(Circulation. 1999;99:312-318.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Hyperkalemia Enhances the Effect of Adenosine on IK,ADO in Rabbit Isolated AV Nodal Myocytes and on AV Nodal Conduction in Guinea Pig Isolated Heart
From the Departments of Anesthesiology (A.E.M., T.E.M., D.M.D.), Medicine (L.B.), and Pharmacology (L.B., D.M.D.), University of Florida, Gainesville.
Correspondence to Donn M. Dennis, MD, Department of Anesthesiology, University of Florida, PO Box 100254, 1600 SW Archer Rd, Gainesville, FL 32610-0254. E-mail Dennis{at}anest2.anest.ufl.edu
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Abstract |
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Background—The atrioventricular (AV) node is insensitive to changes in extracellular potassium concentration, [K+]o, because of the absence of the inward rectifier potassium current (IK1). However, we propose that in the presence of adenosine, elevated [K+]o should increase the adenosine-activated inward rectifier potassium current (IK,ADO) in AV nodal myocytes and hence augment the negative dromotropic effect of the nucleoside.
Methods and Results—The effects of normal (4.8 mmol/L)
and high (8.0 mmol/L) [K+]o on
adenosine-induced changes in resting membrane potential
(Vm), IK,ADO, and membrane resistance
(Rm) in rabbit isolated AV nodal myocytes and in AV nodal
conduction delay (atrium-to-His bundle, AH, interval) in guinea pig
isolated hearts were determined with the use of whole-cell patch-clamp
and His bundle electrogram techniques, respectively. High
[K+]o alone did not significantly affect
membrane current, Rm, or Vm in AV nodal
myocytes. However, high [K+]o in the presence
of adenosine (3 µmol/L) markedly increased
Im (-0.249±0.038 to -0.571±0.111 nA,
P<0.05) at -100 mV and reduced Rm (151±21
to 77±8 M
, P<0.02). Adenosine still
hyperpolarized Vm from -48±2 to -65±1 mV
(P<0.001). High [K+]o alone
did not significantly affect the AH interval in isolated hearts.
However, high [K+]o markedly lengthened the
AH interval prolongation caused by adenosine (4 µmol/L,
7.9±0.8 vs 22.1±3.0 ms, P<0.001). The potentiating
effect of high [K+]o on
adenosine-induced delay in AV nodal conduction was abolished by
BaCl2 (100 µmol/L).
Conclusions—By increasing IK,ADO and decreasing Rm of AV nodal myocytes, elevated [K+]o, augments the depressant effect of adenosine on AV nodal conduction.
Key Words: adenosine • atrioventricular node • potassium • myocytes
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Introduction |
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The negative dromotropic effect of adenosine underlies its therapeutic value for the acute treatment of many types of supraventricular tachyarrhythmias and its role in increasing atrioventricular (AV) nodal conduction delay during myocardial ischemia.1 2 We recently demonstrated in rabbit isolated AV nodal myocytes that adenosine hyperpolarizes the membrane potential (Vm) secondary to activation of the time-independent inward rectifier potassium current (IK,ADO) and inhibits the basal and catecholamine-stimulated calcium current (ICa,L).3 4 These effects of adenosine can at least in part explain its depressant effects on AV nodal conduction.
Adenosine-activated K+ channels belong to the family of inward-rectifying K+ channels through which conductance is increased with elevation in the concentration of extracellular potassium, [K+]o.3 5 6 7 A number of studies have shown that cardiac pacemaker tissue is insensitive to changes in [K+]o under normal physiological conditions.8 9 10 11 The insensitivity of pacemaker cells (ie, sinoatrial and AV nodal myocytes) to changes in [K+]o has been explained by the absence of the main inward rectifier K+ current, IK1.8 However, because elevated [K+]o should increase the conductance of inwardly rectifying K+ channels, such as IK,ADO, we hypothesized that the depressant effect of adenosine on AV nodal tissue will be greater when [K+]o is elevated.
