Mitochondrial ATP-sensitive K+ channels influence force development and anoxic contractility in a flatfish, yellowtail flounder Limanda ferruginea, but not Atlantic cod Gadus morhua heart
Ocean Sciences Centre, Memorial University of Newfoundland, St John's, Newfoundland, Canada AlC 5S7
* Author for correspndence (e-mail: wdriedzic{at}mun.ca
Accepted 25 February 2002
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Summary |
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Key words: adenosine 5'-triphosphate-sensitive potassium channel, fish heart, hypoxia, mitochondria, calcium, yellowtail flounder, Limanda ferruginea, Atlantic cod, Gadus morhua
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Introduction |
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Work by Ganim et al. (1998)
on goldfish, as well as investigations on the Amazonian armoured catfish
acari-bodo Lipossarcus pardalis (T. J. MacCormack, J. Treberg, V. M.
F. Almeida-Val, A. L. Val and W. R. Driedzik, manuscript submitted for
publication), have identified adenosine 5'-triphosphate-sensitive
potassium (KATP) channels in fish hearts. KATP channels
are activated by a decline in the ratio of ATP/ADP, and are therefore most
likely to contribute to cardiac function throughout periods of impaired ATP
production, such as hypoxia. The objective of this study was to evaluate
whether KATP channels are involved in the phenomenon of hypoxic
force potentiation in the yellowtail flounder Limanda ferruginea
heart, and to investigate their role in cardiac performance during anoxia and
reoxygenation in fish species with differing tolerances to cardiac anoxia.
Atlantic cod Gadus morhua were chosen for comparisons, as this
species is considered to have poor cardiac anoxia tolerance
(Gesser and Poupa, 1974
;
Hartmund and Gesser,
1996
).
In mammalian heart, KATP channels have been described on both
the sarcolemmal membrane (sKATP)
(Noma, 1983) and on the inner
mitochondrial membrane (mKATP)
(Inoue et al., 1991
), and
their activity has been linked with the cardioprotection afforded by various
means of preconditioning. sKATP channels facilitate cellular
K+ efflux in mammalian cardiomyocytes, and can therefore alter
membrane electrical properties such as the action potential
(Ganim et al., 1998
) and
extracellular K+ concentrations
(Kantor et al., 1990
;
Venkatesh et al., 1991
;
Wilde et al., 1990
).
mKATP channels allow mitochondrial K+ influx, leading to
decreasing inner mitochondrial membrane potential and swelling of the matrix
in rat heart. Depolarisation also affects mitochondrial Ca2+
handling (Holmuhamedov et al.,
1999
), increases respiration and alters the rate of mitochondrial
ATP synthesis (Holmuhamedov et al.,
1998
, Eells et al.,
2000
). Despite extensive study in mammals, it is still not clear
whether the hypoxic cardioprotection associated with activated KATP
channels is mediated by sarcolemmal or mitochondrial channels, or whether both
play an important part (Sato et al.,
2000
; reviewed by Gross and
Fryer, 1999
).
Differences in excitationcontraction (EC) coupling between
fish and mammalian cardiac muscle may contribute to significant differences in
the functional role of KATP channels in fish cardiomyocytes. Unlike
mammalian cardiomyocytes, which derive the Ca2+ needed for
contraction largely from intracellular stores such as the sarcoplasmic
reticulum (SR), fish cardiomyocytes rely heavily on transsarcolemmal
Ca2+ influx to achieve contraction (Vornanen,
1998,
1999
). The dependence of fish
cardiomyocytes on sarcolemmal Ca2+ flux enhances the importance of
membrane-bound ion channels and transporters in controlling contractility. The
role of KATP channels in fish cardiomyocytes may therefore, be
quite different than that observed for mammals and could be important in
beat-to-beat cardiac function in fish.
The contribution of KATP channels to heart performance during anoxia and reoxygenation was studied using isolated ventricular muscle strip preparations and pharmacological agents targeting sarcolemmal and mKATP channel activity. This study shows that agents altering KATP channel activity can impact on contractility in ventricular muscle from yellowtail flounder, but not Atlantic cod. Species-specific differences in fish cardiac KATP channels may have implications in anaerobic heart performance.
