Integrative Physiology |
From the Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio.
Correspondence to Muhammad Ashraf, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Bethesda Ave, Cincinnati, OH 45267-0529.
| Abstract |
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50% in the diazoxide preconditioned hearts compared with control
I/R hearts. Cell death by apoptosis was also significantly
decreased in diazoxide pretreated hearts (3.2%) as compared with I/R
(11.3%). In conclusion, activation of mitoKATP channel
with diazoxide produces late PC against reperfusion injury. The effect
of mitoKATP channel appears to be dependent on the
PKC-mediated signal pathway.
Key Words: mitochondrial KATP channel myocardial infarction apoptosis protein kinase C electron microscopy
| Introduction |
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2
hours2 and reappears after 24 hours; this reappearance is
referred to as a delayed phase of cardioprotection or a second window
of protection.3 4 Since these initial observations,
several studies have been performed to determine the mechanism(s)
responsible for this remarkable cardioprotective effect in the eventual
hope of finding a clinically useful PC-like drug. In this regard,
administration of the adenosine A1 receptor agonist
2-chloro-N6-cyclopentyladenosine 24 hours before
coronary artery ligation produced a significant reduction in
infarct size.5 Induction of heat shock
proteins3 and antioxidants6 7 could be
responsible for late cardioprotection. The endotoxin derivative
monophosphoryl lipid A also induces delayed PC possibly via inducible
NO synthase and protein kinase C (PKC) signaling pathway8
and through KATP channels.9 Fryer et
al10 reported that
-opioid receptor stimulation also
produced a delayed cardioprotection perhaps via the mitochondrial
KATP (mitoKATP) channel.
Wang and Ashraf11 and Wang et al12 have
recently demonstrated that an opener of the
mitoKATP channel, diazoxide, induced PC through
the activation of the PKC and mitoKATP channel
against Ca2+ overload and ischemic injury
in the rat heart. Thus, several studies have reported that
mitoKATP channel is the end effector of
PC11 12 13 14 and PKC activity is important in
mitoKATP channelmediated
protection.11 12 However, there is no evidence yet whether
the activation of mitoKATP channel also leads to
a second window of protection. Therefore, the present study tested
the hypothesis that activation of mitoKATP
channel can induce delayed protection of myocardium against
lethal ischemic injury via the PKC signaling pathway. | Materials and Methods |
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Experimental Protocols
The entire experimental protocol is summarized in Figure 1
.
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Control Groups
Vehicle saline or 5-hydroxydecanoic acid (5-HD) or chelerythrine
was injected 24 hours before sham operation.
Ischemia/Reperfusion (I/R) Group
Hearts were subjected to reperfusion for 120 minutes after 30
minutes of LCA occlusion.
Diazoxide Pretreatment Group
Diazoxide was found to be a relatively specific opener of
mitoKATP channel at low concentration without any
effect on sarcolemmal KATP
channels.13 14 The dosage of diazoxide used was based on a
previous study.16 Rats were given an
intravenous dose of 7 mg/kg diazoxide. These animals were
pretreated with diazoxide for 12, 24, 48, and 72 hours before I/R.
Blockade of MitoKATP Channel
5-HD was given to test whether a specific blocker of the
mitoKATP channel can abolish the protection.
Diazoxide-pretreated rats were given 5-HD (5 mg/kg, IV), a selective
KATP channel
antagonist,13 10 minutes before I/R on the
second day. In another group, 5-HD was given before diazoxide
pretreatment on the first day.
PKC and MitoKATP Channel
To determine whether the mitoKATP channel
elicits protection via PKC, chelerythrine (5 mg/kg, IV), a selective
PKC inhibitor, was administered before diazoxide
pretreatment on the first day. In another group, it was given 10
minutes before I/R in diazoxide-pretreated rats on the second day.
Determination of Infarct Size and Assessment of Ischemic
Injury With Molecular and Morphological Markers
Modified 2,3,5-Triphenyltetrazolium
Chloride (TTC) Staining
Hearts were perfused retrogradely with 2% TTC followed by
fixation with 4% paraformaldehyde. The heart was
sliced transversely into
3 to 4 slices (
23 mm), and
thinner sections (100 µm) were also cut with a microtome
(Vibratome, Oxford Co). Risk and ischemic regions were
measured.17
HRP Technique
To investigate sarcolemmal integrity and permeability
alterations, the slices after fixation were frozen in liquid nitrogen.
