© 1999 American Heart Association, Inc.
Mini Review |
Sarcolemmal Versus Mitochondrial ATP-Sensitive K+ Channels and Myocardial Preconditioning
From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wis.
Correspondence to Garrett J. Gross, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI. E-mail ggross{at}post.its.mcw.edu
Abstract
Abstract—Ischemic preconditioning (IPC) is a phenomenon in which single or multiple brief periods of ischemia have been shown to protect the heart against a more prolonged ischemic insult, the result of which is a marked reduction in myocardial infarct size, severity of stunning, or incidence of cardiac arrhythmias. Although a number of substances and signaling pathways have been proposed to be involved in mediating the cardioprotective effect of IPC, the overwhelming majority of evidence suggests that the ATP-sensitive potassium channel (KATP channel) is an important component of this phenomenon and may serve as the end effector in this process. Initially, it was hypothesized that the surface or sarcolemmal KATP (sarc KATP) channel mediated protection observed after IPC; however, subsequent evidence suggested that the recently identified mitochondrial KATP channel (mito KATP) may be the potassium channel mediating IPC-induced cardioprotection. In this review, evidence will be presented supporting a role for either the sarc KATP or the mito KATP in IPC and potential mechanisms by which opening these channels may produce cardioprotection; additionally, we will address important questions that still need to be investigated to define the role of the sarc or mito KATP channel, or both, in cardiac pathophysiology.
Key Words: ischemic preconditioning • ATP-sensitive K+ channel • mitochondria • sarcolemma
The ATP-sensitive potassium channel (KATP channel) was discovered by Noma1 in 1983 in isolated membrane patches prepared from guinea pig ventricular myocytes. Subsequently, this channel has been found in other tissues, including the brain, smooth muscle, skeletal muscle, and pancreas, in which it has been shown to be involved in the secretion of insulin. Noma1 originally hypothesized that this channel coupled myocardial metabolism to membrane electrical activity and suggested that opening the KATP channel may serve as an endogenous cardioprotective mechanism. Indeed, this has been shown to be the case, as a number of KATP channel openers have been shown to produce a beneficial effect on the myocardium in numerous models of ischemia,2 and the KATP channel has been demonstrated to be a key component of the phenomenon termed ischemic preconditioning (IPC), in which single or multiple brief periods of ischemia have been shown to produce a marked cardioprotection against injury produced by a subsequent prolonged ischemic insult.3 IPC has been shown to occur in all animals studied, including humans, and has 2 phases, an early phase that lasts for 1 to 3 hours after the IPC stimulus and a delayed phase or second window of protection that appears 12 to 24 hours after the IPC stimulus and lasts for 48 to 96 hours.3 Although the majority of evidence that suggests a role for the KATP channel in IPC has been obtained from studying the acute phase, evidence is accumulating to suggest that the KATP channel may also be the end effector in late preconditioning as well. Therefore, the evidence for a role of the sarcolemmal KATP (sarc) versus the mitochondrial KATP (mito) channel in late IPC will also be discussed.
Evidence for a role of the KATP channel in acute IPC was first presented by Gross and Auchampach4 and Auchampach et al5 in the canine heart. These authors showed that 2 KATP channel antagonists, glibenclamide and sodium 5-hydroxydecanoate (5-HD), blocked the protection produced by IPC and also demonstrated that the KATP channel opener, aprikalim, mimicked the beneficial effect of IPC to reduce infarct size. Subsequently, a plethora of studies in a number of models and species including humans6 confirmed these initial findings and clearly demonstrated that the KATP channel is the likely end effector protein mediating the cardioprotective effect of acute IPC. It should be emphasized at this point, however, that infarct size reduction is considered to be the gold standard in defining the phenomenon of IPC and that other indices of cardioprotection such as a reduction in the incidence of arrhythmias or a decrease in ST segment elevation may not be the result of the same mechanism involved in infarct size reduction after IPC. Therefore, in this review a decrease in infarct size will be used as the index of injury to describe the cardioprotective effect of IPC and the role of KATP channels. In addition, although KATP channel openers and several endogenous triggers, such as adenosine and acetylcholine, have been shown to mimic the infarct size-limiting effect of IPC,2 7 8 these interventions do not share several of the characteristics of preconditioning produced by ischemia, most notably the prolonged memory period (1 to 3 hours) after the preconditioning stimulus, which is not shared by KATP openers or adenosine.9 These compounds generally need to be present just before the ischemic insult or in some cases throughout the ischemic period or even during reperfusion to produce their maximal cardioprotective effects.
