(Circulation. 1998;98:2905-2910.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Coordinate Interaction Between ATP-Sensitive K+ Channel and Na+,K+-ATPase Modulates Ischemic Preconditioning
From the Department of Cardiovascular Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan. Drs Haruna and Kouchi contributed equally to this study.
Correspondence to Tomoyuki Murakami, MD, Department of Cardiovascular Medicine, Kyoto University, Graduate School of Medicine, Kyoto 606-8397, Japan. E-mail tomsan{at}kuhp.kyoto-u.ac.jp
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Abstract |
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Background—We reported that digoxin abolishes the infarct size (IS)-limiting effect of ischemic preconditioning (IPC). Because ATP-sensitive K+ (KATP) channels are involved in IPC, we studied whether Na+,K+-ATPase and KATP channels functionally interact, thereby modulating IPC.
Methods and Results—Rabbits received 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. IPC was elicited by 5 minutes of occlusion followed by 10 minutes of reperfusion. The IS, expressed as a percentage of the area at risk, was 40.2±2.8% in control and 39.8±5.0% in digoxin pretreatment rabbits. Both IPC and pretreatment with cromakalim, a KATP channel opener, reduced IS to 11.8±1.8% and 13.4±2.6% (P<0.05 versus control). Digoxin abolished the reduction in IS induced by IPC (33.5±3.3%), whereas it did not change that induced by cromakalim (18.8±3.0%). In patch-clamp experiments, digoxin was found to inhibit the opening of KATP channels in single ventricular myocytes in which ATP depletion had been induced by metabolic stress. In contrast, digoxin had little effect on the channel opening induced by cromakalim. Moreover, the inhibitory action of digoxin on channel activities was dependent on subsarcolemmal ATP concentration.
Conclusions—The IS-limiting effect of IPC is modulated by an interaction between KATP channels and Na+,K+-ATPase through subsarcolemmal ATP.
Key Words: ATP-sensitive potassium channel • Na+,K+-ATPase • ischemic preconditioning
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Introduction |
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Exposure of the myocardium to
1 brief
periods of ischemia, known as ischemic preconditioning
(IPC),1 produces a marked resistance to
subsequent prolonged episodes of ischemic stress in several
mammalian species.2 3 4 It is now recognized that
ATP-sensitive K+ (KATP)
channels are ubiquitous target effectors of the cardioprotective
process by IPC, independent of species
difference.2 3 4 We have demonstrated in rabbit hearts that the prevention of ischemia-induced reduction of Na+,K+-ATPase activity during the early phase of sustained ischemia contributes to the infarct size (IS)-limiting effect of IPC because pretreatment with digoxin, an inhibitor of Na+,K+-ATPase, abolished the cardioprotective effect of IPC.5 In guinea pig cardiac myocytes, 2 other cardiac glycosides, strophanthidin6 and ouabain,7 suppress the opening of KATP channels by minimizing the consumption of subsarcolemmal ATP by Na+,K+-ATPase. This notion led us to the hypothesis that the IS-limiting effect of IPC and the inhibitory action of digoxin reflect a functional interaction between Na+,K+-ATPase and KATP channels through the ATP concentration ([ATP]) in the subsarcolemmal compartment.
The purpose of the present study was to test this potential interaction. We compared the effect of digoxin on the IS limitation induced by IPC and that by a KATP channel opener, cromakalim, in in vivo rabbit hearts, because it has been shown that KATP channel openers evoke the opening of KATP channels in the presence of relatively high concentrations of subsarcolemmal ATP.8 9 In addition, using patch-clamp techniques on single ventricular myocytes, we examined the effects of digoxin on KATP channel activation.
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Methods |
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Animal Preparation
Female Japanese white rabbits (2.5 to 3.2 kg) were anesthetized with 30 mg/kg sodium pentobarbital IV, intubated, then mechanically ventilated with 100% oxygen by use of a volume-cycled respirator. A fluid-filled catheter was placed in the right femoral artery and was connected to a transducer for measurement of arterial pressure. Ventilation was maintained at 15 to 20 breaths per minute with
40 mL of tidal volume. A left thoracotomy
was performed in the fourth intercostal space, and the pericardium was
opened. A 4-0 silk thread was then passed around the circumflex branch
of the left coronary artery, with its ends being threaded
through a small polyethylene tube. Precordial
electrocardiography was monitored with bipolar
chest leads. Rabbits were allowed 20 minutes to reach a steady state
after surgical preparation. Coronary occlusion was produced by
pulling the snare and clamping it with a mosquito hemostat. Reperfusion
was produced by releasing the clamp.
