA,25 was obtained by using the best-fit values of
AH,, A, and 7Jec for each curve to solve for the hA
corresponding to an AH of 125 msec. *p<0.05,
**p<0.01, and ***p<0.001 compared with control
at the same FCL.
-
100
..
50-
..
i:i * Control
0 l soproterenol
I
20
8
I
19
U
E
U
S
80
60
60
o °**
000
a*
20
JII
40--
IDownloaded from http://circres.ahajournals.org/ by guest on June 15, 2017
20
300
200
100
400
soo
600
^
A1A2 (FCL) msec
constant. K and B were unaltered by ,B-adrenergic
receptor stimulation and blockade (Table 2), further
indicating that they did not alter AV nodal facilitation.
AVNodal Fatigue
The initiation of a tachycardia with a constant HA
interval results in gradual AH prolongation. Figure 6
shows the time course of changes in the AH interval
from beat 2 of the tachycardia until a steady state has
been achieved in a representative experiment. Since
facilitation stabilizes within one cycle6,42 and the recovery variable HA is constant, such changes are due to
fatigue alone. Changes in the AH interval were well
fitted by an exponential relation of the form
AAHn =AAH8s [1 -exp(-n/rfat)]
(3)
where AAH, is change in the AH interval due to fatigue
for the nth beat,
is steady-state change in the AH
AAHSS
.->
80--
0
CONTROL
E= ISOPROTERENOL
SOP-BLOCKED
400
300
250
200
180
160
A1A2 (FCL) mSeC
FIGURE 5. Bar graph showing changes in HA125 (the HA
value at which the AH interval was 125 msec) from the value
at 500 msec (AH4) as a function of A1A2 (facilitation) cycle
length (FCL). Values are mean-+SEM for all seven dogs
under each condition. Differences in AHIA between conditions
were not statistically significant at any FCL.
interval due to fatigue, and Tfat is the time constant for
fatigue onset.
In the experiment illustrated in Figure 6, (3-blockade
increased the magnitude of fatigue (AAHSS). This was a
general finding in all experiments, as shown by the mean
data in Figure 7. mf1t was not affected by 3-adrenergic
receptor stimulation and blockade, averaging 65 + 7
beats under control conditions, 84+18 beats in the
presence of isoproterenol, and 47±4 beats after
,8-blockade (p=NS). The magnitude of AH change due
to fatigue at any steady-state HA interval (AAAH,A) was
a function of HA, of the form
AAHHA=AAHm.exp(-D * HA)+C
(4)
where AAHmax, C, and D are constants. The dashed
lines in Figure 7 show fits to the mean data using
Equation 4 for each condition.
Role of Changes in Rate-Dependent Properties
The basic AV recovery equation (Equation 1) describes the effect of the coupling interval on AV nodal
conduction but does not consider the role of facilitation
or fatigue. It fails, therefore, to account for conduction
changes when the level of facilitation or fatigue is
changing.9"12'48 During sustained rate changes, alterations in both facilitation and fatigue occur. To evaluate
the role of modulation of AV nodal properties at
different heart rates, it is necessary to analyze the
effects of changes in ,B-adrenergic receptor stimulation
on all three rate-dependent AV nodal properties.
We have shown that the contribution of facilitation
and fatigue can be incorporated into Equation 1.48
Facilitation is incorporated by considering HA to be
modulated by the preceding cycle length (according to
Equation 2), and AH. is adjusted to account for the
effect of fatigue (Equation 4). Equation 1 then becomes
AHHA=P+A. exp(-Q/rec)
(5)
Nayebpour et al
P-Adrenergic Effects on Rate Dependence of AV Node
907
estimates of the predicted effects of incomplete recovery alone (from Equation 1), of recovery modified by
facilitation (Equation 2), of fatigue alone (Equation 4),
and of all three processes functioning simultaneously
(Equation 5). Values at each cycle length were subtracted from those at a basic cycle length of 500 msec, to
estimate rate-dependent slowing at any cycle length due
to the influence of each process.
The resulting curves are shown in Figure 8. Isoproterenol (middle panel) accelerates recovery, reducing
the amount of conduction slowing due to incomplete
recovery (dotted line) compared with control (top panel). 8-Adrenergic receptor blockade (bottom panel)
slows recovery and increases the effect of fatigue. These
changes reduce total rate-dependent conduction slowing (solid line) in the presence of isoproterenol and
increase rate-dependent conduction slowing in the presence of /3-blockade. Experimental data (open boxes and
error bars) agree well with the theoretical analysis.