Frozen sections (8 µm) were processed as previously
described.18
The number of HRP-positive cells was counted. Strongly stained cells were categorized as necrotic cells and lightly stained cells represented the transient stage leading to necrosis as confirmed by electron microscopy.19
Terminal Deoxynucleotidyl
TransferaseMediated dUTP Nick End Labeling (TUNEL)
Assay
Apoptosis was assessed with the TUNEL method (MEBSTAIN
Apoptosis Kit II, MBL Co). The frozen sections were first
reacted with 3,3'-diaminobenzidine for HRP staining, and immediately
terminal deoxynucleotidyl transferase buffer was
applied to the specimens as described in the kit. Sections were then
stained with propidium iodide (PI) to visualize nuclei and photographed
with a light microscope equipped with fluorescence optics.
Classification of Cell Injury
The cells were classified as normal, reversibly injured, and
necrotic cells as previously characterized.15 20
An expanded Materials and Methods section is available online at http://www.circresaha.org.
| Results |
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Time-Dependent Reduction of Myocardial Infarct by Stimulation of
MitoKATP Channel
In the I/R group, 62.1±2.4% of the risk area was infarcted. In
the sham control hearts, the left ventricular slices were
stained a brick-red color with TTC, and no HRP-positive material was
observed within myocytes. After 30 minutes of LCA occlusion and 120
minutes of reperfusion, the ischemic region lost the TTC
staining uniformly and a large number of cells were HRP positive as
observed in thick sections (Figures 2
and 3
). In the diazoxide-pretreated
group 24 hours before I/R, the infarct size was significantly decreased
compared with the I/R group (33.3±2.2% versus 62.1±2.4%,
P<0.001) (Table 2
).
HRP-positive cells were also decreased accordingly (Figure 3
).
The cardioprotective effect of pretreatment 12, 48, and 72 hours before
I/R almost disappeared, as shown in Figure 4
.
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Inhibition of the channel with 5-HD 10 minutes before I/R on the second
day completely abolished the delayed cardioprotection (Table 2
).
Similarly, the protection also disappeared in rats that received 5-HD
before diazoxide pretreatment on the first day. The control experiments
in which 5-HD or chelerythrine was given with diazoxide on the first
day or before I/R on the second day exhibited only a 0.24% and 0.19%
TTC-negative area, respectively, in the risk area.
Role of PKC in MitoKATP Channel-Mediated Late
PC
To test the hypothesis that the activation of PKC is important for
the mitoKATP channelmediated reduction of
cellular injury, chelerythrine, which is an inhibitor of
PKC, was given either before diazoxide pretreatment on the first day or
before I/R on the second day. The protection was totally abolished in
both groups and the infarct size was similar to that of the control I/R
group (Table 2
).
Detection and Assessment of In Situ DNA Fragmentation by the
TUNEL Method
In the I/R group, a large number of cells in the infarcted region
were necrotic and had numerous contraction bands, especially in the
center of the infarct zone. These cells were strongly HRP positive,
whereas only a few scattered cells were TUNEL positive. In the border
area adjacent to normal noninfarcted myocardium, many
myocytes underwent apoptosis, ie, were TUNEL positive, and
these cells were slightly HRP positive (Figure 5A
and 5C
). There were still many
myocytes in the ischemic region, especially in the border zone
adjacent to the normal region, which were not stained with TTC, HRP, or
TUNEL, which suggests that these cells were perhaps reversibly injured.
