(Circulation. 2001;103:1577.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Decreased Sarcoplasmic Reticulum Calcium Content Is Responsible for Defective Excitation-Contraction Coupling in Canine Heart Failure
From the Institute of Molecular Cardiobiology, Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md.
Correspondence to Brian O’Rourke, PhD, Johns Hopkins University, Department of Medicine, Division of Cardiology, 844 Ross Building, 720 Rutland Ave, Baltimore, MD 21205. E-mail bor{at}jhmi.edu
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Abstract |
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Background—Altered excitation-contraction (E-C) coupling in canine pacing-induced heart failure involves decreased sarcoplasmic reticulum (SR) Ca uptake and enhanced Na/Ca exchange, which could be expected to decrease SR Ca content (CaSR) and may explain the reduced intracellular Ca (Cai) transient. Studies in other failure models have suggested that the intrinsic coupling between L-type Ca current (ICa,L) and SR Ca release is reduced without a change in SR Ca load. The present study investigates whether CaSR and/or coupling is altered in midmyocardial myocytes from failing canine hearts (F).
Methods and Results—Myocytes were indo-1–loaded via patch pipette (37°C), and Cai transients were elicited with voltage-clamp steps applied at various frequencies. ICa,L density was not significantly decreased in F, but steady-state Cai transients were reduced to 20% to 40% of normal myocytes (N). CaSR, measured by integrating Na/Ca exchange currents during caffeine-induced release, was profoundly decreased in F, to 15% to 25% of N. When CaSR was normalized in F by preloading in 5 mmol/L external Ca before a test pulse at 2 mmol/L Ca, a normal-amplitude Cai transient was elicited. E-C coupling gain was dependent on CaSR but was affected similarly in both groups, indicating that intrinsic coupling is unaltered in F.
Conclusions—A decrease in CaSR is sufficient to explain the diminished Cai transients in F, without a change in the effectiveness of coupling. Therefore, therapeutic approaches that increase CaSR may be able to fully correct the Ca handling deficit in heart failure.
Key Words: sarcoplasmic reticulum • calcium • heart failure
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Introduction |
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It is widely believed that heart muscle contraction is triggered by membrane depolarization via the process of Ca-induced Ca release (CICR1 2 ): Ca entry through the Ca channels during the action potential triggers a large release of Ca from the sarcoplasmic reticulum (SR). The intracellular Ca (Cai) transient is thought to be the summation of local Ca release events occurring at junctions between the transverse-tubule sarcolemmal membrane and the SR ("diads"), where L-type Ca channels and SR Ca release channels are closely apposed. Such local control can explain the main features of CICR, including (1) a high gain (a large Ca release for a small Ca trigger), (2) a graded response (corresponding to the size of Ca current, ICa,L), and (3) the absence of uncontrolled regenerative Ca release (under normal conditions).2 3 Local control is epitomized by the observation of Ca sparks in cardiomyocytes,4 5 and the relationship between ICa,L and spark frequency has been used as a measure of the intrinsic E-C coupling efficiency, or local gain.6 7 In a larger sense, however, the total gain of CICR will depend on both the local effectiveness of coupling between ICa,L and SR release (
) and on the SR Ca load
(CaSR).
Limited information is available about which of these
factors may change in human heart failure. Beuckelmann et
al8 showed that
Cai transients of ventricular
myocytes isolated from failing human hearts have a reduced amplitude
without a change in
ICa,L
and also suggested a decrease in CaSR (ryanodine
had a small effect on the Cai transient in
failing cells). A decreased CaSR has also been
reported by Lindner et al9
and Pieske et al,10 but no
information is available about whether is changed in the failing
human heart, as reported in some rat models of heart
disease.6 7
The canine pacing-induced heart failure model shows a
pattern of E-C coupling changes similar to that of humans:
ICa,L of
normal amplitude triggers Cai transients and
contractions much smaller than normal, whereas SR Ca uptake is markedly
impaired.11 The present
study investigates whether the defect in E-C coupling is due to a
decrease in CaSR, in , or in
both.
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Methods |
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Induction of heart failure,12 isolation of midmyocardial cardiomyocytes,11 13 single-cell electrophysiology studies,11 and Ca measurements11 were carried out as previously described. After 3 to 4 weeks of tachycardic pacing (240 bpm), mongrel dogs showed clinical signs and hemodynamic manifestations of heart failure, including elevated end-diastolic pressures and decreased contractility.12 Isolated myocytes were whole-cell patch-clamped at 37°C. The external solution was K-free (to eliminate inward K currents) and contained (in mmol/L) NaCl 140, CaCl2 2, MgCl2 1, HEPES 5, glucose 10, and niflumic acid 0.1 (Sigma, Cl current blocker), pH adjusted to 7.4 with NaOH. Superfusing solutions were rapidly changed by use of a solenoid-controlled heated switching device.
