Published online before print April 27, 2001, doi: 10.1161/hh0901.089881
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© 2001 American Heart Association, Inc.
Cellular Biology |
Long-Chain Acyl–Coenzyme A Esters and Fatty Acids Directly Link Metabolism to KATP Channels in the Heart
From the Institute of Physiology, Marburg University, Marburg, Germany.
Correspondence to Prof Jürgen Daut, Institute of Physiology, Marburg University, Deutschhausstrasse 2, 35037 Marburg, Germany. E-mail daut{at}mailer.uni-marburg.de
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Abstract |
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Abstract—ATP-sensitive K (KATP) channels are inhibited by cytosolic ATP, a defining property that implicitly links these channels to cellular metabolism. Here we report a direct link between fatty acid metabolism and KATP channels in cardiac muscle cells. Long-chain (LC) acyl–coenzyme A (CoA) esters are synthesized from fatty acids and serve as the principal metabolic substrates of the heart. We have studied the effects of LC acyl-CoA esters and LC fatty acids on KATP channels of isolated guinea pig ventricular myocytes and compared them with the effects of phosphatidylinositol 4,5-bisphosphate (PIP2). Application of oleoyl-CoA (0.2 or 1 µmol/L), a naturally occurring acyl-CoA ester, to the cytosolic side of excised patches completely prevented rundown of KATP channels, but not of Kir2 channels. The open probability of KATP channels measured in the presence of oleoyl-CoA or PIP2 was voltage dependent, increasing with depolarization. Oleoyl-CoA greatly reduced the ATP sensitivity of KATP channels. At a concentration of 2 µmol/L, oleoyl-CoA increased the half-maximal inhibitory concentration of ATP >200-fold. The time course of the decrease in ATP sensitivity was much faster during application of oleoyl-CoA than during application of PIP2. The effects of PIP2, but not of oleoyl-CoA, were inhibited by increasing Ca2+ to 1 mmol/L. Oleate (C18:1; 10 µmol/L), the precursor of oleoyl-CoA, inhibited KATP channels activated by oleoyl-CoA. Palmitoleoyl-CoA and palmitoleate (C16:1) exerted similar reciprocal effects. These findings indicate that LC fatty acids and their CoA-linked derivatives may be key physiological modulators of KATP channel activity in the heart.
Key Words: free fatty acids • acyl-CoA esters • PIP2 • KATP channels
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ATP-sensitive potassium (KATP) channels link energy metabolism with the electrical activity of the heart.1 2 3 This link is functionally important during hypoxia or ischemia. Any imbalance in the ratio between energy supply through coronary arteries and energy expenditure by cardiac myocytes will indirectly modulate electrical activity, because a change in the ATP/ADP ratio, together with acidosis, promotes activation of KATP channels.4 5 6 By increasing K+ efflux and shortening the duration of the action potential, KATP channel activation reduces transsarcolemmal Ca2+ influx and thereby the energy costs of Ca2+-ATPases and actomyosin-ATPase. Hence, in the face of reduced energy supply, KATP channels may provide a means to decrease cytosolic energy demand.
We report here a direct effect of long-chain (LC) acyl–coenzyme A (CoA) esters and fatty acids on the activity of KATP channels in isolated cardiac myocytes. We have shown that LC acyl-CoA esters facilitate the opening of KATP channels by reducing their ATP sensitivity. The precursors of LC acyl-CoA esters, LC fatty acids, were found to inhibit KATP channels. The reciprocal effects of free fatty acids and acyl-CoA esters on KATP channels represent a novel link between energy metabolism and cardiac function.
It has been shown previously that LC acyl-CoA esters
decrease the ATP sensitivity of pancreatic KATP
channels (Kir6.1/SUR1), both in native ß
cells7 and in a heterologous
expression
system,8 9 and it
has been postulated that the site of action of acyl-CoA esters is the
Kir6.2 rather than the SUR
subunit.8 9
However, the effects of acyl-CoA esters on the ATP sensitivity of
cardiac KATP channels are by an order of
magnitude stronger than the effects observed in pancreatic
KATP channels, despite the fact that cardiac and
pancreatic KATP channels have the same 
subunit (Kir6.2). These observations suggest that the ß subunit of
cardiac KATP channels, SUR2A, may also be
involved in the effects of acyl-CoA esters. Recently
phosphatidylinositol 4,5-bisphosphate (PIP2), a
membrane-bound phospholipid involved in G protein–mediated signal
transduction,10 has been
reported to decrease ATP sensitivity of KATP
channels.11 12 13 14
In the present study, we show that the characteristics of the
effects of acyl-CoA esters on cardiac KATP
channels differ substantially from the effects of
PIP2.