An understanding of the mechanism(s) whereby adenosine regulates AV nodal function in the setting of hyperkalemia has both physiological and pathophysiological importance. If elevated [K+]o indeed sensitizes the AV node to the depressant effects of adenosine, it is reasonable to postulate that adenosine-mediated AV nodal conduction block can occur even at interstitial concentrations of adenosine that are subthreshold for its negative dromotropic effect during normokalemic conditions. Thus accumulation of [K+]o may play an important mechanistic role in potentiating the negative dromotropic effect of adenosine and prove to be relevant for the understanding of the mechanisms underlying the rate-dependent actions of adenosine on AV nodal conduction.
Therefore, we studied the effects of hyperkalemia ([K+]o=8.0 mmol/L) on adenosine-induced changes in the electrophysiological properties of rabbit isolated single AV nodal myocytes and in AV nodal conduction delay in guinea pig isolated hearts. Recognizing that nodal myocytes may be mixed with atrial myocytes during the AV nodal cell isolation procedure, we also carried out experiments in isolated atrial myocytes.
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Methods |
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Isolated AV Nodal and Left Atrial Myocytes
All protocols were reviewed and approved by the Animal Use Committee of the University of Florida Health Sciences Center. Single AV nodal and left atrial myocytes were obtained from rabbit hearts (n=17) by enzymatic and mechanical dispersion of the tissues as previously detailed.3 The gigaseal technique for whole-cell patch-clamp recordings was used.12 Voltage-clamp recordings of the inward rectifier potassium currents (IK1, IK,ADO) and the high-threshold basal and stimulated calcium current (ICa,L) were obtained as previously described.3 13 The equilibrium potential of potassium (EK) was calculated with the Nernst equation: EK=(RT/F)ln[Ko/Ki], where RT/F=26.55 mV. In the experiments with adenosine, the concentrations of adenosine used (eg, 3 to 4 µmol/L) were similar to those reported to be the interstitial concentration of adenosine measured during myocardial hypoxia or ischemia.14
Isolated Perfused Hearts
Hartley guinea pig hearts were isolated and prepared with the
Langendorff method as previously described.13 15
Electrocardiograms were recorded with the use of
unipolar electrodes placed on the surface of the left atrium and in the
His bundle position according to the method of Jenkins and
Belardinelli.16 The atrial-to-His bundle (AH) interval, a
measure of AV nodal conduction time, was measured from the atrial and
His bundle electrograms with the use of cursors (Snapshot Storage
Scope, HEM Data Corp).15 Unless otherwise noted, if any of
the interventions caused second- or third-degree AV nodal conduction
block, the most stable measured response value (longest AH interval)
before the onset of AV nodal conduction block was used for data
analysis.
Statistical Analysis
Values are presented as mean±SEM. Tests of statistical
significance were performed with a paired t test and a 1- or
2-way, repeated-measures ANOVA followed by Student-Newman-Keuls testing
(SSPS version 7.5, SPSS, Inc). A value of P<0.05 was
considered statistically significant.
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Results |
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Isolated AV Nodal and Left Atrial Cells
Effect of Elevated [K+]o on Electrophysiological Properties of Atrial and AV Nodal Myocytes in the Absence of Adenosine
Atrial and AV nodal myocytes were distinguished on the basis of morphology and electrophysiological properties.3 High [K+]o caused different responses in atrial and AV nodal cells (Figure 1
, A and B). Increase of
[K+]o from 4.8 to
8.0 mmol/L depolarized atrial myocytes from -77±1 to -65±1 mV
(n=4, P<0.001). In contrast, the Vm
of AV nodal myocytes was insensitive to changes in
[K+]o;
Vm was -49±2 and -48±2 mV in the presence of
4.8 and 8.0 mmol/L
[K+]o, respectively (n=5,
P=0.74).
