(Circulation. 2000;102:800.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Adenosine Primes the Opening of Mitochondrial ATP-Sensitive Potassium Channels
A Key Step in Ischemic Preconditioning?
From the Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Md. Dr Sato is now at the Department of Physiology, Oita Medical University, Hasama, Oita, Japan.
Correspondence to Eduardo Marbán, MD, PhD, Institute of Molecular Cardiobiology, Johns Hopkins University, Ross 844/720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}jhmi.edu
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Abstract |
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Background—Adenosine can initiate ischemic preconditioning, and mitochondrial ATP-sensitive potassium (KATP) channels have emerged as the likely effectors. We sought to determine the mechanistic interactions between these 2 observations.
Methods and Results—The mitochondrial flavoprotein oxidation induced by diazoxide (100 µmol/L) was used to quantify mitochondrial KATP channel activity in intact rabbit ventricular myocytes. Adenosine (100 µmol/L) increased mitochondrial KATP channel activity and abbreviated the latency to mitochondrial KATP channel opening. These potentiating effects were entirely prevented by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (100 µmol/L) or by the protein kinase C inhibitor polymyxin B (50 µmol/L). The effects of adenosine and diazoxide reflected mitochondrial KATP channel activation, because they could be blocked by the mitochondrial KATP channel blocker 5-hydroxydecanoate (500 µmol/L). In a cellular model of simulated ischemia, adenosine mitigated cell injury; this cardioprotective effect was blocked by 5-hydroxydecanoate but not by the surface-selective KATP channel blocker HMR1098. Moreover, adenosine augmented the cardioprotective effect of diazoxide. A quantitative model of mitochondrial KATP channel gating reproduced the major experimental findings.
Conclusions—Our results support the hypothesis that adenosine receptor activation primes the opening of mitochondrial KATP channels in a protein kinase C–dependent manner. The findings provide tangible links among various key elements in the preconditioning cascade.
Key Words: adenosine • ischemia • ion channels • mitochondria
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Ischemic preconditioning (IPC) is the endogenous mechanism whereby brief periods of ischemia paradoxically protect the myocardium against the damaging effects of subsequent prolonged ischemia.1 IPC exists in all species examined, including humans.2 3 4 Although the precise cellular mechanisms responsible for IPC remain elusive, adenosine released by the ischemic heart has been reported to initiate IPC.5 Protein kinase C (PKC) features prominently in the signal transduction pathway between adenosine A1 receptors and the final effector.6 Adenosine and PKC have been shown to activate ATP-sensitive potassium (KATP) channels in cardiac myocytes.7 8 9 Consistent with the idea that KATP channels may be the end effectors of IPC, stimulation of adenosine A1 receptors mimics IPC, and this effect is abolished by the KATP channel inhibitor glibenclamide.10
The cardioprotective effects were initially attributed to sarcolemmal KATP (surfaceKATP) channels.11 12 However, recent studies provide evidence that mitochondrial KATP (mitoKATP) channels are the dominant players. Diazoxide, a selective mitoKATP channel opener in cardiac cells,13 protects rabbit ventricular myocytes in a pelleting model of ischemia,14 improves functional recovery after ischemia in Langendorff-perfused rat and rabbit hearts,15 and reduces infarct size in rabbit hearts.16 On the other hand, the selective mitoKATP channel blocker 5-hydroxydecanoate (5HD)17 antagonizes diazoxide-induced cardioprotection14 15 and abolishes genuine IPC.18 19 20 Furthermore, PKC activation potentiates mitoKATP channel opening in rabbit ventricular myocytes.17
Accordingly, the present study was designed to determine whether adenosine modulates mitoKATP channels. Our results demonstrate that adenosine potentiates mitoKATP channel activation via a PKC-mediated pathway and protects the myocardium from ischemia.
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Methods |
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The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1985).