The effects of acyl-CoA esters on KATP channels in cardiac muscle cells may be functionally important because LC fatty acids, particularly C16 and C18 fatty acids, serve as the main metabolic substrates of the heart. The metabolizable form of these fatty acids is that of acyl-CoA esters, which are synthesized at the outer mitochondrial membrane via acyl-CoA synthetase, imported into the mitochondria, and subsequently metabolized via ß-oxidation. Any impairment of oxidative phosphorylation, for example during cardiac ischemia, is likely to affect the cytosolic concentrations of free fatty acids and the corresponding acyl-CoA esters and thus may modulate the activity of KATP channels in cardiac muscle cells.
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Materials and Methods |
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Ventricular myocytes were isolated from guinea pig hearts using standard enzymatic techniques.15 For single-channel recording, high-resistance pipettes (16 to 20 M
) were used, and only patches containing one
KATP channel were analyzed. The pipette
solution contained (in mmol/L) KCl 145,
CaCl2 1, MgCl2 1, and
HEPES 5 (pH 7.4). The "intracellular" solution contained (in
mmol/L) KCl 150, EGTA 10, and HEPES 10 (pH 7.2). Single-channel
currents were recorded using an Axon Instruments 200B amplifier and
pClamp8 software (sampling rate, 10 kHz; filter, -3 dB at 2 kHz).
Stock solutions of LC acyl-CoA esters (1 mmol/L in water), fatty
acids (40 mmol/L in DMSO), and PIP2 (1
mmol/L in water) were stored at -80°C. Diluted solutions of LC
fatty acids and PIP2 were sonicated on ice for
15 minutes immediately before experiments.
For whole-cell recording, pipette resistances were 2
to 4 M. The pipette solution contained (in mmol/L) KCl 50,
potassium glutamate 65, MgCl2 7.9,
KH2PO4 10, EDTA 5, HEPES
5, K2-ATP 1.9, and
Na3-GTP 0.2 (pH 7.2). The extracellular bath
solution contained (in mmol/L) NaCl 140, KCl 5.4,
CaCl2 1, MgCl2 1,
NaH2PO4 0.33, glucose 10,
and HEPES 5 (pH 7.4). Oleate was solubilized using
methyl–ß-cyclodextrin (Sigma) at a 1:6 molar ratio. Control
experiments were carried out using fatty acid–free
methyl–ß-cyclodextrin (Sigma). All experiments were performed at
room temperature (20°C to 23°C). When appropriate, data are
reported as mean±SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effects of Oleoyl-CoA on Rundown of Cardiac KATP Channels
KATP channels in cardiomyocytes isolated from guinea pig heart were studied using the patch-clamp technique. Inside-out membrane patches were excised from the sarcolemma, and oleoyl-CoA was applied to the intracellular face of the membrane. High-resistance pipettes were used to obtain patches containing only one KATP channel. A typical recording of KATP channel activity after isolating a membrane patch into divalent-free solution containing 150 mmol/L K+ is shown in Figure 1A
. In this example, the open probability
(Po)
immediately after excision was 0.87 and then progressively decreased to
0.035 within 34 minutes, a recognized phenomenon termed
rundown.16 Superfusion of
the intracellular side of the patch with solution containing 1 µmol/L
oleoyl-CoA evoked rapid and complete recovery of channel activity
(Figure 1A). To assess whether oleoyl-CoA could prevent
channel rundown, we excised patches directly into solutions containing
oleoyl-CoA. With 0.2 µmol/L oleoyl-CoA at the intracellular face of
the patch, a constant and sustained level of channel activation
(Po,
0.85 to 0.89 at -60 mV) was observed for 30 minutes
(Figure 1B, 
). In one patch, no rundown was observed
for 90 minutes during application of 1 µmol/L oleoyl-CoA. In accord
with earlier
work,11 12 13 14
we found that PIP2 (5 µmol/L) also prevented
rundown (n=8;
Figure 1B, 
).