Role of Sarc KATP Channels in Acute IPC
Although antagonists of the
KATP channel block the protective effects of IPC
and agonists of the channel mimic its effects, the precise mechanism by
which opening of the KATP channel mediates its
cardioprotective effect remains elusive
(Figure
). Noma1
originally hypothesized that opening of the surface or sarc
KATP channel produced by hypoxia,
ischemia, or pharmacological KATP openers
would enhance the shortening of the cardiac action potential duration
(APD) by accelerating phase 3 repolarization. This enhanced phase 3
repolarization would inhibit calcium entry into the cell via L-type
channels and prevent calcium overload. In addition, membrane
hyperpolarization or the slowing of depolarization
would also inhibit calcium entry and slow or prevent the reversal of
the sodium-calcium exchanger that normally extrudes calcium in exchange
for sodium. The result of these actions would be a reduction in calcium
overload during ischemia and possibly early reperfusion and
subsequent increased cell viability. Indeed, a number of early studies
seemed to support this theory. Initial studies by Cole et
al,10 using an isolated guinea pig right
ventricular wall preparation, showed that the
KATP channel antagonist,
glibenclamide, inhibited the shortening of the action potential during
ischemia and resulted in a poor recovery of
ventricular function after reperfusion as compared with a
control preparation. Similarly, these investigators also found that the
KATP opener pinacidil accelerated the shortening
of APD during ischemia, which resulted in an enhanced recovery
of ventricular function during reperfusion. Subsequently,
Tan et al11 found that preconditioning a guinea pig
papillary muscle with a brief period of ischemia or with a
KATP opener prolonged the time to electrical
uncoupling and that these effects were associated with an enhanced
shortening of APD. In a similar vein, Yao and Gross12
found that the KATP opener bimakalim lowered the
threshold for IPC and that this effect was also associated with an
enhanced rate of action potential shortening in dog hearts.
Schulz et al,13 using anesthetized pigs as
a model of IPC, found that IPC resulted in an enhanced shortening of
APD during the prolonged ischemic period in pigs and that this
was associated with a marked cardioprotective effect as compared with
controls. However, the enhanced shortening of APD was not impressive
(
10%) and seemed unlikely to account for the magnitude of
cardioprotection observed. More recently, Haruna et al14
reported that digoxin, an inhibitor of Na-K ATPase, blocked
the cardioprotective effect of IPC to reduce infarct size in
anesthetized rabbits, whereas digoxin did not block the effect
of the KATP opener cromakalim to reduce infarct
size. These findings were proposed to occur as a result of digoxin
producing an increase in the amount of subsarcolemmal ATP present
as a result of inhibiting Na-K ATPase, which would prevent sarc
KATP channel opening during IPC, whereas the
effect of digoxin would not be expected to block the cardioprotective
effect of a direct opener such as cromakalim. These findings dispute
the idea that the mito KATP channel is the only
one involved in the cardioprotective effect of IPC. Furthermore, Haruna
et al 14 found that diazoxide, a selective mito
KATP opener,15 administered in a
similar or 10-fold higher dose than that shown to produce a reduction
in infarct size after cromakalim administration, did not reduce infarct
size. Given that Garlid et al16 showed that cromakalim and
diazoxide were nearly equally potent at opening mito
KATP channels in reconstituted mitochondria and
were equally potent at enhancing functional recovery in isolated rat
hearts subjected to global ischemia and reperfusion, the
finding in intact rabbit hearts that diazoxide did not reduce infarct
size at a dose that would be expected to be cardioprotective via
opening of mito KATP channels suggests that the
sarc KATP channel plays an important role in the
infarct size–limiting effect of IPC. A role for APD shortening was not
addressed in this study.14
|
1 receptors. It is thought that these receptors
activate a G protein (Gi or Gq) that leads to activation of PKC
and other intracellular kinases, such as tyrosine kinases or the
mitogen-activated protein kinase pathway. Eventually, these
kinases are thought to phosphorylate an end effector
protein such as HSP 27 or the KATP channel. The opening of
sarc and mito KATP channels have both been shown to be
enhanced in the presence of PKC activators such as phorbol
esters (PMA). Opening of the sarc KATP channel has been
proposed to produce cardioprotection via a shortening of phase 3
repolarization of the cardiac action potential and membrane
hyperpolarization, both of which would lead to
reduced calcium overload during ischemia or reperfusion and a
preservation of ATP. A cytoprotective effect of combining the Kir6.2
and SUR2A has also been recently identified. On the other hand, the
mechanism by which opening mito KATP channels produces
cardioprotection is less clear; however, it is thought that a
beneficial effect may occur as the result of K+ entry and
intramitochondrial depolarization. This effect would reduce
mitochondrial calcium overload and cause matrix swelling, which have
been shown to enhance ATP synthesis and stimulate mitochondrial
respiration. Selective agonists and antagonists of the sarc
and mito KATP channels have been identified and are listed
in the Figure.In summary, 3 studies have presented the strongest evidence for a role for sarc KATP in mediating IPC, with infarct size reduction as the end point of irreversible injury. These include those reported by Yao and Gross12 and Schulz et al,13 who showed an association between APD shortening and IPC, and the recent study of Haruna et al,14 who showed a dissociation between the cardioprotective effect of IPC and a KATP opener to reduce infarct size and a lack of effect of diazoxide, a selective mito KATP opener, which suggests that the sarc KATP channel may play an important role in acute IPC.