Preparation of Rabbit Myocytes
Rabbit ventricular myocytes were isolated by
conventional enzymatic dissociation, as described
previously.9 In brief, hearts were excised from
anesthetized (30 mg/kg pentobarbital IV) New Zealand White
rabbits (weighing 1 to 2 kg) and mounted on a Langendorff
apparatus. The heart was perfused with modified
Krebs-Henseleit solution composed of (mmol/L) NaCl 119, KCl 5,
NaHCO3 25,
KH2PO4 1,
MgSO4 1, CaCl2 2, and
glucose 10. The perfusate was bubbled with 95%
O2/5% CO2 and maintained
at 37°C. After 5 minutes of perfusion, hearts were perfused without
Ca2+ for another 5 minutes, after which the
perfusion solution was switched to one containing
collagenase (0.8 mg/mL, Worthington type II). The perfusion
pressure was monitored, and the flow rate was adjusted to maintain
perfusion pressure at 
75 mm Hg. After 25 to 30 minutes of
collagenase perfusion, hearts were removed from the
perfusion apparatus, and the atria were trimmed away. The
ventricles were minced and incubated in a shaking bath for another 5
minutes in collagenase-containing solution. Cells were then
filtered through nylon mesh and washed several times with
Ca2+-free solution. Calcium concentration was
gradually brought back to 1 mmol/L.
Flavoprotein Fluorescence
Opening of mitoKATP channels dissipates
the inner mitochondrial membrane potential established by the proton
pump. This dissipation accelerates electron transfer by the respiratory
chain and, if uncompensated by increased production of electron
donors, leads to net oxidation of the mitochondria. Therefore, the
mitochondrial redox state was monitored by measuring the
autofluorescence of flavin adenine
dinucleotide–linked enzymes in the mitochondria, as
described by Liu et al.14 After isolation, cells were
cultured on laminin-coated coverslips in medium 199 with 5% FBS at
37°C. Experiments were performed the next day. Cells were placed in a
recording chamber and superperfused with external solution
containing (mmol/L) NaCl 140, KCl 5, MgCl2 1,
CaCl2 1, and HEPES 10 (pH 7.4 with NaOH) at room
temperature (22°C). Endogenous flavoprotein
fluorescence was excited for 100 ms every 6 seconds by use of a
xenon arc lamp with a band-pass filter centered at 480 nm. Emitted
fluorescence was recorded at 530 nm by a photomultiplier
tube and digitized. The redox signal was averaged during the excitation
window and calibrated with the values after exposure to
2,4-dinitrophenol (DNP), which uncouples respiration from ATP
synthesis, collapses the mitochondrial potential, and induces maximal
oxidation. Therefore, the values of flavoprotein fluorescence
were expressed as a percentage of the DNP-induced fluorescence.
By focusing on individual myocytes with a x40 objective,
fluorescence was monitored from one cell at a time.
Cellular Model of Simulated Ischemia
A cellular model of simulated ischemia modified from
Vander Heide et al21 was used to quantify cell injury. In
brief, cells were washed with incubation buffer containing (mmol/L)
NaCl 119, NaHCO3 25,
KH2PO4 1.2, KCl 4.8,
MgSO4 1.2, CaCl2 1, HEPES
10, glucose 11, creatine 24.9, and taurine 58.5 and supplemented with
1% basal medium eagle amino acids and 1% minimum essential
medium nonessential amino acids (pH 7.4 with NaOH). An aliquot of each
cell suspension (0.5 mL) was placed into a microcentrifuge tube
and centrifuged for 15 seconds into a pellet. Approximately
0.25 mL of excess supernatant was removed to leave a thin fluid layer
above the pellet, and 0.2 mL of mineral oil was layered on the top of
the pellet to prevent gaseous diffusion. After 60 and 120 minutes of
simulated ischemia, 5 µL of cell pellet was sampled through
the oil layer and mixed with 75 µL of 85 mOsm/L hypotonic staining
solution containing (mmol/L) NaHCO3 11.9,
KH2PO4 0.4, KCl 2.7,
MgSO4 0.8, and CaCl2 1,
along with 0.5% glutaraldehyde and 0.5% trypan blue.