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When KATP channels were allowed to partially run down, we were able to fully restore channel activity by introducing either oleoyl-CoA (n=7) or PIP2 (n=6). However, once the KATP channels had completely run down (Po=0 for at least 5 minutes), they could not be reactivated by either oleoyl-CoA (n=5) or PIP2 (n=6). The mechanism of this apparently irreversible rundown is unknown. It may involve degradation of cytoskeleton elements17 that are known to be included in the inside-out patch.18
Although both oleoyl-CoA and PIP2
rapidly activated KATP channels after
partial rundown, their rate of washout was very slow. After a 15-minute
period of exposure to either of these molecules, almost no rundown of
KATP channels was observed during 30 minutes of
washout with divalent-free solution
(Figure 1B
, arrow). Without prior exposure to oleoyl-CoA or
PIP2, the time course of the rundown was widely
variable from patch to patch
(Figure 1B, inset). Considering the persistent effects of
endogenous molecules such as oleoyl-CoA and
PIP2, the scatter in the time course of the
rundown probably reflects variation in membrane-associated constituents
of the particular excised patch.
Effects of Oleoyl-CoA on the Kinetics of
KATP Channels
The ability of oleoyl-CoA to prevent rundown
facilitated detailed investigation of single-channel kinetics. In the
presence of oleoyl-CoA, the
Po of
KATP channels increased with depolarization
(Figures 2A and 2B, 
), the maximum of
Po was
reached at -20 mV. Both open time distribution and closed time
distribution could be fitted with a single exponential
(Figure 2C). The mean open time (•) increased with
depolarization; the mean closed time () decreased with
depolarization
(Figure 2D). The relation between
Po and
membrane potential measured during application of 5 µmol/L
PIP2 (
) was virtually identical to that
found during application of oleoyl-CoA
(Figure 2B). Having established the relation between
Po and
membrane potential under conditions in which rundown was prevented (by
oleoyl-CoA or PIP2), we tried to determine this
relation in the first 2 minutes after excision of the patch in the
absence of oleoyl-CoA (before rundown). Mean open time (Figure 2D, 
), mean closed time (Figure 2D, ), and
Po
(Figure 2B, •) observed under these conditions were similar to the
values observed in the presence of oleoyl-CoA. The additional long
closed state described
previously19 20 21
was not found in the first 2 minutes after excision of the patch (n=9)
but was clearly identifiable after partial rundown
(Figure 1A). The conductance of KATP
channels determined by linear regression of single-channel currents
measured between -120 and -40 mV
(Figure 2E) was the
same in the control group (85.3±1.1 pS; n=14) and with 1 µmol/L
oleoyl-CoA (85.7±0.94 pS; n=21) or with 5 µmol/L
PIP2 (87.2±1.1 pS; n=17).
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o; • and
Effects of Oleoyl-CoA on ATP
Sensitivity
In the presence of 1 µmol/L oleoyl-CoA, higher
concentrations of ATP were required to inhibit
KATP channels
(Figure 3A). ATP sensitivity reached a steady state within a
few minutes after excision of the patch in solutions containing 0.2, 1,
or 2 mmol/L oleoyl-CoA. No further change in
Po was
observed after repeated application and washout of ATP
(Figure 3B).
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Figure 4A illustrates the ATP dependence in the absence of
oleoyl-CoA determined immediately after excision of the patch. In the
first 2 minutes after excision, the half-maximal inhibitory
concentration (IC50) for ATP was 0.015
mmol/L
(Figure 4C), consistent with the 0.01 to
0.1 mmol/L range reported in the
literature.2 4 5
When oleoyl-CoA was present at a concentration of 0.2 µmol/L,
estimated to be the upper physiological free
concentration of acyl-CoA
esters,22 the
IC50 was shifted from 15 to 244 µmol/L ATP
(Figure 4C). Further increase of oleoyl-CoA concentration to
1 and 2 µmol/L produced, respectively, >60- and 200-fold increases
in IC50. Hence, at least in the native cardiac
myocyte, oleoyl-CoA is capable of profoundly reducing the ATP
sensitivity of sarcolemmal KATP
channels.