Several recent studies using molecular techniques to transfect different KATP channel subunits into KATP-deficient COS-7 cells also shed some light on a possible role for sarc KATP channels in alleviating hypoxic injury and subsequent calcium overload.17 18 KATP channels are composed of 2 proteins, an inwardly rectifying potassium channel (Kir6.x) and a sulfonylurea receptor (SUR) subunit.19 The channel pore region has been shown to be surrounded by 4 Kir6.x subunits, and each subunit requires a SUR subunit to form a functional tetrameric channel.20 At least 2 inwardly rectifying subunits, Kir6.1 and Kir6.2, and 3 sulfonylurea subunits, SUR1, SUR2A, and SUR2B, have been identified and found to form channels with specific characteristics and tissue sites. It has been suggested that SUR1 and Kir6.2 are found in pancreatic islets, SUR2A and Kir6.2 in cardiac and skeletal muscle, and SUR2B and Kir6.1 in vascular smooth muscle.19 Unfortunately, the mito KATP channel has not been cloned as yet. Recently, Okuyama et al19 transfected SUR2A and Kir6.2 into HEK 293 cells and examined the function of this channel by patch clamp techniques. The results showed that this channel had all the characteristics of the native cardiac sarc KATP channel in terms of nucleotide regulation and pharmacology. Interestingly, this channel was weakly activated by nicorandil and was not activated by diazoxide, which supports recent work by Liu et al21 and Sato et al,22 who showed that these 2 KATP channel openers are mitochondrial selective.
Using these same subunits (SUR2A and Kir6.2), Jovanovic et al17 recently transfected COS-7 cells with these genes. In KATP-deficient cells, they found that when these cells were exposed to 3 minutes of chemical hypoxia produced by dinitrophenol (DNP) and subsequently reoxygenated, marked calcium loading occurred. Similar results were obtained in cardiac myocytes expressing the native KATP channel and exposed to DNP. However, when both subunits of the sarc KATP channel, SUR2A and Kir6.2, were cotransfected in the COS-7 cells, the addition of the KATP opener pinacidil attenuated the calcium loading that occurred because of DNP exposure. Similar results were obtained with pinacidil in cardiac myocytes expressing the native sarc KATP channel. These results suggested that sarc KATP channel proteins may have cytoprotective properties when combined to form a functional KATP channel and that the protection observed occurs independently of APD shortening. Future studies are warranted to test the effect of several mito KATP openers such as diazoxide or nicorandil in these transfected cells to see whether cardioprotection occurs or to test the effect of 5-HD to block the protective effect of pinacidil in this system. Because a similar protective effect of transfecting Kir6.2 and SUR1 has also been observed in COS-7 cells against hypoxia-reoxygenation injury,18 it will also be interesting to determine whether there is any specificity when combining other Kir6.x and SUR subunits to produce a functional channel and to determine whether all combinations result in a cardioprotective effect.
