(Circulation. 2000;101:439.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Activation of Mitochondrial ATP-Dependent Potassium Channels by Nitric Oxide
From the Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Md.
Correspondence to Eduardo Marbán, MD, PhD, Director, Institute of Molecular Cardiobiology, 844 Ross Bldg, The Johns Hopkins University School of Medicine, Baltimore MD 21205. E-mail marban{at}jhmi.edu
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Abstract |
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Background—Nitric oxide (NO) has been implicated as a mediator of "second-window" ischemic preconditioning, and mitochondrial ATP-dependent K+ (mitoKATP) channels are the likely effectors. The links between NO and mitoKATP channels are unknown.
Methods and Results—We measured mitochondrial redox potential as an index of mitoKATP channel opening in rabbit ventricular myocytes. The NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP, 0.1 to 1 mmol/L) oxidized the mitochondrial matrix dose-dependently without activating sarcolemmal KATP channels. SNAP-induced oxidation was blocked by the selective mitoKATP channel blocker 5-hydroxydecanoate and by the NO scavenger 2-(4-carboxyphenyl)-4,4',5,5'-tetramethylimidazole-1-oxyl-3-oxide. SNAP-induced mitochondrial oxidation was detectable either by photomultiplier tube recordings of flavoprotein fluorescence or by confocal imaging. SNAP also enhanced the oxidative effects of diazoxide when both agents were applied together. Exposure to 1 mmol/L 8Br-cGMP failed to mimic the effects of SNAP.
Conclusions—NO directly activates mitoKATP channels and potentiates the ability of diazoxide to open these channels. These results provide novel mechanistic links between NO-induced cardioprotection and mitoKATP channels.
Key Words: ischemic preconditioning • nitric oxide • myocytes • mitochondria
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Introduction |
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Nitric oxide is a key signaling molecule that figures prominently in ischemic preconditioning. NO is generated during the oxidation of L-arginine to citrulline, not only in the cytosol but also in mitochondria.1 2 3 During ischemia, the endogenous production of NO in the heart is increased.1 It is also common therapeutic practice to administer exogenous nitrates in acute ischemic syndromes, further boosting the concentration of NO. Although NO has been reported to afford cardioprotection from reperfusion injury,4 5 6 the role of NO during the early phase of ischemic preconditioning is controversial.7 8 9 10 Conversely, several lines of evidence convincingly implicate NO as a mediator of the late phase (second window) of ischemic preconditioning against infarction and stunning.11 12 13 The cardioprotective effects of NO have been explained by several factors, such as microvascular effects,4 antineutrophil action,4 induction of stress protein,14 or modulation of cardiac excitability.7 Recently, Bernardo et al15 reported that delayed ischemic preconditioning is inhibited by 5-hydroxydecanoate (5HD) in the rabbit heart. Because 5HD is a selective blocker of mitochondrial ATP-dependent potassium (mitoKATP) channels in rabbit ventricular cells,16 the ability of 5HD to abolish second-window protection motivated us to look for possible links between NO and mitoKATP channels.
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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 National Institutes of Health (NIH publication 85-23, revised 1985).
Materials
Collagenase (type II) was purchased from
Worthington. Diazoxide, 2,4-dinitrophenol (DNP), sodium cyanide (CN),
SNAP, and 8-bromo cGMP (8Br-cGMP) were obtained from Sigma Chemical Co.
5HD, pinacidil, and
2-(4-carboxyphenyl)-4,4',5,5'-tetramethylimidazole-1-oxyl 3-oxide
(carboxy-PTIO) were purchased from Research Biochemical International.
Diazoxide, SNAP, pinacidil, and carboxy-PTIO were dissolved in DMSO
before they were added to experimental solutions. The final
concentration of DMSO was <0.1%.
Cell Isolation and Measurement of Mitochondrial Redox
State
Rabbit ventricular myocytes were isolated
enzymatically from adult rabbit hearts and placed in primary culture as
described previously.16 17
Experiments were performed over the next day.
