© 1996 American Heart Association, Inc.
Articles |
Protein Kinase C Activates ATP-Sensitive K+ Current in Human and Rabbit Ventricular Myocytes
From the Department of Medicine and Research Center, Montreal Heart Institute (G.-R.L., S.N.), the Department of Medicine, University of Montreal (G.-R.L., S.N.), and the Department of Pharmacology and Therapeutics, McGill University (K.H., D.D., S.N.), Montreal, Quebec, Canada.
Correspondence to Dr Stanley Nattel, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and Methods Results Discussion References |
|---|
Abstract Mediators involved in ischemic preconditioning, such as adenosine and norepinephrine, can activate protein kinase C (PKC), and a variety of observations suggest that both PKC and ATP-sensitive K+ current (IKATP) play essential roles in ischemic preconditioning. PKC is therefore a candidate to link receptor binding to IKATP activation, but it has not been shown whether and how PKC can activate IKATP in the heart. The present study was designed to determine whether PKC can activate IKATP in rabbit and human ventricular myocytes. Under conditions designed to minimize Na+ and Ca2+ currents, dialysis of rabbit ventricular myocytes with pipette solutions containing reduced [ATP] elicited IKATP, with a 50% effective concentration (EC50) of 260 µmol/L. In cells that failed to show IKATP under control conditions, superfusion with 1 µmol/L phorbol 12,13-didecanoate (PDD) elicited IKATP in a fashion that depended on pipette [ATP], with an [ATP] EC50 of 601 µmol/L. PDD-induced IKATP activation was concentration dependent, with an EC50 of 7.1 nmol/L. The highly selective PKC inhibitor bisindolylmaleimide totally prevented IKATP activation by PDD, and in blinded experiments, 1 µmol/L PDD elicited IKATP in eight of nine cells, whereas its non–PKC-stimulating analogue 4
-PDD failed to elicit
IKATP in any of the five cells tested (P=.003).
Similar experiments were conducted in human ventricular
myocytes and showed that 0.1 µmol/L PDD elicited IKATP at
pipette [ATP] of 100 and 400 µmol/L (five of five cells at each
concentration) but not at 1 mmol/L [ATP] (none of five cells). We
conclude that PKC activates IKATP in rabbit and
human ventricular myocytes by reducing channel sensitivity
to intracellular ATP. This finding has potentially important
implications for understanding the mechanisms of ischemic
preconditioning.
Key Words: ischemic preconditioning • myocardial ischemia • cardioprotection • myocardial infarction • G proteins
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and Methods Results Discussion References |
|---|
Ischemic preconditioning, the ability of brief ischemic episodes to protect the heart against subsequent prolonged ischemia, was first demonstrated in dogs by Murry et al1 in 1986 and has subsequently been shown to occur in a wide variety of species.2 3 The precise mechanisms of ischemic preconditioning remain to be elucidated. The KATP channel appears to play an important role in the cardioprotective effects of ischemic preconditioning in dogs,4 5 6 7 rabbits,8 pigs,9 and humans.10 More recent evidence points to an essential role of PKC in ischemic preconditioning.11 12 13 Since PKC can be activated by the stimulation of a variety of receptors involved in ischemic preconditioning, including
1-adrenoceptors13 and adenosine
receptors,4 6 7 14 PKC is a
strong potential candidate to
link receptors stimulated by mediators released during ischemia
to the activation of KATP channels. The purpose of the
present experiments was to determine whether PKC can
activate KATP channels, as determined by effects on
whole-cell currents in myocytes isolated from rabbit and human
ventricular tissue. |
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and Methods Results Discussion References |
|---|
Rabbit ventricular myocytes were isolated from adult New Zealand White rabbits (1.4 to 1.8 kg) by enzymatic dissociation, with methods similar to those previously described.15 In brief, hearts were excised and retrogradely perfused via the aorta with oxygenated (100% O2) Tyrode's solution containing (mmol/L) NaCl 126, KCl 5.4, CaCl2 1.0, MgCl2 1.0, NaH2PO4 0.33, HEPES 10, and glucose 10 at 37°C. The perfusate was then changed to a Tyrode's solution that was nominally Ca2+ free but otherwise had the same composition. When cardiac contraction had ceased, the hearts were perfused with the same solution containing collagenase (0.03%, type II, Sigma Chemical Co) and bovine serum albumin (1.0%, Sigma) for 7 to 9 minutes. Softened ventricular tissues were removed, cut into small pieces, and mechanically dissociated by trituration. The isolated cells were kept in a storage solution containing (mmol/L) KCl 20, KH2PO4 10, glucose 10, potassium glutamate 70, ß-hydroxybutyric acid 10, taurine 10, mannitol 5, and EGTA 5, along with 1% albumin.
Explanted hearts were obtained at the time of heart transplantation
from two patients, aged 31 and 54 years. In both patients, the
underlying heart disease was congestive
cardiomyopathy. Subsequent examination of the right
ventricle by a cardiac pathologist revealed each of the two to be
macroscopically normal, with microscopic abnormalities consisting of
interstitial fibrosis in one heart and subendocardial
fibrosis in the other. Both hearts were initially placed in cold
(4°C) oxygenated Krebs' solution and then transferred to
cardioplegic solution for dissection and coronary artery
cannulation. A portion of the free wall of the right ventricle (
2x4
to 2x5 cm) was removed along with the coronary artery branch
irrigating it, with dissection and arterial cannulation
completed within 20 minutes of excision of the heart. The free wall was
perfused with oxygenated nominally Ca2+-free
Tyrode's solution for 20 to 30 minutes. The solution was then changed
to one containing 200 to 300 U/mL collagenase (CLS II,
Worthington Biochemical) for 60 to 100 minutes. The digested tissue was
cut into small (1.5- to 2-mm3) pieces, placed in the
same high-K+ storage solution as used for rabbit cells, and
gently triturated with a Pasteur pipette. The isolated myocytes were
kept in the medium at least 1 hour before use.
