© 1997 American Heart Association, Inc.
Articles |
Actions of cADP-Ribose and Its Antagonists on Contraction in Guinea Pig Isolated Ventricular Myocytes
Influence of Temperature
From the Department of Pharmacology, University of Oxford (UK).
Correspondence to Dr D.A. Terrar, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. E-mail derek.terrar{at}pharm.ox.ac.uk
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Abstract |
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Abstract Although it is becoming widely accepted that cADP-ribose (cADPR) can regulate calcium release from the endoplasmic reticulum in sea urchin eggs and in a variety of mammalian cell types, it remains controversial whether this substance might influence calcium release during excitation-contraction coupling in cardiac muscle. We have investigated possible actions of cADPR in intact cells isolated from guinea pig ventricle, paying particular attention to the possible influence of temperature. At 36°C, myocyte contraction was influenced by cytosolic application of cADPR in a concentration-dependent manner (showing an
30% increase in contraction with 5 µmol/L cADPR
applied via a patch pipette in myocytes stimulated to fire action
potentials at 1 Hz). Calcium transients measured with fura 2 were also
increased by 5 µmol/L cADPR. Antagonists of cADPR
reduced contraction at 36°C (by 35% with either 50 µmol/L
8-Br-cADPR or 5 µmol/L 8-amino-cADPR applied via the patch
pipette). At room temperature (20°C to 24°C), no significant
effects on contraction were detected with either cADPR or its
antagonists. At 36°C, treatment of the cells with a
mixture of 2 µmol/L ryanodine and 1 µmol/L thapsigargin
to suppress function of the sarcoplasmic reticulum stores of calcium
prevented the action of 5 µmol/L cADPR applied via a patch
pipette. These observations are consistent with an action of
cytosolic cADPR to enhance calcium-induced calcium release from the
sarcoplasmic reticulum in guinea pig ventricular myocytes
at 36°C. The observed influence of temperature under the conditions
of our experiments is one factor that might help to account for failure
to detect actions of cADPR and its analogues in some previous studies.
Key Words: cADP-ribose • ryanodine receptor • cardiac muscle • sarcoplasmic reticulum
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Introduction |
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Evidence continues to accumulate supporting a role for cADP-ribose (cADPR) in regulating calcium release from ryanodine-sensitive stores in a wide variety of tissues.1 2 Since release of calcium from ryanodine-sensitive stores is crucial for contraction of cardiac muscle, the question arises whether cADPR might also play an important regulatory role in the heart. Evidence to date has led to conflicting conclusions. In studies of microsomes and calcium-release channels prepared from cardiac sarcoplasmic reticulum membranes, an early study provided support for regulation of calcium-release channels by cADPR,3 whereas later studies showed either no effect4 or effects that would be expected to be antagonized by ATP at concentrations normally expected to be present in cardiac muscle cytoplasm.5 In intact cardiac muscle cells, evidence from our laboratory has shown that cytosolic application of the cADPR antagonist 8-amino-cADPR6 reduces cardiac muscle contraction, whereas other careful experiments have failed to detect effects of either cADPR or 8-amino-cADPR on calcium transients.7
In an attempt to provide an explanation for these apparently conflicting observations, we have investigated actions of cADPR and its antagonists in intact cells both at room temperature and at 36°C. It appears that actions of cADPR analogues may indeed be influenced by temperature, leading to a possible explanation of the failure to detect actions of these compounds in some previous experiments and providing further evidence that cADPR may play an important regulatory role in the control of cardiac muscle contraction.
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Materials and Methods |
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Cell Isolation
Myocytes were isolated from guinea pig ventricle using methods described previously.8 9 10 Extracellular solution for superfusion of isolated cells contained (mmol/L) NaCl 118.5, NaHCO3 14.5, KCl 4.2, KH2PO4 1.2, MgSO4 1.2, CaCl2 2.5, and glucose 11.1 (pH 7.4, 36°C, 95% O2/5% CO2).