Determination of IS
Animals were subjected to a 30-minute period of
coronary artery occlusion followed by 3 hours of reperfusion.
To achieve IPC, the coronary artery was occluded for 5 minutes,
followed by 10 minutes of reperfusion, before the sustained occlusion
and reperfusion. Rabbits were assigned randomly to 1 of 6 groups,
including the control group, consisting of control animals given
vehicle only; the IPC group, animals given vehicle before IPC; the
digoxin group, animals given digoxin 0.3 mg/kg as a bolus injection 30
minutes before sustained ischemia; the digoxin+IPC group,
animals treated with digoxin before IPC; the cromakalim group, animals
given cromakalim 4 µg · kg-1 ·
min-1 over a period of 10 minutes as an
intravenous infusion 10 minutes before sustained
ischemia; and the digoxin+cromakalim group, animals pretreated
with digoxin 30 minutes before sustained ischemia before
cromakalim treatment. The digoxin and digoxin+IPC groups consisted of
animals from our previous study.5
In each protocol, the heart was rapidly excised at the end of the 3 hours of reperfusion and mounted by the aortic root on a Langendorff apparatus. The snare was retightened, and 0.5% phthalocyanine blue pigment was infused into the perfusate to demarcate the risk zone as the tissue without blue dye. The heart was then removed, and the left ventricle was isolated and cut into transverse slices 2 mm thick. The area at risk (nonblue area) was separated from each slice, weighed, and incubated at 37°C for 15 minutes in 1% triphenyl tetrazolium chloride (TTC) in phosphate buffer, pH 7.4. TTC stained the noninfarcted myocardium deep red. The sections were fixed in 10% formalin solution for >3 hours. Their digital images were then captured with a CCD camera and entered into an Apple Power Macintosh computer. The area at risk and the area of infarction (TTC-negative) were determined with image analysis software, corrected for the weight of each tissue slice, and summed for each heart. The IS was expressed as a percentage of the area at risk.
Single-Cell Preparation and Electrophysiology
Left ventricular myocytes were isolated from
Japanese White rabbits by the collagenase perfusion method.
Single ventricular myocytes were dispersed in a
recording chamber (0.5 mL in volume) on the stage of an
inverted microscope (Nikon, TMD-2) and were superfused with Tyrode's
solution containing (in mmol/L) NaCl 143,
NaH2PO4 0.3, KCl 5.4,
MgCl2 0.5, CaCl2 1.8, and
HEPES/NaOH 5 (pH 7.4 adjusted by NaOH). For experiments using
metabolic inhibition, single cells were preincubated with a
glucose-free Kraft Brühe solution containing
2-deoxyglucose (5.5 mmol/L; Nacalai Tesque), an
inhibitor of glycolysis, at 37°C for >30 minutes.
The pipette solution for KATP current measurement contained (in mmol/L) aspartic acid 130, KCl 10, NaCl 10, MgCl2 1.0, EGTA 10, and K2ATP 0.1 (pH 7.4 adjusted with HEPES/KOH 5). KATP current was activated either by metabolic stress (glucose- and Ca2+-free Tyrode's solution containing 1 mmol/L NaCN) or by cromakalim (100 µmol/L), recorded by ramp pulses applied every 10 seconds at -40-mV holding potential to obtain quasi-instantaneous current-voltage (I-V) relations. All the current data measured by an amplifier (List EPC-7) were directly displayed on a chart recorder (Graphtec, Linerecorder, WR 3320) with on-line acquisition to an NEC personal computer at a Bessel-type cutoff frequency of 1 kHz.
Single KATP channel activity was recorded in either cell-attached, inside-out, or open cell–attached mode. Glucose-free Tyrode's solution was used as a pipette solution. To virtually eliminate the membrane potential, a K+-rich solution was used as a bathing solution. Its composition was (in mmol/L) KCl 150, EGTA 0.5, and HEPES 5 (pH 7.4 adjusted by KOH). In the cell-attached mode, the KATP channels were activated by metabolic inhibition (1 mmol/L NaCN, glucose-free) after incubation with 2-deoxyglucose (>20 minutes at 37°C) or by cromakalim (100 µmol/L). The inhibition of the glycolysis pathway was applied to the myocytes only for metabolic stress–induced opening of the channel.