All the cells studied were rod-shaped and showed clear cross
striations. A small aliquot of the solution containing the isolated
cells was placed in an open perfusion chamber (1 mL) mounted on the
stage of an inverted microscope. After they had adhered to the bottom
of the chamber, the cells were perfused at 3 mL/min with an
oxygenated solution containing (mmol/L) NaCl 135, KCl 5.4,
MgCl2 1.0, CaCl2 1.0,
NaH2PO4 0.33, HEPES 10, and glucose 10 at pH
7.4 (pH adjusted with NaOH). CdCl2 (0.2 mmol/L, Sigma) and
4-aminopyridine (2 mmol/L, Sigma) were added to the
external solution to inhibit Ca2+ current and transient
outward current, respectively. All experiments were conducted at room
temperature (22°C to 25°C). The pipette solution contained (mmol/L)
KCl 140, MgCl2 1.0, HEPES 10, EGTA 5, and GTP 0.1 at pH 7.3
(pH adjusted with KOH). Varying amounts of K2ATP were added
to pipette solutions to obtain the final concentrations desired. The
PKC activator PDD and its non–PKC-stimulating homologue
4-PDD were purchased from ICN Biochemicals. PDD, 4-PDD, and the
IKATP blocker glibenclamide (glyburide, Sigma) were
prepared as stock solutions in DMSO at concentrations of 1 mmol/L
for PDD and 4-PDD and 10 mmol/L for glibenclamide. The highly
selective PKC inhibitor BIM hydrochloride16
was obtained from Calbiochem-Novabiochem International and prepared as
a stock solution of 0.75 mmol/L in DMSO.
Membrane currents were studied with the whole-cell configuration of
the voltage-clamp technique. Data were sampled at 13.3 kHz with an
A/D converter (Digidata 1200, Axon Instruments) and stored on the hard
disk of a computer for subsequent analysis. The
recordings were filtered with a low-pass corner frequency
of 2 kHz. Borosilicate glass electrodes (outer diameter, 1.5 mm) with
resistances of 2 to 5 M
when filled were connected to a
patch-clamp amplifier (Axopatch 200A, Axon Instruments). Junction
potentials were zeroed before the pipette touched the cell. The cell
membrane was held at -40 mV, and 100-millisecond voltage steps to
potentials between -100 and +60 mV were applied at 0.5 Hz in
10-mV increments. Pipette series resistance was compensated to minimize
the duration of the capacitive transient upon 5 mV
hyperpolarizations from -40 mV. Mean series
resistance before and after compensation averaged 6.86±0.36
(mean±SE)
and 2.56±0.16 M, respectively, in rabbit cells and
6.80±0.37 and
2.59±0.15 M, respectively, in human cells. The capacitive time
constant averaged 710±50 microseconds (capacitance, 103.8±7.0
pF)
before and 240±20 microseconds after capacitance compensation in
rabbit myocytes. Corresponding values in human myocytes were 770±20
microseconds (capacitance, 120.0±6.4 pF) and 290±10
microseconds.
To allow sufficient time for dialysis of cell contents by the pipette solution, the first control recordings were obtained at least 10 minutes after membrane rupture. Currents were measured at the end of each clamp step, as a value relative to zero current. Leakage compensation was not used. IKATP was defined as a current that reversed between -90 and -70 mV, showed inward rectification at potentials positive to 0 mV, was associated with a positive shift in holding current at -40 mV, and was strongly inhibited by 10 µmol/L glibenclamide.
Data are presented as mean±SE. Repeated measures comparisons were performed by ANOVA with Scheffé's range test. Contingency data were analyzed with Fisher's exact test. Differences with a two-tailed value of P<.05 were considered statistically significant. Nonlinear curve fitting of concentration-response data was performed with commercially available software that uses a Marquardt procedure for parameter estimation (Sigmaplot, Jandel Scientific).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and Methods Results Discussion References |
|---|
Effects of PKC Activation on IKATP in Rabbit Ventricular Myocytes
Fig 1A
illustrates the effects of
0.1 µmol/L PDD
on currents recorded from a typical rabbit myocyte in the presence
of 400 µmol/L ATP in the pipette. Twenty minutes after membrane
rupture, there was no evidence of spontaneous activation of
IKATP, and the currents recorded showed strong
inward rectification (Fig 1A, a). Within 3 minutes of exposure
to PDD,
a large increase in membrane conductance was observed. Currents in the
presence of PDD (Fig 1A, b) continued to show some inward
rectification, but the latter was less intense than under control
conditions. The addition of 10 µmol/L glibenclamide strongly and
rapidly reversed the conductance-enhancing effects of PDD (Fig
1A,
c). Fig 1B shows the I-V relations from the same cell. Under
control
conditions, the current reverses at -80 mV and shows strong
inward rectification. In the presence of PDD, the reversal potential is
-75 mV, and the slope conductance increases. In contrast to
control conditions, under which strong inward rectification begins at
the reversal potential, rectification is less intense and begins closer
to 0 mV. Glibenclamide strongly inhibits PDD-induced currents and
returns the I-V relation to a pattern resembling that seen under
control conditions.
|
and 
, five cells) or without
(
, four cells) exposure to 1 µmol/L PDD beginning 20 minutes
after the onset of recording. The currents (measured relative
to zero current) were elicited by steps (100 milliseconds) from
-40 to 0 mV. Step current was significantly increased by PDD, an
action inhibited by GLIB (**P<.01 vs CTRL).
Fig 1C
shows the time course of mean
(±SE) currents recorded upon
depolarization to 0 mV from five cells exposed to PDD 20 minutes after
the onset of recording and from four control cells followed in
an identical fashion without PDD. In the absence of PDD, there was no
change in current amplitude over 20 minutes, and cells not exposed to
PDD showed no change in current over the subsequent 15 minutes.
Currents over the first 20 minutes were not different in control cells
compared with cells subsequently exposed to 1 µmol/L PDD. Within 5
minutes of the addition of PDD, however, a marked increase in current
was noted. After 10 minutes of superfusion with PDD alone (30 minutes
after the onset of recording), 10 µmol/L glibenclamide was
added to the PDD-containing superfusate. A marked reduction
in current toward control values was observed within 5 minutes. Note
that a reduction in current was seen even before glibenclamide
exposure. In three cells followed for an additional 10 minutes in the
presence of PDD without exposure to glibenclamide, the current
decreased from a peak value of 3.6±0.7 to 1.4±0.2 nA.
Nevertheless,
the latter value was substantially larger than currents in cells
exposed to glibenclamide in the presence of PDD for a comparable period
of time (mean current, 0.35±0.08 nA; P=.001),
indicating
that the response to glibenclamide cannot be attributed to current
rundown.