Electrophysiology
Action potentials evoked by 2-ms current pulses (2 to 10 nA in
amplitude) at a frequency of 1 Hz were recorded from the cells
using patch-clamp techniques (Axopatch 200 or Axoclamp 2B). Both
conventional whole-cell (ruptured-patch) and
permeabilized-patch (amphotericin B in the pipette
solution at 200 µg/mL) techniques were used. When cADPR or its
antagonists were to be applied to the cytosol, these were
included in the pipette solution. In the case of conventional
whole-cell (ruptured-patch) recording, control records were
taken in the first minute, when it was thought that dialysis from the
pipette to the cytosol was minimal, and compared with records 5 to
7 minutes after rupture of the membrane, when access of the compound to
the cytosol was thought to be well established.11 In
permeabilized-patch experiments, it appeared that cADPR
and its analogues in the pipette solution could not permeate the
amphotericin B channels, and contractions were well maintained over a
period of many minutes. Rupture of the membrane under the pipette led
to changes in contraction (eg, an increase with 5 µmol/L
cADPR or a decrease with 5 µmol/L 8-amino-cADPR) over a
period of 3 minutes as the cADPR analogue in the pipette gained
access to the cytosol. The two methods had advantages and
disadvantages, with the permeabilized patch allowing
more stable control recordings before rupture of the patch,
although it appeared that this method was less effective for long-term
stability of recording (for periods of more than 5 minutes
after rupture), probably as a consequence of amphotericin B entering
the cell and making the cell membrane "leaky." The findings
concerning effects of cADPR were similar for the two methods (see
"Results").
When ryanodine and thapsigargin were applied in the solution superfusing the cells, a tap close to the inflow of the bath was used to switch to the drug-containing solution. In choosing this drug combination, account was taken of the possibility that ryanodine alone reduces calcium release from stores but not calcium uptake and that the mixture with thapsigargin also inhibits the function of the Ca2+-ATPase of the sarcoplasmic reticulum.12
In one series of experiments, the pipette solution contained (mmol/L) KCl 150, MgCl2 5, K2ATP 1, and HEPES 3 (pH 7.2). In a second series of experiments, the pipette solution contained (mmol/L) KCl 140, NaCl 5, MgCl2 2, K2ATP 1, and HEPES 5 (pH 7.2). Contractions with the two solutions appeared approximately similar under the conditions of our experiments.
Temperature Control
The solution was heated by passage through stainless steel tubes
mounted in a heating block on its way to the recording chamber,
where the cells were mounted on a coverslip. The temperature was
monitored by a thermocouple positioned close to the cells. In the
majority of experiments, this temperature was maintained at 36°C; in
others, the power supply to the heating block was turned off, allowing
the solution to cool to room temperature (20°C to 24°C). During
this procedure, the pH of the extracellular solution remained
approximately stable, although a slight acidification from pH 7.4 to
7.3 was observed. If there were any slight acidification of the cytosol
under these conditions, contraction would be expected to be decreased,
although this is likely to be outweighed by other factors leading to
increased contraction at reduced temperature, and indeed, an increase
in contraction was observed at room temperature (see "Results"). As
an additional check of whether a reduction of pH, though small, might
influence our observations, the effects of cADPR were investigated for
one series of experiments with the extracellular pH adjusted to pH 7.2
(mean control shortening under these conditions before application of
cADPR was 7.1±1.3% of resting length for contractions accompanying
action potentials at 1 Hz; see below); the
permeabilized-patch technique followed by membrane
rupture as described above was used to apply 5 µmol/L
cADPR from the pipette solution. This cytosolic application of cADPR
increased cell shortening at 36°C by 31±9% (n=6 cells,
P<.05), a change that was similar to that observed at an
extracellular pH of 7.4 and 36°C (see "Results"); thus, the lack
of effect of cADPR on contraction at room temperature reported below
cannot be attributed to the small reduction in pH alone.
The possibility was also considered that temperature might influence diffusion of substances applied from the patch pipette into the cytosol. This was thought not to be a serious source of error since (1) the Q10 for diffusion-limited processes is no more than 1.3 and therefore any slowing of access would be expected to be small, and (2) when the measurement period for possible changes in contraction was extended for observations at room temperature from 5 to 8 minutes (using the conventional-patch method described above), no further changes were detected.