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Typical records of steady-state current-voltage relations of atrial
and AV nodal myocytes measured in response to a voltage ramp protocol
(during which Vm was changed from -120 to +40 mV
over 6 seconds) are shown in panels C and D, respectively, of Figure 1
. In atrial cells there was a marked inward rectification at
Vms negative to -80 mV that corresponds to
activation of the inwardly rectifying potassium current,
IK1. High
[K+]o increased the
inward component of IK1 over a certain range of
negative potentials. For instance, the amplitude of the inward
component of IK1 at -100 mV was increased from
-0.190±0.028 to -0.580±0.108 nA (n=5, P<0.02). There
was also a small increase in the outward component of
IK1 measured at -40 mV from 0.049±0.008 to
0.056±0.008 nA (P=0.55). In addition, in atrial cells,
hyperkalemic conditions caused a 12±1 mV (P<0.001) shift
of the reversal membrane potential (Vrev) in the
positive direction. In contrast, IK1 was absent
in AV nodal cells that had a relatively small background current with
little inward rectification at Vms more negative
than -50 mV (Figure 1D). Although elevated
[K+]o did not affect this
background current at Vms near to or more
positive than Vrev, there was a small increase in
its inward component measured at Vms more
negative than -80 mV. The amplitude of this current at -40 mV was
0.011±0.003 and 0.008±0.002 nA at 4.8 and 8.0 mmol/L
[K+]o, respectively (n=4,
P=0.44). The mean inward component at -100 mV was
-0.082±0.022 and -0.138±0.039 nA (P=0.30) in the
presence of 4.8 and 8.0 mmol/L
[K+]o, respectively.
Also, elevated [K+]o did
not significantly shift Vrev in AV nodal
myocytes.
Effect of Elevated [K+]o on
Electrophysiological Properties of AV Nodal and
Atrial Myocytes in the Presence of Adenosine
In the presence of high
[K+]o, adenosine
(3 µmol/L) still significantly hyperpolarized the membrane
potential of AV nodal myocytes from -48±2 to -65±1 mV (Figure 2A), although the magnitude of
hyperpolarization was less than that caused at
normal [K+]o (from
-49±2 to -73±2 mV). In contrast to AV nodal myocytes,
adenosine (3 µmol/L) caused only minimal
hyperpolarization in atrial myocytes (Figure 2B) at normal (from -77±1 to -78±1 mV) and high
[K+]o (from -65±1 to
-66±2 mV).
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The steady-state current-voltage relations of AV nodal and atrial
myocytes measured in response to a voltage ramp protocol before and
after the application of adenosine are shown in Figure 3. In contrast to control conditions (ie,
absence of adenosine, Figure 1D), elevation of
[K+]o to 8.0 mmol/L
in the presence of 3 µmol/L adenosine significantly
augmented the membrane current in AV nodal cells (Figure 3, A
and B). The inward component of this current measured at -100 mV (ie,
background+IK,ADO) increased from -0.249±0.038
nA (normal [K+]o) to
-0.571±0.111 nA (high
[K+]o, n=7,
P<0.05). Despite a decrease in the potassium driving force
(EM-EK), the outward
component of this current measured at -40 mV increased from
0.064±0.019 to 0.079±0.021 nA in response to elevation of
[K+]o. In the presence of
adenosine, the Vrev was shifted from
-76±2 to -64±1 mV in the presence of 4.8 and 8.0 mmol/L
[K+]o, respectively
(P<0.001).
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The changes in ramp current recorded in response to the application
of adenosine (3 µmol/L) at either 4.8 and 8.0
mmol/L [K+]o were
markedly smaller in atrial myocytes (Figure 3, C and D). In
atrial myocytes the mean inward component of the current
(IK,ADO+IK1) measured at
-100 mV was -0.264±0.028 and -0.727±0.099 nA at normal and high
[K+]o, respectively (n=7,
P<0.001). The amplitudes of the outward component of the
current measured at -40 mV were 0.109±0.015 and 0.113±0.015 nA at
normal and high [K+]o,
respectively (P=0.85). Considering the fact that elevation
of [K+]o from 4.8 to
8.0 mmol/L alone significantly increased IK1
(from -0.190±0.028 to -0.580±0.108 nA measured at -100 mV), the
additional increase of inward rectifier current caused by application
of adenosine was similar at normal and high
[K+]o (143±11% and
130±9%, respectively).
The effects of [K+]o on
IK,ADO of AV nodal and atrial myocytes are
summarized in Figure 4. As illustrated in
Figure 4, the amplitude of IK,ADO was
greater at 8.0 than 4.8 mmol/L
[K+]o and was larger in
AV nodal cells than in atrial myocytes. This suggests that in the
presence of adenosine, IK,ADO is a major
source of the resting K+ conductance in AV nodal
cells but not in atrial myocytes; its role is significantly increased
with elevated [K+]o.