To further quantify the role of changes in ratedependent properties, we determined the magnitude of
AV conduction change attributable to changes in recovery and fatigue resulting from 3-adrenergic receptor
activation. AH intervals in the presence of isoproterenol were compared with those in the presence of
/3-adrenergic receptor blockade in order to contrast
findings associated with a constant, enhanced level of
,3-adrenergic receptor stimulation (isoproterenol) with
those associated with the absence of /3-mediated effects.
As shown in the top panel of Figure 9, 3-adrenergic
receptor stimulation results in a decrease in the AH
interval, which becomes more marked as cycle length
(or HA interval) decreases. Predicted changes are
TABLE 2. Mean Values of Constants Characterizing Atrioventricular Nodal Recovery, Facilitation, and Fatigue in Seven Dogs
Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017
P3-Blockade
Control
Isoproterenol
85±7t
45+4*
AH' (msec)
54+5
0.6+0.1
1.5±0.3
1.0+0.3
A(sec)
69±4t
43±5
35±2
Trec (msec)
395±128
317±59
425±114
K (msec)
B (msec-1)
0.009±0.003
0.009±0.002
0.010±0.002
AAHmax (msec)
12±1
18±4
24±2t
-2±1
-1±1
0±1
C (msec)
0.006±0.001
D (msec-')
0.008±0.002
0.014±0.003
Values are mean±SEM. AH', AH interval after full recovery at
a cycle length of 500 msec; A, constant; rec, recovery time
constant; K, constant equal to the (theoretical) change in the HA
interval at a facilitation cycle length of 0; B, rate constant; AAHm.,
maximum change in the AH interval due to fatigue; C and D,
constants. AH', A, and Trree were obtained by fitting recovery data
at a cycle length of 500 msec to Equation 1 for each experiment
and averaging the values obtained in all seven experiments. K and
B were obtained by fitting facilitation data in each experiment to
Equation 2. AAHmax, C, and D were obtained by fitting fatigue
data from each experiment to Equation 4, as shown for the mean
data in Figure 7.
*p<0.05, tp<0.001, and tp<0.01 compared with corresponding
control value.
where P is AH0+AAHHA (AH' is AHr. at a cycle length
of 500 msec, and AAHHA is defined as in Equation 4)
and Q is HA+ AHA (for AHA as defined in Equation 2).
Data in each experiment were used to calculate the
constants AH,, A, Trew, K, B, AAHmax, C, and D. The
mean constants for all experiments (Table 2) were
substituted into the corresponding equations to obtain
41n
CONTROL
15-
10..
*
d
_
*@
*@9*
*0
*
C.)
o
ISOPROTERENOL
E
__e00 10-
m
5-.
0
0
o0
_;Q
-0
S
~
0 0
5-
20
0
0
100
200
300
400
BEAT NUMBER
500
600
HA=230 FIGURE 6. Graphs showing
changes in the AH interval
(AAH) as a function of beat
number after the onset of tachy-
20*-
U)
HA=130
* HA=170
*
5
700
cardia in a representative experiment. Solid lines show best-fit
exponential curves. The time
HA= 1 20 course of AH prolongation was
HA=1 60
under all three condiHA=225 similarbut its
magnitude for a
tions,
given H4 interval was greatest in
the presence of 13-blockade, least
in the presence of isoproterenol,
HA= 1 35 and intermediate under control
HA=1 90 conditions.
HA=250
.~ _-
Circulation Research Vol 70, No 5 May 1992
908
20
1
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n 16
E
CONTROL
A ISOPROTERENOL
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Af D\ \
`j, 1 2-
11
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200 300 400 500
VA (msec)
FIGURE 7. Graph showing magnitude offatigue (changes in
the AH interval at steady state) for tachycardias produced by
pacing with the fixed ventriculoatrial (VA) intervals shown.