For selective measurement of ICa,L, the pipette solution contained (in mmol/L) CsCl 110, MgATP 5, HEPES 10, MgCl2 0.4, glucose 5, tetraethylammonium (TEA) 20, and BAPTA 5, pH 7.2. Cs and TEA inhibited outward K currents, and BAPTA was used to buffer Cai. The "pipette-to-bath" liquid junction potential was minimal (-2.7 mV) and was not corrected.
For E-C coupling experiments, the external solution also
contained 30 µmol/L tetrodotoxin (TTX, Sigma; to block sodium
current,
INa).
The pipette solution contained (in mmol/L) potassium glutamate
125, KCl 19, MgCl2 0.5, MgATP 5, NaCl 10, and
HEPES 10, pH 7.25, and 50 µmol/L indo-1 (pentasodium salt,
Calbiochem). The pipette-to-bath liquid junction potential was 
-20
mV and was corrected. Indo-1 fluorescence was excited at 365 nm
and recorded at wavelengths of 405 and 495
nm.11 Cellular
autofluorescence was recorded before rupturing of the
cell-attached patch and was subsequently subtracted.
Cai was calculated according to the equation
Cai=Kdxßx[(R-Rmin)/(Rmax-R)],14
with a
Kd of
844 nmol/L,15
Rmin=1, Rmax=4, ß=2,
and R=405/495 fluorescence ratio.
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Results |
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We previously showed that basal ICa,L density is unaltered in canine tachypacing-induced heart failure at room temperature12 and with minimal Cai buffering.11 In the latter study, however, no provision was made to block potential contaminating currents (eg, background K currents, Ca-activated Cl current, and Na/Ca exchange [NCX] currents), and the kinetics of ICa,L were not examined. Therefore, we first examined in detail the time course of ICa,L inactivation and Ca influx via ICa,L under controlled conditions in the presence of the fast Ca buffer BAPTA.
Analysis of
ICa,L
Depolarizations of 500 ms from -80 mV to
various membrane potentials (VM) were applied
every 4 seconds and were preceded by a 100-ms prepulse to -40 mV to
inactivate
INa.
ICa,L
amplitude (measured as the peak inward minus end of pulse current) was
similar in normal myocytes (N) and myocytes from failing canine hearts
(F) over the potential range from -30 to 40 mV
(Figure 1A
through 1E). The voltage dependence of whole-cell
Ca conductance
[G=ICa,L/(VM-Erev),
where Erev is the apparent reversal potential
for
ICa,L]
normalized to maximum conductance (Gmax) is
shown in
Figure 1F. Data were fitted with a Boltzmann
equation16
(G/Gmax=1/{1+exp[(V0.5-VM)/k]}),
and the activation parameters were unchanged in F
(Table 1).
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From
ICa,L
recordings obtained at 10 mV, Ca entry via L-type Ca channels
was measured as the integral of
ICa,L
for either the first 50 ms after depolarization
(
ICa,L;
the period most relevant to triggering CICR) or for the whole pulse. No
statistically significant differences were found between N and F
(Figure 1G
and
Table 1).
To investigate whether the kinetics of
ICa,L
inactivation are changed in F, the time course of inactivation of
ICa,L
(at 10 mV) was fitted with a double
exponential16 :
ICa,L(t)=A1
exp(-t/
1)+A2
exp(-t/2)+C, where
1 and 2 are the
fast and slow time constants, respectively, and
A1 and A2 are the
corresponding amplitudes of the exponential function. The 2 time
constants, as well as the proportion of total
ICa,L
inactivated with each of them, were also unchanged in F
(Table 1).
E-C Coupling Experiments
ICa,L,
Cai transients, and CaSR
were measured in indo-1–loaded myocytes after conditioning trains of
voltage-clamp depolarizations at different stimulation frequencies.
Figure 2A illustrates typical membrane currents and
Cai transients elicited with depolarizations
from -80 to 10 mV at 1-Hz stimulation (pulse duration 0.3 seconds).
After steady state was attained, the train was interrupted and 10
mmol/L caffeine was applied rapidly, inducing Ca release from the SR.
During caffeine application, Cai rose rapidly
and then decayed exponentially, extruded (mainly) by NCX, which
generated an inward current. Ten seconds after caffeine was washed off,
it was reapplied to ensure that all SR Ca was released with the first
application. The second caffeine application produced no change in
Cai but induced a small (100-pA), slowly
activating inward current (traces marked with asterisk in
Figure 2B).
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Figure 2, C and D, illustrates a similar experiment in F.
