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Department of Physiology II, Nara Medical University, Kashihara, Nara 634-8521, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We hypothesized that O2 wasting of Ca2+
handling in the excitation-contraction coupling in ryanodine-treated
failing hearts might derive from an increased external Ca2+
extrusion via Na+/Ca2+ exchanger and futile
Ca2+ cycling via sarcoplasmic reticulum (SR)
Ca2+-ATPase. We tested this hypothesis by mechanoenergetic
studies using rat left ventricular slices. After the slices were
treated with ryanodine (0.1 µM), 1-Hz free shortening significantly
decreased by 78-85%, whereas the observed O2
consumption (
O2) required for total
Ca2+ handling, increased from 0.79 to 1.13 ml
O2 · min
1 · 100 g
LV1 (155.6% of control). We reconfirmed that
cyclopiazonic acid (10 µM), a blocker of SR Ca2+-ATPase,
decreased O2 by 75-80% in normal
slices. However, 100 µM of cyclopiazonic acid was needed to inhibit
the O2 by 80% after ryanodine
treatment. Blockade of a sarcolemmal Na+/Ca2+
exchanger by KB-R7943 (10 µM) significantly decreased
O2 by 45% after ryanodine treatment
without significant effects on normal slices. Our results indicated
that the O2 increase following ryanodine
treatment was derived from a net change of an increased external
Ca2+ extrusion via Na+/Ca2+
exchanger and futile Ca2+ cycling via SR
Ca2+-ATPase.
excitation-contraction coupling; sarcoplasmic reticulum Ca2+-ATPase; cyclopiazonic acid; recirculation fraction; KB-R7943; sarcolemmal Na+/Ca2+ exchanger
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS WELL KNOWN THAT alterations in intracellular Ca2+ handling of myocardium are closely associated with pathophysiological states, such as ischemia, acidosis, and stunning (13, 14, 23). Abnormalities in cardiac contractile activity induced during such pathological states are explained on the basis of changes in Ca2+ handling via sarcoplasmic reticulum (SR) (27) because SR plays a pivotal role in regulating the intracellular [Ca2+].
Takasago et al. (34) reported that the ryanodine-treated
heart, as a failing heart model, decreased left ventricular
contractility by one-half without decreasing the energy expenditure
used for Ca2+ handling. The disproportionately high
excitation-contraction (E-C) coupling rate of O2
consumption (O2) relative to the
contractility means O2 wasting for the contractility
(12-14, 23, 27, 29, 33). We hypothesized that
O2 wasting for Ca2+ handling in the E-C
coupling in ryanodine-treated failing whole hearts might derive from a
decreased internal Ca2+ recirculation fraction (RF)
(16) and futile Ca2+ cycling via SR
Ca2+-ATPase (16, 28). We tested this
hypothesis by mechanoenergetic studies using rat left ventricular (LV)
slices (18, 19, 32, 37) to directly evaluate the
O2 used for handling of the total Ca2+.
We recently instituted our specific measuring system for myocardial
O2 used for basal metabolism (basal
O2) and for handling of the total amount
of Ca2+ in the E-C coupling under mechanically unloaded
conditions by using 300-µm-thick rat LV myocardial slices (18,
19, 32, 37). We have successfully obtained the increment in
O2 by electrical field stimulation and
have clarified the major origin of the
O2 (32, 37). First,
O2 was increased by the increase in
extracellular [Ca2+] in a dose-dependent manner
(37) but basal O2 without
field stimulation was not affected by the increase in extracellular [Ca2+] (37). Second, the slice motility was
largely suppressed by using 5 mM of 2,3-butanedione monoxime (BDM)
(32), a specific inhibitor of cross-bridge cycling;
however, the increment in O2 by field
stimulation was not inhibited by 5 mM of BDM (37), which
did not affect basal O2
(37). These results suggest that
O2 does not consist of detectable energy
consumption used for residual cross-bridge cycling, if any, under the
free shortening of slices. Third, we observed that 10 µM
cyclopiazonic acid (CPA), a specific blocker of the SR
Ca2+-ATPase, reduced both the increment in
O2 and the motility by 70-80%,
although it did not affect basal O2 of
quiescent slices (32). The similar extent of reduction in
O2 and the motility of rat myocardial
slices strongly suggest that both reductions were caused by
Ca2+ depletion in SR due to inhibition of SR
Ca2+-ATPase. The underlying mechanisms for these
observations were consistent with those reported by Janczewski and
Lakatta (17) in intact rat cardiac myocytes. By taking our
reports on energetics and motility of myocardial slices treated with
BDM and CPA into consideration, we concluded that the
O2 by mechanically unloaded rat slices
is mainly related to energy expenditure used for basal metabolism and
for handling of total amount of Ca2+ in E-C coupling during
1-Hz free shortening.