Role of Mito KATP Channels in Acute IPC
The first study to suggest that an enhanced shortening of APD as a result of sarc KATP activation was not the mechanism responsible for the cardioprotective effect of KATP openers was published by Yao and Gross in 1994.23 These investigators found that a low dose of the KATP opener bimakalim, which did not enhance APD shortening, produced a cardioprotective effect equal to that of 2 higher doses of bimakalim, which produced an enhanced shortening of APD. These authors suggested that an intracellular site of action may be involved in helping to explain the efficacy of bimakalim to reduce infarct size independent of APD shortening. Subsequently, Grover et al24 found that there was no correlation between APD shortening and cardioprotection in dogs after cromakalim administration and that dofetilide, a class III antiarrhythmic drug, which prevented APD shortening in preconditioned hearts, did not antagonize the cardioprotective effect of IPC.25 In addition, studies in isolated nonbeating cardiac myocytes showed a role for the KATP channel in mediating the protective effects of KATP openers or IPC in the absence of a ventricular action potential.26 Taken together, all of these latter studies suggest that the sarc KATP channel may not be the site of action responsible for the cardioprotective effect of IPC and KATP openers and suggested a possible intracellular site of action.
Inoue et al27 first identified an ATP-sensitive K+ channel in the inner mitochondrial membrane (mito KATP) in rat liver by patch clamping giant mitoplasts prepared from rat liver mitochondria. These authors found that the mito KATP channel had several characteristics similar to those of the sarc KATP in that the channel was reversibly inactivated by ATP applied to the matrix side and inhibited by glibenclamide. Subsequently, Paucek et al,28 in Keith Garlid's laboratory, isolated and partially purified a mito KATP channel from beef heart mitochondria that had several characteristics similar to those of the sarc KATP channel. However, the function of these channels appears to be intimately involved in matrix volume control as opposed to electrical activity for sarc KATP. In this regard, opening of mito KATP leads to membrane depolarization, matrix swelling, slowing of ATP synthesis, and accelerated respiration.29 Interestingly, these mito KATP channels are only sensitive to inhibitors of the channel such as 5-HD or glibenclamide when Mg2+, ATP, and a pharmacological or physiological KATP opener such as diazoxide or GTP are present.30
Evidence that the mito KATP channel is important in cardioprotection was first presented by Garlid et al16 in 1997. These investigators used the KATP channel opener diazoxide as a pharmacological tool to demonstrate the importance of mito KATP as the cardioprotective channel responsible for the beneficial effects of KATP openers. They found that, in reconstituted bovine heart mitochondria, diazoxide opened mito KATP with a K1/2 (the concentration at which 50% of the maximal effect on mito KATP is observed) of 0.8 µmol/L while only opening the sarc KATP at 800 µmol/L.16 Subsequently, they observed that diazoxide, at concentrations (5 to 20 µmol/L) that would not open sarc KATP channels, produced an increase in time to contracture and improved functional recovery in isolated rat hearts subjected to global ischemia and reperfusion equal to that produced by a nonselective KATP opener, cromakalim, at similar concentrations. These effects of diazoxide and cromakalim were blocked by the KATP channel antagonists, glibenclamide and 5-HD, which confirmed that these agents were acting via KATP channels. Furthermore, cromakalim and diazoxide were found to be potent activators of K+ fluxes in reconstituted rat heart mitochondria with K1/2 values of 1.1 and 0.49 µmol/L, respectively. These results suggested that diazoxide and perhaps other KATP openers are interacting with the mito KATP channel to produce cardioprotection.
In agreement with the results of Garlid et al,16 recent studies of Liu et al21 and Sato et al31 in Eduardo Marbán's laboratory have also demonstrated that diazoxide is a selective mito KATP opener and suggest that 5-HD may be a selective mito KATP channel inhibitor. To determine whether diazoxide is a selective mito KATP opener, these investigators measured flavoprotein fluorescence (oxidation correlating with mitochondrial depolarization) and sarc KATP current (IKATP) in isolated rabbit ventricular myocytes. They found that diazoxide produced a reversible oxidation of the flavoproteins with an EC50 of 27 µmol/L. This concentration of diazoxide did not affect the sarc KATP channel, which confirmed the selectivity of this KATP opener for the mito KATP channel. Subsequently, they found that diazoxide at 50 µmol/L produced a 50% reduction in rabbit myocytes killed in a model of simulated ischemia, an effect similar to that afforded by IPC in this model.21 These results are in close agreement with those of Garlid et al16 and further suggest that the mito KATP is the mediator of cardioprotection produced by KATP openers.