In the diazoxide-pretreated group, the number of dead cells was
significantly decreased and the number of TUNEL-positive cells was also
decreased to 3.2±0.6% as compared with the I/R group (11.3±1.0)
(Figure 6
and Table 2
). In the
animals treated with 5-HD or chelerythrine, the cell necrosis was
similar to that of the control I/R group.
|
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Subcellular Pathology
The semiquantitative data on the cell injury in various groups are
given in Table 2
. By electron microscopy, the myocytes that were
TTC positive and HRP negative exhibited uniformly dispersed nuclear
chromatin and elongated mitochondria and abundant glycogen dispersed
between myofibrils. These myocytes were classified as normal (Figure 7A
). The myocytes that were TTC and HRP
negative were classified as reversibly injured cells. They were swollen
and nuclear chromatin was slightly aggregated. HRP reaction material
was restricted to T-tubules and to the extracellular space. These cells
were commonly observed in the ischemic area adjacent to normal
myocardium (Figure 7B
and 7C
). HRP-positive myocytes
were placed into 2 categories. In the first category, the cells were
swollen and myofibrils were slightly stained (Figure 5C
), but no
HRP reaction material was seen in T-tubules and mitochondrial cristae
were broken, without the presence of electron-dense deposits. These
cells were found to be TUNEL positive (Figure 7D
). The second
category included myocytes darkly stained with HRP. These cells were
highly swollen; nuclear chromatin was clumped and marginated.
Electron-dense deposits were commonly observed in mitochondria and no
glycogen was present (Figure 7E
). Semiquantitative cell
injury is given in Table 2
.
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| Discussion |
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Late PC via Memory of MitoKATP Channel
We have previously demonstrated that activation of
mitoKATP channel elicits strong protection
against Ca2+ overload11 and
ischemic injury.12 These conclusions are well
supported by several recent studies10 13 14 indicating
that mitoKATP channel is the end effector in
cardioprotection against ischemia during acute PC.
There is enough evidence that many triggering agents of acute PC are also capable of inducing delayed PC. The PC molecules via Gi- or Gq-coupled receptors activate phospholipase C or D and PKC,21 ultimately resulting in opening of ATP-sensitive potassium channels.14 22 Since the discovery of the effect of the mitoKATP channel on ischemia, it has become clear that the mitoKATP channel may play a greater role in late PC. The significance of this channel is further increased by the fact that the mitochondrion is a complex organelle with multiple functions and occupies approximately one third of the myocyte volume.23 It has been reported that synthesis of mitochondrial superoxide dismutase,6 7 catalase,24 nitric oxide synthase,25 and heat shock proteins3 26 may be important in the development of late PC. Heat shock proteins may allow opening of ATP-sensitive potassium channels during delayed cardiac protection.26 The opening of the mitoKATP channel may lead to increased amounts of ATP during ischemia12 and increased antioxidant, manganese superoxide dismutase, after 24 hours of ischemic insult.7 These 2 factors could be operative as a consequence of mitoKATP channel activities. The mitoKATP channel also regulates Ca2+ homeostasis in mitochondria.27
How the protection by the opening of mitoKATP
channel in acute PC disappears within hours and reappears after 24
hours remains to be elucidated. This problem is further hampered by the
lack of molecular characterization of this channel. The participation
of PKC in the opening of these channels is, however, highly attractive.
Activation of KATP channels via PKC could be an
inducer of PC.28 29 The administration of PKC
inhibitor, chelerythrine (before activation of the channel
or 10 minutes before I/R after 24 hours of diazoxide-induced activation
of mitoKATP channel) resulted in loss of
protection against infarct, suggesting that PKC activity is important
for the mitoKATP channelmediated effects.
Recently, Fryer et al10 demonstrated that
-opioid receptor stimulation produced a delayed protection that was
lost by administering a relatively specific blocker of
mitoKATP channel, 5-HD, 5 minutes before I/R in
48 hours
1 receptor agonistpretreated rats.
We recently demonstrated that the activity of PKC is important for
mitoKATP channelmediated effects on the
Ca2+ paradox11 and ischemic
injury.12 PKC isoforms
and ß1 are translocated to
the myocyte nuclei and PKC
to mitochondria after diazoxide
pretreatment,12 and PKC activates the
mitoKATP channel
simultaneously.30 This finding may have
implications for the late PC induced by diazoxide treatment. It has
also been reported that 2 major isoforms in rat heart, PKC
and
,
are translocated during brief episodes of transient ischemia
from the cytosol to the membrane and nucleus.31 As
suggested by Yellon and Baxter,32 the nuclear
translocation of PKC isoforms may be important in the modification of
gene-regulatory processes leading to synthesis of effector proteins
responsible for delayed PC. To support this rationale, administration
of chelerythrine before activation of mitoKATP
channel on the first day or before I/R on the second day abolished the
late PC. The present study supports a central role of
PKC-mitoKATP channel signaling pathway
responsible for both acute12 and late PC against
ischemia. Therefore, in light of existing knowledge, it is
likely that PKC could modulate the increased
mitoKATP channel activity in the late PC.