MitoKATP channel activity was monitored
noninvasively by measuring flavoprotein fluorescence as an
index of mitochondrial redox state with or without
simultaneous whole-cell membrane current recordings
(as indicated).16 17 18 Cells were superfused with external
solution containing (in mmol/L) NaCl 140, KCl 5,
CaCl2 1, MgCl2 1, and HEPES
10 (pH adjusted to 7.4 with NaOH) at room temperature (
22°C).
Endogenous flavoprotein fluorescence was excited
for 100 ms every 6 seconds by a xenon arc lamp with a bandpass 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 at the end of each
experiment by exposure to DNP, which uncouples respiration from ATP
synthesis and induces maximal oxidation. Therefore, the values of
flavoprotein fluorescence are expressed as a percentage of the
DNP-induced fluorescence. Individual myocytes were observed
with a x40 objective to monitor fluorescence 1 cell at a
time.
Confocal Imaging of Flavoprotein Fluorescence
Confocal images were obtained with a Diaphot 300 inverted
fluorescence microscope with a PCM-2000 confocal scanning
attachment (Nikon, Inc).17 18 Fluorescence was
excited by the 488-nm line of an argon laser, and the emission at 505
to 535 nm was recorded. A time series of images was collected at
intervals of 10 seconds, and baseline, diazoxide, SNAP, SNAP+5HD, CN,
and DNP images were enhanced by averaging of 7 sequential images having
stable mean fluorescence intensities during exposure to each
agent. Images were analyzed on a personal computer with the
software program Simple32 (Compix, Inc).
Data Analysis
To evaluate the effects of pharmacological agents on
flavoprotein fluorescence, the slope of relative change in the
fluorescence during drug application was calculated by a
least-squares method. The best-fit line is indicated by a dotted line
in Figure 1
(A, B, and C),
Figure 3 (top), and Figure 4 (A and B). Pooled data are
presented as mean±SEM, and the number of cells or experiments
is shown as n. Statistical comparison was evaluated by 1-way ANOVA,
with a value of P<0.05 considered significant.
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Electrophysiological Recordings
In some experiments (Figure 3
), whole-cell currents and
flavoprotein fluorescence were measured
simultaneously. The internal pipette solution contained
(in mmol/L) potassium glutamate 120, KCl 25,
MgCl2 0.5, K-EGTA 10, HEPES 10, and MgATP 1 (pH
adjusted to 7.2 with KOH). Whole-cell currents were elicited every 6
seconds from a holding potential of -80 mV by 2 consecutive steps to
-40 mV (for 100 ms) and 0 mV (for 380 ms), and flavoprotein
fluorescence was excited during the 100-ms step to -40 mV. To
quantify IK,ATP, currents at 0 mV were
measured 200 ms into the pulse.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effects of SNAP on mitoKATP Channels
Figure 1A
shows the time course of flavoprotein
fluorescence in a cell exposed first to diazoxide, then to
SNAP, and finally again to diazoxide. In the first application,
diazoxide reversibly oxidized the flavoproteins. Subsequent exposure to
SNAP alone gradually increased flavoprotein oxidation with a slope of
0.59%/min. After a 15-minute exposure to SNAP, mitochondrial oxidation
persisted even 5 minutes after washout. Although NO has been reported
to inhibit respiration,2 19 20 the
present changes are in the opposite direction to those that would
be expected from such an effect (in which case the mitochondrial matrix
would have been reduced, as it is with
CN-).18 Note also that the second
exposure to diazoxide after SNAP increased flavoprotein oxidation above
the levels reached in the first application, with less of a lag during
the second exposure (4 minutes, versus 8 to 9 minutes during the first
exposure).