PDD did not result in IKATP activation when
[ATP]p was >1 mmol/L, suggesting that the compound
shifts the sensitivity of the current to intracellular ATP rather than
activating it directly. To evaluate further the dependence of PDD
action on [ATP]i, we determined the frequency of
IKATP activation in cells studied with a variety of
[ATP]p in the presence and absence of 1 µmol/L PDD.
IKATP was defined as described in "Materials and
Methods." All cells not exposed to PDD were followed for at least 20
minutes, because in our experience, if IKATP is not
activated spontaneously within 20 minutes of recording,
it fails to activate thereafter in the absence of
interventions. Cells exposed to PDD were followed for at least 20
minutes before exposure to ensure that there was no spontaneous
IKATP activation. The results are shown in Fig 2A.
Under control conditions, 16 of 21 cells (76%)
showed spontaneous IKATP activation at [ATP]p
of 100 µmol/L. At [ATP]p of 200 µmol/L, 6 of 11
cells (55%) showed IKATP. In the presence of PDD, all 10
cells at either of these [ATP]p levels showed
IKATP. When [ATP]p was increased to 400
µmol/L, PDD resulted in IKATP activation in 80% of
cells, whereas spontaneous IKATP activation was seen in
only 16% of cells. As [ATP]p was increased further, the
prevalence of IKATP activation by PDD decreased, and no
IKATP activation occurred at [ATP]p of 1
mmol/L. The data shown in Fig 2A were fitted to the equation
given in
the figure legends, providing the curves shown in the figure. In the
absence of PDD, the [ATP]p associated with a 50% maximal
incidence of IKATP activation was 260 µmol/L. The
half-maximal prevalence of IKATP activation by PDD
occurred at [ATP]p of 601 µmol/L. The Hill
coefficient
was increased by 47% (from 3.0 to 4.4) in the presence of PDD,
compatible with a small change in cooperativity. These results show
that PDD activates IKATP in a fashion that depends
on [ATP]i and suggest that PDD acts by modifying the
sensitivity of the channel receptor for ATP.
|
) of 1 µmol/L PDD. Kd values
for [ATP]p in control (CTRL) and PDD groups were 260 and
601 µmol/L, respectively, and the Hill coefficients were 2.97 and
4.36, respectively. B, Concentration-response curves for
PDD-induced IKATP activation at [ATP]p of 400
µmol/L. The Kd for PDD is 7.1 nmol/L.
We further characterized
the actions of PDD by studying the
concentration dependence of PDD-induced IKATP activation.
Cells that showed no spontaneous IKATP activation over 20
minutes of observation in the presence of 400 µmol/L
[ATP]p were exposed to PDD at each of the concentrations
shown in Fig 2B, with one drug concentration studied for each
cell. The
prevalence of IKATP activation was a function of PDD
concentration, with a half-maximal effective concentration
(EC50) of 7.1 nmol/L and near-maximal effects seen at a
concentration of 100 nmol/L.
To establish the role of PKC in
IKATP activation by PDD, we
performed the experiments illustrated in Fig 3. We first
evaluated the changes in PDD action caused by the highly selective PKC
inhibitor BIM. Cells showing no spontaneous
IKATP in the presence of 400 µmol/L [ATP]p
were exposed to 30 nmol/L BIM. Five minutes later, PDD was added to the
superfusate at a concentration of 100 nmol/L. As shown in
Fig 3A, BIM had no effect on membrane currents but fully
prevented
IKATP activation by PDD. Similar results were obtained in
all five cells studied with this protocol. In the next series of
experiments, we compared the effects of PDD at the maximal
concentration used (1 µmol/L) with those of the inactive congener
4-PDD at the same concentration. These experiments were performed in
a blinded fashion, with coded stock solutions of either PDD or 4-PDD
prepared by a third party, so that the investigators were unaware of
the identity of the solutions until the series of experiments was
completed. Although PDD activated IKATP in eight of
nine cells, 4-PDD failed to elicit IKATP in any of the
five cells to which it was administered (P=.003 versus PDD,
Fisher's exact test). Fig 3B shows currents before and
after exposure
to 4-PDD in a typical experiment.
|
Activation of IKATP by PDD in Human
Ventricular Myocytes
To determine the potential relevance of our
findings to humans, we
studied the effects of PDD superfusion on human ventricular
myocytes. Myocytes without spontaneous IKATP after 20
minutes of observation were exposed to 100 nmol/L PDD for 10 minutes,
and then 10 µmol/L glibenclamide was added to the
superfusate. Fig 4A shows an example from a
typical cell studied at [ATP]p of 400 µmol/L. Under
control conditions (Fig 4A, a), inwardly rectifying currents
were seen
at potentials negative to 0 mV, and an outwardly rectifying current was
present at more positive potentials. A small transient outward
current was also present, consistent with previous reports
of incomplete block of this current by 2 mmol/L
4-aminopyridine in human atrium.17 Five
minutes after PDD was added to the superfusate, a
substantial increase in membrane conductance was noted (Fig 4A,
b).
Five minutes after the addition of glibenclamide, there was strong
inhibition of the conductance induced by PDD (Fig 4A, c). Fig
4B shows
the I-V relations for the cell whose results are presented in
Fig 4A. In the presence of PDD, large outward currents that
rectify
inwardly at voltages positive to +10 mV were seen, and the reversal
potential was -75 mV. Glibenclamide returned the I-V relation
to a form resembling that under control conditions, with a decrease in
current amplitudes. Mean currents recorded at 0 mV are shown in Fig
4C for human cells studied with this protocol: five cells at
[ATP]p of 100 µmol/L and five cells at
[ATP]p of 400 µmol/L. PDD caused significant
increases
in current, which were reversed almost completely by the addition of
glibenclamide. In five additional cells studied at [ATP]p
of 1 mmol/L, PDD failed to activate IKATP in any,
indicating that in human cells, as in the rabbit, PDD only
activates IKATP at reduced
[ATP]i.
|
), and during exposure
to both PDD and GLIB ( |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and Methods Results Discussion References |
|---|
We have shown that a PKC-activating phorbol ester (PDD) induces currents with properties of IKATP at reduced [ATP]i in rabbit and human ventricular myocytes. The effect is related to [PDD] (EC50 of 7.1 nmol/L) and is mediated by the activation of PKC, as indicated by the lack of effect of a high concentration of a structural analogue without PKC-stimulating properties (4
-PDD) and by the ability of a PKC
inhibitor to prevent IKATP activation. These
results indicate that PKC-induced phosphorylation can
activate IKATP and thereby provide a link between
ligands that bind to PKC-coupled membrane receptors and
IKATP-mediated cardioprotection induced by ischemic
preconditioning.