The mitoKATP channel was activated with
diazoxide, which is quite a potent antihypertensive agent that
acts as a result of relaxation of arteriolar smooth muscle while having
no direct effect on cardiac function.33 Diazoxide is also
highly protective against the ischemic injury in low
concentrations because of the opening of the
mitoKATP channel, but it is without any effect on
action potential duration.14 The acute effect of diazoxide
on ischemic injury has been attributed to the direct activation
of mitoKATP channel.12 13 14 However,
this study demonstrates that opening of the
mitoKATP channel also produces delayed
cardioprotection 24 hours after initial treatment. Because of the
prolonged half-life of diazoxide in human (72 hours),34 it
could also be argued that the drug is trapped in mitochondrial
membranes for a longer duration and thus induces the PC effect. The
half-life of diazoxide is even smaller in rats after
12
hours.35 However, the lack of effect after 12 hours
(Figure 4
) supports this argument.
It is well established that diazoxide is a relatively selective opener of the mitoKATP channel.13 14 It is possible that it also works on the sarcolemmal KATP channel. However, at a low dose, it rather opens the mitoKATP channel14 and also had very little effect on the plasma glucose in the rat.36
The mild and brief hypotension associated with diazoxide treatment could possibly trigger PC responses regardless of mitoKATP channel activation. It is unlikely that brief hemodynamic responses caused by diazoxide treatment are sufficient to induce myocardial ischemia to elicit adaptive responses. Thornton et al37 recently reported that PC induced by adenosine A1 receptor activation with R-N6-(phenyl-2R-isopropyl)-adenosine was not caused by bradycardia, because cardiac pacing could not prevent the protection. Thus, the use of relatively specific inhibitors of both mitoKATP channel and PKC preclude the involvement of hemodynamic factors in the delayed PC reported in this study.
A major effect of diazoxide pretreatment was the reduction in infarct size. The mechanism by which opening of the mitoKATP channel produces protection against reperfusion injury remains to be determined. The mitochondrial role in regulating Ca2+ homeostasis may be pivotal in cardioprotection. As reviewed by Gross and Fryer,38 the opening of the mitoKATP channel causes depolarization of mitochondria, thus reducing Ca2+ overload during reperfusion. The electron microscopic examination of lightly HRP-stained areas within the infarct zone revealed that mitochondria were swollen but were devoid of calcium containing electron-dense deposits known to be present in the dead cells.39 40 The study by Holmuhamedov et al27 in which isolated preloaded mitochondria released their Ca2+ contents on opening of the mitoKATP channel with diazoxide supports our findings on reduced Ca2+ accumulation by mitochondria in the diazoxide-pretreated hearts. Thus, one of the beneficial effects of mitoKATP channel activation could be reduced Ca2+ overload in mitochondria and an increased amount of ATP contents,12 both being the major parameters of cell viability.
Finally, the cell death by both necrosis (oncosis) and apoptosis was drastically reduced in the preconditioned myocardium. Although the occurrence of apoptosis in the ischemic myocardium is controversial,41 reperfusion is known to accelerate its presence in the ischemic myocardium.42 In this study, TUNEL-positive cells were significantly reduced after PC in the border areas compared with the center of the infarcted zone where only a few TUNEL-positive cells were present. By electron microscopy, these cells in the preconditioned myocardium were nearly normal, with intact sarcolemma exhibiting no altered permeability. However, a limited number of cells lost their cell membrane permeability allowing the entry of extracellular tracer (HRP) into the cytoplasm; mitochondria were swollen but without the presence of electron-dense deposits. Although these ischemic cells do not meet the typical criteria for an apoptotic cell, it appears that TUNEL positivity in the ischemic myocardium indicates a transient stage of cell necrosis.43 44 This study is in agreement with previous studies45 46 that found that PC reduces apoptosis.