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Materials and methods |
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Tissue preparation
Animals were killed by a sharp blow to the head and doubly pithed. The
heart was quickly excised and placed in cold, oxygenated bathing solution. The
bathing medium was a standard solution for marine teleosts and included (in
mmol l-1): 150 NaCl, 5.0 KCl, 0.17 MgSO4, 1.5
CaCl2, 0.17 NaH2PO4, 2.33
Na2HOP4, 11.0 NaHCO3, with pH set to 7.8 at 6
°C. Glucose (5.0 mmol l-1) was added as a metabolic fuel
(Driedzic and Bailey, 1994).
The ventricle was dissected free of the atrium and bulbous arteriosus,
bisected, and a strip approximately 1.5 mm wide and <10 mm in length was
cut longitudinally from each section.
Preparations were mounted vertically in a tissue bath using a Plexiglas
clamp and affixed to a Harvard Apparatus (South Natick, MA, USA) isometric
force transducer (Model 60-2994) with 3-0 surgical silk. Each chamber
contained 30 ml of bathing medium held at 6 °C and gassed with either 0.5
% CO2, balance O2 (oxygenated) or 0.5 % CO2,
balance N2 (anoxia). Ganim et al.
(1998) have shown that
KATP channels are sensitive to acclimation temperature in fish, so
in an attempt to reflect physiological conditions, experiments were run close
to the acclimation temperature of the animals. Each preparation was subjected
to only one treatment and run in parallel with appropriate control
preparations in each instance.
Strips were positioned between platinum electrodes on the Plexiglas clamp
and stimulated to contract by field stimulation using a Grass model S9
stimulator with voltage set at 150 % threshold and 5 ms duration. Strips were
stretched to optimum length for maximum force production and allowed 30 min to
stabilise at a pacing rate of 0.2 Hz. Pacing frequency was 0.2 Hz for all
experiments and spontaneously contracting strips were eliminated from
statistical analysis. Free-swimming Atlantic cod at a temperature similar to
that used in the present study (6.4 °C) were found to have heart rates of
approximately 0.33 Hz under normoxic conditions
(Claireaux et al., 1995). Heart
rate is not available for yellowtail flounder but in a similar species,
Pseudopleuronectes americanus, heart rate was about 0.6 Hz under
normoxia at 10 °C (Cech et al.,
1977
). Since ventricle strip preparations in the present study
were made to contract at their maximum level of force development, a lower
pacing frequency of 0.2 Hz was chosen to compensate for possible increases on
energy demand in the tissue. This pacing frequency also facilitated
comparisons with existing data on cardiac performance in other flatfish and
Atlantic cod (Gesser and Poupa,
1974
).
Anoxic conditions were induced rapidly and reversibly by replacing the oxygenated medium in the tissue bath with nitrogen-gassed medium. A reservoir of medium was maintained at 6 °C in a water-jacketed condenser and equilibrated with 0.5 % CO2, balance N2. During the switch to anoxia, the tissue bath was gassed with 0.5 % CO2, balance N2 and flushed with 150 ml of anoxic medium. Mechanical disturbance was minimal during the switch, and preliminary experiments using a reservoir of oxygenated medium found the process had no effect on force development or the contractile characteristics of the preparation. The switch from oxygenated to anoxic medium required <1 min and dissolved oxygen in the bath was routinely <0.1 mg l-1. To achieve reoxygenation the bath was gassed with 0.5 % CO2, balance O2, resulting in saturation within approximately 1 min.
The response of ventricular muscle to anoxia and reoxygenation was first assessed in the absence of pharmacological agents. Control strips were gassed with 0.5 % CO2, balance O2 for 85 min while treatment preparations were subjected to a 35 min period of anoxia followed by 30 min of reoxygenation.