Microscopic examination was performed 2 to 5 minutes after mixing to
determine the permeability of the cells to trypan blue. Cells permeable
to trypan blue were counted as stained (ie, irreversibly injured) and
expressed as a percentage of the total cells counted (>300 for each
sample). In the control group, cells were pelleted and sampled at 60
and 120 minutes. For the adenosine-treated group,
adenosine at a concentration of 100 µmol/L was added to
the solution 15 minutes before the pelleting. Cells treated with
adenosine in the presence of 500 µmol/L 5HD or in the
presence of 30 µmol/L HMR1098 were likewise pelleted and
sampled. In another series of experiments, cells exposed to various
concentrations of diazoxide with or without 100 µmol/L
adenosine were pelleted and sampled after 60 minutes of
simulated ischemia. Once applied, drugs were not washed out and
thus were present throughout the period of simulated
ischemia. Experiments were performed at 37°C. Individual
experiments in each group were performed on cells isolated from
different hearts.
Chemicals
Collagenase (type II) was purchased from
Worthington. Adenosine, diazoxide,
8-(p-sulfophenyl)-theophylline (SPT), polymyxin B, and DNP
were obtained from Sigma Chemical Co. Sodium 5HD was purchased from
Research Biochemicals International. HMR1098 was a gift from Hoechst
Marion Roussel Chemical Research (Frankfurt, Germany).
Adenosine, diazoxide, and SPT were dissolved in dimethyl
sulfoxide before being added into experimental solutions. The final
concentration of dimethyl sulfoxide was <0.1%.
Quantitative Modeling of Channel Function
To rationalize the opening of mitoKATP
channels underlying flavoprotein oxidation, we implemented Markov
gating models of the Hodgkin-Huxley type (Figure 7B
).22 As a first approximation, we assumed that
flavoprotein oxidation parallels mitoKATP channel
opening. Simulations were executed by use of Origin
(Microcal Software) on a personal computer (Figure 7C and 7D).
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, ß,
Data Analysis
Data are presented as mean±SEM, and the number of cells
or experiments is shown as n. Cell pelleting data were analyzed
by ANOVA combined with the Fisher post hoc test, and
fluorescence data were analyzed by the Student
t test.23 24 A value of
P<0.05 was considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The effects of adenosine on mitoKATP channels were examined by measuring flavoprotein oxidation elicited by diazoxide. Figure 1A
shows
representative recordings of flavoprotein
fluorescence in a cell exposed twice to diazoxide. Diazoxide
(100 µmol/L) reversibly oxidized flavoproteins via the opening
of mitoKATP channels.14 Subsequent
exposure to adenosine (100 µmol/L) alone had no effects
on flavoprotein fluorescence, but a second application of
diazoxide in the continued presence of adenosine increased
flavoprotein fluorescence above the levels reached in the first
application. Note also that in the presence of adenosine, the
second application of diazoxide elicited oxidation more quickly than
the first. As summarized in Figure 1B, diazoxide (100
µmol/L) reversibly increased flavoprotein oxidation to 42±5% of the
DNP value (n=5). Adenosine (100 µmol/L) significantly
increased the diazoxide-induced flavoprotein oxidation to 57±4% of
the DNP value (n=5, P<0.01). Figure 1C summarizes
the latency to mitoKATP activation, measured as
the time required to increase flavoprotein oxidation to 20% of maximal
after application of diazoxide. The exposures to diazoxide in the
presence of adenosine abbreviated the latency from 6.6±1.1 to
4.3±0.5 minutes (n=5, P<0.05). Repeated applications of
diazoxide alone neither potentiate nor accelerate flavoprotein
oxidation.17
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To confirm that adenosine potentiated and accelerated the
oxidative effect of diazoxide via stimulation of adenosine
A1 receptors, we examined the effects of the
adenosine A1 receptor
antagonist SPT. When 100 µmol/L SPT was present
in the perfusate, adenosine (100 µmol/L) failed
to augment the oxidative effect of diazoxide and did not abbreviate the
latency to mitoKATP activation (Figure 2A). As summarized in Figure 2B, in the presence of SPT (100 µmol/L) with adenosine