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We estimated the changes in membrane resistance
(Rm) of single AV nodal and atrial myocytes
caused by adenosine and high
[K+]o. The
Rm of cells was calculated from the slope
conductance of the steady-state current-voltage relation close to the
point of zero current potential. Changes in Rm of
AV nodal and atrial myocytes in response to extracellular application
of elevated [K+]o and
adenosine are summarized in Figure 5. The Rm of AV
nodal myocytes in control condition was quite high (1163±314 M) and
was not significantly changed by elevated
[K+]o (894±237 M,
P=0.40). The Rm of atrial myocytes was
much smaller (109±9 M) and was also not significantly changed by
elevated [K+]o (91±11
M, P=0.20). Application of adenosine in the
presence of 4.8 mmol/L
[K+]o reduced
Rm of AV nodal cells by 87% (1163±314 to
151±21 M) and of atrial myocytes by 28% (109±9 to 79±4 M).
Additional increases in IK,ADO caused by elevated
[K+]o further decreased
Rm in AV nodal myocytes (to 77±8 M,
P<0.02) but did not significantly affect
Rm in atrial myocytes (to 68±8 M,
P=0.30).
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compared with
4.8 mmol/L [K+]o and presence of
adenosine for AV nodal myocytes.
Effect of Elevated [K+]o on the
Inhibitory Effect of Adenosine on
Isoproterenol-Stimulated ICa,L in AV Nodal
Myocytes
To exclude the possibility that elevated
[K+]o may enhance the
effect of adenosine on IK,ADO by causing
an increase in the affinity of the
A1-adenosine receptor for
adenosine, a separate set of experiments was carried out on AV
nodal cells. Specifically, the effect of elevated
[K+]o on
A1-adenosine receptor–mediated
inhibition by adenosine of isoproterenol (100
nmol/L)-stimulated ICa,L
(ß-ICa,L) was investigated. In contrast to its
activation of IK,ADO, adenosine-induced
inhibition of ß-ICa,L was not dependent on
[K+]o (Figure 6). Adenosine (3 µmol/L)
reduced ß-ICa,L from -2.04±0.11 to
-1.76±0.12 nA (n=3; P<0.001) at normal
[K+]o. However, the
magnitude of this effect of adenosine on
ß-ICa,L (-1.87±0.15 nA) was not significantly
changed by high
[K+]o.
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Potentiation of Negative Dromotropic Effect of Adenosine by
Elevated [K+]o in Isolated Hearts
Potassium-induced changes in the negative dromotropic effect of
adenosine were studied in guinea pig isolated heart. In the
first series of experiments (n=5), concentration-response relations for
this effect of adenosine in the presence of 4.8 and 8.0
mmol/L [K+]o were
obtained (Figure 7). In the absence of
adenosine, hyperkalemia did not significantly
change the AH interval (39.3±2.7 at 4.8 mmol/L
[K+]o vs 44.3±3.9 at
8.0 mmol/L [K+]o;
n=5; P=0.23). Adenosine caused a
concentration-dependent lengthening of the AH interval in hearts
treated with 4.8 and 8.0 mmol/L
[K+]o. However, high
[K+]o markedly enhanced
the negative dromotropic effect of adenosine. There was a
significant upward and leftward shift of the adenosine
concentration-response relation in hearts exposed to hyperkalemic
conditions (Figure 7). Likewise, the pD2
(-log EC50) values of adenosine to
prolong the AH interval in the presence of normal
[K+]o, high
[K+]o, and after washout
of high [K+]o (ie, normal
[K+]o) were 5.26±0.03
(5.5 µmol/L), 5.67±0.06 (2.1 µmol/L), and 5.29±0.05
(5.1 µmol/L), respectively. In addition, the threshold
concentration of adenosine required to prolong the AH interval
was significantly lower (P<0.05) in hearts perfused with
8.0 mmol/L [K+]o
(Figure 7). Furthermore, AV nodal conduction block occurred at
lower concentrations of adenosine in hearts that were exposed
to elevated [K+]o. Taken
together, these data demonstrate that the negative dromotropic effect
of adenosine was significantly enhanced by high
[K+]o.