In the present study, we planned to make pathophysiological myocardial
slices mimick the O2 wasting failing whole heart model (34) after a long treatment with a low concentration of
ryanodine. We then evaluated the origin of
O2 used for handling of the total
Ca2+ in the pathophysiological slices by using a specific
pharmacological tool of CPA to inhibit SR Ca2+-ATPase
(18, 19, 32, 37). We also evaluated the contribution of
external Ca2+ extrusion (4, 5, 11, 27) for
O2 used for handling of the total
Ca2+ by using a specific blocker, KB-R7943 (10 µM), to
inhibit Na+/Ca2+ exchange (20,
36).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Left Ventricular Myocardial Slice Preparation
Forty-five adult male Wistar rats (Charles River Japan; Yokohama, Japan) weighing 350 ± 24 g were anesthetized with pentobarbital sodium (50 mg/kg ip). All of the experimental procedures were described previously in detail (18, 32, 37). Briefly, the whole heart was excised after perfusion with Tyrode solution at 12°C and was gassed with 100% O2 for 5 min. Each myocardial slice was cut into 300-µm-thick slices in parallel with the epicardium with a microslicer (model DTK-3000, Dosaka EM; Kyoto, Japan). We obtained 10-18 slices from each heart. The slices were stored in 18°C Tyrode solution for 30 min and then in 25°C Tyrode solution, and were gassed with 100% O2 for 30 min. The composition of Tyrode solution (in mmol/l) was 136.0 NaCl, 5.4 KCl, 1.0 MgCl2 · 6H2O, 0.33 NaH2PO4 · 2H2O, 0.9 CaCl2 · 2H2O, 10.0 glucose, and 5.0 HEPES, with pH corrected to 7.4 with NaOH at 30°C.Image Analysis of Free Shortening of Myocardial Slices
Seventeen myocardial slices from 11 rats were used for image analysis of slice free shortening. One slice was placed in a 3-ml chamber for oximetry. The slice was gently superfused with Tyrode solution at ~5 ml/min for 10 or 20 min, while the magnetic stirrer was rotated. During image analysis, the airtight chamber was closed and the stirrer was turned off. Slice free shortening was evoked by 1-Hz field stimulation as described previously (32, 37).We monitored and recorded the video image of slice free shortening for 3 min and nonstimulated slice image for 2 min with a microscopic video recording system (model SZH-131DA), a charge-coupled device color camera (model CS220, Olympus; Tokyo, Japan) and Victor cassette recorder model HR-D380. For quantitative analysis of slice free shortening, a video area analyzer (model C3153, Hamamatsu Photonics; Shizuoka, Japan) detected differences in light intensity between the slice and the surrounding field within a selected area (5 mm × 10 mm). The detected signals were then transmitted to a computer (model PC-98, NEC; Tokyo, Japan) for evaluation of free shortening as the relative changes in slice surface area (motility index) (32, 37). We used mean values of motility index from five free shortenings as motility index in each sampling time of 3, 33, 69, 105, 141, 159, and 171 s.
Assessment of O2 of Myocardial
Slices
O2 and mechanically unloaded
myocardial O2 during free shortening as
a decreasing rate in [O2] of the solution in the
oximetric chamber. O2 of a set of slices
was measured polarographically with an oxygen electrode (model 1T-125,
Instech Labs; Plymouth Meeting, PA) as described previously (18,
32, 37). This oximetric system was calibrated at three different
[O2] (in mg/l): 0 (5% Na2SO3
solution), 7.3 (Tyrode solution saturated with air), and 35.1 (Tyrode
solution saturated with 100% O2) at 30°C in each experiment. Volume (in liters) of Tyrode in the chamber was measured at
the end of the three time-repeated measurements (Fig.