Compared with N, the fast component of the depolarization-evoked
Cai transient was markedly reduced. Caffeine
application triggered a reduced rise in Cai and
only a small inward NCX current. Just as in N, a second caffeine
application induced no Cai rise and a slowly
activating inward current.
Similar results were obtained at frequencies of 0.5 and 0.25
Hz (pulse duration 0.5 seconds; not shown).
ICa,L
amplitude and
ICa,L
showed a trend toward lower values in F, but this difference was not
statistically significant
(Table 2; see Discussion). Compared with
ICa,L, a
disproportionately large and unequivocal decrease was observed in the
Cai transients recorded in F. Both the rate
of rise of Cai
(
Cai/t;
Figure 2E) and the amplitude of the early rapidly rising
phase of the Cai transient
(Cai;
Figure 2F) were markedly reduced at all stimulation
frequencies, the former being only 6% to 16% of N
(Table 2).
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NCX current generated by caffeine Ca release was measured as
the difference between currents recorded during the first and
second caffeine applications. CaSR (as total
[Ca], CaT) was determined by integrating NCX
current by use of the equation CaT
(µmol/L)=76xNCX current integral (pC)/cell capacitance (pF), as
previously described17 (see
also Negretti et al18 ).
CaSR in N was between 80 and 120 µmol/L,
values comparable to reports in rat
cells.18 In contrast, F had
markedly reduced CaSR at all the stimulation
frequencies used (14% to 25% of N,
Figure 2G and
Table 2). The amplitude of the caffeine-induced
Cai transients (another indication of
CaSR) was similarly reduced in F
(Table 2).
A more exact CaSR estimation should take into account the components of cytosolic Ca removal via non-NCX mechanisms (sarcolemmal Ca pump and mitochondrial Ca buffering), representing 28% and 12% of total non–SR-mediated Ca transport in N and F, respectively.17 Therefore, all CaSR values reported here underestimate the difference between groups and could be corrected by multiplying by 1.28 and 1.12 for N and F, respectively.
How Much of the Cai
Transient in N Is Due to Ca Entry?
Depolarization-evoked Cai
transients were recorded in N immediately after a caffeine release,
and thus with SR Ca load depleted
(Figure 3A). Cai/t in the first
Cai transient after caffeine was greatly
reduced, to 17% of the precaffeine steady-state value
(Figure 4B).
ICa,L
was also slightly increased, indicating a partial relief from
Ca-dependent inactivation
(Figure 4A). Cai/t in N cells
with SR depleted was close to the steady-state
Cai/t in F, as discussed above. This
result suggested that most of the Cai/t in
F was likely to be due to transsarcolemmal Ca entry via
ICa,L
and reverse NCX, with little contribution from SR release. Although the
caffeine release experiments indicated that there was still a residual
CaSR in F at steady state (14% to 25% of N),
it appears that this pool is not readily releasable, perhaps because of
a low at low
CaSR.19
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Increasing SR Load in F
Because these experiments suggested that the marked
decrease in Cai transient amplitude in failing
cells could be explained by the decrease in SR Ca load and did not
necessitate the postulation of a decrease in , we tested whether
adjustment of CaSR to similar levels in N and F
resulted in Cai transients with similar
characteristics.
Myocytes from failing hearts were superfused with an
external solution containing 5 mmol/L Ca while a train of
depolarizations was applied at 0.5 Hz (see
Figure 3B for the voltage protocol). After reaching a steady
state in 5 mmol/L Ca
(Figure 3C), the solution was rapidly changed (for 1 pulse)
to 2 mmol/L Ca. In this way, CaSR could be
maintained at a higher level while
ICa,L
was instantaneously restored to that typically observed at 2
mmol/L Ca. The Cai transient recorded with
the intercalated pulse in 2 mmol/L Ca
(Figure 3D) was thus triggered by a control
ICa,L
but had CaSR equal to the steady-state load in
5 mmol/L Ca. The latter was measured by caffeine application
(Figure 3E) immediately after steady state was attained once
more in 5 mmol/L Ca. Mean
ICa,L
was close to the steady-state
ICa,L in
2 mmol/L Ca shown in the previous experiments
(Figure 4A), and CaSR was close to N
levels
(Figure 4C). Cai/t was also
similar to N
(Figure 4B), consistent with the hypothesis that the
defect in E-C coupling is primarily due to impaired SR Ca loading. This
experiment was performed in 16 cells from 3 F hearts (16/3) compared
with 16/4 N.
