797
Load-Insensitive Relaxation Caused by
Hypoxia in Mammalian Cardiac Muscle
LEONARD H.S. CHUCK, MARK A. GOETHALS, WILLIAM W. PARMLEY, AND
DIRK L. BRUTSAERT
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SUMMARY The relaxation of isolated cardiac muscles from mammals was recently shown to be
sensitive to the loading conditions because the time course of relaxation could be changed by changing
the load. This effect apparently is related to the amount and functional status of the sarcoplasmic
reticulum. The purpose of this study was to determine whether hypoxia affected the load sensitivity of
papillary muscles isolated from both rats and cats. We used three mechanical tests to establish the
presence of load-sensitive relaxation. First, we superimposed records of isotonic contractions at
increasing afterloads up to isometric contraction. From these records we measured the ratio (tRi)
which was the time from the initiation of the contraction to the initial decay of force at each isotonic
afterload, divided by the time it took for the force of an isometric contraction to relax to that same
afterload. If the tRi was less than 1.0, then the muscle was load sensitive. Hypoxia caused the loss of
load-sensitive relaxation in isotonically contracting rat papillary muscles since the tRi ratios were not
significantly different from 1.0 at all afterloads. Both hypoxia and caffeine were required to make cat
papillary muscles load insensitive. Second, during hypoxia, loads added in midcontraction did not
induce early relaxation in rat papillary muscles, but still did so in cat muscles. Hypoxia plus caffeine
eliminated this load-induced early relaxation in cat papillary muscles. Third, physiologically contracting muscles made hypoxic did not lengthen earlier in response to an additional load. This decrease of
load sensitivity under hypoxic conditions could contribute to the relaxation abnormalities observed
during regional wall motion studies. Circ Res 48: 797-803, 1981
REGIONAL and global abnormalities of relaxation
in the myocardium critically affect the evaluation
of left ventricular function in patients with heart
disease. To date, however, the underlying mechanisms for these abnormalities have not been fully
elucidated. Recent studies (Brutsaert et al., 1978a,
1978b; LeCarpentier et al., 1979) on the nature of
relaxation in mammalian cardiac muscle introduced
the concept that relaxation depends on the load
imposed on the relaxing muscle. This concept may
provide a basis for analyzing relaxation abnormalities of the ventricles. Muscular relaxation occurs
when the load imposed upon the muscle exceeds
the load-bearing ability of that muscle. In this process, the sarcoplasmic reticulum (SR) sequesters
calcium, inactivates the contractile process, and
decreases the muscle's load-bearing ability. If at
this point the load exceeds the load-bearing capacity of the muscle, then relaxation occurs. The recent
studies on relaxation of cardiac muscles were performed on muscles with extensive and active sarcoplasmic reticular systems. In these studies, a midcontraction increase of the imposed load initiated
From the Department of Physiology, University of Antwerp, Antwerp,
Belgium, and the Cardiovascular Research Institute and Department of
Physiology, University of California, San Francisco, California.
This work was supported in part by National Heart, Lung, and Blood
Institute Program Project Grant HL 25847.
Address for reprints: Dr. William W. Parmley, CVRI and Department
of Physiology, Room 1186 Moffitt Hospital, University of California, San
Francisco, California 94143.
Received April 1, 1980; accepted for publication December 14, 1980.
early relaxation, perhaps because the SR sequestered enough calcium to lower the muscle's loadbearing ability, overwhelming the muscle's ability
to cope with the additional loads. Thus, in these
muscles with an active SR, relaxation is load sensitive or "dependent." In contrast to this, in cardiac
muscles with a sparse or inactive SR, the activating
calcium would remain, activation of the contractile
proteins persists, and relaxation would be load insensitive. Additional loads imposed in mid-contraction would not cause earlier relaxation. Since the
relaxation of these muscles depends on a slower
removal of calcium to lower the activation level,
this type of relaxation has been called activation
dependent and is synonymous with load-insensitive
relaxation.
The relaxation of normal mammalian hearts results from an interaction between the intrinsic load
sensitivity of the muscle and the loading conditions
imposed upon that muscle. Thus, relaxation abnormalities in diseased hearts could reflect changes of
either of these factors: a decreased intrinsic load
sensitivity of the muscles or a decreased load imposed upon these muscles. In vitro studies on muscles isolated from rats have successfully converted
load-sensitive cardiac muscles to load-insensitive
muscles, probably by perturbing the SR uptake of
activating calcium (LeCarpentier et al., 1979).