(100 µmol/L), diazoxide increased flavoprotein oxidation to
38±9% of the DNP value (n=4). This degree of oxidation was comparable
to that achieved by exposure to diazoxide alone (41±6% of the DNP
value, n=4). Furthermore, the latency to mitoKATP
activation was not abbreviated when the adenosine was
co-applied with SPT (6.8±1.3 versus 6.5±1.4 minutes, n=4,
P=NS) (Figure 2C). We also examined whether
activation of endogenous PKC by adenosine results
in mitoKATP channel activation. Chelerythrine and
calphostin C, both of which are reported to be more selective PKC
inhibitors, enhanced the emitted fluorescence
signal nonspecifically. Therefore, polymyxin B was used to inhibit
endogenous PKC in the present experiments. As shown in
Figure 3, in the presence of polymyxin B
(50 µmol/L), adenosine (100 µmol/L) did not alter
the oxidative effect of diazoxide (43±3% versus 42±2% of the DNP
value, n=5, P=NS) and could not abbreviate the latency to
mitoKATP activation (7.9±0.9 versus 8.4±0.7
minutes, n=5, P=NS).
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To verify that the diazoxide-induced flavoprotein oxidation observed in
the presence of adenosine reflects the activation of
mitoKATP channels, the effects of the
mitoKATP channel blocker 5HD were examined. 5HD
(500 µmol/L) suppressed diazoxide-induced flavoprotein oxidation
from 39±4% to 9±2% of the DNP value (n=4, P<0.01), even
with the concomitant application of adenosine (Figure 4). These results indicate that
adenosine primes the opening of mitoKATP
channels through the adenosine A1
receptor–mediated activation of PKC.
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Our finding that adenosine increases diazoxide-induced
mitochondrial oxidation begs the question of whether adenosine
potentiates diazoxide-induced cardioprotection. Figure 5 plots the fraction of cells stained by
60 minutes of simulated ischemia as a percentage of the total
number of viable cells before ischemia. Diazoxide decreased the
percentage of cells stained during 60 minutes of ischemia, in a
concentration-dependent manner. Inclusion of 100 µmol/L
adenosine alone significantly decreased the extent of cell
staining during ischemia. In addition, the cardioprotective
effects of diazoxide were significantly augmented by
simultaneous application of 100 µmol/L
adenosine. The cardioprotection in the presence of both
diazoxide (100 µmol/L) and adenosine (100 µmol/L)
surpassed the level achieved by diazoxide alone (11±1%, n=5).
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P<0.005 and
In the next series of experiments, we tested the idea that
mitoKATP channels rather than
surfaceKATP channels act as effectors for
cardioprotection afforded by adenosine. As shown in
Figure 6, simulated
ischemia for 60 and 120 minutes stained 37±2% (n=6) and
47±2% (n=4) of cells, respectively (control group). Inclusion of
adenosine (100 µmol/L) significantly decreased the cells
stained during ischemia to 21±2% (n=6) after 60 minutes and
27±3% (n=4) after 120 minutes of ischemia
(adenosine-treated group, P<0.001 versus control group). The
cardioprotective effects of adenosine were abolished by
500 µmol/L 5HD (40±4% after 60 minutes and 49±3% after 120
minutes of ischemia). In contrast, the selective
surfaceKATP channel inhibitor HMR1098
(30 µmol/L) did not abolish the cardioprotection by
adenosine. These results indicate that adenosine primes
the opening of mitoKATP channels and thereby
protects myocytes against ischemic damage.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Diazoxide targets mitoKATP but not surfaceKATP channels in heart cells and oxidizes the mitochondrial matrix by opening mitoKATP channels.14 The oxidative effects of diazoxide are reversible and reproducible: under basal conditions, the degree of oxidation is identical during first and second exposures to diazoxide, and there is no significant difference in the latencies during first and second exposures.14 17 In the present study, we found that adenosine potentiated the oxidative effects of diazoxide and abbreviated the latency to mitoKATP channel activation on the application of diazoxide (Figure 1
).