Figure 4D illustrates the results of this experiment
in individual cells. The relationship between CICR gain [calculated as
(Cai/t)/ICa,L20 ]
and CaSR (as NCX current integral, in fC/pF, not
transformed to [CaT]) was similar in N cells
and F cells with increased SR load. Within individual cells, CICR gain
was usually well correlated with CaSR. When all
cells were plotted together, more scatter in the data was evident, but
it was evident that N and F data were interspersed. In each cell, we
calculated as
(Cai/t)/(ICa,LxCaSR)
and found no difference between N and F
(Figure 4E).
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Discussion |
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Consistent with a previous study from this laboratory,11 we report here that CICR gain (as defined to include both
and
CaSR) is decreased in heart failure: membrane
depolarization triggered markedly reduced Cai
transients, although no significant difference could be seen in
ICa,L.
The decrease in CICR gain could be explained by a similarly marked
reduction in CaSR, whereas no change in was
observed.
ICa,L
Measurements
We measured
ICa,L
both with Cai buffered and in the presence of
physiological Cai
transients. Both measurements showed a tendency toward a decreased
ICa,L
density in F, but the difference was not statistically significant.
This trend suggests that a decrease in
ICa,L
could potentially contribute to the defective E-C coupling in this
model but does not account for the majority of the difference between
groups.
CICR Gain Versus the Effectiveness of
Coupling
The concept of CICR gain usually means the magnitude of
SR Ca release triggered by a given
ICa,L.2 21
Because in these previous
studies2 21
CaSR was kept constant, any variations in CICR
gain were equivalent to variations in . In the present study, we
needed to differentiate between CaSR and ,
because a decrease in either could induce the decrease in CICR gain in
heart failure. We measured SR release flux as
Cai/t, and we measured both Ca entry and
CaSR as integrals of
ICa,L
and NCX current, respectively. CICR gain was dramatically reduced in F
because of the decreased CaSR. This deficit in F
could be reversed when CaSR was increased to
normal levels, indicating that there is no decrease in
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Pacing-Induced Canine Heart Failure
Model
After 3 to 4 weeks of tachycardic pacing, canine hearts
exhibit a markedly decreased contractility in vivo
(with increased end-diastolic pressure and decreased
systolic rate of rise of left ventricular
pressure12 ).
Consistent with that, isolated cells show
Cai transients that are slowed and of decreased
amplitude.11 Previous
studies from this laboratory indicated a main defect in
Cai removal
mechanisms,11 with both a
decrease in SR Ca uptake and an increase in NCX Ca extrusion, which, in
itself, might be expected to decrease CaSR. This
is also the prediction of a refined computer model of the failing heart
cell.22 The experiments
reported here confirm the marked decrease in
CaSR in this model, which is largely responsible
for the decreased Cai transients. Although we
purposely controlled the experimental conditions for this study,
extrapolation of this conclusion to action potential–evoked Ca
transients in vivo requires consideration of the changes in action
potential evident in heart failure, as well as differences in
modulatory factors (external and internal), which may be altered by the
disease.
The present findings are inconsistent with the
hypothesis that the E-C coupling abnormalities in heart failure are the
result of defects at the level of the SR release channel, such as
decreases in either the number of
channels23 24 or
rate of release,23 or the
effectiveness of coupling (). Further investigation will be
necessary to determine whether our conclusions are model-specific or
can be generalized to humans.
Comparison With Other Heart Failure
Models
Although a decreased CaSR is
thought to be a major part of the defective E-C coupling in human heart
failure,9 there have been few
estimates of CaSR in animal models of heart
failure and even fewer quantitative measurements. In a rat
hypertrophy model without overt heart failure, cell
contractility has been shown to be increased in
parallel with an increase in
CaSR.25
In a model of overt heart failure induced by combined aortic
insufficiency and stenosis in
rabbits,26 a 26% decrease
in (externally stimulated) myocyte twitches was reported, with a trend
toward a decrease in both the Cai transient and
CaSR (estimated as the amplitude of
caffeine-induced Cai transients; see note on
method below).
To the best of our knowledge, only 1 other animal model of heart failure, a postinfarction rat model, has shown a significant decrease in the Cai transient associated with a reduction in CaSR.27
In contrast, changes in , with unchanged
CaSR, have been reported in 2 rat models, in 1
of which diminished Cai transients were
explained by a decrease in
.6 In another study,
increases in Cai transients in cells from
spontaneously hypertensive rats could be accounted for by an increase
in (again, with no change in
CaSR7 ).
The change in could be due a change in the number of Ca sparks (of
otherwise normal kinetics and amplitude) triggered by a given
ICa,L6
or to changes in the Ca spark amplitude ("big
sparks"7 ). Whether a
changed will induce a change in the steady-state
Cai transients in these (rat) models is
controversial (because of compensatory changes in
CaSR28 ),
but the present experiments demonstrate that this is not the case
in the canine pacing–induced model.