Potential Role of PKC in Modulating IKATP
A
variety of lines of evidence suggest that PKC may couple
receptor stimulation to IKATP activation. Ischemic
preconditioning in dogs, swine, and rabbits appears to be due to the
activation of IKATP resulting from adenosine
receptor
stimulation.6 7 8 9 14
Inhibition of PKC prevents
ischemic preconditioning in rabbit hearts,11
suggesting that PKC is an essential mediator for ischemic
preconditioning mediated by adenosine receptor stimulation. A
recent publication indicates that repeated acetylcholine exposure
activates IKATP by a PKC-mediated
mechanism.18
PKC has been shown to regulate IKATP activity in insulinoma cells.19 20 21 Two studies demonstrated that IKATP was activated by phorbol esters,19 20 whereas one study showed inhibition.21 Recently, Light et al22 showed that brief exposure to a purified constitutively active preparation containing four PKC isoforms inhibited IKATP in inside-out patches from rabbit ventricle, while reducing the Hill coefficient from 2.2 to 1.2 without changing the Ki for ATP.22 The change in Hill coefficient suggests that, at ATP concentrations >100 µmol/L, PKC should increase IKATP, a prediction confirmed in subsequent experiments (P. Light and R. French, personal communication) and consistent with our results. Recent studies by Dunne23 also demonstrate that PKC can either increase or decrease IKATP. The latter showed that short exposure of permeabilized insulinoma cells to PMA inhibits IKATP, whereas longer exposures (>5 minutes) produce important stimulation. It is probable that there is variability in the effect of different PKC isoforms, with the net response observed depending on the mix of isoforms present and/or activated by an intervention, experimental conditions, and the relative time course of inhibitory and stimulatory actions. We did not observe inhibitory actions in our experiments, but we did not study very low ATP concentrations (<100 µmol/L) and the effects of brief exposure to PDD, conditions that would have favored the demonstration of inhibitory effects of PKC. The present study is the first of which we are aware demonstrating directly that PKC activates IKATP in cardiac ventricular myocytes. Since PKC acted by shifting IKATP sensitivity to [ATP]i, this mechanism would be expected to operate only under conditions of reduced high-energy phosphate concentration, such as in acute myocardial ischemia.
Kirsch et al24 were the first to show that
activated -subunits of inhibitory G proteins
can stimulate IKATP, an action that occurs under
conditions of reduced [ATP]i. Ito et al25
subsequently showed that muscarinic receptor stimulation can similarly
activate IKATP channels. Terzic et
al26 showed that exogenous G protein subunits and
adenosine or acetylcholine (in the presence of GTP)
activate IKATP in inside-out patches from
guinea pig ventricles, but only in the presence of ATP at reduced
[ATP]i. More recently, Ito et al27
demonstrated that GTP-
-S in the bath activates
IKATP in inside-out patches from guinea pig
ventricular myocytes by shifting the EC50 for
ATP inhibition of channel opening from 19.5 to 110 µmol/L without
changing the Hill coefficient. Bath application of GTP in the presence
of pipette adenosine or acetylcholine activated
IKATP in a way similar to GTPS. In many systems, the
actions of inhibitory G proteins are mediated by the
activation of phospholipase C and PKC,28 and PKC mediates
pertussis toxin–sensitive G protein–dependent preconditioning
in rabbit and rat hearts.11 13 29
Therefore, it is
possible that there is an important cardioprotective signal
transduction system involving the activation of membrane receptors by
ligands (adenosine, acetylcholine, and -receptor
agonists) that are coupled by inhibitory G proteins to PKC,
which in turn activates IKATP in settings of
impaired myocardial metabolism that cause reduced
[ATP]i.
Potential Importance of Our Findings
A variety of factors are
known to modulate IKATP
activity by decreasing the sensitivity of the channel to
[ATP]i. These include intracellular concentrations of
ADP, protons and lactate, metabolic inhibition, and
K+ channel
openers.30 31 32 33 34
The present study
adds an additional potential modulator to this list. PKC differs from
previously described modulators of IKATP in being part of
the signal transduction system for endogenous ligands
released during acute myocardial ischemia, making it a
potential mediator for endogenous cardioprotective
mechanisms like ischemic preconditioning.
Ischemic preconditioning occurs in humans,35 36 37 and there is evidence that it plays a role in limiting infarct size among patients who experience angina before their infarctions.38 39 Clinically important manifestations of ischemic preconditioning are likely to occur in a variety of other situations.3 Both endogenous adenosine receptor stimulation37 and IKATP activation10 appear to be essential for ischemic preconditioning to occur in humans, as is the case for rabbits. Adenosine receptor blockade and inhibition of PKC block ischemic preconditioning in rabbit cardiomyocytes in vitro.40 Our observation that PKC activates IKATP in rabbit ventricular myocytes sheds light on the mechanism of these previous findings by suggesting that PKC may be the mechanism underlying IKATP activation. Since we observed comparable phenomena in human ventricular myocytes, it is quite possible that PKC plays a similar role in linking adenosine receptor activation to IKATP in humans.
Potential Limitations
We used the whole-cell patch-clamp
method for these
experiments, as have many previous investigators studying
IKATP.34 41 42 This system has
the advantage
of stability and relative lack of IKATP rundown, which is
common in excised-patch single-channel
experiments.43 On the other hand, the whole-cell
system has a number of important limitations that must be recognized.
PKC activation must be produced indirectly by phorbol esters, requiring
careful controls with PKC inhibitors and inactive
analogues. The intracellular milieu is controlled by dialysis of
pipette contents, which requires time to achieve a steady state and
results in some uncertainty about precise intracellular contents.