The results agree qualitatively and quantitatively with those of Sato
et al,17 in which PKC-activating phorbol ester (phorbol
12-myristate 13-acetate) augmented and accelerated the
mitochondrial oxidation induced by diazoxide. These findings led us to
test the idea that PKC is downstream from the adenosine
A1 receptor and precedes the activation of
mitoKATP channels. Both the
A1 receptor antagonist SPT and the
PKC inhibitor polymyxin B prevented the ability of
adenosine to augment and accelerate the oxidative effect of
diazoxide (Figures 2 and 3). Moreover, the
mitoKATP channel inhibitor 5HD
blocked diazoxide-induced mitochondrial matrix oxidation in the
presence of adenosine (Figure 4). These results taken
together suggest that adenosine A1
receptors link to mitoKATP channels through
PKC.
We have observed 2 classes of effects of agents on
mitoKATP channels. The KATP
channel openers diazoxide and pinacidil open the channels directly,
leading to net mitochondrial oxidation.14 17 In contrast,
adenosine and PKC-stimulating phorbol esters act to prime the
channels17 : instead of opening them directly, these agents
potentiate the subsequent opening of mitoKATP
channels. Thus, we propose the mechanism depicted schematically in
Figure 7A. MitoKATP
channels exist in 3 distinct states: resting, primed, and open.
"Virgin" myocardium contains only resting channels.
Such channels cannot open directly; they must first traverse through
several intermediate nonconducting states before opening. Diazoxide
application to resting channels initiates the opening process, but a
delay is introduced by the obligatory transit through intermediate
nonconducting states. Adenosine and PKC activators
shift mitoKATP channels into the primed
conformation, from which they can open in response to subsequent direct
activation. Diazoxide readily opens channels that are primed; however,
the response in virgin myocardium is slow, because the
primed channel state is unpopulated. To test whether the scheme in
Figure 7A suffices to reproduce our findings, we created an
equivalent Markov model for quantitative simulation (Figure 7B).22 We assume that virgin channels are all in
the C1 state; exposure to adenosine or
PKC activators shifts the channels into the primed C*
state. Exposure to diazoxide initiates channel opening, either along
the upper (virgin) trajectory (C1
C2 C3
C4 O) or along the lower (preconditioned) one
(C* O*). The simulation results in Figure 7C reveal that
exposure of virgin myocardium to diazoxide opens the
channels with some delay. In contrast, Figure 7D shows that
diazoxide opens primed channels briskly and intensely. Note that
adenosine itself does not open the channels; it merely shifts
them into a primed state from which they can open much more
readily.
The sort of mechanism proposed in Figure 7 has close parallels
in numerous studies of ion channels. The model itself is a direct
adaptation of the classical Hodgkin-Huxley gating scheme for
voltage-dependent potassium channels.22 The proposed
regulatory mechanism also has well-established precedents. For example,
L-type calcium channels open in response to membrane depolarization,
but they do so quite infrequently in the basal "resting" state.
cAMP-dependent phosphorylation shifts the channels into
"primed" states, from which they open much more vigorously in
response to depolarization, but such phosphorylation
does not suffice to open the channels.25 26
Pharmacological agonists (eg, Bay K8644, Bayer) can open calcium
channels directly in a manner quite analogous to the ability of
diazoxide to open mitoKATP
channels.25 Although the model rationalizes the
pharmacology and regulation of mitoKATP channels
in a biologically plausible manner, we must stress that it is
presented primarily for heuristic reasons; the details (eg, the
precise number of nonconducting states) are underconstrained and
subject to refinement as more data become available.
The model proposed in Figure 7 rationalizes the combined effects
of adenosine and diazoxide: cardioprotection would be maximized
if both priming and direct activation are operative. Similar reasoning
may explain the cardioprotective effects of adenosine itself.