Relevance to Human Disease
Midmyocardial cells isolated from failing human hearts
showed unchanged
ICa,L
and decreased Cai
transients.8 The latter could
be due to a decrease in SR Ca content, which has been qualitatively
estimated from the amplitude of caffeine-induced
Cai transients by Lindner et
al.9 It is worthwhile to note
that interpretation of the results of such experiments is not
straightforward. For example, it is known that the peak of the
Cai rise can be blunted by Ca extrusion through
NCX, because significant inward current can be recorded by the time
Cai reaches its
peak.29 Because NCX may be
increased in F, it may blunt the peak of the caffeine transient more in
F than in N, biasing the results. In the present study, we looked
at both the caffeine-evoked Cai transient and
the NCX current integral under voltage-clamp conditions, and
reassuringly, both parameters led to the same
conclusion.
A defective SR loading in heart failure was also indicated by Pieske et al.10 Using rapid cooling contractures in intact cardiac muscle strips, they showed that in failing muscles, CaSR decreased both during rest and with increasing frequency of stimulations, unlike the response of nonfailing muscle.10
It is important to note that the E-C coupling changes
reported here and
previously11 in the pacing
canine model are remarkably similar to human disease. Just as in human
disease, F cells showed decreased Cai transients
and a decreased CaSR, with little change in
ICa,L.
In the present study, we could also show that is not changed,
because F cells with a normalized CaSR showed
normal Cai transients. No information is yet
available on whether the coupling effectiveness is changed in human
heart failure. If this conclusion can be extrapolated to the human
disease, it could have an important clinical significance, indicating
that therapeutic strategies that could restore
CaSR (by stimulation or overexpression of
sarcoplasmic/endoplasmic reticulum Ca2+-ATPase [SERCA], for
example30 ) could be expected
to fully restore E-C coupling and cell contractility.
If a decrease in were involved as well, this would not necessarily
be the
case.
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Acknowledgments |
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This study was supported by NIH grants RO1-HL-61711 (to Dr O’Rourke) and the Specialized Center of Research (SCOR) on Sudden Cardiac Death and Heart Failure (NIH P50-HL-52307). We are grateful to SCOR investigators Eduardo Marbán, David Kass, and Gordon Tomaselli for helpful discussions and guidance. We also thank Richard Tunin for help with dog preparation and surgery.
Received September 6, 2000; revision received October 12, 2000; accepted October 13, 2000.
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D. Terentyev, I. Gyorke, A. E. Belevych, R. Terentyeva, A. Sridhar, Y. Nishijima, E. Carcache de Blanco, S. Khanna, C. K. Sen, A. J. Cardounel, et al. Redox Modification of Ryanodine Receptors Contributes to Sarcoplasmic Reticulum Ca2+ Leak in Chronic Heart Failure Circ. Res., December 5, 2008; 103(12): 1466 - 1472. [Abstract] [Full Text] [PDF]
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 P. T. Caldwell, P. A. Thorne, P. D. Johnson, S. Boitano, R. B. Runyan, and O. Selmin Trichloroethylene Disrupts Cardiac Gene Expression and Calcium Homeostasis in Rat Myocytes Toxicol. Sci., July 1, 2008; 104(1): 135 - 143. [Abstract] [Full Text] [PDF]
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 Y.-H. Yeh, R. Wakili, X.-Y. Qi, D. Chartier, P. Boknik, S. Kaab, U. Ravens, P. Coutu, D. Dobrev, and S. Nattel Calcium-Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs With Congestive Heart Failure Circ Arrhythmia Electrophysiol, June 1, 2008; 1(2): 93 - 102. [Abstract] [Full Text] [PDF]
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 V. Bito, F. R. Heinzel, L. Biesmans, G. Antoons, and K. R. Sipido Crosstalk between L-type Ca2+ channels and the sarcoplasmic reticulum: alterations during cardiac remodelling Cardiovasc Res, January 15, 2008; 77(2): 315 - 324. [Abstract] [Full Text] [PDF]
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S. Lehnart and A. R. Marks Regulation of Ryanodine Receptors in the Heart Circ. Res., October 12, 2007; 101(8): 746 - 749. [Full Text] [PDF]
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T. Guo, X. Ai, T. R. Shannon, S. M. Pogwizd, and D. M. Bers Intra Sarcoplasmic Reticulum Free [Ca2+] and Buffering in Arrhythmogenic Failing Rabbit Heart Circ. Res., October 12, 2007; 101(8): 802 - 810. [Abstract] [Full Text] [PDF]