Measurement of Cell Contractions
Cell shortening accompanying action potentials stimulated at 1
Hz was measured from the video image of the cells viewed
microscopically (Cohu 4710 or Pulnix 765E CCD camera) as described
previously.6 13 Spatial resolution was 1 in 1024 pixels,
and time resolution was 20 ms/point (acquisition board and software
from Brian Reece Scientific). Cell shortening is quoted in the text as
percent resting length.
Measurement of Fluorescence
Cells were loaded with fura 2-AM (5 µmol/L for 20
minutes) and excited by light from a Xenon arc lamp (PTI) via a quartz
fiberoptic positioned close to the cell at a wavelength of either
340±7.5 or 380±7.5 nm, with collection of the emitted
fluorescence at 510±20 nm (interference filters from Molecular
Probes), as described previously.6 14 Fluorescent
light was detected with a Photonic Science Isis III intensified CCD
camera (time resolution of transients was 20 ms/point; acquisition and
software were from Brian Reece Scientific). Fluorescence
signals were very consistent in response to successive stimuli
in the steady state (before and during application of drug), and
switching of excitation wavelength was therefore carried out between
stimuli (averaging eight transients at each excitation wavelength,
collected in the following sequence: four at 340 nm, eight at 380 nm,
and four at 340 nm). Transients in the absence of drug applied to the
cytosol were stable over the period of the experiments (see Fig 6
).
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Statistics
Student's paired t test was used for the majority of
experiments in which measurements were made on single cells; unpaired
t tests were used when observations on two groups of cells
were to be made. A value of P<.05 was used to indicate
statistical significance. Data are quoted in the text as
mean±SEM.
Sources of Drugs
8-Amino-cADPR and fura 2-AM were obtained from Molecular Probes.
cADPR and 8-Br-cADPR were obtained from Sigma, and thapsigargin and
ryanodine were from Calbiochem.
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Results |
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Experiments at 36°C
In myocytes stimulated to fire action potentials at a frequency of 1 Hz, the accompanying contraction was well maintained over the time scale of our experiments: with conventional whole-cell patch recording, the mean change at 5 minutes after rupture of the cell membrane in 17 cells was a reduction of 3±4% (expressed as a percentage of cell shortening measured within 1 minute of rupture of the patch membrane, when dialysis was minimal; cells were maintained at 36°C; P>.05; mean cell shortening in these experiments was 8.1±0.8% of resting length). In contrast, inclusion of 5 µmol/L cADPR in the patch pipette solution caused a marked increase in contraction, as shown in Fig 1A
. Under these conditions, the effects
appeared to develop over the period expected for dialysis of the
cytosol (2 to 3 minutes11 ). In 13 cells exposed to
cytosolic application of 5 µmol/L cADPR, contraction was
increased by 25±7% (measured at 5 minutes, again expressed as a
percentage of contraction measured within 1 minute; cells were
maintained at 36°C; P<.05).
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One potential disadvantage of this procedure, particularly with high
concentrations of cADPR in the pipette, is that cADPR may enter the
cell and exert effects on contraction even during the first minute,
when control measurements were made. In another series of experiments,
control records were obtained with the
permeabilized-patch technique (amphotericin B in the
pipette), and then the membrane was ruptured by applying reduced
pressure to allow access to the cytosol of the cADPR, which had been
included in the pipette solution (the cADPR being considered too large
to permeate the amphotericin-induced pores before physical rupture of
the membrane). Under these conditions, 5 µmol/L cADPR
increased contraction by 30±5% (compared with contractions before
rupture of the patch; n=9 cells, 36°C, P<.05; Fig 1B
).
The effects of cytosolically applied cADPR on myocyte contraction were
dependent on the concentration in the patch pipette. Fig 2 shows a log(concentration)-response
curve in which concentrations of cADPR between 10 pmol/L and
10 µmol/L were applied to the cytosol by rupturing the
patch membrane as described for the first method described above (open
symbols). The second method using the permeabilized
patch followed by membrane rupture was used for 10 nmol/L and
for 5, 50, and 100 µmol/L cADPR (solid symbols). It can
be seen that the effects were broadly similar with the two approaches
and that the effects were maximal under these experimental conditions
at a concentration of 5 µmol/L. The EC50
under these conditions appeared to be between 2 and 3
µmol/L. A curve was not fitted to the data, since a simple
model relating drug binding and effect seemed not to be appropriate in
view of evidence that the effect of cytosolically applied cADPR
appeared to be biphasic: at 10 nmol/L cADPR there was a small
but statistically significant reduction in contraction found with both
the conventional whole-cell patch and the
permeabilized-patch techniques followed by rupture
(reduction of 10±2% [n=6 for conventional method] and of 11±3%
[n=7 for permeabilized method], P<.05 in
both cases). When the pipette concentration was further reduced to 10
pmol/L, there were no significant changes in contraction.