The contribution of KATP channels to contractility in
ventricular muscle from yellowtail flounder and cod during anoxia and
reoxygenation was next assessed using glibenclamide, an inhibitor of both
sarcolemmal and mKATP channels
(Hu et al., 1999). Both
control and treatment strips were subjected to a 35 min period of anoxia
followed by 30 min of reoxygenation. Glibenclamide (5 µmol l-1)
was initially applied to the treatment bath during the first minute following
stabilisation with the control bath receiving vehicle dimethyl-sulfoxide
(DMSO). Chemicals were reapplied immediately following the switch to anoxia,
to maintain a constant concentration in the bath.
The functional contribution of mKATP channels in the yellowtail
flounder heart was next investigated using sodium 5-hydroxydecanoic acid
(5HD), a highly specific inhibitor of mKATP channel function.
Trials were as above with 100 µmol l-1 5HD
(Sato et al., 2000) added to
the treatment bath in each instance and run parallel to untreated
preparations.
Diazoxide (50 µmol l-1;
Hu et al., 1999), a specific
mKATP channel opener, was also used to assess the effects of
mKATP channels in anaerobic performance and recovery in ventricular
strips from yellowtail flounder and Atlantic cod. Control preparations
received vehicle DMSO. Doses for all agents were chosen from the lower end of
the range of concentrations commonly used in mammalian studies, in order to
minimise the risk of toxic side effects.
Drugs
All chemicals were purchased from Sigma (St Louis, MO, USA) with the
exception of 5HD, which was purchased from ICN Biomedicals (Aurora, OH, USA).
Stock solutions of glibenclamide (5 mmol l-1) and diazoxide (18
mmol l-1) were prepared in DMSO and stored at -20 °C in
aliquots until just before use. A 100 mmol l-1 stock solution of
5HD was prepared in bathing medium and frozen in portions until just before
use. All chemicals were pipetted directly into the tissue bath.
Data analysis and statistics
Force transducers were interfaced to a MacLab/2E computerised unit and data
were collected online using the accompanying Chart software for Macintosh.
Data were recorded for a duration of 30s at 5 min intervals, and statistical
analysis is based on the average of six contractions at each recording
interval. Peak tension (% force) and resting tension were calculated using
Microsoft Excel, and are expressed as a percent of initial tension
development. Data from untreated, anoxia/reoxygenation trials were pooled for
more accurate comparisons with untreated oxygenated preparations and
5HD-treated preparations. Anoxia/reoxygenation trials in which DMSO was
applied to preparations were also pooled for comparisons against
glibenclamide- and diazoxide-treated strips. Statistical analysis of data was
performed using SPSS version 10.1 for Windows. The significance of changes in
% force and resting tension between treatments was tested using a parametric
repeated measures analysis. Within treatment differences were tested using a
one-way analysis of variance (ANOVA). P values of less than 0.05 were
considered to be statistically significant.
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Results |
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Force production increased significantly above oxygenated levels in yellowtail flounder following exposure to anoxia, peaking at 122±13 % after 10 min. Force then declined over the balance of the anoxic period, but remained above levels observed for oxygenated preparations. Force recovered significantly above anoxic levels at reoxygenation before continuing to decline at a rate approximately equal to that observed before reoxygenation. Resting tension consistently fell rapidly by approximately 10 % during the initial 10 min of anoxia, before stabilising and diminishing at a rate similar to oxygenated controls. Reoxygenation did not affect resting tension.
Atlantic cod
Ventricle strips from cod exhibited a decay in force production and resting
tension under oxygenated conditions similar to that observed for yellowtail
flounder. In previous experiments on Atlantic cod, ventricle preparations
under oxygenated conditions lost between 10 and 15 % of force development over
30 min (Gesser and Jørgensen, 1982;
Hartmund and Gesser, 1996).