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F. Swift, N. Tovsrud, U. H. Enger, I. Sjaastad, and O. M. Sejersted The Na+/K+-ATPase {alpha}2-isoform regulates cardiac contractility in rat cardiomyocytes Cardiovasc Res, July 1, 2007; 75(1): 109 - 117. [Abstract] [Full Text] [PDF]
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 D. M. Bers Altered Cardiac Myocyte Ca Regulation In Heart Failure. Physiology, December 1, 2006; 21(6): 380 - 387. [Abstract] [Full Text] [PDF]
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 L.-S. Song, E. A. Sobie, S. McCulle, W. J. Lederer, C. W. Balke, and H. Cheng Orphaned ryanodine receptors in the failing heart. PNAS, March 14, 2006; 103(11): 4305 - 4310. [Abstract] [Full Text] [PDF]
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X. Ai, J. W. Curran, T. R. Shannon, D. M. Bers, and S. M. Pogwizd Ca2+/Calmodulin-Dependent Protein Kinase Modulates Cardiac Ryanodine Receptor Phosphorylation and Sarcoplasmic Reticulum Ca2+ Leak in Heart Failure Circ. Res., December 9, 2005; 97(12): 1314 - 1322. [Abstract] [Full Text] [PDF]
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 S. Saba, A. M. Janczewski, L. C. Baker, V. Shusterman, E. C. Gursoy, A. M. Feldman, G. Salama, C. F. McTiernan, and B. London Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha} Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1456 - H1467. [Abstract] [Full Text] [PDF]
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Z. Kubalova, D. Terentyev, S. Viatchenko-Karpinski, Y. Nishijima, I. Gyorke, R. Terentyeva, D. N. Q. da Cunha, A. Sridhar, D. S. Feldman, R. L. Hamlin, et al. Abnormal intrastore calcium signaling in chronic heart failure PNAS, September 27, 2005; 102(39): 14104 - 14109. [Abstract] [Full Text] [PDF]
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L.-S. Song, Y. Pi, S.-J. Kim, A. Yatani, S. Guatimosim, R. K. Kudej, Q. Zhang, H. Cheng, L. Hittinger, B. Ghaleh, et al. Paradoxical Cellular Ca2+ Signaling in Severe but Compensated Canine Left Ventricular Hypertrophy Circ. Res., September 2, 2005; 97(5): 457 - 464. [Abstract] [Full Text] [PDF]
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 S. E. Lehnart, X. H.T. Wehrens, and A. R. Marks Defective Ryanodine Receptor Interdomain Interactions May Contribute to Intracellular Ca2+ Leak: A Novel Therapeutic Target in Heart Failure Circulation, June 28, 2005; 111(25): 3342 - 3346. [Full Text] [PDF]
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D. M. Harris, G. D. Mills, X. Chen, H. Kubo, R. M. Berretta, V. S. Votaw, L. F. Santana, and S. R. Houser Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca2+ Release Circ. Res., March 18, 2005; 96(5): 543 - 550. [Abstract] [Full Text] [PDF]
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G. K. R. Soppa, R. T. Smolenski, N. Latif, A. H. Y. Yuen, A. Malik, J. Karbowska, Z. Kochan, C. M. N. Terracciano, and M. H. Yacoub Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1468 - H1476. [Abstract] [Full Text] [PDF]
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U. Kirchhefer, H. A. Baba, G. Hanske, L. R. Jones, P. Kirchhof, W. Schmitz, and J. Neumann Age-dependent biochemical and contractile properties in atrium of transgenic mice overexpressing junctin Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2216 - H2225. [Abstract] [Full Text] [PDF]
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G. F. Tomaselli and D. P. Zipes What Causes Sudden Death in Heart Failure? Circ. Res., October 15, 2004; 95(8): 754 - 763. [Abstract] [Full Text] [PDF]
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I. A. Hobai, C. Maack, and B. O'Rourke Partial Inhibition of Sodium/Calcium Exchange Restores Cellular Calcium Handling in Canine Heart Failure Circ. Res., August 6, 2004; 95(3): 292 - 299. [Abstract] [Full Text] [PDF]
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M.E Diaz, H.K Graham, and A.W Trafford Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy Cardiovasc Res, June 1, 2004; 62(3): 538 - 547. [Abstract] [Full Text] [PDF]
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C.M.N. Terracciano, J. Hardy, E.J. Birks, A. Khaghani, N.R. Banner, and M.H. Yacoub Clinical Recovery From End-Stage Heart Failure Using Left-Ventricular Assist Device and Pharmacological Therapy Correlates With Increased Sarcoplasmic Reticulum Calcium Content but Not With Regression of Cellular Hypertrophy Circulation, May 18, 2004; 109(19): 2263 - 2265. [Abstract] [Full Text] [PDF]