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) and the
permeabilized-patch technique (
). Stimulation
frequency was 1 Hz at 36°C. *Significant (P<.05)
change.
If the actions of cADPR were associated with an increased sensitivity
of calcium-induced calcium release (CICR) from the sarcoplasmic
reticulum, the actions would be expected to be suppressed when the
function of sarcoplasmic reticulum was inhibited. This possibility was
tested using a mixture of 2 µmol/L ryanodine (to
interfere with release channels) and 1 µmol/L
thapsigargin (to inhibit the Ca2+-ATPase of the
sarcoplasmic reticulum). Under these conditions, mean cell shortening
was 6.4±0.5% of resting length. Fig 3
shows that when 5 µmol/L cADPR was applied via the patch
pipette to cells pretreated with the ryanodine/thapsigargin mixture,
there was no significant increase in contraction in contrast with the
increase reported above in the absence of ryanodine and thapsigargin
(permeabilized-patch method). The observations are
therefore consistent with an enhancing effect of cADPR on CICR
from the sarcoplasmic reticulum.
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It is interesting to note that the small but statistically significant reduction of contraction with 10 nmol/L cADPR was also prevented by exposure of the cells to 2 µmol/L ryanodine and 1 µmol/L thapsigargin (increase of 7±8%, n=7 cells, permeabilized-patch method, P>.05).
8-Br-cADPR has been reported to be a competitive antagonist
of cADPR in the sea urchin egg preparation.15 The effects
of this compound were tested in a series of experiments at two
concentrations of 8-Br-cADPR in the pipette solution (conventional
whole-cell patch method). When 5 µmol/L 8-Br-cADPR was
applied to the cytosol, contraction was reduced by 23±4% (n=7 cells,
P<.05). A larger reduction of contraction of 37±8% (n=7
cells, P<.05) was observed when 50 µmol/L
8-Br-cADPR was applied to the cytosol (P<.05 for a
comparison of the two sample means) as shown in Fig 4. The observations are therefore similar
to those previously reported for another cADPR antagonist,
8-amino-cADPR (applied to the cytosol via a theta-glass
microelectrode6 ). To test for the effects of 8-amino-cADPR
under the conditions of the present experiments, a further series
of observations was made with 5 µmol/L 8-amino-cADPR
applied via the patch pipette; again, contraction was found to be
reduced by 35±7% (n=8 cells, P<.05) in the presence of
this antagonist. The observations made when using these
cADPR analogues are therefore consistent with a suppression by
the two antagonists of an enhancing influence of
endogenous cADPR on CICR.
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If 8-Br-cADPR can inhibit the influence of endogenous
cADPR, the question arises whether it might prevent the actions of
exogenous cADPR applied via the patch pipette. This was tested in
experiments in which 5 µmol/L 8-Br-cADPR and 5
µmol/L cADPR were both added to the pipette solution. Under
these conditions, there was no significant change in the amplitude of
contraction (decrease of 5±4%, n=6 cells, conventional whole-cell
method, 36°C). This antagonistic effect of 5
µmol/L 8-Br-cADPR could be overcome by increasing the
concentration of cADPR in the patch pipette to 50 µmol/L
in the continued presence of 5 µmol/L 8-Br-cADPR (Fig 4).
This was the case both when a conventional patch method was used, as
described above (an increase of 20±5%, n=9 cells, P<.05),
and in experiments in which the second method was used to allow control
measurements with permeabilized patches before rupture
of the membrane (an increase of 28±11%, n=6 cells,
P<.05).