In summary, the data support our hypothesis that opening of the mitoKATP channel leads to late PC via the PKC signaling pathway. Translocation of PKC to nuclei and mitochondria may be essential in the signal transduction for late PC.
| Acknowledgments |
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Received June 2, 1999; accepted September 15, 1999.
| References |
|---|
|
|
|---|
2. Van Winkle DM, Thornton JD, Downey JM. The natural history of preconditioning: cardioprotection depends on duration of transient ischemia and time to subsequent ischemia. Coron Artery Dis. 1991;2:613619.
3.
Marber MS, Latchman DS, Walker JM, Yellon DM.
Cardiac stress protein elevation 24 hours after brief ischemia
or heat stress is associated with resistance to myocardial infarction.
Circulation. 1993;88:12641272.
4.
Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H,
Hori M, Kamada T, Tada M. Delayed effects of sublethal ischemia
on the acquisition of tolerance to ischemia. Circ
Res. 1993;72:12931299.
5. Baxter GF, Yellon DM. Time course of delayed myocardial protection after transient adenosine A1-receptor activation in the rabbit. J Cardiovasc Pharmacol. 1997;29:631638.[Medline] [Order article via Infotrieve]
6.
Hoshida S, Kuzuya T, Fuji H, Yamashita N, Oe H,
Hori M, Suzuki K, Taniguchi NC, Tada M. Sublethal ischemia
alters myocardial antioxidant activity in canine heart. Am J
Physiol. 1993;264:H33H39.
7.
Zhou X, Zhai X, Ashraf M. Direct evidence that
initial oxidative stress triggered by preconditioning contributes to
second window of protection by endogenous antioxidant
enzyme in myocytes. Circulation. 1996;93:11771184.
8. Elliott GT. Monophosphoryl lipid A induces delayed preconditioning against cardiac ischemia-reperfusion injury. J Mol Cell Cardiol. 1998;30:317.[Medline] [Order article via Infotrieve]
9.
Mei DA, Elliott GT, Gross GJ.
KATP channels mediate late preconditioning
against infarction produced by monophosphoryl lipid A. Am J
Physiol. 1996;271:H2723H2729.
10.
Fryer RM, Hsu AK, Eells JT, Nagase H, Gross GJ.
Opioid-induced second window of cardioprotection: potential role of
mitochondrial KATP channels. Circ Res. 1999;84:846851.
11.
Wang YG, Ashraf M. Role of protein kinase C in
mitochondrial KATP channel-mediated protection against
Ca2+ overload injury in rat myocardium.
Circ Res. 1999;84:11561165.
12.
Wang YG, Hirai K, Ashraf M. Activation of
mitochondrial ATP sensitive K+ channel for
cardiac protection against ischemic injury is dependent on
protein kinase C activity. Circ Res. 1999;85:731741.
13.
Liu Y, Sato T, ORourke B, Marbán E.
Mitochondrial ATP-dependent potassium channels: novel effectors of
cardioprotection. Circulation. 1998;97:24632469.
14.
Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN,
Darbenzio RB, DAlonzo AJ, Lodge NJ, Smith MA, Grover GJ.
Cardioprotective effect of diazoxide and its interaction with
mitochondrial ATP-sensitive K+ channels: possible mechanism of
cardioprotection. Circ Res. 1997;81:10721081.
15.
Miyawaki H, Ashraf M. Ca++
as a mediator of ischemic preconditioning. Circ Res. 1997;80:790799.
16. Baines CP, Liu GS, Birincioglu M, Cohen MV, Downey JM. Diazoxide, a mitochondrial KATP-channel opener, is cardioprotective in ischemic rabbit myocardium. Circulation. 1998;98(suppl I):I-343.
17. Farb A, Kolodgie FD, Jenkins M, Virmani R. Myocardial infarct extension during reperfusion after coronary artery occlusion: pathologic evidence. J Am Coll Cardiol. 1993;21:12451253.[Abstract]
18.