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W. E Louch, V. Bito, F. R Heinzel, R. Macianskiene, J. Vanhaecke, W. Flameng, K. Mubagwa, and K. R Sipido Reduced synchrony of Ca2+ release with loss of T-tubules--a comparison to Ca2+ release in human failing cardiomyocytes Cardiovasc Res, April 1, 2004; 62(1): 63 - 73. [Abstract] [Full Text] [PDF]
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 H. Reuter, T. Han, C. Motter, K. D. Philipson, and J. I. Goldhaber Mice overexpressing the cardiac sodium-calcium exchanger: defects in excitation-contraction coupling J. Physiol., February 1, 2004; 554(3): 779 - 789. [Abstract] [Full Text] [PDF]
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F. G. Akar, R. C. Wu, I. Deschenes, A. A. Armoundas, V. Piacentino III, S. R. Houser, and G. F. Tomaselli Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H602 - H609. [Abstract] [Full Text] [PDF]
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M. J Janse Electrophysiological changes in heart failure and their relationship to arrhythmogenesis Cardiovasc Res, February 1, 2004; 61(2): 208 - 217. [Abstract] [Full Text] [PDF]
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C. R. Weber, V. Piacentino III, S. R. Houser, and D. M. Bers Dynamic Regulation of Sodium/Calcium Exchange Function in Human Heart Failure Circulation, November 4, 2003; 108(18): 2224 - 2229. [Abstract] [Full Text] [PDF]
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T. R. Shannon, S. M. Pogwizd, and D. M. Bers Elevated Sarcoplasmic Reticulum Ca2+ Leak in Intact Ventricular Myocytes From Rabbits in Heart Failure Circ. Res., October 3, 2003; 93(7): 592 - 594. [Abstract] [Full Text] [PDF]
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D. M. Bers, D. A. Eisner, and H. H. Valdivia Sarcoplasmic Reticulum Ca2+ and Heart Failure: Roles of Diastolic Leak and Ca2+ Transport Circ. Res., September 19, 2003; 93(6): 487 - 490. [Full Text] [PDF]
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T. R. Shannon, T. Guo, and D. M. Bers Ca2+ Scraps: Local Depletions of Free [Ca2+] in Cardiac Sarcoplasmic Reticulum During Contractions Leave Substantial Ca2+ Reserve Circ. Res., July 11, 2003; 93(1): 40 - 45. [Abstract] [Full Text] [PDF]
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A. A. Armoundas, I. A. Hobai, G. F. Tomaselli, R. L. Winslow, and B. O'Rourke Role of Sodium-Calcium Exchanger in Modulating the Action Potential of Ventricular Myocytes From Normal and Failing Hearts Circ. Res., July 11, 2003; 93(1): 46 - 53. [Abstract] [Full Text] [PDF]
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R. C. Balijepalli, A. J. Lokuta, N. A. Maertz, J. M. Buck, R. A. Haworth, H. H. Valdivia, and T. J. Kamp Depletion of T-tubules and specific subcellular changes in sarcolemmal proteins in tachycardia-induced heart failure Cardiovasc Res, July 1, 2003; 59(1): 67 - 77. [Abstract] [Full Text] [PDF]
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G. Antoons, M. Ver Heyen, L. Raeymaekers, P. Vangheluwe, F. Wuytack, and K. R. Sipido Ca2+ Uptake by the Sarcoplasmic Reticulum in Ventricular Myocytes of the SERCA2b/b Mouse Is Impaired at Higher Ca2+ Loads Only Circ. Res., May 2, 2003; 92(8): 881 - 887. [Abstract] [Full Text] [PDF]
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V. Piacentino III, C. R. Weber, X. Chen, J. Weisser-Thomas, K. B. Margulies, D. M. Bers, and S. R. Houser Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes Circ. Res., April 4, 2003; 92(6): 651 - 658. [Abstract] [Full Text] [PDF]
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 M Scoote, P A Poole-Wilson, and A J Williams The therapeutic potential of new insights into myocardial excitation-contraction coupling Heart, April 1, 2003; 89(4): 371 - 376. [Abstract] [Full Text] [PDF]
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S. M Pogwizd, K. R Sipido, F. Verdonck, and D. M Bers Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis Cardiovasc Res, March 15, 2003; 57(4): 887 - 896. [Full Text] [PDF]
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S. R. Houser and K. B. Margulies Is Depressed Myocyte Contractility Centrally Involved in Heart Failure? Circ. Res., March 7, 2003; 92(4): 350 - 358. [Abstract] [Full Text] [PDF]