Since hypoxia also can inhibit SR vesicle uptake
of calcium (Schwartz et al., 1973), within the framework of our concept of muscle relaxation hypoxia
798
CIRCULATION RESEARCH
could alter relaxation. We therefore examined the
effects of hypoxia on the load sensitivity of relaxation in isolated mammalian heart muscle.
Methods
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Right ventricular papillary muscles from 14 cats
after sodium pentobarbital anesthesia (40 mg/kg),
and left ventricular papillary muscles from 11 adult
rats (Sprague-Dawley) after decapitation, were removed quickly and mounted in a temperature-controlled (29°C) bath of Krebs-Ringer's solution. The
solution was composed of (mM) NaCl, 118; KC1, 4.7;
MgSCV7H2O, 1.2; CaCl2-6H2O, 2.5 or 5.0; and dextrose, 4.5. This solution was gassed with a mixture
of 95% oxygen, 5% carbon dioxide. The measured
pH was 7.4 and the measured osmolality was 290
mOsmol. The muscles were stimulated by 5-msec
pulses, the intensity of which was kept 10% above
the mechanical threshold. These stimuli were delivered by an American Electronics Laboratories 104A
stimulator through platinum field electrodes. The
stimulation rate was 12/min for cats and 6/min for
rats (Henderson et al., 1974).
While the mural end of the muscle was held in a
phosphor-bronze clip, the tendinous end was tied
with 7-0 Deknatel (Surgical Tevdek, Code 103 T)
thread and vertically mounted to a previously described electromagnetic lever system (Brutsaert
and Claes, 1974). This lever system allowed simultaneous monitoring of force and length as well as
feedback control of the load. Records of force and
length were obtained on both a Hewlett-Packard
7848A pen recorder and a Tektronix 4601-1/611
Storage Display/Hard copy unit combination.
After at least 2 hours of beating isotonically
against a moderate afterload, the muscle was
stretched to the peak of its length—active force
curve (lma*). Muscles were included in this study
only if they demonstrated ratios of resting to total
force at lmax of 0.15 or less in cats and 0.20 or less in
rats, in agreement with previously published empiric criteria for the selection of "suitable" muscles
(Henderson and Brutsaert, 1973, Brutsaert and
Claes, 1974; Brutsaert and Housmans, 1977).
After developed force had become stable at lmax,
three types of experiments were performed. First, a
series of superimposed isotonic contractions was
recorded from a preloaded up to an isometric contraction, each contraction being separated by at
least eight equally loaded beats to negate transient
load-dependent changes (Parmley et al., 1969; Jewell and Rovell, 1973). At each afterload, the time
from the initiation of the contraction to the initial
decay of force was compared to the time for the
force of the isometric contraction to reach that
same force. This ratio was called the time to relaxation (tRi). If this tRi ratio was below 1.0, in which
case the isotonic force began to decay before the
isometric force reached that load, then relaxation
was termed load sensitive. If tRi equaled 1.0, then
relaxation was load insensitive. Second, a series of
VOL. 48, No. 6, JUNE 1981
superimposed isotonic contractions was recorded
during which mid-contraction load changes (load
clamps) were imposed. These loading and unloading
steps could be of equal magnitude such that the
final load was always the same. For example, we
could initially have the muscle contract against a
2.0-g load, then switch to a 2.5-g load near peak
shortening. We could, on the other hand, start at a
3.0-g load and then switch to a 2.5-g load. Alternatively, we could keep the load at 2.5 g throughout
the contraction. By superimposing the responses to
these three loading conditions on a single record,
we could determine whether an increase in load
during the contraction caused an early relaxation,
i.e., load-sensitive relaxation. Third, a series of contractions was recorded during which a physiological
sequence of relaxation was created to mimic closely
that observed in the intact heart. Thus, the isotonicisometric sequence normally used in in vitro studies
was reversed to an isometric-isotonic relaxation sequence (Tamiya et al., 1977, 1979; Wiegner and
Bing, 1977; Goethals et al., 1978). This physiological
relaxation sequence was achieved by unloading the
muscle against a second mechanical stop at the
moment of peak shortening so that muscle length
was kept at the peak shortening length until force
returned to the preloaded force. This maneuver
prevented further muscle shortening beyond the
peak shortening length that the unloading step
would have caused under non-physiological relaxation. Under these "physiological" conditions, the
force decreased back to the preload before the
muscle lengthened back to its preloaded length.