Exposing preparations to anoxia resulted in a significant decline in force
production relative to pre-anoxic levels, falling to 34.6±6.3 % of
initial after 30 min. Anoxic force development was not significantly different
from that observed for oxygenated controls. Following reoxygenation, force
recovered to levels much higher than those observed for oxygenated controls
(78.3±10.9 % compared with 46.0±15.4 %). Although preparations
showed significant force recovery relative to anoxic levels, recovery was
non-significant when compared with oxygenated preparations, owing to high
variation in the recovering strips. Cod preparations did not exhibit the same
rapid decay in resting tension at the onset of anoxia, as was observed for
yellowtail flounder preparations, and were generally unaffected by anoxia or
reoxygenation.
KATP contribution
Yellowtail flounder
Fig. 2 shows peak tension
and resting tension data for yellowtail flounder ventricle preparations
exposed to anoxia and reoxygenation and treated with agents to alter
KATP-channel activity. Fig.
2A shows that the response to DMSO (vehicle for glibenclamide and
diazoxide) alone is no different from untreated preparations, and confirms the
biphasic pattern of force development following anoxia and reoxygenation.
Blocking KATP channels with glibenclamide
(Fig. 2B) decreased force
production significantly under oxygenated conditions in preparations from
yellowtail flounder. The inset graph (Fig.
2B) illustrates the specific effects of glibenclamide treatment on
force development (% force from glibenclamide treated strips minus % force
from DMSO treated strips over time). Despite an overall decrease in force
development, preparations continued to respond similarly to anoxia and
reoxygenation. Glibenclamide had no effect on resting tension in yellowtail
flounder ventricle preparations.
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The mKATP channel agonist diazoxide significantly eliminated the potentiation of force production observed in untreated preparations exposed to anoxia (Fig. 2C). The inset graph (Fig. 2C) shows the specific effects of diazoxide treatment on force development (% force from diazoxide-treated preparations % force from DMSO-treated preparations over time). Diazoxide-treated preparations did show significant force recovery over anoxic levels when reoxygenated, but still tended to be weaker than untreated strips. Resting tension also tended to be more stable during anoxia in diazoxide-treated strips, with no rapid decline observed at the onset of anoxia. However, differences were not statistically significant. Inhibiting mKATP channels with 5HD (Fig. 2D) initially preserved force development under oxygenation in yellowtail flounder heart preparations. As 5HD was dissolved in bathing medium, the appropriate controls for this treatment are presented in Fig. 1A. 5HD did not significantly affect peak tension or resting tension during anoxia and reoxygenation. The inset graph (Fig. 2D) shows the specific effects of 5HD treatment on force development (% force from 5HD treated strips minus % force from untreated control strips over time).
Atlantic cod
Fig. 3 gives force and
resting tension for Atlantic cod ventricular muscle preparations exposed to
anoxia and reoxygenation and treated with agents to alter KATP
channel activity. Glibenclamide, diazoxide and 5HD had no noticeable influence
on force development or resting tension in cod ventricle preparations under
the conditions tested. Force development in all preparations decreases under
anoxia to approximately 33 % of the initial value. Upon reoxygenation, strips
immediately recover to approximately 88 % of initial force development.
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Discussion |
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In Atlantic cod ventricular preparations, anoxia initially results in a
loss in force development followed by a stabilisation. In previous
investigations on Atlantic cod (Gesser and
Poupa, 1974; Hartmund and
Gesser, 1996
) in which anoxia was simulated at 15 °C using
sodium cyanide, a much more rapid decline in force development was observed,
followed by a similar stabilisation. Given that anoxia should be induced more
gradually using only N2, and that test temperature (6 °C) was
lower in the current study, the slower time course of force decay and
stabilisation agrees well with existing data. Resting tension declined
slightly during oxygenation in cod preparations, subsequently stabilising
during anoxia. Force development under anoxia was not substantially different
from control preparations. In vivo, Atlantic cod show a decrease in
heart rate during environmental hypoxia but maintain cardiac output by
increasing stroke volume (Fritsche and
Nilsson, 1989
). As such, power output both in vivo and
with our ventricular strips is defended reasonably well, presumably through
anaerobic metabolism under anoxia. Reoxygenating cod preparations led to
restoration of force development under all treatment conditions.