Brief (2 to 5 minutes) exposure of the myocytes to streptolysin O (0.02
to 0.08 U/mL, Nacalai Tesque) produced tiny holes on the cell membrane
and allowed us to control the [ATP] just beneath the membrane by
changing the [ATP] of the bathing solution.7
The inside-out mode was achieved by excising the patch membrane
into ATP-free bath solution. Patch pipettes were prepared by pulling
borosilicate glass capillaries (Hilgenberg) at 2 to 3 M
for
whole-cell and at 5 to 7.5 M for single-channel recordings
when filled with pipette solution.
Data Analyses
The mean patch currents (I) for single-channel events were
measured as the average difference between baseline (all channels
closed) and open channel currents. The unitary amplitude (i) was
estimated by the analysis of the amplitude distribution by use
of pCLAMP software version 6.1 (Axon Instruments Inc) at a Bessel-type
cutoff frequency of 100 Hz at a sample frequency of 1 kHz. The mean
number of open channels (NP) was given by the product of the number
of available channels in the patch (N) and the probability of their
being open (P). NP was estimated by dividing the mean patch currents
(I=NPi) by unitary amplitude (i) as I/i.
Drugs
Digoxin (Sigma Chemical Co) was dissolved in distilled water at
1 mmol/L (stock solution) and glibenclamide (Sigma) in DMSO at
1 mmol/L (stock solution). Streptolysin O was dissolved in the
bathing solution at a final concentration of 0.08 U/mL immediately
before every experiment and was used within 3 to 4 hours after
preparation.7 All experiments were carried out
at 36°C.
Statistical Analyses
The differences in time courses of hemodynamics
change between groups, and time courses were analyzed by 2-way
ANOVA with repeated measurements. In the IS study, the differences
between groups were compared by 1-way ANOVA with Scheffé's post
hoc test. A level of P<0.05 was accepted as statistically
significant. In the electrophysiological
study, statistical analyses were performed with an unpaired
Student's t test.
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Results |
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Hemodynamics
The hemodynamic data are summarized in Table 1
. No significant differences were
observed in mean arterial pressure or heart rate among the
6 groups at any of the experimentally determined time points.
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Infarct Size
Data from the study of IS are summarized in Table 2. Body weights, left
ventricular weights, and area-at-risk weights did not
differ significantly among any of the experimental groups. However, IS
weights were significantly smaller in the IPC, cromakalim, and
digoxin+cromakalim groups than in the control group.
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Figure 1 shows the IS as a percentage of
the area at risk in each experiment. IPC and cromakalim reduced the
size of the infarct compared with control (11.8±1.8% and 13.4±2.6%
versus 40.5±2.8%, respectively; P<0.05). The
administration of 0.3 mg/kg digoxin had no effect on the IS compared
with controls (39.8±5.0%) but significantly reduced the beneficial
IS-limiting effects of IPC (33.5±3.3%). In contrast, it did not
affect such effects induced by cromakalim (18.8±3.0%).
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Effects of Digoxin on KATP Channel Activities
Whole-Cell Experiments
Exposure of a myocyte preincubated with 2-deoxyglucose to glucose-
and Ca2+-free Tyrode's solution containing
1 mmol/L NaCN activated outward conductance at a holding
potential of -40 mV, usually within 10 minutes (Figure 2A). Quasi-instantaneous I-V
relationships (Figure 2B-1) showed that the conductance induced by
metabolic stress reversed at -83 mV and was inhibited by
extracellular glibenclamide 1 µmol/L) (Figure 2A, d and e).
Difference currents for metabolic stress–induced and
glibenclamide-sensitive components (b-a in Figure 2C-1 and d-e in
Figure 2C-3) showed reversal potentials of -85 mV, close to the
estimated equilibrium potential for K+
(EK) under these experimental conditions. These
findings suggest that the current induced by metabolic
inhibition is carried by the activation of KATP
channels.
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External application of digoxin reversibly suppressed the conductance
induced by metabolic stress (Figure 2A
, b and c) without
altering the reversal potential (Figure 2B-2). Current components
sensitive to digoxin (b-c in Figure 2C-2) reversed at a potential of
-82 mV, which is also close to EK. Similar
findings were observed in 3 other experiments. Percentage inhibitions
of outward current at 0 mV were calculated as 100x(b-c)/b as in
Figures 2B and 2C-2 and were 89.6±3.3% (n=4). Thus, digoxin appeared
to inhibit the KATP channel current.