1) for a set of slices. The mean ± SD per volume of Tyrode was 2.58 ± 0.06 ml (n = 65 measurements).
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We first examined the mean value of the background
O2 without myocardial slices in the
Tyrode-filled chamber at the beginning and end (0.75 ± 0.19 mg
O2/min, n = 65) of each measurement. We measured the wet weight of each set of slices (73.0 ± 11.7 mg, n = 65 sets of slices). We calculated
O2 of slices by subtracting the
background O2 (A; mg
O2/min) from the measured O2
(B; in mg O2/min) with myocardial slices.
Myocardial O2 (ml
O2 · min1 · 100 g
LV1) was calculated as [(B 
A)/slice wet weight (in grams)] × volume of Tyrode
solution in the chamber (in liters) × [22.4 (liters)/32 (gram)] × 100 g.
Experimental Procedure
BasalO2 without stimulation of
the quiescent slices was obtained during the first 2 min (open bars in
Fig. 1). O2 with 1-Hz stimulation of
free-shortening slices was obtained during the next 3 min (striped bars
in Fig. 1). O2 used for handling of the
total Ca2+ (
O2) is
obtained by subtracting basal O2 from
O2 with 1-Hz stimulation. Basal
O2 and
O2 were compared in two different ways, i.e., among the first, second, and third measurement of O2 in the same set of slices, and among
different set of slices under the comparable protocol (Fig. 1).
Experimental Protocol
We used six protocols (see also Fig. 1) for the following four studies.Study 1: effect of ryanodine on slice free shortening.
We determined the inhibitory effect of 0.1 µM ryanodine by comparing
the motility index in normal Tyrode (NT) solution (see Fig. 1) in the
third measurements in protocol 3 with that after ryanodine
treatment in protocol 1 (Fig.
2). Eleven slices in protocol 1 and six slices in protocol 3 were used from 11 rats.
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Study 2: effect of ryanodine (0.1 µM) on basal
O2 and
O2.
We investigated the effect of ryanodine by comparing both
O2 forms after ryanodine treatment in
protocol 1 with both of O2 in
protocol 3 (see Figs. 3 and
4).
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Study 3: effect of CPA on basal O2
and O2.
We investigated the effect of 10 µM CPA on both of
O2 after ryanodine by comparing (Fig. 1)
both of O2 after ryanodine treatment in
protocol 2 with those in protocol 1 (7 sets of
slices from 7 rats in each protocol). We also investigated the effect of 10 µM CPA on both basal O2 and
O2 in normal slices by comparing
(Fig. 1) both basal O2 and
O2 in protocol 4 with that
in protocol 3 (7 sets of slices from 7 rats in each
protocol). We investigated the effect of 100 µM CPA on both
basal O2 and O2 after ryanodine in protocol
2 (8 sets of slices from 5 rats) compared with those in
protocol 1 (Fig. 4).
Study 4: effects of KB-R7943 (10 µM) on basal
O2 and
O2.
We investigated the effect of KB-R7943 on both types of
O2 after ryanodine treatment by
comparing (Fig. 1) both types of O2
after ryanodine in protocol 5 with those in protocol
1 (6 sets of slices from 6 rats in each protocol) (see Fig.
5). We investigated the effect of
KB-R7943 on both types of O2 in normal slices by comparing (see Fig. 1) both types of
O2 in protocol 6 with those
in protocol 3 (11 and 6 sets of slices from 9 rats in each
protocol).