Tamiya et al. (1979) and Goethals et al. (1978) both
have shown that the isotonic relaxation velocity
depends on the extent of shortening from the peak
shortening length. Thus, the afterload imposed
upon the muscles was adjusted to maintain the
same absolute extent of muscle shortening under
experimental as under control conditions. Load sensitivity was examined during physiological relaxation by applying small additional load clamps after
the force had returned to the preload. Load sensitivity was present when the muscles could not tolerate these small load clamps and thus lengthened
prematurely. If, however, these added loads were
tolerated very well, muscle relaxation was load insensitive.
After control measurements, hypoxia was induced by gassing the bathing solution with 95%
nitrogen-5% carbon dioxide. Rat papillary muscles
were studied 5 minutes after hypoxia began (Henderson and Brutsaert, 1973), but cat papillary muscles were studied 30 minutes after hypoxia began
(Tyberg et al., 1970). With cat muscles, SR calcium
uptake was suppressed further by adding caffeine
(1 to 10 mM) to the bath from a 100 mM caffeine in
Krebs-Ringer's stock solution.
At the conclusion of all experiments, muscle
length at lmax and muscle weight were measured.
Muscle cross-sectional area was calculated assum-
HYPOXIA AND CARDIAC RELAXATION/Chuck
ing a cylindrical muscle with a density of 1.0.
Results
Hypoxia changed load-sensitive relaxation under
control conditions to load-insensitive relaxation in
each of 11 rat papillary muscles. This result was
based on an analysis of superimposed records of
isotonic contractions from a preloaded up to an
isometric contraction. Under control conditions
(Fig. 1A), note the clear difference (at the arrow)
between the time for the initial decay of force
during a lightly afterloaded contraction compared
to the time for the isometric force to relax to that
same force. Lightly afterloaded isotonic contractions bear the imposed load for a much shorter
duration than does the isometric contraction; i.e.,
the relaxation or decay of force is earlier for lightly
loaded muscles. Hypoxia eliminated this difference
799
et al.
in load bearing capacity (see arrow of Fig. 1C).
Hypoxia caused load-insensitive relaxation. The
records from a series of afterloaded contractions
during which abrupt load alterations were imposed
(load clamps) midway through a contraction show
that relaxation was load sensitive under control
conditions (Fig. IB). When the load was increased
in midcontraction (as in contraction c of Fig. IB),
the force began to decay earlier than it would have
if the load had been kept at the same final load (as
in contraction b of Fig. IB). Hypoxia completely
eliminated this difference in the time to the decay
of force.
Hypoxia diminished load sensitivity in all six cat
papillary muscles examined, as is evident by the
decrease in the difference between the time to the
decay of isotonic compared to the isometric force
on Fig. 2, A and C. Although the load sensitivity of
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HYPOXIA
CONTROL
.90
100 ms
.95
10
40
30
20
10
'/Imax
100 ms
.95
1.0
f(mN)
30
IOL
FIGURE 1 Superimposed isotonic contractions were recorded at increasing afterloads from a preloaded to an
isometric contraction in a typical rat papillary muscle. These records were taken under control conditions (A) and
during hypoxia (C). In panels B and D are superimposed records from an isometric, a preloaded isotonic, and three
afterloaded isotonic contractions. During contraction "a," the afterload was constant, but in contraction "c" it was
increased by 10 mN to equal the afterload of contraction "a." During contraction "b," the afterload was decreased by
10 mN to equal that load of contraction "a." Panel B was the control condition; panel D, during hypoxia. The arrows
indicate the portion of the records used to assess the presence or absence of load sensitive relaxation. Muscle
characteristics: length = 8.0 mm, cross-sectional area = 0.75 mm2, total stress = 9.23 g/mm2, resting/total stress =
0.195.
800
CIRCULATION RESEARCH
CONTROL
VOL. 48, No. 6, JUNE 1981
HYPOXIA
i/i max
200 ms
.95
1.0
30
f(mN)
20
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10
D
l/lr
200 ms
30
f(mN)
20
10
2 Superimposed isotonic contractions were recorded either at increasing afterloads (A, C) or during which
load was changed (B, D) in a typical cat papillary muscle. The format is the same as in Figure 1 with records under
control conditions on the left (A, B) and during hypoxia on the right (C, D). Muscle characteristics: length = 6.0 mm,
cross-sectional area = 2.68 mm2, total stress = 10.47g/mm', resting/'total stress = 0.134.
FIGURE
relaxation was diminished, relaxation never became
fully load insensitive. Note, in Figure 2D, that loads
added in mid-contraction still caused earlier relaxation.