Results (mean ±SEM) were obtained from curve fits to the
type of data presented in Figure 6. Dashed curves represent
best-fit exponentials to mean data. **p<0.01 and
***p<0.001 compared with control values.
0
100
shown by the solid curve and agree well with experimental data. The mathematical analysis allows us to
attribute the observed AH reductions to changes in
underlying AV nodal properties. At cycle lengths >500
msec, the AH reduction caused by isoproterenol is
attributed to a time-independent (tonic) action. As
cycle length is reduced, the acceleration of recovery
produced by /3-adrenergic receptor stimulation becomes
important and accounts for over half of the consequent
acceleration in conduction at cycle lengths between 200
and 300 msec. Whereas a reduction of fatigue may also
play a role at very rapid heart rates, it is predominantly
the change in AV nodal recovery that accounts for the
rate-dependent effects of sympathetic stimulation on
AV nodal conduction.
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Discussion
We have shown that the degree of 3-adrenergic
receptor activation can control the processes that govern the AV nodal response to changes in heart rate.
Enhanced receptor activation reduces the conduction
slowing effect of increases in heart rate, whereas f3-adrenergic receptor blockade enhances the negative dromotropic effect of supraventricular tachycardia.
...RECOVERY
-- RECOVERY+FACILITATION
--- FATIGUE
TOTAL PREDICTED
Eo OBSERVED
.
10
-10
a)
(1)
CONTROL
Effects of Sympathetic Nerve Stimulation
To determine whether graded sympathetic nerve
stimulation alters the rate-dependent properties of the
AV node, an additional five dogs were studied. The
effects of sympathetic nerve stimulation on recovery in
a typical experiment are shown in Figure 10. Overall,
sympathetic nerve stimulation reduced Tw, from 71+3
msec (control) to 57±4 msec (p<0.001) at a stimulation
frequency of 5 Hz and 48±2 msec (p<0.001 versus
control) at 10 Hz. In keeping with the decentralization
of sympathetic cardiac nervous input, Trec in the presence of ,B-blockade (65±3 msec) was not significantly
different from control values.
Figure 11 shows results for fatigue-induced conduction slowing in the presence of varying degrees of
sympathetic tone. Sympathetic stimulation caused a
graded reduction in the magnitude of fatigue, which was
statistically significant only for a VA interval of 50 msec
during 10-Hz stimulation. In contrast, facilitation was
not altered by sympathetic stimulation, with the maximum left shift of the recovery curve averaging 45±9
msec under control conditions, 35±4 msec during 5-Hz
sympathetic stimulation, 36+8 msec during 10-Hz stimulation, and 30±3 msec after 83-blockade (no statistically significant differences).
.. ~0a
a
10 90
..
-ap-BLOCKED
70
5030-10-
100
I
200
I
I
3B 0 4(0
BCL
(msec)
I
500
FIGURE 8. Graphs showing predicted ratedependent changes in theAH interval (AAH)
due to incomplete recovery, recovery modified
by facilitation, and fatigue as a function of
basic cycle length (BCL). Mean characterizing constants determined experimentally (Table 2) were substituted into Equations 1, 2,
and 4, respectively (see text), to obtain predictions shown. As BCL decreases, incomplete
recovery is expected to increase the AH interval to an extent indicated by the dotted lines.
Facilitation attenuates the effects of recovery,
and when this action offacilitation is incorporated, the AH slowing is predicted by the
dashed lines. Changes due to combined recovery and facilitation were added to those
resultingfrom fatigue alone to obtain the total
rate-dependent AH prolongation predicted
(solid lines). The latter are in close agreement
with experimentally observed values
(mean ±SEM).
Nayebpour et al f-Adrenergic Effects on Rate Dependence of AV Node
909
(CONTROL BCL)
400
300
n
U
500
600
.
o -2
0
.0
In -4,
E
_E
Ir -61
n0-
I..RECOVERY
-O- ~FATIGUE
--- TONIC
-t
TOTAL
o~~~~~OBSERVED
/1
-10
10
10
._____.w
,.,~
SO
z
PROPORTION OF TOTAL
jB-ADRENERGIC EFFECT
6 iO ,-W0~~
C)
~
~
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-.
,
.O
200
100
..