To determine whether mitoKATP channels are
involved in SNAP-induced mitochondrial oxidation, we applied 5HD, a
selective mitoKATP channel blocker. Figure 1, B and C, shows that 1 mmol/L 5HD reversed (B) or
prevented (C) the SNAP-induced flavoprotein oxidation. Figure 1D
summarizes the amplitude of diazoxide-induced flavoprotein oxidation
during the first [DIAZO(1)] and second exposures to diazoxide after
the application of SNAP [DIAZO(2) SNAP]. Pretreatment with SNAP
significantly enhanced the effects of diazoxide-induced oxidation; we
have previously shown that repeated exposures to diazoxide alone do not
produce potentiation.17 Figure 1E summarizes the
latency to mitoKATP channel activation, measured
as the time required to increase flavoprotein fluorescence to
20% of its maximal value after washing in diazoxide. The latency was
significantly abbreviated during the second exposure to diazoxide after
SNAP. Figure 1F summarizes the effects of 5HD on the
SNAP-induced fluorescence changes and verifies that 5HD
significantly and consistently inhibits SNAP-induced
mitochondrial oxidation. These results indicate that SNAP-induced
mitochondrial oxidation is mediated by activation of
mitoKATP channels.
Effects of SNAP on Flavoprotein Fluorescence Detected by
Confocal Imaging
To further confirm the NO-induced activation of
mitoKATP channels, the effect of SNAP on
flavoprotein fluorescence was measured by confocal imaging.
Fluorescence was low under control conditions (Figure 2A), but exposure to diazoxide reversibly
increased fluorescence (B; washout image in C). Subsequent
exposure to SNAP also increased flavoprotein fluorescence (D),
but SNAP-induced oxidation was inhibited by additional application of
5HD (E). Images were calibrated at the end of the experiment by
exposure to cyanide (F) and DNP (G). The patchy distribution of
fluorescence in the confocal images is typical of
mitochondria,17 18 confirming that NO oxidizes the
mitochondrial matrix by activation of mitoKATP
channels.
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Effects of SNAP on mitoKATP and Sarcolemmal
KATP Channels
To test the selectivity of NO on mitoKATP
versus sarcolemmal KATP channels, we examined the
effects of SNAP on flavoprotein fluorescence and whole-cell
currents simultaneously. In Figure 3, application of 0.5 mmol/L SNAP
without preexposure to diazoxide gradually oxidized the mitochondrial
matrix with a slope of 0.78%/min. SNAP-induced oxidation was inhibited
by coapplication of 1 mmol/L 5HD. In the continued presence of
5HD, subsequent exposure to 100 µmol/L pinacidil (a mixed
mitoKATP/surface KATP
agonist)16 failed to induce mitochondrial oxidation. In
contrast, Figure 3 (bottom) shows that SNAP had no effect on
sarcolemmal KATP channels, because pinacidil
activated sarcolemmal KATP channels
despite the presence of 5HD. These results are
representative and reproducible. A 20-minute exposure
to SNAP (0.5 mmol/L) had no significant effect on whole-cell
current (before, 5.6±6.1 pA versus after, 12.9±4.8 pA at 0 mV, n=4,
P=NS). Nevertheless, in the presence of 1 mmol/L 5HD, a
10-minute exposure to 100 µmol/L pinacidil increased sarcolemmal
KATP current (554.9±82.9 pA at 0 mV, n=4,
P<0.001 versus before). These results indicate that SNAP
selectively activates mitoKATP channels.
Furthermore, Figure 3 demonstrates that SNAP-induced activation
of mitoKATP channels does not require preexposure
to diazoxide. Finally, the finding that 5HD suppresses the
mitochondrial oxidation induced by pinacidil, but not the agonist
effect on IK,ATP, demonstrates that 1
mmol/L 5HD is a selective inhibitor of
mitoKATP channels in rabbit
ventricular cells.16 17
Mediation by NO Independent of cGMP
To verify that the SNAP-induced changes are actually mediated by
the release of NO, we tested the effects of carboxy-PTIO, an NO
scavenger,21 on the SNAP-induced flavoprotein oxidation.