To more clearly address a possible role for mito
KATP in mediating IPC, Sato et al31
recently attempted to demonstrate that protein kinase C (PKC), a potent
postulated intermediate in the signaling pathway responsible for
IPC,32 could modulate mito KATP
channel activity. In this regard, Sato et al32 showed that
diazoxide (100 µmol/L) produced a marked increase in
flavoprotein oxidation in isolated rabbit ventricular
myocytes with no effect on IKATP. The
phorbol ester phorbol 12-myristate 13-acetate (PMA) had no
effect on flavoprotein fluorescence by itself but potentiated
and accelerated the effect of diazoxide to activate mito
KATP. The inactive phorbol ester 4
-phorbol was
without effect, and the effect of diazoxide and PMA+diazoxide was
blocked by 5-HD. These authors also demonstrated that 5-HD was a
selective inhibitor of mito KATP in
their myocyte model. That 5-HD is a selective blocker of the mito
KATP channel is a subject of some debate,
however, given that several studies in other models have suggested that
5-HD can block the shortening of the cardiac action potential during
ischemia33 and inhibit
K+ efflux from the cell during
hypoxia,34 effects that would both be expected
from blocking the sarc KATP channel. Diazoxide
has also been shown to have effects on mitochondrial
metabolism and membrane potential that are independent of
its effect on KATP channels,35 so
one needs to be cautious when targeting any drug to be selective for a
given process. Nevertheless, in spite of these caveats, the evidence
presented by Garlid et al,16 Liu et
al,21 and Sato et al31 is convincing and
suggests that the mito KATP may be an important
component in mediating the cardioprotective effects of
KATP openers and IPC. That 5-HD has been shown to
block IPC in various species in which infarct size reduction has been
the end point of injury supports a role for mito
KATP in IPC.5 In support of these
findings, Gogelein et al36 have recently described the
pharmacology of a new KATP channel
antagonist, HMR 1883, which appears to be a
cardioselective sarc KATP
antagonist. Interestingly, these authors have preliminary
data to suggest that this compound does not block IPC in rabbit hearts
at doses that block the shortening of the cardiac action
potential.37 In addition, preliminary results from
Marbán's laboratory (E. Marbán, unpublished observations,
1998) suggest that this compound has no effect on mito
KATP channels as assessed by changes in
flavoprotein fluorescence in the presence of diazoxide. Given
that Grover et al38 have previously described a
KATP opener, BMS-180448, which produced a
glibenclamide-reversible cardioprotective effect in isolated guinea pig
hearts that was independent of action potential shortening, these
results suggest that it is possible to synthesize site-specific
KATP modulators that would have a greater
therapeutic window than those currently available. For instance,
opening of the sarc KATP channel by nonselective
openers such as pinacidil has been shown to exhibit proarrhythmic
effects and also result in excess hypotension, unwanted effects that
may negate the cardioprotective properties of these
agents.2 A compound such as nicorandil or BMS-180448 would
have advantages, since a selective mito KATP
opener would possess cardioprotective properties without the
proarrhythmic and marked hypotensive effects expected of a nonselective
KATP opener. Conversely, a selective
antagonist of the sarc KATP channel,
such as HMR 1883, might be expected to possess antiarrhythmic
properties without interfering with the mito KATP
channel and would not be expected to block IPC. Indeed, studies by
Billman et al39 have shown that HMR 1883 is a potent
antifibrillatory agent in a canine model of chronic
ischemia.
Sarc Versus Mito KATP Channels in Delayed Preconditioning
Delayed preconditioning against infarction has been reported 12 to 24 hours after a preconditioning stimulus and has been primarily shown to occur in dogs40 and rabbits.41 A number of pathophysiological stressors and pharmacological agents, including ischemia,40 41 heat shock,41 an adenosine A1 receptor agonist,42 free radicals,43 and the nontoxic endotoxin derivative monophosphoryl lipid A (MLA), have been shown to produce delayed preconditioning. Evidence that the KATP channel may be an end effector in delayed preconditioning was first reported by Mei et al44 in 1996. These authors found that MLA produced a dose-related reduction in infarct size in dogs that was associated with an enhanced shortening of the monophasic action potential, which suggested that MLA may be increasing sarc KATP activation. However, the protective effect of MLA was completely antagonized by both glibenclamide and 5-HD, which suggests that the mito KATP channel may also be involved. Similar results were obtained in rabbits by Elliott et al.45 Obviously, more studies are needed to determine the relative importance of the sarc versus the mito KATP channel in mediating the protective effect of MLA.