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Statistics
All data were means ± SD, except for the motility data, which were means ± SE. Multiple comparisons were performed by one-way and repeated-measures ANOVA and Bonferroni t-test. Student's unpaired t-test was used for the percent inhibition values obtained by CPA and KB-R7943 and the percent decrease of slice image between control and ryanodine treatment. In all statistical tests, P < 0.05 were considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Free Shortening of Rat Myocardial Slice After Ryanodine Treatment
In protocol 3 (Fig. 2A), motility index values were fairly constant between 69 (0.54 ± 0.56%) and 141 s (0.48 ± 0.49%) during the first measurement in NT. Each motility index at the same time during the first, second, and the third measurements in NT was not significantly different among the three repeated measurements (P < 0.05). Although motility index at 3 s (initial free-shortening) was not significantly different among them (P < 0.05), these values were significantly higher than those at 33-171 s throughout the first to third measurements. However, motility index values later than 69 s did not decrease significantly during all three measurements.In protocol 1 (see Fig. 2B), motility index values were fairly constant between 69 (0.63 ± 0.41%) and 141 s (0.59 ± 0.34%) during the first measurement in NT. Motility index at 105 s during the second measurement with ryanodine was 0.37 ± 0.18% and was significantly smaller than the corresponding value during the first measurement in NT. Motility index during the third measurement after ryanodine treatment were significantly different from those during the first and second measurements (P < 0.05). The value was also significantly decreased by 75% from corresponding values during the third measurement in NT in protocol 3 (see Fig. 2A) (P < 0.05). Motility index values at 3 s at the first, second, and third measurements in protocol 1 were significantly different among them (P < 0.05).
If the presently observed reduction of the motility index is due to the
decrease of maximal area of slice image at each shortening, the slice
after treatment of ryanodine or with treatment of CPA would cause the
contracture. However, there were no significant difference in the
maximal area of slice image at each shortening between the first
measurement of NT and the third measurement after ryanodine treatment
at 1 min of 1-Hz stimulation (P < 0.05). We also have
observed no significant decrease of maximal area of slice treated with
CPA (10 µM) during 1-Hz stimulation, although the data are not shown
(32). Furthermore, the basal
O2 of the slice obtained without 1-Hz
electrical stimulation did not increase after ryanodine treatment
(protocol 1) or with CPA treatment (protocol 4), suggesting no slice contracture.
Basal O2 and
O2 After Ryanodine Treatment
O2 values at first, second, and third
measurements were not significantly different. Three-minute 1-Hz
stimulation inserted during ryanodine treatment did not affect basal
O2 at the second measurement. Thus basal
O2 was unaffected during and after
ryanodine treatment compared with that in NT. Mean basal
O2 values ranged between 1.94 and 2.44 ml O2 · min1 · 100 g
LV1, corresponding to our previous values (15, 27,
33).
Each O2 at the second measurement
during ryanodine treatment did not significantly increase from that at
the first measurement in NT (protocols 1 and 2).
However, O2 after ryanodine treatment (the third O2) significantly increased
from that at the first measurement in NT (protocol 1) (Fig.
3). Furthermore, O2 after ryanodine
treatment at the third measurement in protocol 1 was higher
than that at the third measurement in protocol 3, although not statistically significant (P = 0.06) (Fig. 4).
Effect of CPA on Basal O2 and
O2 After Ryanodine Treatment
O2, irrespective of
ryanodine treatment. On the other hand, CPA significantly decreased
O2, from 0.86 to 0.16 ml
O2 · min1 · 100 g
LV1, by 80.1 ± 16.4% (means ± SD of the
second O2 in protocol 4). The
third O2 in different sets of slices in
protocols 3 and 4 were compared, indicating that
O2 were 0.84 ml
O2 · min1 · 100 g
LV1 with NT and 0.16 ml
O2 · min1 · 100 g
LV1 with CPA (see Fig. 4). The CPA-induced inhibition was
74.8 ± 22.6% of the third O2 in
NT in protocol 3. Therefore, without ryanodine treatment,
the fraction of CPA-sensitive O2 was
74.8-81.8%. However, the third O2
in different sets of slices in protocols 1 and 2 were compared, indicating that O2
were 1.13 ml O2 · min1 · 100 g LV1 after ryanodine treatment and 0.69 ml
O2 · min1 · 100 g
LV1 after ryanodine treatment in the presence of CPA of
10 µM (Fig. 4). The effect of CPA was presented by an inhibition by
only 41.2 ± 15.5% of the third O2
in protocol 1. Thus the fraction of 10-µM CPA-sensitive
O2 was significantly decreased after
ryanodine treatment (P < 0.05). However, a high
concentration (100 µM) of CPA largely decreased
O2 to 0.29 ± 0.26 of ml
O2 · min1 · 100 g
LV1 (77% inhibition) (Fig. 4).