Figure 4A shows that coapplication of
carboxy-PTIO with SNAP prevented the flavoprotein oxidation (slope
<0%/min). Because many (but not all) of the effects of NO occur via a
cGMP-dependent pathway,22 23 we tested whether NO-induced
activation of mitoKATP is mimicked by 8Br-cGMP.
Figure 4B shows that exposure to this cell-permeable cGMP
analogue did not increase flavoprotein oxidation, nor did pretreatment
with 8Br-cGMP enhance diazoxide-induced oxidation. The effects of the
NO scavenger and 8Br-cGMP were observed reproducibly. Figure 4, C and D, shows that carboxy-PTIO abolished the enhancing effects of
SNAP on diazoxide-induced oxidation, confirming that the SNAP-induced
change is mediated by release of NO. Figure 4, E and F,
summarizes data for 8Br-cGMP, confirming that it fails to mimic the
effects of SNAP.
The pooled data in Figure 5 reveal that
SNAP significantly increases the slope of percent change in
flavoprotein oxidation and that the SNAP-induced effect is inhibited by
5HD and carboxy-PTIO. The inset shows the dose-response relationship
between SNAP concentration and flavoprotein oxidation. Taken together
with the results in Figure 4, these experiments support the idea
that SNAP activates mitoKATP channels
dose-dependently via a direct effect of NO, not mediated by cGMP.
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Effects of SNAP in the Presence of Diazoxide
We previously reported that protein kinase C (PKC)
activation enhances diazoxide-induced changes without affecting basal
flavoprotein fluorescence.16 This finding
indicates that the modulation of mitoKATP by PKC
may depend on whether the channels are in the open or closed state when
the kinase becomes active. To test for analogous state-dependent
changes in the case of NO, we quantified the effects of SNAP on
channels that had already been opened by diazoxide. Figure 6A shows that 1 mmol/L SNAP rapidly
enhanced diazoxide-induced oxidation when applied after the effect of
diazoxide had reached steady state. Note that in this case, the effects
of SNAP were reversible. Figure 6C shows that carboxy-PTIO
abolished the enhancing effect of SNAP on diazoxide-induced oxidation,
and Figure 6E demonstrates that 8Br-cGMP failed to mimic the
effects of SNAP on mitoKATP in the presence of
diazoxide. Figure 6, B, D, and F, summarizes data for
coadministration of diazoxide with SNAP, SNAP+carboxy-PTIO, and
8Br-cGMP, respectively. These results indicate that NO enhances
mitoKATP channels preactivated by
diazoxide. Channels that are already open appear to be more susceptible
to the potentiating actions of NO than channels that are in the closed
state.
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Discussion |
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Our data reveal that NO selectively activates mitoKATP channels but not sarcolemmal KATP channels. The modulation of mitoKATP channels by NO is manifested in 2 ways. One is the gradual oxidation induced by NO alone, and the other is potentiation of mitoKATP channels preopened by diazoxide. The latter effect resembles that of phorbol esters that turn on PKC and enhance diazoxide-induced oxidation,16 but unlike NO, phorbol esters alone do not suffice to activate the channels. It is possible that the 2 observations share a common pathway, inasmuch as reactive oxygen species (such as the NO product peroxynitrite) are known to activate PKC.13 24 25 Shinbo and Iijima26 reported that the application of the NO donor NOR-3 increased the open probability of agonist-activated surface KATP channels in cardiac myocytes, whereas NOR-3 had no effect in the absence of channel agonists. We have found that PKC primes ventricular surface KATP channels to open in response to agonists or to metabolic inhibition, but basal activity is unaffected.27 28 These findings again resemble the rapid enhancement of mitoKATP by NO in the presence of diazoxide but differ in the inability of the modulator to alter basal activity. Although the structural relationship between surface and mitoKATP channels is unknown,29 the results suggest that the 2 channels may share regulatory pathways sensitive to NO, as is the case for PKC.16 27 29 In pancreatic ß cells, NO has been argued to inhibit glycolysis, leading to a secondary activation of surface KATP channels.30 However, SNAP did not increase whole-cell KATP current in the present study, consistent with the finding that NO alone did not activate single KATP channels in cell-attached mode in guinea pig ventricular myocytes.26 The mitoKATP channel is not especially sensitive to changes in bulk [ATP], remaining closed even at 0.5 mmol/L [ATP].31 Considering these observations, it seems unlikely that the effects of NO on mitoKATP channels reflect inhibition of glycolysis.