300
~
RECOVERY
--- ~~~~FATIGUE
~~~TONIC
500
400
600
FIGURE 9. Top panel: Graph showing reductions in theAH
interval (AH) resulting from 8-adrenergic receptor stimulation at a given hA (recovery) intervaL BCL, basic cycle
length. Values in the presence of isoproterenol were compared
with values in the absence of i3-adrenergic receptor stimulation (fi-adrenergic receptor blockade). The mathematical
modelpresented in the text was used to estimate the reduction
in the AH interval due to the acceleration of recovery (dotted
line) and attenuation of fatigue (dashed line) caused by
P-adrenergic receptor stimulation as a function of steadystate h4 intervaL These were added to the time-independent
(tonic, line with dashes and dots) change in the AH interval
resulting from isoproterenol in order to predict the total AH
interval reductions (solid curve) produced by fB-adrenergic
stimulation. The latter are in close agreement with experimental observations. Bottom panel: Graph showingproportion of
the overall AH interval reduction caused by f-adrenergic
receptor stimulation due to tonic actions and to changes in
recovery and fatigue at each M4 intervaL
HA INTERVAL (msec)
Comparison With Previous Studies of Sympathetic
Effects on the AV Node
Sympathetic nerve stimulation,26-28 exogenous fl-agonists,8,29,30 and baroreflex-mediated increases in sympathetic tone31,32 all enhance AV nodal conduction by
activating 3-adrenergic receptors. Ferrier and Dresel8
showed that basal AV nodal conduction time at rapid
heart rates is reduced by epinephrine, suggesting a
reduction in AV nodal fatigue. Wallick et aP28 showed
that the acceleration of AV conduction caused by
sympathetic nerve stimulation is magnified by tachycardia. The AH interval shortening produced by isoproterenol infusion in humans similarly depends on the
atrial activation rate.49 Although the processes underlying rate-dependent responses of the AV node have been
extensively characterized with selective pacing protocols,5,13,16,18,24,50 their modulation by sympathetic tone
has not been analyzed.
We found that f3-adrenergic receptor blockade increased the amount of rate-dependent fatigue in dogs
with intact sympathetic nerves. In addition, 3-blockade
slowed the recovery of AV nodal conduction after preceding activation. 13-Adrenergic receptor stimulation decreased fatigue and accelerated recovery. fB-Adrenergic
receptor activation produced qualitatively similar effects
whether caused by the intravenous infusion of an exogenous agonist (isoproterenol) or by electrically stimulating the nervous outflow from the left stellate ganglion.
The effect of isoproterenol was quantitatively smaller. It
is possible that larger doses of isoproterenol might have
been more effective, but preliminary studies suggested
that the doses used produced near-maximal changes in
the AH interval. The lesser effects of isoproterenol were
more likely due to the high level of resting sympathetic
tone in open-chest dogs with sympathetic nerves intact.
30
E1 CONTROL
2000
o
A
150-
7/
100--
SYMP#1
KM SYMP#2
f -BLOCKED
20--
SYMP#1
0 SYMP/J2
V
fl-BLOCKED
_
15
41
E:
E
25-E-
CONTROL
C,
65
LI
10
5--
50
..I
0VA=200
H1A2 (msec)
FIGURE 10. Typical recovery curves obtained under control
conditions, during 5-Hz stimulation of left stellate ganglion
ansae (symp #1), during 10-Hz stimulation (symp #2), and
in the presence of 13-blockade. The time constant of each
curve (in milliseconds) is indicated by an arrow.
VA=1 00
VA=50
FIGURE 11. Bar graph showing magnitude of fatigue
(mean ±SEM changes in the AH interval [AAH]) resulting
from tachycardia with the ventriculoatrial (VA) intervals
indicated. Sympathetic stimulation at 5 Hz (symp #1) and 10
Hz (symp #2) tended to reduce fatigue, with statistical
significance (**p<0.01 compared with control) occurring
with 10-Hz stimulation at the shortest VA interval tested.
910
Circulation Research Vol 70, No 5 May 1992
The effects of ,3-adrenergic receptor blockade support
this contention. Nadolol had a large effect on AV nodal
conduction in sympathetically intact dogs but a small and
statistically nonsignificant effect in dogs with stellate
ganglion outflow decentralized.
Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017
Possible Ionic Mechanisms of Adrenergic Effects on
AV Nodal Recovery and Fatigue
The precise ionic mechanisms of AV nodal recovery
and fatigue remain unknown. It is likely that AV nodal
recovery is related to the time required for reactivation
of L-type calcium channels.424648 ,B-Adrenergic stimulation accelerates the recovery of slow channel action
potentials51 and promotes the reactivation of calcium
current in single guinea pig ventricular myocytes.52 An
acceleration of the recovery of calcium current from
inactivation is thus a probable explanation of the more
rapid recovery of AV nodal conduction during ,B-adrenergic receptor stimulation. AV nodal fatigue may be
related to ion accumulation or depletion, metabolic
dysfunction, or electrogenic transport mechanisms. If
extracellular potassium accumulation plays a role in AV
nodal fatigue, it is possible that the ability of ,B-adrenergic stimulation to stimulate Na+,K+-ATPase activity53,54 accounts for its fatigue-attenuating properties.
Potential Limitations of Our Findings
We studied several levels of adrenergic tone in our
dogs: resting basal tone in an open-chest, anesthetized
preparation; a constantly increased level of l3-adrenergic
receptor stimulation resulting from either continuous isoproterenol infusion or graded left stellate ganglion stimulation; and the absence of ,B-adrenergic stimulation resulting from 13-blockade with nadolol. We have not examined
the complex changes in rate-dependent AV nodal properties that may occur with continuously changing levels of
sympathetic activity.55'56 Although such studies would
have been interesting, they are beyond the scope of the
present article. Direct membrane actions of 1-blockers
can be a complicating factor in electrophysiological studies. Nadolol, however, is devoid of any direct membrane
actions,57 and all of its effects can be safely attributed to
,B-adrenergic receptor blockade.
We used the HA interval as an index of AV nodal
recovery time. The relative merits of the HA interval and
the AA interval as indexes of the AV nodal recovery
period have been disputed, and resolution of this issue is
beyond the capability of the methods used in this study.
Levy et a16 have shown that the HA interval determines
AV nodal conduction independent of basic cycle length,
and Billette and M6tayer58 have reported that consideration of the HA interval can explain complex properties of
AV nodal functional refractoriness.
Potential Significance
Autonomic tone is well known to regulate AV nodal
conduction. The present investigation, along with our
previous study of vagal influences,42 indicates that the
autonomic nervous system controls processes, particularly
AV nodal recovery and fatigue, that determine the AV
nodal response to changes in heart rate. Although there
are data in the literature suggesting that the magnitude of
sympathetic effects on AV nodal function is heart rate
dependent,28 our work is the first to establish the changes
in functional properties of the AV node that underly this
rate-dependent action. Furthermore, we have been able to.
demonstrate quantitatively that an increase in the rate of
recovery after activation is the most important contributor
to the actions of ,B-adrenergic receptor activation on AV
nodal conduction at rapid rates.
Changes in AV nodal functional properties are potentially important mechanisms of autonomic nervous system
action. It is well known, for example, that 1 :1 AV conduction is maintained during exercise at cycle lengths much
shorter than the Wenckebach cycle length measured by
rapid atrial pacing. Our results suggest that the acceleration of AV nodal recovery and attenuation of fatigue
resulting from increases in sympathetic tone and decreases
in vagal tone may contribute to the physiological maintenance of 1:1 conduction during exercise. The acceleration
of AV nodal recovery and lessening of fatigue caused by
13-adrenergic receptor stimulation may account for the
role of sympathetic activation in the occurrence of AV
nodal reentry.33,35,36 On the other hand, enhancement of
fatigue and slowing of AV nodal recovery may contribute
to the salutary effects of f-adrenergic receptor blockers in
supraventricular arrhythmias.38-41
Conclusions
We have shown that the degree of 83-adrenergic
receptor activation modulates discrete rate-dependent
properties of the AV node. These actions decrease AV
nodal conduction slowing by tachycardia when sympathetic tone is high and increase the negative dromotropic effects of tachycardia in the presence of ,B-adrenergic receptor blockade. The accommodation properties
of the AV node to changes in heart rate are under
reciprocal control of both limbs of the autonomic nervous system and constitute a heretofore little-recognized target for autonomic regulation of AV nodal
function. Further work needs to be done to clarify the
underlying mechanisms of dynamic AV nodal properties and of the autonomic effects on them.
Acknowledgments
The authors thank Lise de Repentigny for typing the
manuscript, Nancy Turmel and Christine Villemaire for technical help, and Squibb Pharmaceuticals (Canada) for supplying the nadolol used to produce ,3-blockade.
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M Nayebpour, M Talajic and S Nattel
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Circ Res. 1992;70:902-911
doi: 10.1161/01.RES.70.5.902
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