In the experiment shown in Figure 3A, cromakalim 100 µmol/L evoked an outward current at a holding
potential of -40 mV (Figure 3A). Because of the reversal potential
(-83 mV; Figure 3A, a and b; 3B; and 3C-1) and block by glibenclamide
(Figure 3A, e and f), the cromakalim-induced conductance was considered
to be due to the activation of KATP channels.
Extracellular digoxin 1 and 10 µmol/L did not significantly
suppress the KATP current induced by cromakalim
(Figure 3A, b and d; 3B; and 3C-2). Failure of digoxin to inhibit the
current was also observed in a total of 4 experiments, and percent
inhibitions at 0 mV were 10.7±4.0% (P=NS versus
control).
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Cell-Attached Experiments
The effect of digoxin on single KATP channel
activity was also examined in the cell-attached mode (Figure 4). KATP channels
were opened by either metabolic stress (A) or cromakalim
100 µmol/L (B). KATP channel currents were
recorded as an upward deflection at 0 mV under these experimental
conditions. Exposure of myocytes preincubated with 2-deoxyglucose
5.5 mmol/L to NaCN 1 mmol/L for 15 to 20 minutes produced the
opening of single channels (Figure 4A), as did application of
cromakalim into both pipette and external solutions (Figure 4B).
Glibenclamide 0.5 µmol/L inhibited both channel activities.
Figure 4C summarizes the data obtained in both protocols at various
concentrations of digoxin and glibenclamide 0.5 µmol/L. Digoxin
applied outside the pipette blocked the channel activities by
metabolic inhibition in a reversible and
concentration-dependent manner. In contrast, it had no effect on the
channel activities evoked by cromakalim.
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Inside-Out and Open Cell–Attached Experiments
Figure 5 shows the data obtained in
inside-out (A) and open cell–attached modes (B and C). Excision of
patch membrane into an ATP-free solution produced a robust opening of
those single-channel currents that were sensitive to glibenclamide
(1 µmol/L; Figure 5A). In the absence of internal ATP, the
channels ran down gradually. The findings indicated that single-channel
events were openings of KATP channels. Digoxin
1 µmol/L applied to the internal side of the patch membrane had
no effect (only 5.5±2.5% inhibition of control).
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In the open cell–attached mode (Figure 5B), we were able to open the
channel by reducing extracellular [ATP] through tiny membrane holes
made by streptolysin O.7 In fact, raising
extracellular ATP from 0 to 1 mmol/L reversibly closed the channel
(Figure 5B). As in the experiments with cromakalim, digoxin 1
µmol/L was without effect on the channel activity thus obtained.
Figure 5C summarizes the percentage of residual patch current in
digoxin 1 µmol/L and glibenclamide 1 µmol/L in the open
cell–attached mode.
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Discussion |
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Effects of Digoxin on IS in In Vivo Rabbit Hearts
We have previously demonstrated that pretreatment with digoxin, an inhibitor of Na+,K+-ATPase, attenuated the KATP channel–mediated IS-limiting effect of IPC in the rabbit heart.5 Interestingly, however, we found in the present study that digoxin did fail to block the salutary IS-limiting effect of cromakalim. To explain this discrepancy, we focused on the interaction of Na+,K+-ATPase and KATP channels, because sarcolemmal molecules consuming subsarcolemmal ATP, such as Na+,K+-ATPase, have been shown to alter the channel function through the change in subsarcolemmal [ATP].6 7 10 11 The activation of KATP channels is dependent on subsarcolemmal [ATP] during ischemia,12 13 whereas KATP channel openers can open the channel in the presence of relatively high concentrations of ATP.8 9 It is therefore likely that an interaction between the Na+,K+-ATPase and the channel via subsarcolemmal ATP would affect the IS-limiting action of IPC as well as its blockade by digoxin. This idea is not contradictory to the findings in previous studies14 15 using nuclear magnetic resonance spectroscopy15 that myocardial [ATP] levels were relatively preserved in the preconditioned compared with nonpreconditioned hearts. This method cannot measure intracellular gradient of ATP because of the nonhomogeneous distribution of mitochondria,16 glycolysis-dependent ATP production,10 or membrane molecule–induced consumption of ATP.6 7 10 11 During sustained ischemia, subsarcolemmal [ATP] could be low enough to activate KATP channels in the preconditioned heart even though gross [ATP] remains relatively preserved, because the activities of sarcolemmal enzymes, especially Na+,K+-ATPase, which consume subsarcolemmal ATP, are not attenuated during the early phase of sustained ischemia.5
We used a single 5-minute IPC stimulus in the present study. It has been reported that bradykinin antagonists can block cardioprotection only when 1 cycle, but not 4 cycles, of IPC is used.17 In contrast, we confirmed that digoxin inhibited even the IS-limiting effect induced by 3 cycles of IPC (data not shown). It appears that the IS-limiting effect by IPC requires Na+,K+-ATPase activity to open KATP channels.