Both NO and mitoKATP channels have been implicated in the delayed phase of preconditioning known as the "second window" of protection.11 12 13 MitoKATP channel opening is cardioprotective during ischemia,17 32 whereas blockade of mitoKATP channels abolishes both classic and second-window protection. The present study establishes NO as an endogenous mitoKATP channel opener that may be able to recruit cardioprotection in the second window. NO may play a particularly prominent role in the second window because of changes in gene expression, notably the upregulation of nitric oxide synthase that occurs within 24 hours of conditioning ischemia. Although the relationships between mitoKATP channel activation and cardioprotection remain elusive, the opening of channels in the inner membrane may dissipate the mitochondrial potential established by the proton pump, perhaps blunting the Ca2+ overload that would otherwise occur as a result of the large driving force for Ca2+ entry into mitochondria during ischemia.16 17 It was recently reported that mitoKATP channel openers release Ca2+ from Ca2+-loaded mitochondria.33 The uncoupling by diazoxide appears to be much gentler than that which can be induced by agents such as DNP34 ; indeed, severe uncoupling should be harmful to myocytes, because energy production is critically reduced. We speculate that NO, functioning as an endogenous mitoKATP channel opener, may titrate the coupling level of the mitochondria to an optimum that blunts mitochondrial calcium overload without significantly undermining ATP synthetic capacity.
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Acknowledgments |
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This study was supported by the NIH (grant R37-HL-36957 to Dr Marbán and ROI-54598 to Dr O’Rourke), a Japan Heart Foundation and Bayer Yakuhin Research Grant Abroad (to Dr Sasaki), a Banyu Fellowship in Lipid Metabolism and Atherosclerosis (to Dr Sato), and the Deutsche Forschungsgemeinschaft (to Dr Ohler).
Received July 7, 1999; accepted August 4, 1999.
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S. M. Davidson and M. R. Duchen Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance Cardiovasc Res, July 1, 2006; 71(1): 10 - 21. [Abstract] [Full Text] [PDF]
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D. V. Cuong, N. Kim, J. B. Youm, H. Joo, M. Warda, J.-W. Lee, W. S. Park, T. Kim, S. Kang, H. Kim, et al. Nitric oxide-cGMP-protein kinase G signaling pathway induces anoxic preconditioning through activation of ATP-sensitive K+ channels in rat hearts Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1808 - H1817. [Abstract] [Full Text] [PDF]
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M. Juhaszova, C. Rabuel, D. B. Zorov, E. G. Lakatta, and S. J. Sollott Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res, May 1, 2005; 66(2): 233 - 244. [Abstract] [Full Text] [PDF]
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A. Das, L. Xi, and R. C. Kukreja Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis: ESSENTIAL ROLE OF NITRIC OXIDE SIGNALING J. Biol. Chem., April 1, 2005; 280(13): 12944 - 12955. [Abstract] [Full Text] [PDF]
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A. Sarre, N. Lange, P. Kucera, and E. Raddatz mitoKATP channel activation in the postanoxic developing heart protects E-C coupling via NO-, ROS-, and PKC-dependent pathways Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1611 - H1619. [Abstract] [Full Text] [PDF]
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G. Wang, D. A. Liem, T. M. Vondriska, H. M. Honda, P. Korge, D. M. Pantaleon, X. Qiao, Y. Wang, J. N. Weiss, and P. Ping Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1290 - H1295. [Abstract] [Full Text] [PDF]
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L. Xi, M. Taher, C. Yin, F. Salloum, and R. C. Kukreja Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1{alpha} and AP-1 and iNOS signaling Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2369 - H2375. [Abstract] [Full Text] [PDF]