Further evidence to support a role for KATP channels in delayed preconditioning has been suggested by 3 recent studies using heat stress as the preconditioning stimulus. Hoag et al46 and Pell et al47 both subjected rabbits to heat stress (42°C, 15 minutes) and found a reduction in infarct size and an increase in heat shock protein (HSP 72) expression. In both studies, glibenclamide and 5-HD completely blocked the heat shock–induced reduction in infarct size. Similarly, Joyeux et al48 found that the reduction in infarct size observed in isolated rat hearts induced by heat stress was also blocked by glibenclamide and 5-HD. Although these studies suggest an important role for KATP channels in several forms of delayed preconditioning, further studies are still necessary with ischemia per se and an adenosine receptor agonist to further determine the similarities or differences concerning a role for KATP channels in acute versus delayed preconditioning.
Summary and Future Directions
Evidence has been presented that clearly suggests that the myocardial KATP channel is the most likely candidate to serve as the end effector protein in acute or delayed IPC. Studies to date are not unequivocal in favor of the sarc versus the mito KATP channel, and it would not be surprising if there were cross talk between the 2 channels and if both were involved to some extent in IPC. Molecular cloning of the KATP channel subunits Kir6.x and SUR has shown that there are a number of subtypes that are differently regulated and possess their own pharmacology. Future studies are needed with cloned channels and knockout mice to better understand how these channels are regulated under normal and ischemic conditions. Hopefully, the mito KATP channel will be cloned in the near future and will allow us to more accurately determine the role of this channel in IPC.
Another important challenge will be to more clearly determine
mechanisms by which opening of either the sarc or mito
KATP channel produces beneficial effects in IPC.
Some of the potential mechanisms that have been proposed are summarized
in the Figure
. Mechanisms responsible for cardioprotection due
to sarc KATP have already been discussed and
include shortening of the cardiac action potential and membrane
hyperpolarization, which would lead to a reduction
in calcium overload and a preservation of ATP. All of these actions
have been described in various studies and are well documented to occur
in IPC3 and after administration of
KATP openers.2 Recent studies by
Jovanovic et al17 18 suggest that injury-resistant
cells can be produced by transfecting cells with specific
KATP channel subunits in the absence of an action
potential, which suggests that the channel proteins produce
cardioprotection by an as-yet-unknown mechanism that requires further
investigation.
Consequences of opening the mito KATP channel include depolarization of the intramitochondrial membrane as K+ enters, a transient swelling of the intramitochondrial space that may lead to increased respiration via the electron transport chain. In this regard, Halestrap49 suggested that if cell swelling, such as occurs during ischemia, were to activate both the sarc and mito KATP channels simultaneously by stretch-induced protein phosphorylation, a loss of K+ would occur from the cytosol and an increase in K+ into the mitochondria would be expected to occur that might produce intramitochondrial swelling and a subsequent increase in ATP production. Membrane depolarization produced by the K+ entry would also be expected to reduce mitochondrial calcium entry through the calcium uniport, thus reducing calcium overload. In addition, Holmuhamedov et al29 have shown that preloaded mitochondria release calcium in response to activation by a KATP channel opener, which suggests that a cell in which calcium overload is already present may also be protected by a KATP opener or enhanced activation of the channel after IPC. Furthermore, Vanden Hoek et al50 have suggested that reactive oxygen species released by mitochondria during a brief period of hypoxia can precondition isolated myocytes, and Park et al51 have shown that IPC reduces superoxide production and prevents the impairment of state 3 mitochondrial respiration induced by ischemia and reperfusion. The interaction between the mito KATP channel and free radicals is not known; however, several studies have demonstrated that free radicals open sarc KATP channels.52 53 Thus, it is possible that such an interaction may also occur within mitochondria. Obviously, the regulation of mito KATP is a fruitful area for further investigation at the cellular and subcellular levels. Finally, one must not lose sight of the necessity for more carefully designed studies at the whole-animal, organ, or cellular level to confirm or reject the information gained in the molecular biology studies.
Acknowledgments
This work was supported by NIH Grant HL 08311. The authors thank Anna Hsu and Jeannine Moore for their assistance in experiments discussed that originated in their own laboratory.
Received December 4, 1998; accepted March 1, 1999.