Despite the fact that adenosine does not suffice to open
mitoKATP channels, it shifts channels into the
primed state, from which they can be opened much more readily by
endogenous stimuli during ischemia (most likely ATP
depletion and/or ADP accumulation,27 although
changes in guanine nucleotides28 or nitric
oxide29 may also play a role). Thus, adenosine can
be cardioprotective without direct channel opening.
The salient novel finding from the present study is that the
cardioprotection induced by adenosine can be inhibited by the
mitoKATP channel blocker 5HD but not by HMR1098
(Figure 6). Unlike 5HD, HMR109830 targets
surfaceKATP without suppressing
mitoKATP channels: HMR1098 at the concentration
used in the present study (30 µmol/L) inhibits surface
KATP currents activated by
metabolic inhibition and by
surfaceKATP channel opener P-1075 but has no
effect on mitoKATP channels in rabbit
ventricular cells.31 These results, taken
together, indicate that cardioprotective effects of adenosine
are mediated by the opening of mitoKATP
channels.
How might IPC be explained from the present results? We conjecture that in preconditioned myocardium, adenosine receptor activation primes mitoKATP channels in a PKC-dependent manner. Consequently, rapid and robust opening of mitoKATP channels during lethal ischemia protects myocytes against ischemic damage. In agreement with this notion, Miura et al32 have reported that the adenosine A1 receptor agonist R-phenylisopropyl-adenosine mimics the infarct size-limiting effects of IPC; this protection is prevented by the PKC inhibitor calphostin C and the mitoKATP channel inhibitor 5HD. The findings further implicate mitoKATP channels and provide tangible links among various key elements in the preconditioning cascade.
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Acknowledgments |
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This study was supported by National Institutes of Health (NIH) grant R37 HL-36957 (to Dr Marbán), a Banyu Fellowship in Lipid Metabolism and Atherosclerosis (to Dr Sato), and NIH grant R01 HL-54598 (salary support to Dr O’Rourke). Dr Marbán holds the Michel Mirowski, MD, Professorship of Cardiology.
Received January 28, 2000; revision received March 15, 2000; accepted March 16, 2000.
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D. K. Arrell, S. T. Elliott, L. A. Kane, Y. Guo, Y. H. Ko, P. L. Pedersen, J. Robinson, M. Murata, A. M. Murphy, E. Marban, et al. Proteomic Analysis of Pharmacological Preconditioning: Novel Protein Targets Converge to Mitochondrial Metabolism Pathways Circ. Res., September 29, 2006; 99(7): 706 - 714. [Abstract] [Full Text] [PDF]
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A. Hassouna, M. Loubani, B. M. Matata, A. Fowler, N. B. Standen, and M. Galinanes Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium Cardiovasc Res, February 1, 2006; 69(2): 450 - 458. [Abstract] [Full Text] [PDF]
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A. Kher, K. K. Meldrum, M. Wang, B. M. Tsai, J. M. Pitcher, and D. R. Meldrum Cellular and molecular mechanisms of sex differences in renal ischemia-reperfusion injury Cardiovasc Res, September 1, 2005; 67(4): 594 - 603. [Abstract] [Full Text] [PDF]
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T. Okada, H. Otani, Y. Wu, T. Uchiyama, S. Kyoi, R. Hattori, T. Sumida, H. Fujiwara, and H. Imamura Integrated pharmacological preconditioning and memory of cardioprotection: role of protein kinase C and phosphatidylinositol 3-kinase Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H761 - H767. [Abstract] [Full Text] [PDF]
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V. Shneyvays, D. Leshem, T. Zinman, L. K. Mamedova, K. A. Jacobson, and A. Shainberg Role of adenosine A1 and A3 receptors in regulation of cardiomyocyte homeostasis after mitochondrial respiratory chain injury Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2792 - H2801. [Abstract] [Full Text] [PDF]
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K. Shinmura, K. Tamaki, T. Sato, H. Ishida, and R. Bolli Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K+ channels via the EP3 receptor Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2093 - H2101. [Abstract] [Full Text] [PDF]