The response of yellowtail flounder heart preparations to anoxia was quite
different than that observed in Atlantic cod preparations. A common finding in
almost all experiments with yellowtail flounder (with the exception of
treatment with diazoxide) is a transient but substantial potentiation of force
and a decline in resting tension at the onset of anoxia. Reoxygenation leads
to a small and short-lived increase in force production followed by a decline
in performance, similar to that seen in preparations maintained for an
equivalent period under oxygenation. The potentiation of force shown by
yellowtail flounder ventricle preparations exposed to nitrogen-induced anoxia
is comparable with that shown by other species of flatfish subjected to
acidosis (Gesser and Poupa,
1979; Hoglund and Gesser,
1987
; Poupa and Johansen,
1975
). These observations also agree well with in vivo
studies on the winter flounder that do not display a bradycardic response and
actually significantly increase cardiac output in response to hypoxia
(Cech et al., 1977
).
Increases in cardiac twitch force production in fish are generally agreed
to result from increased intracellular Ca2+ levels
([Ca2+]i) (Tibbits
et al., 1991). Indirect evidence suggests that acidotic force
potentiation in ectothermic vertebrates is due to a release of stored
mitochondrial Ca2+ (Gesser and
Poupa, 1978
). We suggest below that the increase in force
development of ventricular strips from yellowtail flounder under anoxia is
also related to the release of Ca2+ from the mitochondria.
Our results show the presence of mKATP channels in ventricular
muscle of yellowtail flounder. Under anoxic conditions, diazoxide completely
eliminated the transient elevation in force development and stabilised resting
tension. Acute activation of mKATP channels with diazoxide has been
shown to depolarise the inner mitochondrial membrane in the rat heart at 30
°C, leading to a rapid reduction in mitochondrial Ca2+ content
and inhibited mitochondrial Ca2+ uptake
(Holmuhamedov et al., 1999).
If the potentiation of force during anoxia in flounder is due to a bolus
release of mitochondrial Ca2+, then our results seem to contrast
with those observed in mammals, in that the activation of mKATP
channels in the flounder heart seems to stabilise
[Ca2+]i during anoxia. It is possible that in the
flounder heart, diazoxide releases mitochondrial Ca2+ more slowly
than in the rat heart, probably due to the relatively extreme low temperature
(6 °C) used in this experiment. Following a period of diazoxide treatment,
mitochondrial Ca2+ content should already be reduced, so that when
subjected to anoxia, any large force potentiation resulting from a bolus
release of mitochondrial Ca2+ will be eliminated. The observed
preservation of resting tension in diazoxide-treated preparations supports
this interpretation. Changes in resting tension are thought to reflect
alterations in resting [Ca2+]i
(Driedzic and Gesser, 1994
),
therefore the observed decrease in resting tension at the onset of anoxia in
untreated strips would presumably be due to a decrease in
[Ca2+]i activity. If diazoxide treatment triggers a more
gradual release of mitochondrial Ca2+ to the cytoplasm, it may act
to protect [Ca2+]i during anoxia and overcome a net loss
in activity. This could lead to the observed preservation of resting
tension.
5HD, a mKATP antagonist, protected against force loss under oxygenated conditions. On the basis of available information, we are unable to suggest the mechanism for this response. The important point though is that these observations provide evidence for mKATP channels in the yellowtail flounder heart. 5HD had no impact under anoxia suggesting that mKATP channels are already closed under these conditions. This implies that energy status is maintained under anoxia through a strong anaerobic metabolism
Glibenclamide, a general KATP-channel antagonist, significantly
reduced force development in flounder ventricle preparations during
oxygenation, but did not affect the characteristics of force development
during anoxia or recovery. This, along with the observation that 5HD seemed to
have the opposite effect on twitch force development in flounder ventricle
strips, suggests that the force loss incurred with glibenclamide may be a
result of a sarcolemmal rather than mKATP channel contribution.
sKATP channel activity increases in isolated goldfish
cardiomyocytes acclimated to low temperatures (7°C)
(Ganim et al., 1998).