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, N=3.7).Because KATP channels have been reported to become insensitive to sulfonylurea drugs in the presence of PIP2,23 we also tested the effects of glibenclamide (10 µmol/L). We found that application of oleoyl-CoA (1 µmol/L) rendered KATP channels insensitive to the KATP channel blocker glibenclamide (n=3, not illustrated).
Differences Between the Effects of
Oleoyl-CoA and PIP2
The time course of the equilibration of oleoyl-CoA with
the membrane was studied using the protocol illustrated in
Figure 5A. One minute after excision of the patch, ATP
(1 mmol/L) and oleoyl-CoA (1 µmol/L) were applied and
mean Po
was recorded in 1-minute intervals (•; n=5). The
Po
stabilized at values of 
0.5 within 3 minutes after addition of
oleoyl-CoA. The same protocol was used to study the time course of the
equilibration of PIP2 (2 µmol/L; ; n=9).
The time course of the change in
Po,
which probably reflects the time course of the change in ATP
sensitivity,13 14
was substantially faster with oleoyl-CoA than with
PIP2.
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The effects of oleoyl-CoA on the
Po of
cardiac KATP channels were independent of
divalent cations, as illustrated in
Figure 5B. After activation by oleoyl-CoA, the
Po of
KATP channels was unaffected by application of
1 mmol/L Ca2+ (10 minutes observation;
n=7). Application of 1 mmol/L Ca2+ plus
1 mmol/L Mg2+ also had no effect (n=3;
not illustrated). Even after removal of oleoyl-CoA from the
superfusate, when the KATP channels
still had a very high
Po,
application of Ca2+ did not decrease
Po (n=4;
not illustrated). In contrast, the stimulatory effect of
PIP2 was completely blocked by 1 mmol/L
Ca2+ within 2 to 4 minutes (n=4;
Figure 5C). Removal of Ca2+ in
the continued presence of PIP2 restored channel
activity within 20 seconds (n=4).
Oleoyl-CoA did not affect cardiac inward-rectifier channels, which are most likely members of the Kir2 subfamily.24 When oleoyl-CoA was applied to a patch containing a single KATP channel together with a single Kir channel, activity of the latter channel ceased within 1 to 5 minutes, whereas the activity of the KATP channel persisted (n=11). In contrast, 5 µmol/L PIP2 prevented rundown of both inward-rectifier and KATP channels (n=5).
Effects of Free Fatty Acids on Cardiac
KATP Channels
Under physiological conditions,
oleoyl-CoA is synthesized from oleate. We therefore tested whether this
fatty acid affected channel function. KATP
channels activated by 1 µmol/L oleoyl-CoA were blocked by
intracellular application of 10 µmol/L oleate within 30 seconds
(Figure 6A; n=13). The
trans-isomer of oleate,
elaidate (10 to 20 µmol/L), exerted no inhibitory effect
(n=4; not shown). When a patch contained both a single
KATP and a single Kir2 channel (of which the
rundown was prevented by PIP2), oleate
selectively blocked the KATP channel (n=4). Once
complete oleate-induced block was attained, reversal of inhibition was
not observed during a 10- to 20-minute washout period. The channel
block also could not be reversed by application of 5 µmol/L
PIP2 in addition to 1 µmol/L oleoyl-CoA. The
poor reversibility of oleate was probably secondary to its slow rate of
washout from the patch lipid
bilayer.25
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Modulation of the cardiac KATP channel is not restricted to oleoyl-CoA and oleate. We found that 1 µmol/L palmitoleoyl-CoA (C16:1 acyl group) also activated single KATP channels after partial rundown and reduced ATP sensitivity (n=4; not shown). In another series of experiments, we compared the inhibitory effects of oleate (C18:1) with those of palmitoleate (C16:1). Palmitoleate (10 to 20 µmol/L) was less potent than oleate at inhibiting acyl-CoA ester–activated channels. At a concentration of 20 µmol/L, palmitoleate initially induced partial channel block, which converted to full block after 4 to 8 minutes of exposure (n=4; not shown).