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S. Kimura, G.-X. Zhang, A. Nishiyama, T. Shokoji, L. Yao, Y.-Y. Fan, M. Rahman, T. Suzuki, H. Maeta, and Y. Abe Role of NAD(P)H Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Cardioprotection of Ischemic Reperfusion Injury by Angiotensin II Hypertension, May 1, 2005; 45(5): 860 - 866. [Abstract] [Full Text] [PDF]
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 T. Sato, T. Saito, N. Saegusa, and H. Nakaya Mitochondrial Ca2+-Activated K+ Channels in Cardiac Myocytes: A Mechanism of the Cardioprotective Effect and Modulation by Protein Kinase A Circulation, January 18, 2005; 111(2): 198 - 203. [Abstract] [Full Text] [PDF]
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A. K. S. Camara, Q. Chen, S. S. Rhodes, M. L. Riess, and D. F. Stowe Negative inotropic drugs alter indexes of cytosolic [Ca2+]-left ventricular pressure relationships after ischemia Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H667 - H680. [Abstract] [Full Text] [PDF]
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B. O'Rourke Evidence for Mitochondrial K+ Channels and Their Role in Cardioprotection Circ. Res., March 5, 2004; 94(4): 420 - 432. [Abstract] [Full Text] [PDF]
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W. R. Tracey, W. P. Magee, J. J. Oleynek, R. J. Hill, A. H. Smith, D. M. Flynn, and D. R. Knight Novel N6-substituted adenosine 5'-N-methyluronamides with high selectivity for human adenosine A3 receptors reduce ischemic myocardial injury Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2780 - H2787. [Abstract] [Full Text] [PDF]
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J. P. Headrick, B. Hack, and K. J. Ashton Acute adenosinergic cardioprotection in ischemic-reperfused hearts Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1797 - H1818. [Abstract] [Full Text] [PDF]
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 Y. Nakae, S. Kohro, Q. H. Hogan, and Z. J. Bosnjak Intracellular Mechanism of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channel Activation with Isoflurane Anesth. Analg., October 1, 2003; 97(4): 1025 - 1032. [Abstract] [Full Text] [PDF]
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Y. Uchiyama, H. Otani, T. Okada, T. Uchiyama, H. Ninomiya, M. Kido, H. Imamura, S. Nakao, and K. Shingu Integrated pharmacological preconditioning in combination with adenosine, a mitochondrial KATP channel opener and a nitric oxide donor J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 148 - 159. [Abstract] [Full Text] [PDF]
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S. B. Digerness, P. S. Brookes, S. P. Goldberg, C. R. Katholi, and W. L. Holman Modulation of mitochondrial adenosine triphosphate-sensitive potassium channels and sodium-hydrogen exchange provide additive protection from severe ischemia-reperfusion injury J. Thorac. Cardiovasc. Surg., April 1, 2003; 125(4): 863 - 871. [Abstract] [Full Text] [PDF]
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Z.-Q. Zhao and J. Vinten-Johansen Myocardial apoptosis and ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 438 - 455. [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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K. Mubagwa and W. Flameng Adenosine, adenosine receptors and myocardial protection: An updated overview Cardiovasc Res, October 1, 2001; 52(1): 25 - 39. [Abstract] [Full Text] [PDF]
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T. L. Clanton and P. F. Klawitter Physiological and Genomic Consequences of Intermittent Hypoxia: Invited Review: Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown J Appl Physiol, June 1, 2001; 90(6): 2476 - 2487. [Abstract] [Full Text] [PDF]
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D. K. Arrell, I. Neverova, H. Fraser, E. Marban, and J. E. Van Eyk Proteomic Analysis of Pharmacologically Preconditioned Cardiomyocytes Reveals Novel Phosphorylation of Myosin Light Chain 1 Circ. Res., September 14, 2001; 89(6): 480 - 487. [Abstract] [Full Text] [PDF]
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