Finally, at positive voltages, the very large currents carried by
IKATP can result in a significant voltage drop across the
series resistance and impaired voltage control. We dealt with the
latter by performing all statistical analyses on the basis of
current elicited by a depolarization from -40 to 0 mV, during
which voltage control was always adequate.
We found that
IKATP induced by PDD showed rundown over
time. Possible contributing mechanisms may include the spontaneous
rundown of IKATP channels,43 a
time-dependent desensitization to PDD, and deleterious effects of
large transmembrane currents passed in the presence of
IKATP on membrane and/or cellular function. In addition,
time-dependent currents such as the inward rectifier K+
current at negative voltages and inward tail currents upon return from
negative potentials to the holding potential decreased when
IKATP was activated (eg, see Fig 1A, b, and Fig
4A,
b). Inward tails partially recovered when IKATP was
inhibited with glibenclamide, but time-dependent currents at
negative potentials showed little, if any, recovery (Fig 1A, c,
and Fig 4A, c). These types of changes were noted in all
experiments. In the
absence of IKATP activation, currents remained stable over
time (eg, see Fig 3A and 3B). Changes in
time-dependent currents in
the presence of IKATP may reflect channel cross talk,
direct effects of large currents on the membrane and/or cell, or other
unidentified mechanisms. The mechanisms underlying these changes and
their potential relevance to ischemic preconditioning remain to
be established in future work.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported by operating grants from the Medical Research Council of Canada, the Quebec Heart Foundation, and the Fonds de Recherche de l'Institut de Cardiologie de Montréal. Dr Li is a Fonds de la Recherche en Santé du Québec (FRSQ) Research Scholar. Dr Duan was supported by a Medical Research Council postgraduate studentship. The authors thank Ling-Yu Ye for technical assistance, Dr Carrier for help in obtaining human ventricular tissue samples, and Luce Bégin for secretarial help with the manuscript.
Received August 8, 1995; accepted November 30, 1995.
|
References |
|---|
|
TopAbstractIntroductionMaterials and Methods Results Discussion References |
|---|
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124-1136.
2. Downey JM. Ischemic preconditioning: nature's own cardioprotective intervention. Trends Cardiovasc Med. 1992;2:170-176.
3. Kloner RA, Yellon D. Does ischemic preconditioning occur in patients? J Am Coll Cardiol. 1994;24:1133-1142. [Abstract]
4.
Grover GJ, Sleph PG, Dzwonczyk S. Role of
myocardial ATP-sensitive potassium channels in mediating
preconditioning in the dog heart and their possible interaction with
adenosine A1-receptors.
Circulation. 1992;86:1310-1316.
5.
Gross GJ, Auchampach JA. Blockade of
ATP-sensitive potassium channels prevents myocardial preconditioning in
dogs. Circ Res. 1992;70:223-233.
6.
Auchampach JA, Gross GJ. Adenosine
A1 receptors, KATP channels, and
ischemic preconditioning in dogs. Am J
Physiol. 1993;264:H1327-H1336.
7.
Yao Z, Gross GJ. A comparison of
adenosine-induced cardioprotection and ischemic
preconditioning in dogs: efficacy, time course, and role of
KATP channels. Circulation. 1994;89:1229-1236.
8.
Walsh RS, Tsuchida A, Daly JJF, Thornton JD, Cohen MV,
Downey JM. Ketamine-xylazine anaesthesia permits a
KATP channel antagonist to attenuate
preconditioning in rabbit myocardium.
Cardiovasc Res. 1994;28:1337-1341.
9.
Van Winkle DM, Chien GL, Wolff RA, Soifer BE, Kuzume
K, Davis RF. Cardioprotection provided by adenosine
receptor activation is abolished by blockade of the KATP
channel. Am J Physiol. 1994;266:H829-H839.
10.
Tomai F, Crea F, Gaspardone A, Versaci F, De Paulis R,
Penta de Peppo A, Chiariello L, Gioffrè PA.
Ischemic preconditioning during coronary angioplasty is
prevented by glibenclamide, a selective ATP-sensitive K+
channel blocker. Circulation. 1994;90:700-705.
11.
Ytrehus K, Liu Y, Downey JM. Preconditioning
protects ischemic rabbit heart by protein kinase C
activation. Am J Physiol. 1994;266:H1145-H1152.
12.
Mitchell MB, Meng X, Ao L, Brown JM, Harken AH,
Banerjee A. Preconditioning of isolated rat heart is mediated by
protein kinase C. Circ Res. 1995;76:73-81.
13.
Hu K, Nattel S. Mechanisms of ischemic
preconditioning in rat hearts: involvement of
1B-adrenoceptors, pertussis toxin–sensitive G
proteins, and protein kinase C.
Circulation. 1995;92:2259-2265.
14.
Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson
RA, Downey JM. Protection against infarction afforded by
preconditioning is mediated by A1 adenosine
receptors in rabbit heart. Circulation. 1991;84:350-356.
15.
Duan D, Fermini B, Nattel S. Potassium channel
blocking properties of propafenone in rabbit atrial myocytes.
J Pharmacol Exp Ther. 1993;264:1113-1123.
16.
Toullec D, Pianetti P, Coste H, Bellevergue P,
Grand-Perret T, Ajakane M, Baudet V, Boissin P, Boursier E, Loriolle F,
Duhamel L, Charon D, Kirilovsky J. The bisindolylmaleimide GF
109203X is a potent and selective inhibitor of protein
kinase C. J Biol Chem. 1991;266:15771-15781.
17.
Wang Z, Fermini B, Nattel S. Effects of
flecainide, quinidine, and 4-aminopyridine on transient
and sustained outward currents in human atrial myocytes.
J Pharmacol Exp Ther. 1995;272:184-196.
18.
Wang YG, Lipsius SL. Acetylcholine
activates a glibenclamide-sensitive K+ current
in cat atrial myocytes. Am J Physiol. 1995;268:H1322-H1334.
19. Müller M, Szewczyk A, De Weille JR, Lazdunski M. ATP-sensitive K+ channels in insulinoma cells are activated by nonesterified fatty acids. Biochemistry. 1992;31:4656-4661. [Medline] [Order article via Infotrieve]
20.
De Weille JR, Schmid-Antomarchi H, Fosset M, Lazdunski
M. Regulation of ATP-sensitive K+ channels in
insulinoma cells: activation by somatostatin and kinase C, the role of
cAMP. Proc Natl Acad Sci U S A. 1989;86:2971-2975.