Given the potent effects of oleoyl-CoA and oleate on
KATP activity in inside-out patches, we also
expected to see an effect in whole-cell recordings. After
failing to activate KATP channels in
whole-cell configuration with oleoyl-CoA in the pipette solution, we
superfused the cell with a water-soluble form of oleate. Application of
400 µmol/L oleate, solubilized with
methyl–ß-cyclodextrin,26
for 10 minutes had no effect on whole-cell currents
(Figure 6B). However, when oleate was washed out, the
current-voltage relation changed in a way typical for activation of
KATP channels
(Figure 6B), an effect that we refer to as the "washout
phenomenon." The outward current at 0 mV increased from 78±35 to
1688±287 pA (n=13). The delay to the maximal outward current
recorded was in the range 1.5 to 14 minutes; the median was 5.5
minutes. Because in most of the experiments the outward current
continued to rise until the cell was damaged (unless oleate was
reapplied), we do not know how long the increased outward current can
be maintained.
Reintroduction of oleate abolished the increase in outward
current and brought the current-voltage relation back to control (n=3).
The washout phenomenon was not observed when methyl–ß-cyclodextrin
alone was introduced and subsequently washed out (n=6; not shown). The
most likely explanation for these findings is that oleate diffused into
the cytosol of the cardiomyocytes and served as substrate
for acyl-CoA synthetase
(Figure 7). On washout, the concentration gradient for oleate
was reversed and it diffused out of the cell, allowing
membrane-impermeable oleoyl-CoA synthesized in the cell to
activate KATP channels by decreasing
their ATP sensitivity.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our findings show that the coupling between KATP channels and energy metabolism in the heart may be more complex than previously realized. The LC acyl-CoA esters oleoyl-CoA and palmitoleoyl-CoA shift the relation between ATP concentration and Po of KATP channels to higher ATP concentrations. This brings the half-maximal inhibitory concentrations of ATP closer to the physiological range and would facilitate the opening of KATP channels during periods of metabolic impairment, for example, under conditions of myocardial ischemia or hypoxia.
Recently, LC acyl-CoA esters have been shown to
activate native KATP channels in
inside-out patches excised from pancreatic ß
cells.7 Pancreatic and
cardiac KATP channels have the same subunits
(Kir6.2) but have different ß subunits: SUR1 in pancreatic ß cells
and SUR2A in
cardiomyocytes.5 27
The shift in the
ATP-Po
relation in cardiomyocytes reported here
(Figure 4C) is dramatically greater than the 2- to 3-fold
increase in IC50 induced by 1 µmol/L
oleoyl-CoA in pancreatic KATP channels
(Kir6.2/SUR1) expressed in
Xenopus
oocytes.9 Because truncated
Kir6.2 channels (Kir6.2
C36) were activated by oleoyl-CoA to
the same extent as pancreatic KATP channels, it
was concluded that the Kir6.2 subunit was the site of action of
oleoyl-CoA in
pancreas.8 9 The
much more dramatic action of oleoyl-CoA in native
cardiomyocytes suggests that the ß subunit SUR2A (but not
SUR1), or some other membrane-associated regulatory protein, may also
contribute to the effects of oleoyl-CoA on cardiac
KATP channels.
We also found that LC acyl-CoA esters prevented rundown
(Figure 1B) and reactivated
KATP channels after partial rundown
(Figure 1A) after excision of the patches. As long as
micromolar concentrations of oleoyl-CoA were present,
KATP channels exhibited sustained activity (not
interrupted by long closures) in the absence of ATP. Under these
conditions, the closed-time distribution could be fitted by a single
exponential, and the channels were insensitive to glibenclamide. These
findings are consistent with the idea that oleoyl-CoA may
induce a shift of the conformation of KATP
channels toward a ligand-insensitive
state,19 similar to the
effects of nucleoside diphosphates. Furthermore, our analysis
of the kinetics of cardiac KATP channels has
revealed a pronounced voltage dependence of the
Po
observed immediately after excision of the patch (before rundown) and
in the presence of oleoyl-CoA or
PIP2.