Karnovsky MJ. The ultrastructural basis of
capillary permeability studied with peroxidase as a tracer.
J Cell Biol. 1967;35:213236.
19. Oguro T, Onodera T, Aida K, Ashraf M. Ultrastructural effects of hydrogen peroxide on the sarcolemma of rat heart. Am J Cardiovasc Pathol. 1992;4:265276.[Medline] [Order article via Infotrieve]
20.
Miyawaki H, Zhou X, Ashraf M. Calcium
preconditioning elicits strong protection against ischemic
injury via protein kinase C signaling pathway. Circ Res. 1996;79:137146.
21. Downey JM, Cohen MV. Signal transduction in ischemic preconditioning. Z Kardiol. 1995;84:7786.
22.
Jaburek M, Yarov-Yarovoy V, Paucek P, Garlid KD.
State-dependent inhibition of the mitochondrial
KATP channel by glyburide and 5-hydroxydecanoate
acid. J Biol Chem. 1998;273:1357813582.
23. Ashraf M, Park WH, Grupp I, Schwartz A. Distribution of 3H-nitrendipine in the isolated perfused rat heart as revealed by electron microscopic autoradiography. J Mol Cell Cardiol. 1986;18:265272.[Medline] [Order article via Infotrieve]
24.
Brown JM, Grosso MA, Terada LS, Whitman GJ,
Banerjee A, White CW, Harken AH, Repine JE. Endotoxin pretreatment
increases endogenous myocardial catalase activity and
decreases ischemia-reperfusion injury of isolated rat hearts.
Proc Natl Acad Sci U S A. 1989;86:25162520.
25. Maulik N, Engelman DT, Watanabe M, Engelman RM, Maulik G, Cordis GA, Das DK. Nitric oxide signaling in ischemic heart. Cardiovasc Res. 1995;30:593601.[Medline] [Order article via Infotrieve]
26. Hoag JB, Qian YZ, Nayeem MA, DAngelo M, Kukreja RC. ATP-sensitive potassium channel mediates delayed ischemic protection by heat stress in rabbit heart. Am J Physiol. 1997;273:H2458H2464.
27.
Holmuhamedov EL, Jovanovic S, Dzeja PP, Jovanovic A,
Terzic A. Mitochondrial ATP-sensitive K+ channels modulate
cardiac mitochondrial function. Am J Physiol. 1998;275:H1567H1576.
28. Armstrong SC, Liu GS, Downey JM, Ganote CE. Potassium channels and preconditioning of isolated rabbit cardiomyocytes: effects of glyburide and pinacidil. J Mol Cell Cardiol. 1995;27:17651774.[Medline] [Order article via Infotrieve]
29.
Meldrum DR, Cleveland JC, Rowland RT, Banerjee A,
Harken AH, Meng X. Early and delayed preconditioning: differential
mechanisms and additive protection. Am J Physiol. 1997;273:H725H733.
30. Light P. Regulation of ATP-sensitive potassium channels by phosphorylation. Biochim Biophys Acta. 1996;1286:6573.[Medline] [Order article via Infotrieve]
31.
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;76:7381.
32. Yellon DM, Baxter GF. A "second window of protection" or delayed preconditioning phenomenon: future horizons for myocardial protection. J Mol Cell Cardiol. 1995;27:10231034.[Medline] [Order article via Infotrieve]
33. Sundaresan PR. Autonomic drugs. In: Berkow, ed. The Merck Manual of Diagnosis and Therapy. Rahway, NJ: Merck and Co, Inc; 1982:23442371.
34. Calesnick B, Katchen B, Black J. Importance of dissolution rates in producing effective diazoxide blood levels in man. J Pharm Sci. 1965;54:12771280.[Medline] [Order article via Infotrieve]
35. Dayton PG, Pruitt AW, Faraj BA, Israili ZH. Metabolism and disposition of diazoxide: a mini-review. Drug Metab Dispos. 1975;3:226229.[Medline] [Order article via Infotrieve]
36.
Quast U, Cook NS. In vitro and in vivo comparison of
two K+ channel openers, diazoxide and cromakalim, and their
inhibition by glibenclamide. J Pharmacol Exp Ther. 1989;250:261271.