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P. J Hanley, K V Gopalan, R. A Lareau, D K Srivastava, von Martin Meltzer, and J. Daut {beta}-Oxidation of 5-hydroxydecanoate, a Putative Blocker of Mitochondrial ATP-Sensitive Potassium Channels J. Physiol., March 1, 2003; 547(2): 387 - 393. [Abstract] [Full Text] [PDF]
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J. V. Haist, C. N. Hirst, and M. Karmazyn Effective protection by NHE-1 inhibition in ischemic and reperfused heart under preconditioning blockade Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H798 - H803. [Abstract] [Full Text] [PDF]
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J. D. McCully and S. Levitsky The mitochondrial KATP channel and cardioprotection Ann. Thorac. Surg., February 1, 2003; 75(2): S667 - 673. [Abstract] [Full Text] [PDF]
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 A. Munoz, M. Nakazaki, J. C. Goodman, R. Barrios, C. G. Onetti, J. Bryan, and L. Aguilar-Bryan Ischemic Preconditioning in the Hippocampus of a Knockout Mouse Lacking SUR1-Based KATP Channels Stroke, January 1, 2003; 34(1): 164 - 170. [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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K. H H Lim, S. A Javadov, M. Das, S. J Clarke, M-S. Suleiman, and A. P Halestrap The effects of ischaemic preconditioning, diazoxide and 5-hydroxydecanoate on rat heart mitochondrial volume and respiration J. Physiol., December 15, 2002; 545(3): 961 - 974. [Abstract] [Full Text] [PDF]
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M. L. Riess, A. K. S. Camara, E. Novalija, Q. Chen, S. S. Rhodes, and D. F. Stowe Anesthetic Preconditioning Attenuates Mitochondrial Ca2+ Overload During Ischemia in Guinea Pig Intact Hearts: Reversal by 5-Hydroxydecanoic Acid Anesth. Analg., December 1, 2002; 95(6): 1540 - 1546. [Abstract] [Full Text] [PDF]
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T. Kamishima and J. M. Quayle Mitochondrial Ca2+ uptake is important over low [Ca2+]i range in arterial smooth muscle Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2431 - H2439. [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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O. Oldenburg, M. V Cohen, D. M Yellon, and J. M Downey Mitochondrial KATP channels: role in cardioprotection Cardiovasc Res, August 15, 2002; 55(3): 429 - 437. [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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D. Garcia-Dorado, M. Ruiz-Meana, F. Padilla, A. Rodriguez-Sinovas, and M. Mirabet Gap junction-mediated intercellular communication in ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 456 - 465. [Abstract] [Full Text] [PDF]
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G.F Baxter Role of adenosine in delayed preconditioning of myocardium Cardiovasc Res, August 15, 2002; 55(3): 483 - 494. [Abstract] [Full Text] [PDF]
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Y.-P. Wang, H. Maeta, K. Mizoguchi, T. Suzuki, Y. Yamashita, and M. Oe Intestinal ischemia preconditions myocardium: role of protein kinase C and mitochondrial KATP channel Cardiovasc Res, August 15, 2002; 55(3): 576 - 582. [Abstract] [Full Text] [PDF]
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H. F del Valle, E. C Lascano, and J. A Negroni Ischemic preconditioning protection against stunning in conscious diabetic sheep: role of glucose, insulin, sarcolemmal and mitochondrial KATP channels Cardiovasc Res, August 15, 2002; 55(3): 642 - 659. [Abstract] [Full Text] [PDF]
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N B Standen Cardioprotection by preconditioning: KATP channels, metabolism, or both? J. Physiol., August 1, 2002; 542(3): 666 - 666. [Full Text] [PDF]
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P. J Hanley, M. Mickel, M. Loffler, U. Brandt, and J. Daut KATP channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart J. Physiol., August 1, 2002; 542(3): 735 - 741. [Abstract] [Full Text] [PDF]
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R. Rajashree, J. C. Koster, K. P. Markova, C. G. Nichols, and P. A. Hofmann Contractility and ischemic response of hearts from transgenic mice with altered sarcolemmal KATP channels Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H584 - H590. [Abstract] [Full Text] [PDF]
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 H. J. Ranki, G. R. Budas, R. M. Crawford, A. M. Davies, and A. Jovanovic 17{beta}-Estradiol regulates expression of KATP channels in heart-derived H9c2 cells J. Am. Coll. Cardiol., July 17, 2002; 40(2): 367 - 374. [Abstract] [Full Text] [PDF]