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According to the single-cell data, the observed potentiation of the
negative dromotropic effect of adenosine by elevated
[K+]o might be
attributable to an increase in magnitude of
IK,ADO. To test this hypothesis, the effect of
[K+]o on
adenosine-induced AH prolongation was determined in the
presence of BaCl2 (100 µmol/L), a
selective blocker of IK,Ach,ADO at this
concentration.17 Addition of BaCl2
to the perfusion medium abolished this potassium-induced potentiation
of the negative dromotropic action of adenosine (Figure 8).
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Discussion |
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This report is the first to demonstrate that extracellular potassium at concentrations commonly observed during various physiological and pathophysiological conditions such as physical exercise18 and myocardial ischemia,19 20 21 respectively, markedly enhances the negative dromotropic effect of adenosine by a mechanism involving potentiation of IK,ADO. The data presented also support the hypothesis that IK,ADO plays an important role in the depressant action of adenosine on the AV node.
Differential Effects of Elevated [K+]o on
Atrial and AV Nodal Cell Electrophysiology
Our observation that isolated AV nodal cells, in contrast to
atrial myocytes, are insensitive to changes in
[K+]o is fully
consistent with results of previous studies with multicellular
preparations.10 11 Likewise, DeMello and
Hoffman22 reported that a high concentration of
K+ caused a loss of excitability of rabbit atrial
muscle, whereas action potentials were still present in the AV
node. In addition, [K+]o
as high as 7.5 mmol/L did not significantly affect conduction
through the AV node of the rabbit isolated heart.11 This
lack of sensitivity of the AV nodal cells to changes in
[K+]o, compared with
atrial myocytes, can be explained by the relatively low
K+ conductance (gK) during
diastole in nodal tissue, a feature attributable to the
absence of IK1 in AV nodal cells. Conductance
through inwardly rectifying K+ channels can be
described by the product of the potassium driving force
(Vm-EK) and
[K+]o.20 23 24 25
Why Does Elevated [K+]o Potentiate the
Negative Dromotropic Effect of Adenosine?
Hyperkalemia markedly sensitized the AV node to
the effect of adenosine, both at the cellular and whole heart
level in 2 different species, by augmenting
IK,ADO. We suggest that potentiation of the
negative dromotropic effect of adenosine by elevated
[K+]o is due to (1) a
decreased space constant (
) for propagation of an action potential
secondary to augmentation of adenosine-activated
potassium conductance; and (2) prolongation of the refractory period of
AV nodal myocytes because of (a) a slowed time course of deactivation
of the delayed rectifier potassium current (IK),
(b) a prolonged time of recovery from inactivation of
ICa,L and ICa,T, (c) an
increased steady-state inactivation of ICa,L and
ICa,T, and (d) an increased amplitude of
threshold current needed to elicit an action potential. In contrast,
because elevated [K+]o
did not affect the inhibition by adenosine of
ß-ICa,L, an effect mediated by the
A1-adenosine receptor, it is highly
unlikely that the potentiating effects of
[K+]o on the negative
dromotropic effect of adenosine is due to an increase in the
inhibition of ICa,L or an increase in the
affinity of adenosine for the
A1-adenosine receptor.
Space Constant ()
According to 1-dimensional cable theory,26 the
distribution of transmembrane potential along a cardiac fiber is
described by the equation
Vm=Vm,0e(-x/).
Vm, Vm,0, and are the
membrane potential at distance x along a fiber, membrane potential at
the origin (ie, x=0), and space constant, respectively. The space
constant (), defined as the distance along a fiber over which
Vm exponentially falls to 37% of its value at
the point of current application, is equal to
Rm/ri. Therefore, assuming
that the internal or longitudinal resistance (ri)
of a unit length of cable is constant during activation of
IK,ADO,27 changes in input
resistance (Rm) will directly reflect changes in
. As shown in Figure 5, in the presence of elevated
[K+]o, adenosine
markedly reduced Rm of AV nodal cells, which in
turn is likely to have resulted in a decrease in .