Observations at Room Temperature
The possible influence of temperature on the actions of cADPR and
its analogues was investigated in another series of experiments in
which the heating system normally used to warm the solution before it
entered the recording chamber was switched off. Under these
conditions, contraction accompanying action potentials at 1 Hz was
again well maintained (reduction of 3±5%, n=10 cells,
P>.05; changes were measured at 5 minutes and expressed as
a percentage of contraction measured within 1 minute of rupture of the
patch membrane). Observations with 5 µmol/L cADPR,
50 µmol/L 8-Br-cADPR, or 5 µmol/L
8-amino-cADPR in the patch pipette are shown in Fig 5. It can be seen that none of the cADPR
analogues caused significant changes in contraction under these
conditions (for 5 µmol/L cADPR, there was a reduction of
13±6% [n=13 cells, P>.05]; for 50 µmol/L
8-Br-cADPR, there was a decrease of 5±6% [n=7 cells,
P>.05]; and for 5 µmol/L 8-amino-cADPR,
there was an increase of 11±9% [n=5 cells, P>.05]). In
contrast, the changes seen at 36°C are shown in the same bar graph
(mean values for cADPR and 8-Br-cADPR are reported above; for 5
µmol/L 8-amino-cADPR, there was a reduction of 35±7% [n=8
cells, P<.05]). It is clear that temperature exerted a
profound influence on the actions of cADPR and its analogues.
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One possibility that deserves consideration is that since reduction of temperature from 36°C to room temperature leads to an increase in contraction, the observed lack of effect of cADPR at room temperature might simply reflect a marked increase in basal inotropic state and magnitude of the calcium transient under these conditions. To investigate this possibility, we carried out a series of experiments with extracellular calcium concentration reduced from 2.5 to 1.8 mmol/L. Under these conditions, myocyte contraction accompanying action potentials at 1 Hz was reduced from 9.7±0.7% at 2.5 mmol/L to 8.7±0.4% at 1.8 mmol/L calcium; the magnitude of this reduced contraction at room temperature and 1.8 mmol/L calcium was therefore similar to that at 36°C and 2.5 mmol/L calcium (8.1±0.8%). In myocytes maintained at room temperature and 1.8 mmol/L calcium, no significant increase in contraction was observed when 5 µmol/L cADPR was applied to the cytosol via patch electrodes (the mean change was a reduction of 2±5%; n=11 cells, P>.05). However, at 36°C and 1.8 mmol/L calcium, application of 5 µmol/L cADPR via the patch electrode did cause an increase in contraction of 29±10% (n=6 cells, P<.05), similar to that reported above for cells at 36°C and 2.5 mmol/L calcium. It seems unlikely therefore that an increased inotropic state at room temperature can be the sole reason for the lack of significant increase in contraction by cytosolically applied cADPR under these conditions.
Effects of cADPR on Calcium Transients
The reduction in contraction caused by cytosolically applied
8-amino-cADPR has previously been shown to be associated with a
corresponding decrease in the calcium transient accompanying the action
potential in cardiac ventricular cells.6 In
another series of experiments, we have investigated whether the
increase in contraction caused by 5 µmol/L cADPR is also
associated with changes in calcium transients measured with fura 2. The
experiments were carried out at 36°C. Fig 6A shows that the calcium transient was
well maintained 5 minutes after rupture of the patch membrane in the
absence of cADPR in the pipette solution, whereas when 5
µmol/L cADPR was applied to the cytosol, there was a
substantial increase in the recorded calcium transient (Fig 6B).
Mean changes are shown in the bar graph in Fig 6C.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The main findings reported in the present study are that the contraction of cardiac ventricular myocytes was significantly increased by cADPR and decreased by its antagonists at 36°C but that possible effects of these compounds were not detected at room temperature under the conditions of our experiments. The temperature sensitivity of the actions of cADPR analogues may be one important factor leading to reports of the lack of effects of these analogues when studied at room temperature, although the possible influence of other additional factors cannot be ruled out.