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 S. Reiken, M. Gaburjakova, S. Guatimosim, A. M. Gomez, J. D'Armiento, D. Burkhoff, J. Wang, G. Vassort, W. J. Lederer, and A. R. Marks Protein Kinase A Phosphorylation of the Cardiac Calcium Release Channel (Ryanodine Receptor) in Normal and Failing Hearts. ROLE OF PHOSPHATASES AND RESPONSE TO ISOPROTERENOL J. Biol. Chem., January 3, 2003; 278(1): 444 - 453. [Abstract] [Full Text] [PDF]
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R. Sah, R. J Ramirez, G. Y Oudit, D. Gidrewicz, M. G Trivieri, C. Zobel, and P. H Backx Regulation of cardiac excitation-contraction coupling by action potential repolarization: role of the transient outward potassium current (Ito) J. Physiol., January 1, 2003; 546(1): 5 - 18. [Abstract] [Full Text] [PDF]
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I. Sjaastad, J A. Wasserstrom, and O. M Sejersted Heart failure - a challenge to our current concepts of excitation-contraction coupling J. Physiol., January 1, 2003; 546(1): 33 - 47. [Abstract] [Full Text] [PDF]
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M. Scoote and A. J Williams The cardiac ryanodine receptor (calcium release channel): Emerging role in heart failure and arrhythmia pathogenesis Cardiovasc Res, December 1, 2002; 56(3): 359 - 372. [Abstract] [Full Text] [PDF]
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D.A. Eisner and A.W. Trafford Heart Failure and the Ryanodine Receptor: Does Occam's Razor Rule? Circ. Res., November 29, 2002; 91(11): 979 - 981. [Full Text] [PDF]
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A. M. Gomez, B. Schwaller, H. Porzig, G. Vassort, E. Niggli, and M. Egger Increased Exchange Current but Normal Ca2+ Transport via Na+-Ca2+ Exchange During Cardiac Hypertrophy After Myocardial Infarction Circ. Res., August 23, 2002; 91(4): 323 - 330. [Abstract] [Full Text] [PDF]
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Y. Li, E. G. Kranias, G. A. Mignery, and D. M. Bers Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes Circ. Res., February 22, 2002; 90(3): 309 - 316. [Abstract] [Full Text] [PDF]
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R. Sah, R. J. Ramirez, and P. H. Backx Modulation of Ca2+ Release in Cardiac Myocytes by Changes in Repolarization Rate: Role of Phase-1 Action Potential Repolarization in Excitation-Contraction Coupling Circ. Res., February 8, 2002; 90(2): 165 - 173. [Abstract] [Full Text] [PDF]
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C. R. Weber, V. Piacentino III, K. S. Ginsburg, S. R. Houser, and D. M. Bers Na+-Ca2+ Exchange Current and Submembrane [Ca2+] During the Cardiac Action Potential Circ. Res., February 8, 2002; 90(2): 182 - 189. [Abstract] [Full Text] [PDF]
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A. R. Marks, S. Reiken, and S. O. Marx Progression of Heart Failure: Is Protein Kinase A Hyperphosphorylation of the Ryanodine Receptor a Contributing Factor? Circulation, January 22, 2002; 105(3): 272 - 275. [Full Text] [PDF]
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D. M. Bers Calcium and Cardiac Rhythms: Physiological and Pathophysiological Circ. Res., January 11, 2002; 90(1): 14 - 17. [Full Text] [PDF]
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S. Reiken, M. Gaburjakova, J. Gaburjakova, K.-l. He, A. Prieto, E. Becker, G.-h. Yi, J. Wang, D. Burkhoff, and A. R. Marks {beta}-Adrenergic Receptor Blockers Restore Cardiac Calcium Release Channel (Ryanodine Receptor) Structure and Function in Heart Failure Circulation, December 4, 2001; 104(23): 2843 - 2848. [Abstract] [Full Text] [PDF]
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R. Sah, R. J. Ramirez, and P. H. Backx Modulation of Ca2+ Release in Cardiac Myocytes by Changes in Repolarization Rate: Role of Phase-1 Action Potential Repolarization in Excitation-Contraction Coupling Circ. Res., February 8, 2002; 90(2): 165 - 173. [Abstract] [Full Text] [PDF]
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C. R. Weber, V. Piacentino III, K. S. Ginsburg, S. R. Houser, and D. M. Bers Na+-Ca2+ Exchange Current and Submembrane [Ca2+] During the Cardiac Action Potential Circ. Res., February 8, 2002; 90(2): 182 - 189. [Abstract] [Full Text] [PDF]
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Y. Li, E. G. Kranias, G. A. Mignery, and D. M. Bers Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes Circ. Res., February 22, 2002; 90(3): 309 - 316. [Abstract] [Full Text] [PDF]
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