The effects of acyl-CoA esters and
PIP2 on KATP channels
share some interesting properties. (1) They have no effect on
Po
before rundown. (2) They nonetheless shift the ATP sensitivity under
these conditions, suggesting a change in ATP binding affinity. (3) They
prevent inhibition of KATP channels by
sulfonylureas. On the other hand, the effects of acyl-CoA esters and
PIP2 differ in several important aspects. (1)
The effects of oleoyl-CoA are not affected by changes in
[Ca2+]i
(Figure 5), in contrast to the effects of
PIP2.16
(2) The decrease in ATP sensitivity induced by oleoyl-CoA is relatively
rapid
(Figure 5), whereas PIP2 equilibrates
with KATP channels with a much slower time
course.13 14 (3)
The effects of oleoyl-CoA appear to be restricted to
KATP channels, given that oleoyl-CoA did not
prevent rundown of cardiac inward-rectifier channels; in contrast,
PIP2 activates various members of the
inward-rectifier channel family and prevents their
rundown.12 28 29
(4) It has been suggested that the effects of
PIP2 and other phosphatidylinositol phosphates
on KATP channels are related to the number of
negative charges of the head
group.10 12 13 14
Such an electrostatic mechanism cannot fully explain the effect of
oleoyl-CoA on ATP sensitivity. This is consistent with the
observation that the effect was not antagonized by divalent cations,
which would be expected to shield the negative charges. Taken together,
these data suggest that LC acyl-CoA esters and
PIP2 modulate KATP
channels via different mechanisms. Furthermore, because
PIP2 is mainly liberated via second-messenger
cascades, whereas the cytosolic concentrations of LC acyl-CoA esters
depend on cellular energy metabolism, the function of the
two ion channel modulators in cardiac muscle cells may also be quite
different.
During restriction of blood flow through the coronary arteries (myocardial ischemia), ß-oxidation of fatty acids is inhibited and accumulation of fatty acids and their metabolic intermediates readily occurs.30 The mechanisms underlying the redistribution of free fatty acids between different cellular pools are incompletely understood and strongly depend on the experimental conditions.31 During low-flow ischemia, the total cellular concentration of acyl-CoA esters in cardiac muscle rises within 5 minutes.30 31 During this time, action potential duration decreases, K+ efflux rises, and contractile function is disturbed without any concomitant change in bulk ATP concentration.32 It appears possible that the increase in acyl-CoA esters may contribute to the opening of KATP channels during the first 5 minutes of low-flow ischemia. The resulting shortening of the action potential would lead to a reduction in transsarcolemmal Ca2+ influx and to a decrease in both contractility and energy expenditure of cardiac muscle cells. Thus, the modulation of KATP channels by LC acyl-CoA esters may provide a mechanism to counterbalance energy supply and energy expenditure of the heart during the initial phase of low-flow ischemia.
We have found that KATP channels in guinea pig cardiomyocytes can be inhibited by the unsaturated fatty acids oleate and palmitoleate. These observations are consistent with a previous report33 describing inhibition of KATP channels in rat cardiomyocytes by the unsaturated fatty acids arachidonic, linoleic, and eicosatrienoic acid. Free fatty acids also accumulate during cardiac ischemia, but with a much slower time course than acyl-CoA esters.30 31 34 Interestingly, action potential duration also shows a spontaneous recovery after prolonged ischemia,32 35 which might be related to inhibition of KATP channels by LC fatty acids. It is not yet clear to what extent fatty acids accumulate during hypoxia or anoxia. Nevertheless, it is tempting to speculate that the delayed closure of KATP channels in cardiac muscle cells observed after prolonged substrate-free hypoxia36 may be attributable to accumulation of endogenous free fatty acids.
In conclusion, our results suggest that the principal metabolic substrates of the heart, acyl-CoA esters and free fatty acids, may link changes in myocardial energy metabolism to changes in the electrical activity of the heart by modulating the activity of ATP-sensitive potassium channels.
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Acknowledgments |
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This study was supported by the Ernst and Berta Grimmke Stiftung, the Deutsche Forschungsgemeinschaft (Grant Da177/7-3), and the P.E. Kempkes Stiftung.
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Footnotes |
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Original received December 28, 2000; revision received March 9, 2001; accepted March 9, 2001.
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References |
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