Glibenclamide had no effect on action potential duration in goldfish myocytes
when tested at the acclimation temperature
(Ganim et al., 1998
), but we
cannot rule out the possibility that it could affect the characteristics of
the action potential in yellowtail flounder cardiomyocytes. Our results
suggest that sKATP channels are normally active on a beat to beat
basis in the yellowtail flounder heart at this temperature and may therefore
be important in the regulation of contractility.
The observation of impaired force development in glibenclamide-treated
preparations is unexpected and again difficult to explain using the available
literature on either mammalian or fish heart. Theoretically, blocking
sKATP-channel activity with glibenclamide should lengthen the
duration of the action potential and enhance Ca2+ influx through
L-type channels. Inhibiting sKATP activity should decrease net
cellular K+ efflux and cause the sarcolemmal membrane potential to
become less polarised. A more positive membrane potential could, in turn,
increase reverse Na+/Ca2+ exchange, which has been shown
to contribute a significant amount of activator Ca2+ at more
depolarised membrane potentials in the fish heart
(Vornanen, 1999). By all
accounts, glibenclamide should facilitate increased twitch-force development
through enhanced Ca2+ influx across the sarcolemmal membrane.
Further investigations on the membrane events associated with sKATP
channel opening are necessary to explain this observation.
Altering KATP channel activity in cod ventricle strips did not
affect force development or resting tension under any of the conditions
tested. The data suggest that Atlantic cod do not have cardiac KATP
channels that are sensitive to the pharmacological agents used, or that all of
the factors needed to alter channel activity are not present in this tissue.
KATP-channel activity is sensitive to ATP concentration,
Mg2+ and other nucleotide concentrations, as well as a host of
other factors (Terzic et al.,
1995). The characteristics of the intracellular environment in cod
may lead to differences in the activation state of KATP channels,
and hence the effectiveness of channel modulators in this animal. In addition,
evolutionary differences within teleost fish, and between fish and mammals may
influence the sensitivity of KATP channels to pharmacological
manipulation.
KATP channels are known to exist in mammalian cardiac muscle;
however, direct evidence of their presence in ectothermic myocardium has yet
to be presented. Gamperl et al.
(2001) have shown in the in
situ rainbow trout Oncorhynchus mykiss heart that a 5 min period
of anoxic preconditioning eliminates decreases in resting cardiac function,
maximum cardiac output and maximum stroke volume associated with 15 min of
anoxic exposure. Although not addressed in their study, KATP
channels are generally agreed to play a key role in the cardioprotection
afforded by hypoxic preconditioning in cardiac muscle
(Gross and Fryer, 1999
),
suggesting that these channels are functional in the fish heart. Further
evidence of the presence of KATP channels in ectothermic
vertebrates has been provided by studies on isolated mitochondria from the
frog Rana temporaria (St-Pierre
et al., 2000
). When isolated mitochondria were subjected to
anoxia, membrane potential gradually declined to a new steady state. The
activation of mKATP channels under hypoxia in isolated mammalian
mitochondria results in a similar depolarisation of membrane potential
(Holmuhamedov et al., 1998
),
again consistent with the contention that KATP channels are present
in ectothermic vertebrates.
This study provides further evidence for the presence of KATP channels in a fish heart and the potential importance of these channels in the control of cardiac function. The novel effects of mKATP-channel modulators in yellowtail flounder heart imply differences exist in the function of this channel over those known for mammalian systems. Alterations in KATP-channel activity may be the cellular mechanism that underlies previous observations of increased hypoxic cardiac output in flatfish. For example, decreased resting tension may be associated with larger end diastolic volume. This, coupled with increased force, could lead to greater stroke volume and cardiac output. The influence of channel modulation on contractility revealed by this study also suggests a prospective role for these channels in EC coupling in the fish heart. Future studies should address in more detail the exact means by which KATP channels influence contractility and their involvement in hypoxic cardioprotection.
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Acknowledgments |
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