Deactivation of IK
Slow deactivation of IK has been shown to
delay the recovery of excitability and cause Wenckebach periodicity in
guinea pig isolated ventricular myocytes.28
Because of a slowed time course of IK
deactivation, the membrane resistance is lower in the early phase of
diastole and therefore a greater depolarizing current must
be applied during this time to attain threshold than one applied later
in diastole. In keeping with this interpretation, Howarth
et al29 showed that the kinetics of
IK in rabbit AV nodal myocytes could be
responsible for changes in cell excitability during
diastole. On the other hand, Salata et al30
found the time course of IK deactivation in
rabbit ventricular myocytes to be highly dependent on
Vm (ie, marked slowing on depolarization). If
voltage-dependent IK deactivation is similar in
rabbit AV nodal myocytes, this can be a potential mechanism whereby
elevated [K+]o
potentiates the negative dromotropic effect of adenosine
because the Vm of these cells is significantly
more positive in the presence of adenosine and high
[K+]o.
Steady-State Inactivation of ICa,L and
ICa,T
Because at high
[K+]o the
adenosine-induced hyperpolarization was
less than at normal [K+]o
(-65±1 mV and -73±2 mV, respectively), it is anticipated that the
magnitude of depolarizing currents (ICa,L and
especially ICa,T) will be reduced because of
steady-state inactivation of these calcium channels. Because the inward
calcium current is the major determinant of Vmax
of the AV nodal action potential, the negative dromotropic effect of
adenosine should be greater in the presence of high
[K+]o.
Recovery From Inactivation of ICa,L and
ICa,T
In the presence of adenosine and high
[K+]o, and therefore at a
less negative Vm, the recovery of
ICa,L and ICa,T channels
from inactivation will be slower than that in the presence of
adenosine and normal
[K+]o. As a result, the
adenosine-induced prolongation of the refractory period of the
AV node should be greater in the setting of
hyperkalemia.
Threshold Current
Because of a low gK, the resting
Vm of AV nodal cells is in the range of -43 to
-60 mV, values that are considerably more positive than
EK (-90 mV, assuming
[K+]i=140
mmol/L).3 27 31 Even if
[K+]o is elevated up to
8 mmol/L, EK remains negative to
Vm (EK will be -78 mV). In
other words, the increase in gK that takes place
in the presence of adenosine and high
[K+]o will still produce
hyperpolarization of the membrane of AV nodal
myocytes. In addition, according to the Goldman-Hodgkin-Katz
equation,32 an increase in gK will
increase the influence of the K+ gradient on
Vm. Therefore, at a given magnitude of
hyperpolarization but with a higher level of
gK, a greater depolarizing current (or local
circuit current) would be required to achieve
Vth.
Implications
The results of this study significantly expand our understanding
of the mechanism(s) whereby adenosine modulates single AV nodal
cell electrophysiology and AV nodal conduction. Modulation of the
effects of adenosine on AV nodal conduction by extracellular
K+ has significant
physiological and
pathophysiological implications. The observation
that elevated [K+]o
sensitizes the AV node to the depressant effects of adenosine
provides a means whereby adenosine can cause AV nodal
conduction block, even at concentrations that are ordinarily
subthreshold for its negative dromotropic effect under normokalemic
conditions. This finding is particularly important because
adenosine and K+ may be concomitantly
released in increased amounts into the interstitium under a variety of
conditions.33 34 For example, during imbalances between
oxygen supply and demand (eg, hypoxia or ischemia),
cardiac adenosine formation is markedly
increased.35 Similarly, during myocardial
ischemia21 and physical exercise,35
[K+]o may rise up to as
much as 8 to 12 mmol/L. Finally, the findings here reported also
provide a foundation for future studies to understand the mechanism(s)
whereby drugs modulate the intrinsic rate-dependent
physiological properties of the AV node.
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Acknowledgments |
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This work was supported by the Florida Affiliate of the American Heart Association (No. 9701753), National Institutes of Health (HL-56785-01), I. Heermann Anesthesia Foundation, and FAER/Zeneca New Investigator Award.
Received April 29, 1998; revision received August 17, 1998; accepted September 9, 1998.
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