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Z. Ren, Q. Yang, H. Storm Floten, and G.-W. He Hypoxic preconditioning in coronary microarteries: role of EDHF and K+ channel openers Ann. Thorac. Surg., July 1, 2002; 74(1): 143 - 148. [Abstract] [Full Text] [PDF]
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J. Han, N. Kim, H. Joo, and E. Kim Ketamine abolishes ischemic preconditioning through inhibition of KATP channels in rabbit hearts Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H13 - H21. [Abstract] [Full Text] [PDF]
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E. W. Dickson, R. J. Tubbs, W. A. Porcaro, W. J. Lee, D. J. Blehar, R. E. Carraway, C. E. Darling, and K. Przyklenk Myocardial preconditioning factors evoke mesenteric ischemic tolerance via opioid receptors and KATP channels Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H22 - H28. [Abstract] [Full Text] [PDF]
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D. A. Liem, P. D. Verdouw, H. Ploeg, S. Kazim, and D. J. Duncker Sites of action of adenosine in interorgan preconditioning of the heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H29 - H37. [Abstract] [Full Text] [PDF]
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M. Tonkovic-Capin, G. J. Gross, Z. J. Bosnjak, J. S. Tweddell, C. M. Fitzpatrick, and J. E. Baker Delayed cardioprotection by isoflurane: role of KATP channels Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H61 - H68. [Abstract] [Full Text] [PDF]
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P. Dos Santos, A. J. Kowaltowski, M. N. Laclau, S. Seetharaman, P. Paucek, S. Boudina, J.-B. Thambo, L. Tariosse, and K. D. Garlid Mechanisms by which opening the mitochondrial ATP- sensitive K+ channel protects the ischemic heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H284 - H295. [Abstract] [Full Text] [PDF]
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T. J. MacCormack and W. R. Driedzic Mitochondrial ATP-sensitive K+ channels influence force development and anoxic contractility in a flatfish, yellowtail flounder Limanda ferruginea, but not Atlantic cod Gadus morhua heart J. Exp. Biol., May 15, 2002; 205(10): 1411 - 1418. [Abstract] [Full Text] [PDF]
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H. Liu, H. Y. Zhang, X. Zhu, Z. Shao, and Z. Yao Preconditioning blocks cardiocyte apoptosis: role of KATP channels and PKC-epsilon Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1380 - H1386. [Abstract] [Full Text] [PDF]
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B. Pouzet, J.-B. Lecharny, M. Dehoux, S. Paquin, M. Kitakaze, J. Mantz, and P. Menasche Is there a place for preconditioning during cardiac operations in humans? Ann. Thorac. Surg., March 1, 2002; 73(3): 843 - 848. [Abstract] [Full Text] [PDF]
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P. Korge, H. M. Honda, and J. N. Weiss Protection of cardiac mitochondria by diazoxide and protein kinase C: Implications for ischemic preconditioning PNAS, February 20, 2002; (2002) 52713199. [Abstract] [Full Text] [PDF]
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 D.V. Cokkinos Can metabolic manipulation reverse myocardial dysfunction? Eur. Heart J., December 1, 2001; 22(23): 2138 - 2139. [PDF]
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 P. E. LIGHT, H. D. KANJI, J. E. M. FOX, and R. J. FRENCH Distinct myoprotective roles of cardiac sarcolemmal and mitochondrial KATP channels during metabolic inhibition and recovery FASEB J, December 1, 2001; 15(14): 2586 - 2594. [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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 K. N. Jew and R. L. Moore Glibenclamide improves postischemic recovery of myocardial contractile function in trained and sedentary rats J Appl Physiol, October 1, 2001; 91(4): 1545 - 1554. [Abstract] [Full Text] [PDF]
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J. An, S. G. Varadarajan, E. Novalija, and D. F. Stowe Ischemic and anesthetic preconditioning reduces cytosolic [Ca2+] and improves Ca2+ responses in intact hearts Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1508 - H1523. [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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H. J. Ranki, G. R. Budas, R. M. Crawford, and A. Jovanovic Gender-specific difference in cardiac ATP-sensitive K+ channels J. Am. Coll. Cardiol., September 1, 2001; 38(3): 906 - 915. [Abstract] [Full Text] [PDF]
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M. Haller, S. L. Mironov, and D. W. Richter Intrinsic Optical Signals in Respiratory Brain Stem Regions of Mice: Neurotransmitters, Neuromodulators, and Metabolic Stress J Neurophysiol, July 1, 2001; 86(1): 412 - 421. [Abstract] [Full Text] [PDF]
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