21. Wollheim CB, Dunne MJ, Peter-Reisch B, Bruzzone R, Pozzan T, Petersen OH. Activators of protein kinase C depolarize insulin-secreting cells by closing K+ channels. EMBO J. 1988;7:2443-2449. [Medline] [Order article via Infotrieve]
22. Light PE, Allen BG, Walsh MP, French RJ. Regulation of adenosine triphosphate-sensitive potassium channels from rabbit ventricular myocytes by protein kinase C and type 2a protein phosphatase. Biochemistry. 1995;34:7252-7257. [Medline] [Order article via Infotrieve]
23.
Dunne MJ. Phorbol myristate acetate and
ATP-sensitive potassium channels in insulin-secreting
cells. Am J Physiol. 1994;267:C501-C506.
24.
Kirsch GE, Codina J, Birnbaumer L, Brown AM.
Coupling of ATP-sensitive K+ channels to A1
receptors by G proteins in rat ventricular
myocytes. Am J Physiol. 1990;259:H820-H826.
25.
Ito H, Tung RT, Sugimoto T, Kobayashi I, Takahashi K,
Katada T, Ui M, Kurachi Y. On the mechanism of G protein ß
subunit activation of the muscarinic K+ channel in guinea
pig atrial cell membrane. J Gen Physiol. 1992;99:961-983.
26. Terzic A, Tung RT, Inanobe A, Katada T, Kurachi Y. G proteins activate ATP-sensitive K+ channels by antagonizing ATP-dependent gating. Neuron. 1994;12:885-893. [Medline] [Order article via Infotrieve]
27. Ito H, Vereecke J, Carmeliet E. Mode of regulation by G protein of the ATP-sensitive K+ channel in guinea-pig ventricular cell membrane. J Physiol. 1994;478.1:101-108.
28. Martin TFJ. Receptor regulation of phosphoinositidase C. In: Taylor CW, ed. Intracellular Messengers. Oxford, UK: Pergamon Press; 1993:63-87.
29. Thornton JD, Liu GS, Downey JM. Pretreatment with pertussis toxin blocks the protective effects of preconditioning: evidence for a G-protein mechanism. J Mol Cell Cardiol. 1993;25:311-320. [Medline] [Order article via Infotrieve]
30. Findlay I. Effects of ADP upon the ATP-sensitive K+ channel in rat ventricular myocytes. J Membr Biol. 1988;101:83-92. [Medline] [Order article via Infotrieve]
31.
Deutsch N, Weiss JN. ATP-sensitive
K+ channel modification by metabolic inhibition
in isolated guinea-pig ventricular myocytes.
J Physiol (Lond). 1993;465:163-179.
32. Keung EC, Li Q. Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes. J Clin Invest. 1991;88:1772-1777.
33.
Fan Z, Makielski JC. Intracellular
H+ and Ca2+ modulation of trypsin-modified
ATP-sensitive K+ channels in rabbit ventricular
myocytes. Circ Res. 1993;72:715-722.
34.
Nakayama K, Fan Z, Marumo F, Hiraoka M.
Interrelation between pinacidil and intracellular ATP concentrations on
activation of the ATP-sensitive K+ current in guinea pig
ventricular myocytes. Circ
Res. 1990;67:1124-1133.
35.
Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW Jr,
Herrmann HC, Laskey WK. Adaptation to ischemia during
percutaneous transluminal coronary angioplasty:
clinical, hemodynamic, and metabolic
features. Circulation. 1990;82:2044-2051.
36. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet. 1993;342:276-277. [Medline] [Order article via Infotrieve]
37. Walker DM, Walker JM, Pugsley WB, Pattison CW, Yellon DM. Preconditioning in isolated superfused human muscle. J Mol Cell Cardiol. 1995;27:1349-1357.[Medline] [Order article via Infotrieve]
38.
Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti
P, Pantoli D, Rusticali F. Prodromal angina limits infarct size:
a role for ischemic preconditioning.
Circulation. 1995;91:291-297.
39.
Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L,
Matthews RV, Burstein S, Gibson CM, Poole WK, Cannon CP, McCabe CH,
Braunwald E, for the TIMI 4 investigators. Previous angina alters
in-hospital outcome in TIMI 4: a clinical correlate to
preconditioning? Circulation. 1995;91:37-47.
40. Armstrong S, Ganote CE. In vitro ischaemic preconditioning of isolated rabbit cardiomyocytes: effects of selective adenosine receptor blockade and calphostin C. Cardiovasc Res. 1995;29:647-652. [Medline] [Order article via Infotrieve]
41.
Arena JP, Kass RS. Enhancement of potassium
sensitive current in heart cells by pinacidil: evidence for modulation
of the ATP-sensitive potassium channel. Circ
Res. 1989;65:436-445.
42. Ogbaghebriel A, Shrier A. Differential responsiveness of atrial and ventricular myocytes to potassium channel openers. J Cardiovasc Pharmacol. 1995;25:65-74. [Medline] [Order article via Infotrieve]
43.
Takano M, Qin D, Noma A. ATP-dependent decay and
recovery of K+ channels in guinea pig cardiac
myocytes. Am J Physiol. 1990;258:H45-H50.