Hypoxia added to 5 mM caffeine changed loadsensitive relaxation under control conditions to
load-insensitive relaxation in each of six cat papillary muscles examined. Although 5 mM caffeine did
not cause load-insensitive relaxation in cat papillary
muscles (Fig. 3, A and B), the additional imposition
of hypoxic conditions did (Fig. 3, C and D). With
both of these interventions, note that the load does
not affect relaxation in either the series of afterloaded contractions (3C), or the series of loadclamped contractions (3D).
Hypoxia alone depressed force development of
both isotonic and isometric contractions and
shortened the overall contraction duration. This
decrease and shortening were more apparent in cat
papillary muscles (Fig. 2) than in rat papillary muscles (Fig. 1).
Species differences in the tolerance to hypoxia
and/or caffeine were apparent in Figure 4, a plot of
the relative force against the time to the initiation
of relaxation (tRi) at that same force. A relative
time to initiation of relaxation ratio (tRi) of 1.0
indicated load-insensitive relaxation. Under control conditions, the difference in time to relaxation
(tRi) was less than 1.0 at relative forces less than
0.5 in both rat and cat papillary muscles. In rat
HYPOXIA AND CARDIAC RELAXATION/C/IMC* et al.
5 mM
+ Hypoxia
Caffeine
0.9
ll'max
1.0
f(mN)
8r
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papillary muscles, the slope and intercept of the
regression line were 0.40 ± 0.02 and 0.68 ± 0.01
under control conditions. In cat papillary muscles,
the slope and intercept of the regression were 0.61
± 0.02 and 0.51 ±0.1 under control conditions. Rat
and cat papillary muscles displayed load-sensitive
relaxation. Hypoxia induced load-insensitive relaxation, as indicated by a tRi ratio close to 1.0 in rat
papillary muscles. During hypoxia, the slope and
intercept of the regression line were 0.08 ± 0.03 and
0.95 ± 0.02. Caffeine also raised the tRi ratios,
calculated from the data of LeCarpentier et al.
(1979), toward 1.0 and thus caused load-insensitive
relaxation in rat papillary muscle. The slope and
intercept of this regression line were 0.06 ± 0.04 and
0.96 ± 0.03. In cat papillary muscle, however, caf-
a.
09-
02
0.4
801
0.6
0.8
10
Reiotive Force ( o / b )
FIGURE 4 The time to the initial decay of force during
an isotonic (C) compared to an isometric (D) contraction
(time to relaxation—tRi) plotted against the relative
force development (a/b) in rat papillary muscles. The
linear regression lines have been drawn through the
points for control conditions (O), after hypoxia (A), and
after caffeine (%). Load insensitivity exists when tRi (c/
d) is 1.0 (along the dotted line) at all relative forces such
as shown for hypoxia or caffeine. Load sensitivity exists
when tRi is less than 1.0 as is the case under control
conditions for these papillary muscles below relative
forces of 0.5.
FIGURE 3 Superimposed isotonic
contractions were recorded either at
increasing afterloads (A, C) or during
which load was changed (B, D) in a
typical cat papillary muscle. The format is the same as in Figure 1. The
records on the left were taken after five
mM caffeine alone (A, B), and the records on the right were taken after caffeine plus hypoxia (C, D). Muscle characteristics: length = 6.0 mm, cross-sectional area = 0.77 mm2, total stress =
7.24 g/mm2, resting/total stress =
0.069.
feine and hypoxia both were needed to induce the
same level of load insensitivity with a regression
slope and intercept of 0.08 ± 0.04 and 0.99 ± 0.03
during hypoxia plus caffeine. Caffeine alone did not
alter the slope and intercept of the regression line
from control conditions.
During the isometric-isotonic physiological relaxation sequence studied in six cat papillary muscles,
hypoxia caused relaxation to be less load sensitive
(Fig. 5). When the load clamp was added just after
the force returned to the preload under control
conditions (top two traces of Fig. 5), this load step
caused an earlier lengthening of the muscle to its
lmax length. This lengthening occurred quickly as
the additional load was borne for 67 msec. The
imposition of loads larger than shown would reduce
the time during which the muscle could bear the
load, and would be accompanied by a more rapid
lengthening. During hypoxia (middle two traces), a
much larger absolute as well as relative load was
imposed on the muscle. The load step was only 7.8%
of the afterload under control conditions, but was
56% of the afterload under hypoxic conditions. Despite this huge load, the added load was borne for
almost twice as long under hypoxic conditions; i.e.,
relaxation was more load sensitive than under control conditions. In other experiments during which
the clamped load-to-afterload ratio under hypoxia
was similar to that ratio under control conditions,
no discernible changes in the time course of relaxation during hypoxia were observed. Note that the
load sensitivity was restored quickly after the muscle was reoxygenated (bottom two traces of Fig. 5).