The observations at 36°C with the antagonists 8-Br-cADPR and 8-amino-cADPR applied via a patch pipette are similar to the reductions in myocyte contraction reported for 8-amino-cADPR applied from a theta-glass microelectrode.6 However, lower concentrations of 8-amino-cADPR were required in the present experiments when this antagonist was applied via a patch pipette rather than from a "sharp" theta-glass electrode, as might be expected from the improved access of drugs to the cytoplasm under these conditions (since the diameter of the open end of a patch pipette is expected to be much larger than the tip of a theta-glass electrode).
In the case of 8-amino-cADPR, we have suggested that the reduction in myocyte contraction may arise from competitive inhibition of endogenous cADPR, which normally acts to sensitize CICR to calcium.6 We have said that a direct effect of 8-amino-cADPR on the CICR ryanodine receptor could not be excluded, although we have pointed out that such an effect could not result from simple channel block, since the calcium-releasing actions of caffeine were not prevented by this compound. The observation that 8-Br-cADPR, which is another substance found to be a competitive antagonist of cADPR in the sea urchin preparation,15 also reduces myocyte contraction provides further support for our hypothesis of antagonism of endogenous cADPR in myocytes. The ability to overcome the actions of 8-Br-cADPR by increasing the concentration of cADPR is also consistent with competitive antagonism rather than block of release channels by the antagonist. Furthermore, there was a close parallel between the observations that higher concentrations of 8-Br-cADPR than of 8-amino-cADPR are required to competitively antagonize the actions of cADPR on calcium release from sea urchin egg microsomes15 and that reduction of myocyte contraction shows a similar difference in sensitivity to these two compounds.
The observations reported in the present study are the first demonstration that cADPR, which is known to act as an agonist in the sea urchin egg preparation, can increase contraction in intact cardiac muscle cells. As with the reductions of contraction observed with the antagonist 8-amino-cADPR,6 the increase in contraction with 5 µmol/L of the agonist cADPR was shown to be prevented by exposure to drugs that interfere with the function of the sarcoplasmic reticulum. The observations therefore support a role of cADPR to increase calcium release from the sarcoplasmic reticulum, perhaps by increasing the calcium sensitivity of CICR. The finding that 5 µmol/L cADPR applied to the cytosol also increased calcium transients measured with fura 2 provides further support for this hypothesis.
If the hypothesis of antagonism between either 8-Br-cADPR or 8-amino-cADPR and endogenous cADPR is correct, temperature sensitivity might arise from an influence of temperature on the enzymes (for example ADP-ribosyl cyclase and cADPR hydrolase) that regulate the endogenous levels of cADPR and that are known to be present in cardiac muscle.16 17 Thus, at room temperature there may be reduced endogenous levels of cADPR in the cytoplasm, so that this mechanism for increasing the calcium sensitivity of CICR might be suppressed, leading to reduced effects of the antagonists. Another possibility to account for the temperature sensitivity of the antagonists is that the binding of antagonists to their postulated inhibitory sites might be temperature sensitive.
In this context, it is interesting that the actions of the cADPR agonist also show a high temperature sensitivity. In the sea urchin egg system, it has been suggested that cADPR may act via a binding protein to influence the ryanodine receptor and that the actions may be modulated by calmodulin.18 There is also intriguing evidence that the FK-506 binding protein (FKBP), which has been associated with the actions of cADPR,19 may also influence cardiac muscle contraction.20 Recent experiments have shown that the exchange reaction between soluble FKBP-12.6 and the FKBP-ryanodine receptor complex is temperature sensitive.21 Temperature sensitivity either of the binding of cADPR to the postulated binding proteins or of the interaction between the binding protein complex with the CICR channel (ryanodine receptor) might account for the temperature sensitivity of the agonist cADPR. If such mechanisms were to occur, they might also contribute to the temperature sensitivity of the antagonists, 8-amino-cADPR and 8-Br-cADPR.
In summary, the observations reported in the present study provide further support for the hypothesis that cADPR might function as an important cytosolic regulator of cardiac muscle contraction. The temperature sensitivity of these effects of cADPR and its antagonists may provide important clues concerning mechanism of action and may help to explain previous negative reports concerning cADPR actions.
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Acknowledgments |
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This study was supported by The Wellcome Trust and by The Japan Heart Foundation. We thank Prof H.C. Lee, University of Minnesota, for helpful discussions.
Received June 4, 1997; accepted September 17, 1997.
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