37.
Thornton JD, Liu GS, Olsson RA, Downey JM.
Intravenous pretreatment with
A1-selective adenosine analogues protects
the heart against infarction. Circulation. 1992;85:659665.
38.
Gross GJ, Fryer RM. Sarcolemmal versus
mitochondrial ATP-sensitive K+ channels and
myocardial preconditioning. Circ Res. 1999;84:973979.
39. Ashraf M, Bloor CM. X-ray microanalysis of mitochondrial deposits in ischemic myocardium. Virchows Arch B Cell Pathol. 1976;22:287297.
40.
Jennings RB, Schaper J, Hill ML, Steenbergen C, Reimer
KA. Effect of reperfusion late in the phase of reversible
ischemic injury: changes in cell volume, electrolytes,
metabolites and ultrastructure. Circ Res. 1985;56:262278.
41. Buja LM. Modulation of the myocardial response to ischemia. Lab Invest. 1998;78:13451373.[Medline] [Order article via Infotrieve]
42. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest. 1994;94:16211628.
43.
Ohno M, Takemura G, Ohno A, Misao J, Hayakawa Y,
Minatoguchi S, Fujiwara T, Fujiwara H. "Apoptotic" myocytes
in the infarct area in rabbit hearts may be oncotic myocytes with DNA
fragmentation: analysis by immunogold electron microscopy
combined with in situ nick end- labeling. Circulation. 1998;98:14221430.
44. Rink A, Fung KM, Trojanowski JQ, Lee VM, Neugebauer E, McIntosh TK. Evidence of apoptotic cell death after experimental traumatic brain injury in the rat. Am J Pathol. 1995;147:15751583.[Abstract]
45.
Piot CA, Padmanaban D, Ursell PC, Sievers RE, Wolfe CL.
Ischemic preconditioning decreases apoptosis in rat
hearts in vivo. Circulation. 1997;96:15981604.
46. Maulik N, Yoshida T, Engelman RM, Deaton D, Flack JE III, Rousou JA, Das DK. Ischemic preconditioning attenuates apoptotic cell death associated with ischemia/reperfusion. Mol Cell Biochem. 1998;186:139145.[Medline] [Order article via Infotrieve]
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E. R. Gross, J. N. Peart, A. K. Hsu, J. A. Auchampach, and G. J. Gross Extending the cardioprotective window using a novel {delta}-opioid agonist fentanyl isothiocyanate via the PI3-kinase pathway Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2744 - H2749. [Abstract] [Full Text] [PDF] |
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S. Barrere-Lemaire, N. Combes, C. Sportouch-Dukhan, S. Richard, J. Nargeot, and C. Piot Morphine mimics the antiapoptotic effect of preconditioning via an Ins(1,4,5)P3 signaling pathway in rat ventricular myocytes Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H83 - H88. [Abstract] [Full Text] [PDF] |
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X. Wang, C. Yin, L. Xi, and R. C. Kukreja Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2070 - H2077. [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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X.-L. Tang, Y.-T. Xuan, Y. Zhu, G. Shirk, and R. Bolli Nicorandil induces late preconditioning against myocardial infarction in conscious rabbits Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1273 - H1280. [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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D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF] |
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G. Taimor Mitochondria as common endpoints in early and late preconditioning Cardiovasc Res, August 1, 2003; 59(2): 266 - 267. [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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J. Peart, L. Willems, and J. P. Headrick Receptor and non-receptor-dependent mechanisms of cardioprotection with adenosine Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H519 - H527. [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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P A J Krijnen, R Nijmeijer, C J L M Meijer, C A Visser, C E Hack, and H W M Niessen Apoptosis in myocardial ischaemia and infarction J. Clin. Pathol., November 1, 2002; 55(11): 801 - 811. [Abstract] [Full Text] [PDF] |
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K.M. Lawrence, A. Chanalaris, T. Scarabelli, M. Hubank, E. Pasini, P.A. Townsend, L. Comini, R. Ferrari, A. Tinker, A. Stephanou, et al. KATP Channel Gene Expression Is Induced by Urocortin and Mediates Its Cardioprotective Effect Circulation, September 17, 2002; 106(12): 1556 - 1562. [Abstract] [Full Text] [PDF] |
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R. Ockaili, F. Salloum, J. Hawkins, and R. C. Kukreja Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial KATP channels in rabbits Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1263 - H1269. [Abstract] [Full Text] [PDF] |