Effects of Digoxin on KATP Channel Activities in
Isolated Rabbit Myocytes
In the present study, as in the findings in in vivo rabbit for
myocardial ischemia, whole-cell experiments using patch-clamp
techniques demonstrated that digoxin reversibly inhibits the
KATP current induced by metabolic
stress, but its inhibitory action was largely attenuated
when the current was activated by cromakalim. In the
cell-attached mode, digoxin also inhibited single
KATP channel currents activated by
metabolic stress in a reversible and
concentration-dependent manner, but not those activated by
cromakalim.
Therefore, the digoxin-induced inhibition of KATP channels appeared to depend on subsarcolemmal [ATP]. This was also supported by the experimental finding that digoxin was without effect in the inside-out or open cell–attached modes. In the former, excision of patch membrane into an ATP-free solution produced opening of KATP channels. The inhibition by digoxin was then negligible, indicating that the drug does not affect the channel directly. In the latter mode, through tiny membrane holes, subsarcolemmal [ATP] could be "concentration-clamped" at a desired level by [ATP] in the bathing extracellular solution.7 Under these conditions, digoxin was also unable to inhibit the channel. The findings again suggest that Na+,K+-ATPase and KATP channel functionally interact through subsarcolemmal ATP.
We have previously reported that angiotensin II mediates the closure of KATP channels through inhibition of adenylate cyclase, which transits from ATP to cAMP in guinea pig myocytes.7 Conversely, Liu et al18 showed that pretreatment with angiotensin II caused an IS-limiting effect in the rabbit heart. Angiotensin II potentially opens KATP channels by stimulating protein kinase C activation, although the relationship between protein kinase C and KATP channels still remains controversial.19 20 In angiotensin II–induced cardioprotection, this stimulatory pathway may act on KATP channels more prominently over the inhibitory pathway via adenylate cyclase.
Cardioprotection by KATP Channel Activation
In the present study, we assumed that both IPC- and
cromakalim-mediated IS-limiting effects were derived from the
activation of sarcolemmal KATP channels. These
beneficial effects have been thought to be due to the shortening of
myocardial action potential duration (APD) and the subsequent reduction
in Ca2+ entry into
myocytes.12 13 However, Yao and
colleagues21 demonstrated in dogs that bimakalim,
a KATP channel opener, conferred the IS-limiting
effect at a dose that produced no shortening of APD. Likewise, Grover
et al22 23 reported that the IS-limiting effects
of cromakalim and IPC are preserved despite concomitant treatment with
dofetilide, an antiarrhythmic agent with class III action, at a
concentration sufficient to abolish the cromakalim- and IPC-induced
shortening of APD.
Recently, mitochondrial KATP channels have drawn considerable attention as targets for the action of KATP channel openers.24 Garlid et al25 have shown that diazoxide, a potent mitochondrial but weak sarcolemmal KATP channel opener, improves postischemic functional recovery and decreases lactate dehydrogenase release during reperfusion in isolated perfused rat and rabbit hearts subjected to global ischemia. However, the theory that mitochondrial KATP channels alone contribute to the cardioprotection by IPC and KATP channel openers cannot explain the dissociation of the inhibitory effects of digoxin on IS between IPC and cromakalim that we showed in this study. The potency of diazoxide to achieve cardioprotection was reported to be comparable to that of cromakalim in rabbit heart.25 However, we found that diazoxide given in the same protocol as cromakalim did not induce any IS-limiting effect (IS, 33.4±5.9%, n=7) even at a 10-fold higher dose (40 µg · kg-1 · min-1) than that of cromakalim used in the present study (4 µg · kg-1 · min-1). Thus, sarcolemmal KATP channels also play an important role in the IS-limiting effect of IPC and cromakalim in the in vivo rabbit model of regional myocardial ischemia. Because there was little relationship between APD shortening and cardioprotection in terms of KATP channel openers,21 22 23 further studies are necessary to examine the precise mechanism(s) underlying the KATP channel–mediated cardioprotection.