Effect of KB-R7943 on Basal O2 and
O2 With or Without Ryanodine
Treatment
O2, irrespective of ryanodine treatment
(see Fig. 5). KB-R7943 did not significantly decrease
O2 (1.03 ± 0.41 vs. 0.90 ± 0.40 ml O2 · min1 · 100 g
LV1) in normal slices without ryanodine treatment in
protocol 6. The third O2 in
protocols 3 and 6 were compared, indicating that
O2 were 0.98 ± 0.35 ml
O2 · min1 · 100 g
LV1 with NT and 0.90 ± 0.40 ml
O2 · min1 · 100 g
LV1 with KBR7943 (Fig. 5). The KB-R7943-induced
inhibition was only 17.4 ± 41.4% of the third
O2 in protocol 3, indicating
no significant decrease in O2 by
KB-R7943 in normal slices.
The third O2 in protocols 1 and 5 were compared, indicating that
O2 were 1.25 ± 0.32 ml
O2 · min1 · 100 g
LV1 after ryanodine treatment and 0.70 ± 0.37 ml
O2 · min1 · 100 g
LV1 (P < 0.05) after ryanodine treatment
with KB-R7943 (Fig. 5). The KB-R7943-induced inhibition was 44.9 ± 20.6% of the third O2 in
protocol 1, indicating KB-R7943-induced inhibition on O2 significantly increased after
ryanodine treatment (P < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We successfully made pathophysiological O2 wasting rat
myocardial slices by mimicking the O2 wasting failing whole
heart model (16, 34) after a long treatment with a low
concentration of ryanodine. The failing heart halved left ventricular
contractility without decreasing O2 used
for Ca2+ handling (34). The disproportionately
high E-C coupling O2 relative to the
contractility means O2 wasting for the contractility (12-14, 23, 27, 29, 33). In the present study, the
effect of 0.1 µM of ryanodine was confirmed by the observation that
long-term treatment with ryanodine abolished a "negative force
staircase phenomenon" (8) or "Woodworth phenomenon"
(6, 30) and decreased the initial free shortening in the
rat myocardial slice. O2 of slices
after ryanodine treatment increased from 0.79 to 1.13 ml
O2 · min1 · 100 g
LV1 by 55.6%. On the other hand, the motility index for
free shortening was largely decreased by ~80% after ryanodine
treatment. This may be due to futile Ca2+ cycling
(11, 21, 27, 29) and/or a reduced Ca2+ content
in the SR (7, 30) resulting from a Ca2+ leak
(24, 35) during interstimulus interval (5,
25).
Effect of CPA on Basal O2 and
O2
O2 used for total Ca2+
handling in E-C coupling, i.e., O2,
and O2 used for basal metabolism (basal
O2). However, it is not composed of the
detectable O2 used for the residual
cross-bridge cycling under mechanically unloaded slices (32,
37). In the present study, neither ryanodine nor CPA treatment,
even a much higher CPA concentration, affected basal
O2. Thus
O2 is obtained by subtracting basal
O2 from O2 of the stimulated slices as
previously reported (32, 37).
The present results showing that CPA decreased the
O2 used for total Ca2+
handling by ~80% in normal slices are consistent with our previous results showing that ~70% of O2 used
for total Ca2+ handling is derived from the SR
Ca2+-ATPase (32). In normal rat hearts, 80%
of Ca2+ was intracellular RF, i.e., the SR
Ca2+-ATPase plays a main role in Ca2+ handling
(1, 2, 5, 15, 32).
In muticellular preparations of rabbit papillary muscle or ventricular trabeculae, complete blockade of SR Ca2+-ATPase by CPA cannot be attained because the rapid cooling contractures to assess the SR Ca2+ load were not completely abolished by 100 µM of CPA. The remaining caffeine- and ryanodine-sensitive SR Ca2+ release must have occurred after CPA treatment (4). The discrepancy in CPA effects between this and our observation seems to be partly related to the difference of activation mechanism on Ca2+ release from SR.