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Y. Wang, N. Ahmad, M. Kudo, and M. Ashraf Contribution of Akt and endothelial nitric oxide synthase to diazoxide-induced late preconditioning Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1125 - H1131. [Abstract] [Full Text] [PDF]
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Q. Qin, X.-M. Yang, L. Cui, S. D. Critz, M. V. Cohen, N. C. Browner, T. M. Lincoln, and J. M. Downey Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H712 - H718. [Abstract] [Full Text] [PDF]
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Z. Xu, X. Ji, and P. G. Boysen Exogenous nitric oxide generates ROS and induces cardioprotection: involvement of PKG, mitochondrial KATP channels, and ERK Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1433 - H1440. [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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E. Murphy Primary and Secondary Signaling Pathways in Early Preconditioning That Converge on the Mitochondria to Produce Cardioprotection Circ. Res., January 9, 2004; 94(1): 7 - 16. [Abstract] [Full Text] [PDF]
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O. Oldenburg, Q. Qin, T. Krieg, X.-M. Yang, S. Philipp, S. D. Critz, M. V. Cohen, and J. M. Downey Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H468 - H476. [Abstract] [Full Text] [PDF]
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M. Joyeux-Faure, C. Arnaud, D. Godin-Ribuot, and C. Ribuot Heat stress preconditioning and delayed myocardial protection: what is new? Cardiovasc Res, December 1, 2003; 60(3): 469 - 477. [Abstract] [Full Text] [PDF]
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 J. S. Cameron, K. E. Hoffmann, C. Zia, H. M. Hemmett, A. Kronsteiner, and C. M. Lee A role for nitric oxide in hypoxia-induced activation of cardiac KATP channels in goldfish (Carassius auratus) J. Exp. Biol., November 15, 2003; 206(22): 4057 - 4065. [Abstract] [Full Text] [PDF]
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S. P. Jones, Y. Teshima, M. Akao, and E. Marban Simvastatin Attenuates Oxidant-Induced Mitochondrial Dysfunction in Cardiac Myocytes Circ. Res., October 17, 2003; 93(8): 697 - 699. [Abstract] [Full Text] [PDF]
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J. N. Weiss, P. Korge, H. M. Honda, and P. Ping Role of the Mitochondrial Permeability Transition in Myocardial Disease Circ. Res., August 22, 2003; 93(4): 292 - 301. [Abstract] [Full Text] [PDF]
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F. Salloum, C. Yin, L. Xi, and R. C. Kukreja Sildenafil Induces Delayed Preconditioning Through Inducible Nitric Oxide Synthase-Dependent Pathway in Mouse Heart Circ. Res., April 4, 2003; 92(6): 595 - 597. [Abstract] [Full Text] [PDF]
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C. Arnaud, D. Godin-Ribuot, S. Bottari, A. Peinnequin, M. Joyeux, P. Demenge, and C. Ribuot iNOS is a mediator of the heat stress-induced preconditioning against myocardial infarction in vivo in the rat Cardiovasc Res, April 1, 2003; 58(1): 118 - 125. [Abstract] [Full Text] [PDF]
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N. Sasaki, M. Murata, Y. Guo, S.-H. Jo, A. Ohler, M. Akao, B. O'Rourke, R.-P. Xiao, R. Bolli, and E. Marban MCC-134, a Single Pharmacophore, Opens Surface ATP-Sensitive Potassium Channels, Blocks Mitochondrial ATP-Sensitive Potassium Channels, and Suppresses Preconditioning Circulation, March 4, 2003; 107(8): 1183 - 1188. [Abstract] [Full Text] [PDF]
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R. M Bell, H. L Maddock, and D. M Yellon The cardioprotective and mitochondrial depolarising properties of exogenous nitric oxide in mouse heart Cardiovasc Res, February 1, 2003; 57(2): 405 - 415. [Abstract] [Full Text] [PDF]