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K. Shimizu, Z. Lacza, N. Rajapakse, T. Horiguchi, J. Snipes, and D. W. Busija MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1005 - H1011. [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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J. Neckar, O. Szarszoi, L. Koten, F. Papousek, B. Ost'adal, G. J Grover, and F. Kolar Effects of mitochondrial KATP modulators on cardioprotection induced by chronic high altitude hypoxia in rats Cardiovasc Res, August 15, 2002; 55(3): 567 - 575. [Abstract] [Full Text] [PDF] |
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H. H. Patel, A. K. Hsu, J. N. Peart, and G. J. Gross Sarcolemmal KATP Channel Triggers Opioid-Induced Delayed Cardioprotection in the Rat Circ. Res., August 9, 2002; 91(3): 186 - 188. [Abstract] [Full Text] [PDF] |
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M. Kudo, Y. Wang, M. Xu, A. Ayub, and M. Ashraf Adenosine A1 receptor mediates late preconditioning via activation of PKC-delta signaling pathway Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H296 - H301. [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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R. M. Fryer, H. H. Patel, A. K. Hsu, and G. J. Gross Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1184 - H1192. [Abstract] [Full Text] [PDF] |
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M. Xu, Y. Wang, A. Ayub, and M. Ashraf Mitochondrial KATP channel activation reduces anoxic injury by restoring mitochondrial membrane potential Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1295 - H1303. [Abstract] [Full Text] [PDF] |
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R. Carroll, V. A Gant, and D. M Yellon Mitochondrial KATP channel opening protects a human atrial-derived cell line by a mechanism involving free radical generation Cardiovasc Res, September 1, 2001; 51(4): 691 - 700. [Abstract] [Full Text] [PDF] |
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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] |
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Z. Yao, B. C. McPherson, H. Liu, Z. Shao, C. Li, Y. Qin, T. L. Vanden Hoek, L. B. Becker, and P. T. Schumacker Signal transduction of flumazenil-induced preconditioning in myocytes Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1249 - H1255. [Abstract] [Full Text] [PDF] |
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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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M. Xu, Y. Wang, K. Hirai, A. Ayub, and M. Ashraf Calcium preconditioning inhibits mitochondrial permeability transition and apoptosis Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H899 - H908. [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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S. Pepe Dysfunctional ischemic preconditioning mechanisms in aging Cardiovasc Res, January 1, 2001; 49(1): 11 - 14. [Full Text] [PDF] |
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S. L. Hale and R. A. Kloner Effect of combined KATP channel activation and Na+/H+ exchange inhibition on infarct size in rabbits Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2673 - H2677. [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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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] |
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T. Sato Signaling in Late Preconditioning : Involvement of Mitochondrial KATP Channels Circ. Res., December 3, 1999; 85(12): 1113 - 1114. [Full Text] [PDF] |
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S. Ovide-Bordeaux, R. Ventura-Clapier, and V. Veksler Do Modulators of the Mitochondrial KATP Channel Change the Function of Mitochondria in Situ? J. Biol. Chem., November 17, 2000; 275(47): 37291 - 37295. [Abstract] [Full Text] [PDF] |
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M. Akao, A. Ohler, B. O'Rourke, and E. Marban Mitochondrial ATP-Sensitive Potassium Channels Inhibit Apoptosis Induced by Oxidative Stress in Cardiac Cells Circ. Res., June 22, 2001; 88(12): 1267 - 1275. [Abstract] [Full Text] [PDF] |
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M. Murata, M. Akao, B. O'Rourke, and E. Marban Mitochondrial ATP-Sensitive Potassium Channels Attenuate Matrix Ca2+ Overload During Simulated Ischemia and Reperfusion: Possible Mechanism of Cardioprotection Circ. Res., November 9, 2001; 89(10): 891 - 898. [Abstract] [Full Text] [PDF] |
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