Effect of CPA and KB-R7943 on O2
After Ryanodine Treatment
O2 to the
similar extent by 10 µM of CPA in normal slices. Leaked
Ca2+ from SR may increase the activity of SR
Ca2+-ATPase, and consequently, the
O2 would increase.
It has been reported (28) that the affinity of SR
Ca2+-ATPase for CPA is dependent on the conformational
state of the enzyme related to the Ca2+ binding. If the
affinity of SR Ca2+-ATPase for CPA decreases after
ryanodine treatment, much higher concentrations of 100 µM CPA are
needed to inhibit the SR Ca2+-ATPase and thus
O2 in the ryanodine-treated slices.
However, the other possibility, whether the L-type Ca2+
current is directly or secondarily depressed by higher concentration (100 µM) of CPA, could not be excluded, although the effect of CPA at
higher concentration on L-type Ca2+ current is not well
known (4, 26). Ryanodine also may interfere with
interaction of CPA and the SR Ca2+-ATPase (9,
10).
Recently, KB-R7943, a novel inhibitor of the sarcolemmal
Na+/Ca2+ exchanger, has been introduced
(20, 36). The result showing no effect of KB-R7943 on the
O2 in normal slices indicates that
neither mode of sarcolemmal Na+/Ca2+ exchanger
contributes to the O2 to the
detectable extent. However, KB-R7943 decreased
O2 by 44.9% compared with the
increased O2 after ryanodine
treatment. The result would suggest the increased external
Ca2+ extrusion via sarcolemmal
Na+/Ca2+ exchanger (27),
regardless of its underlying mechanism (4, 5, 11). This
suggestion is supported by previous reports (2, 16)
showing the decrease in internal Ca2+ RF (indicated by the
exponential decay beat constant) after ryanodine treatment. The
increased external Ca2+ extrusion would result in the
increase in O2 used for total Ca2+ handling after ryanodine treatment, because the
external Ca2+ extrusion consumes more energy via
sarcolemmal Na+/Ca2+ exchanger and
Na+-K+-ATPase system, having 1 Ca2+: 1 ATP stoichiometry, than that of the internal
Ca2+ RF via SR Ca2+-ATPase, having 2 Ca2+:1 ATP stoichiometry (23, 27, 29, 32, 33).
The present results indicate that the increased
O2 used for total Ca2+
handling after ryanodine treatment is derived from a net change of
futile Ca2+ cycling via SR Ca2+-ATPase and an
increased (energetically more wasting) external Ca2+
extrusion. Furthermore, other energy-consuming processes such as sarcolemmal Ca2+- ATPase may contribute to
O2 used for total Ca2+
handling. Further study is required to clarify the origin of O2 wasting use due to the futile Ca2+ cycling
via SR or sarcolemma.
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ACKNOWLEDGEMENTS |
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We thank Yukishige Akagi, of the Okayama Rail Road Model Shop, for generously custom-making our oximetric chamber system.
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FOOTNOTES |
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This study was supported in part by a Grant-in-Aid for Scientific Research (11470277) from the Ministry of Education, Science, Sports and Culture.
Address for reprint requests and other correspondence: H. Kohzuki, Dept. Physiology II, Nara Medical Univ., 840 Shijo-cho, Kashihara, Nara 634-8521, Japan (E-mail: hkohzuki{at}naramed-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 2 October 2000; accepted in final form 26 March 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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), second (
), and third
(
) measurements (protocol 3). B:
MI of slice treated with NT (
), and NT after ryanodine treatment (
)
in sequence (protocol 1). Values are means (SE was omitted
for simplification). *P < 0.05, significant difference
between the second measurement with ryanodine and the third measurement
after ryanodine from 3 to 171 s of 1-Hz field stimulation.
§P < 0.05, significant difference between the first
measurement with NT and the second measurement with ryanodine from 105 to 171 s. #P< 0.05, significant difference of initial
MI between the first measurement with NT and the second measurement
with ryanodine.