Discussion
The term "load-sensitive relaxation" (Brutsaert
et al., 1978a, 1978b; LeCarpentier et al., 1979) was
introduced to describe certain load-dependent characteristics of mammalian cardiac muscle. One
expression of this phenomenon is illustrated in Figure 1A. Contractions at low afterloads exhibit force
traces during relaxation which fall well inside the
outer force envelope of an isometric contraction.
CIRCULATION RESEARCH
802
0.9 r
•max
CONTROL
1.0
REOXYGENATION
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FIGURE 5 Three sets of mechanical records taken before, during, or after hypoxia in a typical cat papillary
muscle. Each set consists of two superimposed afterloaded contractions during which isometric relaxation
preceded isotonic lengthening (physiological relaxation). Under control conditions (top two traces), a small
load clamp equaling 7.8% of afterload was imposed (at
the arrow) just after the force returned to the preload.
This added load lengthened the muscle rather abruptly.
During hypoxia, a load stop equal to 56% of the afterload
still could not lengthen the muscle as abruptly. The
bottom panel shows that relaxation was again sensitive
to small additional loads after reoxygenation. Muscle
characteristics: length = 7.0 mm, cross-sectional area
= 1.35 mm2, resting/total stress = 0.13.
This early relaxation presumably occurs because
the imposed load exceeds the load-bearing capacity
of the muscle at that point. One hypothesis for this
behavior is the following. At low afterloads, the
muscle shortens further and faster than at high
loads. This greater recycling of cross-bridges could
make more calcium available for uptake by the
sarcoplasmic reticulum, thus reducing the calcium
available to cross-bridge sites. This would shorten
the duration of the muscle's load-bearing capacity.
Evidence supporting the importance of the sarcoplasmic reticulum in this phenomenon is considerable and has been summarized recently (Brutsaert
et al., 1980). The purpose of this study was to
determine whether hypoxia, which can affect the
function of the sarcoplasmic reticulum, could alter
load-dependent relaxation.
Our present experiments have shown that hypoxia diminished the load sensitivity of relaxation
in mammalian cardiac muscle. Hypoxia has been
VOL. 48, No. 6, JUNE
1981
shown to suppress the reuptake of calcium by the
sarcoplasmic reticulum (Schwartz et al., 1973; Brodie et al., 1976), and this action should prolong
activation because it would prolong the period during which calcium remains in the vicinity of the
actomyosin cross-bridges. This could explain the
observed diminution of load sensitivity. Hypoxia
also decreased force development and shortened
the time to peak force (TTP), indicating a decrease
in both the level and duration of activation. These
possibly could occur as a result of a decrease in
calcium released from the SR because of a decrease
in calcium uptake by the SR.
With hypoxia and/or ischemia imposed upon
load-sensitive muscles, relaxation abnormalities
may arise because of diminished loading conditions
during relaxation. During relaxation of the heart,
one such primary loading condition probably results
from the release of the potential energy accumulated during the systolic deformation of the ventricles (Rushmer et al., 1953; Suga, 1979). When ventricular wall fibers relax, this energy is returned to
the system and drives the ventricular walls toward
their resting configuration. In the present study and
consistent with previous observations (Tyberg et
al., 1969, 1970; Bing et al., 1971; Henderson and
Brutsaert 1973; Henderson et al., 1974), hypoxia
markedly depressed systolic performance. Extrapolated to the heart, this depression of systolic performance would result in diminished potential energy stored in these deformed walls and thus decreased conditions during relaxation (Papapietro et
al., 1979). In addition to systolic deformation in the
intact heart, other loading factors must also be
considered. With ischemic conditions, in addition
to hypoxia, the pH, osmolality, and ionic activity
may also be altered as well as the substrate depleted. The effects of all of these factors on load
sensitivity of relaxation are presently under investigation.
Acknowledgments
We thank A. Van Weert, M. Michiels, W. Delnat, M.H.
Briscoe, and W. Bleumers for the technical assistance, and M.
Hurtado for typing the manuscript.
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Circ Res. 1981;48:797-803
doi: 10.1161/01.RES.48.6.797
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