This article has been cited by other articles:
 |
|
 |
|
  V. Garg, J. Jiao, and K. Hu Regulation of ATP-sensitive K+ channels by caveolin-enriched microdomains in cardiac myocytes Cardiovasc Res, April 1, 2009; 82(1): 51 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Jiao, V. Garg, B. Yang, T. S. Elton, and K. Hu Protein Kinase C-{epsilon} Induces Caveolin-Dependent Internalization of Vascular Adenosine 5'-Triphosphate-Sensitive K+ Channels Hypertension, September 1, 2008; 52(3): 499 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-D. Jiao, V. Garg, B. Yang, and K. Hu Novel functional role of heat shock protein 90 in ATP-sensitive K+ channel-mediated hypoxic preconditioning Cardiovasc Res, January 1, 2008; 77(1): 126 - 133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Mosca Cardioprotective effects of stretch are mediated by activation of sarcolemmal, not mitochondrial, ATP-sensitive potassium channels Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1007 - H1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Garg and K. Hu Protein kinase C isoform-dependent modulation of ATP-sensitive K+ channels in mitochondrial inner membrane Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H322 - H332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Traverse, Y. Chen, M. Hou, Y. Li, and R. J. Bache Effect of K+ATP Channel and Adenosine Receptor Blockade During Rest and Exercise in Congestive Heart Failure Circ. Res., June 8, 2007; 100(11): 1643 - 1649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Spear, S. K. Prabu, D. Galati, H. Raza, H. K. Anandatheerthavarada, and N. G. Avadhani beta1-Adrenoreceptor activation contributes to ischemia-reperfusion damage as well as playing a role in ischemic preconditioning Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2459 - H2466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Hausenloy and D. M. Yellon Survival kinases in ischemic preconditioning and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 240 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Prabu, H. K. Anandatheerthavarada, H. Raza, S. Srinivasan, J. F. Spear, and N. G. Avadhani Protein Kinase A-mediated Phosphorylation Modulates Cytochrome c Oxidase Function and Augments Hypoxia and Myocardial Ischemia-related Injury J. Biol. Chem., January 27, 2006; 281(4): 2061 - 2070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Turner, K. Fujimoto, A. Suzuki, A. Stadnicka, Z. J. Bosnjak, and W.-M. Kwok The Interaction of Isoflurane and Protein Kinase C-Activators on Sarcolemmal KATP Channels Anesth. Analg., June 1, 2005; 100(6): 1680 - 1686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ye, W. Zhou, and H.-C. Lee Activation of rat mesenteric arterial KATP channels by 11,12-epoxyeicosatrienoic acid Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H358 - H364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. V. Quinn, Y. Cui, J. P. Giblin, L. H. Clapp, and A. Tinker Do Anionic Phospholipids Serve as Cofactors or Second Messengers for the Regulation of Activity of Cloned ATP-Sensitive K+ Channels? Circ. Res., October 3, 2003; 93(7): 646 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Irie, J. Gao, G. R. Gaudette, I. S. Cohen, R. T. Mathias, A. E. Saltman, and I. B. Krukenkamp Both Metabolic Inhibition and Mitochondrial KATP Channel Opening Are Myoprotective and Initiate a Compensatory Sarcolemmal Outward Membrane Current Circulation, September 9, 2003; 108(90101): II-341 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Saltman, T. O. Aksehirli, V. Valiunas, G. R. Gaudette, N. Matsuyama, P. Brink, and I. B. Krukenkamp Gap junction uncoupling protects the heart against ischemia J. Thorac. Cardiovasc. Surg., August 1, 2002; 124(2): 371 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Pagel, J. G. Krolikowski, F. Kehl, B. Mraovic, J. R. Kersten, and D. C. Warltier The Role of Mitochondrial and Sarcolemmal KATP Channels in Canine Ethanol-Induced Preconditioning In Vivo Anesth. Analg., April 1, 2002; 94(4): 841 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Pouzet, J.-B. Lecharny, M. Dehoux, S. Paquin, M. Kitakaze, J. Mantz, and P. Menasche Is there a place for preconditioning during cardiac operations in humans? Ann. Thorac. Surg., March 1, 2002; 73(3): 843 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Nakano, S. Suga, T. Takeo, Y. Ogawa, T. Suda, T. Kanno, and M. Wakui Intracellular Ca2+ Modulation of ATP-Sensitive K+ Channel Activity in Acetylcholine-Induced Activation of Rat Pancreatic {beta}-Cells Endocrinology, February 1, 2002; 143(2): 569 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Y. Jun, I. D. Kong, S. D. Koh, X. Y. Wang, B. A. Perrino, S. M. Ward, and K. M. Sanders Regulation of ATP-sensitive K+ channels by protein kinase C in murine colonic myocytes Am J Physiol Cell Physiol, September 1, 2001; 281(3): C857 - C864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, E. Takashi, M. Xu, A. Ayub, and M. Ashraf Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial KATP Channels by Diazoxide Circulation, July 3, 2001; 104(1): 85 - 90. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Stamm, I. Friehs, D. B. Cowan, H. Cao-Danh, S. Noria, M. Munakata, F. X. McGowan Jr., and P. J. del Nido Post-ischemic PKC inhibition impairs myocardial calcium handling and increases contractile protein calcium sensitivity Cardiovasc Res, July 1, 2001; 51(1): 108 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-i. Ito, T. Sato, and M. Arita Protein kinase C isoform-dependent modulation of ATP-sensitive K+ channels during reoxygenation in guinea-pig ventricular myocytes J. Physiol., April 1, 2001; 532(1): 165 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Gross, M. Gare, W. G. Toller, J. R. Kersten, D. C. Warltier, and P. S. Pagel Ethanol Enhances the Functional Recovery of Stunned Myocardium Independent of KATP Channels in Dogs Anesth. Analg., February 1, 2001; 92(2): 299 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hu, D. Mochly-Rosen, and M. Boutjdir Evidence for functional role of epsilon PKC isozyme in the regulation of cardiac Ca2+ channels Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2658 - H2664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Pagel, W. G. Toller, E. R. Gross, M. Gare, J. R. Kersten, and D. C. Warltier KATP channels mediate the beneficial effects of chronic ethanol ingestion Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2574 - H2579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Tang, M. H. Weil, S. Sun, A. Pernat, and E. Mason KATP channel activation reduces the severity of postresuscitation myocardial dysfunction Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1609 - H1615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Gross and R. M. Fryer Mitochondrial KATP Channels : Triggers or Distal Effectors of Ischemic or Pharmacological Preconditioning? Circ. Res., September 15, 2000; 87(6): 431 - 433. [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ribalet, S. A. John, and J. N. Weiss Regulation of Cloned