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G. Lebuffe, P. T. Schumacker, Z.-H. Shao, T. Anderson, H. Iwase, and T. L. Vanden Hoek ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H299 - H308. [Abstract] [Full Text] [PDF]
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M. Joyeux, C. Arnaud, D. Godin-Ribuot, P. Demenge, D. Lamontagne, and C. Ribuot Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts Cardiovasc Res, August 15, 2002; 55(3): 619 - 625. [Abstract] [Full Text] [PDF]
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L. Xi, D. Tekin, E. Gursoy, F. Salloum, J. E. Levasseur, and R. C. Kukreja Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H5 - H12. [Abstract] [Full Text] [PDF]
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T.-M. Lee, S.-F. Su, T.-F. Chou, and C.-H. Tsai Pharmacologic preconditioning of estrogen by activation of the myocardial adenosine triphosphate-sensitive potassium channel in patients undergoing coronary angioplasty J. Am. Coll. Cardiol., March 6, 2002; 39(5): 871 - 877. [Abstract] [Full Text] [PDF]
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S. Krick, O. Platoshyn, M. Sweeney, S. S. McDaniel, S. Zhang, L. J. Rubin, and J. X.-J. Yuan Nitric oxide induces apoptosis by activating K+ channels in pulmonary vascular smooth muscle cells Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H184 - H193. [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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S. Krick, O. Platoshyn, S. S. McDaniel, L. J. Rubin, and J. X.-J. Yuan Augmented K+ currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L887 - L894. [Abstract] [Full Text] [PDF]
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J. Mullenheim, R. Rulands, T. Wietschorke, J. Fra{beta}dorf, B. Preckel, and W. Schlack Late Preconditioning is Blocked by Racemic Ketamine, But Not by S(+)-Ketamine Anesth. Analg., August 1, 2001; 93(2): 265 - 270. [Abstract] [Full Text] [PDF]
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K. Nandagopal, T. M. Dawson, and V. L. Dawson Critical Role for Nitric Oxide Signaling in Cardiac and Neuronal Ischemic Preconditioning and Tolerance J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 474 - 478. [Abstract] [Full Text]
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T. C. Zhao, D. S. Hines, and R. C. Kukreja Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial KATP channels Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1278 - H1285. [Abstract] [Full Text] [PDF]
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S. Wang, J. Cone, and Y. Liu Dual roles of mitochondrial KATP channels in diazoxide-mediated protection in isolated rabbit hearts Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H246 - H255. [Abstract] [Full Text] [PDF]
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A. Lochner, E. Marais, S. Genade, and J. A. Moolman Nitric oxide: a trigger for classic preconditioning? Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2752 - H2765. [Abstract] [Full Text] [PDF]
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B. O'Rourke Myocardial KATP Channels in Preconditioning Circ. Res., November 10, 2000; 87(10): 845 - 855. [Abstract] [Full Text] [PDF]
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S. Okubo, N. L. Bernardo, G. T. Elliott, M. L. Hess, and R. C. Kukreja Tyrosine kinase signaling in action potential shortening and expression of HSP72 in late preconditioning Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2269 - H2276. [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. Zhao, L. Xi, J. Chelliah, J. E. Levasseur, and R. C. Kukreja Inducible Nitric Oxide Synthase Mediates Delayed Myocardial Protection Induced by Activation of Adenosine A1 Receptors : Evidence From Gene-Knockout Mice Circulation, August 22, 2000; 102(8): 902 - 907. [Abstract] [Full Text] [PDF]
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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]
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