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Acknowledgments |
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This work was supported by Grants-in-Aid on Priority Areas of Channel-Transporter Correlation and research grants (09670713) from the Japanese Ministry of Education, Science, and Culture.
Received March 30, 1998; revision received August 7, 1998; accepted August 20, 1998.
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Circ Res. 1997;81:1072–1082.KATP channels
mediate the cardioprotection of ischemic preconditioning (IPC).
In the present study, digoxin, an inhibitor of
Na+,K+-ATPase, was found to reduce the infarct
size–limiting effect caused by IPC, whereas it did not change that
caused by cromakalim, a KATP channel opener, in the in vivo
rabbit heart. In single rabbit ventricular myocytes,
digoxin suppressed KATP channels opened by ATP depletion
with metabolic stress but not those opened by cromakalim.
This inhibitory action by digoxin on the channel activities
was dependent on subsarcolemmal ATP concentration. Thus, the infarct
size–limiting effect of IPC is modulated by an interaction between
KATP channels and Na+,K+-ATPase
through subsarcolemmal ATP.
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 G. J. Gross and J. N. Peart KATP channels and myocardial preconditioning: an update Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H921 - H930. [Abstract] [Full Text] [PDF]
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 S. Sanada, K. Node, H. Asanuma, H. Ogita, S. Takashima, T. Minamino, M. Asakura, Y. Liao, A. Ogai, J. Kim, et al. Opening of the adenosine triphosphate-sensitive potassium channel attenuates cardiac remodeling induced by long-term inhibition of nitric oxide synthesis: Role of 70-kDa S6 kinase and extracellular signal-regulated kinase J. Am. Coll. Cardiol., September 4, 2002; 40(5): 991 - 997. [Abstract] [Full Text] [PDF]
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 G A Rongen, J P van Dijk, E E van Ginneken, D F Stegeman, P Smits, and M J Zwarts Repeated ischaemic isometric exercise increases muscle fibre conduction velocity in humans: involvement of Na+-K+-ATPase J. Physiol., May 1, 2002; 540(3): 1071 - 1078. [Abstract] [Full Text] [PDF]
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 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]
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 R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
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 H. G. Glitsch Electrophysiology of the Sodium-Potassium-ATPase in Cardiac Cells Physiol Rev, October 1, 2001; 81(4): 1791 - 1826. [Abstract] [Full Text] [PDF]
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S. Sanada, M. Kitakaze, H. Asanuma, K. Harada, H. Ogita, K. Node, S. Takashima, Y. Sakata, M. Asakura, Y. Shinozaki, et al. Role of mitochondrial and sarcolemmal KATP channels in ischemic preconditioning of the canine heart Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H256 - H263. [Abstract] [Full Text] [PDF]
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H. Takano, X.-L. Tang, and R. Bolli Differential role of KATP channels in late preconditioning against myocardial stunning and infarction in rabbits Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2350 - H2359. [Abstract] [Full Text] [PDF]
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 T. Sato, N. Sasaki, J. Seharaseyon, B. O'Rourke, and E. Marban Selective Pharmacological Agents Implicate Mitochondrial but Not Sarcolemmal KATP Channels in Ischemic Cardioprotection Circulation, May 23, 2000; 101(20): 2418 - 2423. [Abstract] [Full Text] [PDF]
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G. J. Gross and R. M. Fryer Sarcolemmal Versus Mitochondrial ATP-Sensitive K+ Channels and Myocardial Preconditioning Circ. Res., May 14, 1999; 84(9): 973 - 979. [Abstract] [Full Text] [PDF]
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G A Rongen, J P van Dijk, E E van Ginneken, D F Stegeman, P Smits, and M J Zwarts Repeated ischaemic isometric exercise increases muscle fibre conduction velocity in humans: involvement of Na+-K+-ATPase J. Physiol., May 1, 2002; 540(3): 1071 - 1078. [Abstract] [Full Text] [PDF]
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