Atp-Sensitive K Channels by Phosphorylation, Mgadp, and Phosphatidylinositol Bisphosphate (Pip2): A Study of Channel Rundown and Reactivation J. Gen. Physiol., September 1, 2000; 116(3): 391 - 410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sato, N. Sasaki, B. O'Rourke, and E. Marban Adenosine Primes the Opening of Mitochondrial ATP-Sensitive Potassium Channels : A Key Step in Ischemic Preconditioning? Circulation, August 15, 2000; 102(7): 800 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Gaudette, I. B. Krukenkamp, A. E. Saltman, H. Horimoto, and S. Levitsky Preconditioning with PKC and the ATP-sensitive potassium channels: a codependent relationship Ann. Thorac. Surg., August 1, 2000; 70(2): 602 - 608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Hopper, C. R. Forrest, H. Xu, A. Zhong, W. He, J. Rutka, P. Neligan, and C. Y. Pang Role and mechanism of PKC in ischemic preconditioning of pig skeletal muscle against infarction Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R666 - R676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. V. Hoek, L. B. Becker, Z.-H. Shao, C.-Q. Li, and P. T. Schumacker Preconditioning in Cardiomyocytes Protects by Attenuating Oxidant Stress at Reperfusion Circ. Res., March 17, 2000; 86(5): 541 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-H. Xie, M. Horie, and M. Takano Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism PNAS, December 21, 1999; 96(26): 15292 - 15297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Spinale Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest Ann. Thorac. Surg., November 1, 1999; 68(5): 1934 - 1941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Carmeliet Cardiac Ionic Currents and Acute Ischemia: From Channels to Arrhythmias Physiol Rev, July 1, 1999; 79(3): 917 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. Bernardo, M. D'Angelo, S. Okubo, A. Joy, and R. C. Kukreja Delayed ischemic preconditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1323 - H1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hu, G.-R. Li, and S. Nattel Adenosine-induced activation of ATP-sensitive K+ channels in excised membrane patches is mediated by PKC Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H488 - H495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Albert and D. A. Ford Protein kinase C translocation and PKC-dependent protein phosphorylation during myocardial ischemia Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H642 - H650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Haruna, M. Horie, I. Kouchi, R. Nawada, K. Tsuchiya, M. Akao, H. Otani, T. Murakami, and S. Sasayama Coordinate Interaction Between ATP-Sensitive K+ Channel and Na+,K+-ATPase Modulates Ischemic Preconditioning Circulation, December 22, 1998; 98(25): 2905 - 2910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Peers and E Carpenter Inhibition of Ca2+-dependent K+ channels in rat carotid body type I cells by protein kinase C J. Physiol., November 1, 1998; 512(3): 743 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Shimoni, P. E. Light, and R. J. French Altered ATP sensitivity of ATP-dependent K+ channels in diabetic rat hearts Am J Physiol Endocrinol Metab, October 1, 1998; 275(4): E568 - E576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Z. Simkhovich, K. Przyklenk, and R. A. Kloner Role of protein kinase C as a cellular mediator of ischemic preconditioning: a critical review Cardiovasc Res, October 1, 1998; 40(1): 9 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Miyamae, M. M. Rodriguez, S. A. Camacho, I. Diamond, D. Mochly-Rosen, and V. M. Figueredo Activation of varepsilon protein kinase C correlates with a cardioprotective effect of regular ethanol consumption PNAS, July 7, 1998; 95(14): 8262 - 8267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kouchi, T. Murakami, R. Nawada, M. Akao, and S. Sasayama KATP channels are common mediators of ischemic and calcium preconditioning in rabbits Am J Physiol Heart Circ Physiol, April 1, 1998; 274(4): H1106 - H1112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gysembergh, H. Margonari, J. Loufoua, A. Ovize, X. Andre-Fouet, Y. Minaire, and M. Ovize Stretch-induced protection shares a common mechanism with ischemic preconditioning in rabbit heart Am J Physiol Heart Circ Physiol, March 1, 1998; 274(3): H955 - H964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Miyawaki, Y. Wang, and M. Ashraf Oxidant stress with hydrogen peroxide attenuates calcium paradox injury: role of protein kinase C and ATP-sensitive potassium channel Cardiovasc Res, March 1, 1998; 37(3): 691 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yokoshiki, M. Sunagawa, T. Seki, and N. Sperelakis ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells Am J Physiol Cell Physiol, January 1, 1998; 274(1): C25 - C37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tsuchiya, M. Horie, M. Watanuki, C. A. Albrecht, K. Obayashi, H. Fujiwara, and S. Sasayama Functional Compartmentalization of ATP Is Involved in Angiotensin II–Mediated Closure of Cardiac ATP-Sensitive K+ Channels Circulation, November 4, 1997; 96(9): 3129 - 3135. [Abstract] [Full Text]
|
|
|
|
|
|
J. B. Hoag, Y.-Z. Qian, M. A. Nayeem, M. D'Angelo, and R. C. Kukreja ATP-sensitive potassium channel mediates delayed ischemic protection by heat stress in rabbit heart Am J Physiol Heart Circ Physiol, November 1, 1997; 273(5): H2458 - H2464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu, W. D. Gao, B. O'Rourke, and E. Marban Priming effect of adenosine on KATP currents in intact ventricular myocytes: implications for preconditioning Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1637 - H1643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S Carr, R. J Hill, H. Masamune, S. P Kennedy, D. R Knight, W.R. Tracey, and D. M Yellon Evidence for a role for both the adenosine A1 and A3 receptors in protection of isolated human atrial muscle against simulated ischaemia Cardiovasc Res, October 1, 1997; 36(1): 52 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Miyawaki and M. Ashraf Ca2+ as a Mediator of Ischemic Preconditioning Circ. Res., June 19, 1997; 80(6): 790 - 799. [Abstract] [Full Text]
|
|
|
|
|
|
A. Babenko and G. Vassort Enhancement of the ATP-Sensitive K+ Current by Extracellular ATP in Rat Ventricular Myocytes : Involvement of Adenylyl Cyclase–Induced Subsarcolemmal ATP Depletion Circ. Res., April 19, 1997; 80(4): 589 - 600. [Abstract] [Full Text]
|
|
|
|
|
|
P. E. Light, A. A. Sabir, B. G. Allen, M. P. Walsh, and R. J. French Protein Kinase C–Induced Changes in the Stoichiometry of ATP Binding Activate Cardiac ATP-Sensitive K+ Channels: A Possible Mechanistic Link to Ischemic Preconditioning Circ. Res., September 1, 1996; 79(3): 399 - 406. [Abstract] [Full Text]
|
|
|
|
|
|
C. Vahlhaus, R. Schulz, H. Post, R. Onallah, and G. Heusch No Prevention of Ischemic Preconditioning by the Protein Kinase C Inhibitor Staurosporine in Swine Circ. Res., September 1, 1996; 79(3): 407 - 414. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||