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Vol. 59, Issue 2, 225-230, February 2001
Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Maryland (Y.L., G.R., B.O., E.M., J.S.); and Maryland Research Laboratories, Otsuka American Pharmaceutical Inc., Rockville, Maryland (Y.L.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Many mammalian cells have two distinct types of ATP-sensitive potassium (KATP) channels: the classic ones in the surface membrane (sKATP) and others in the mitochondrial inner membrane (mitoKATP). Cardiac mitoKATP channels play a pivotal role in ischemic preconditioning, and thus represent interesting drug targets. Unfortunately, the molecular structure of mitoKATP channels is unknown, in contrast to sKATP channels, which are composed of a pore-forming subunit (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2A, or SUR2B). As a means of probing the molecular makeup of mitoKATP channels, we compared the pharmacology of native cardiac mitoKATP channels with that of molecularly defined sKATP channels expressed heterologously in human embryonic kidney 293 cells. Using mitochondrial oxidation to index mitoKATP channel activity in rabbit ventricular myocytes, we found that pinacidil and diazoxide open mitoKATP channels, but P-1075 does not. On the other hand, 5-hydroxydecanoic acid (5HD), but not HMR-1098, blocks mitoKATP channels. Although pinacidil is a nonselective activator of expressed sKATP channels, diazoxide did not open channels formed by Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac sKATP channels) or Kir6.2/SUR2B. P-1075 activated all the KATP channels, except Kir6.1/SUR1 channels. Glybenclamide potently blocked all sKATP channels, but 5HD only blocked channels formed by SUR1/Kir6.1 or Kir6.2 (IC50s of 66 and 81 µM, respectively). This potency is similar to that for block of mitoKATP channels (IC50 = 95 µM). In addition, HMR-1098 potently blocked Kir6.2/SUR2A channels (IC50 = 1.5 µM), but was 67 times less potent in blocking Kir6.1/SUR1 channels (IC50 = 100 µM). Our results demonstrate that mitoKATP channels closely resemble Kir6.1/SUR1 sKATP channels in their pharmacological profiles.
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Introduction |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Lethal
injury to the heart can be dramatically blunted by brief conditioning
periods of ischemia. Such "ischemic preconditioning" (IPC) (Murry
et al., 1986
) exists in all species examined, including humans (Cohen
and Downey, 1993). Although the precise mechanism of IPC remains
elusive, much attention has focused on the potential role of
ATP-sensitive potassium (KATP) channels as the
effectors of protection. Cardiac myocytes contain two distinct
KATP channels: the classic one in the sarcolemma
(Noma, 1983) and another in the mitochondrial inner membrane
(mitoKATP channel) (Inoue et al., 1991). Although
the cardioprotection was originally attributed to sarcolemmal
KATP channels, recent evidence has pinpointed
mitoKATP channels as the key effectors of
cardioprotection (Garlid et al., 1997; Liu et al., 1998, 1999).
Molecular studies have revealed that surface membrane
KATP (sKATP) channels are
octameric complexes of four pore-forming Kir6.x subunits and four
sulfonylurea subunits (Aguilar-Bryan et al., 1998). Two isoforms of Kir
(Kir6.1 and Kir6.2) and three of SUR (SUR1, SUR2A, and SUR2B) have been
identified. sKATP channels are broadly
distributed but quite tissue-specific in their expression patterns. For
example, Kir6.2/SUR1 forms the pancreatic 
-cell sKATP channel, whereas Kir6.2/SUR2A is the
cardiac sKATP channel (Yokoshiki et al., 1998).
Kir6.1/SUR2B and Kir6.2/SUR2B form vascular smooth muscle
sKATP channels (Isomoto et al., 1996; Yamada et al., 1997) and various permutations have been reported in neuronal cells (Miller et al., 1999). However, the molecular structure of the
mitoKATP channel has not been determined. In this
study, we compared the pharmacological profiles of the native
mitoKATP channels in rabbit ventricular myocytes
with heterologously expressed KATP channels in
HEK293 cells. Mitochondrial oxidation was used as an indirect index of
mitoKATP channel opening in myocytes (Liu et al.,
1998). All possible combinations of sKATP
subunits (Kir6.1/SUR1, Kir6.1/SUR2A, Kir6.1/SUR2B, Kir6.2/SUR1,
Kir6.2/SUR2A, and Kir6.2/SUR2B) were heterologously expressed in HEK293
cells, and their pharmacology was characterized with the whole-cell,
patch-clamp technique. Comparison of the results reveals striking
similarities between the pharmacological profiles of Kir6.1/SUR1 and
mitoKATP channels.
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The investigation conforms with The Guide for the Care and Use of Laboratory Animals, published by the National Research Council in 1996 and approved by the Institutional Animal Care and Use Committee.
Chemicals. Collagenase (type II) was purchased from Worthington (Freehold, NJ). Diazoxide was obtained from Sigma Chemical Co. (St. Louis, MO). Pinacidil and 5-hydroxydecanoic acid sodium (5HD) were purchased from Research Biochemical International (Natick, MA). HMR-1098 was a gift from Aventis Pharma (Frankfurt, Germany) and P-1075 was a gift from Leo Pharmaceutical Products (Ballerup, Denmark). Diazoxide, pinacidil, and P-1075 were dissolved in dimethyl sulfoxide before being added into experimental solutions. The final concentration of dimethyl sulfoxide was < 0.1%.
Flavoprotein Fluorescence and Electrophysiology of Rabbit
Ventricular Myocytes.
Ventricular myocytes were isolated from
adult rabbit hearts by conventional enzymatic dissociation (Liu et al.,
1996). Cells were then cultured on laminin-coated coverslips in M199
culture medium with 5% fetal bovine serum at 37°C. Experiments were
performed over the next 2 days. For whole-cell patch recordings, the
internal pipette solution contained 120 mM K-glutamate, 25 mM KCl, 0.5 mM MgCl2, 10 mM K-EGTA, 10 mM HEPES, and 1 mM
MgATP, pH 7.2 with KOH. The external solution included 140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM
MgCl2, and 10 mM HEPES, pH 7.4 with NaOH.
Whole-cell currents were elicited every 6 s from a holding
potential of 
80 mV by two consecutive steps to 40 mV (for 100 ms)
and 0 mV (for 380 ms). Currents at 0 mV were measured 200 ms into the
pulse. Endogenous flavoprotein fluorescence was excited using a xenon arc lamp with a bandpass filter centered at 480 nm, but only during the
100-ms step to 40 mV to minimize photobleaching. Emitted fluorescence
was recorded at 530 nm by a photomultiplier tube and digitized
(Digidata 1200; Axon Instruments, Foster City, CA). Relative
fluorescence was averaged during the excitation window and calibrated
using the values after dinitrophenol and sodium cyanide exposure (Liu
et al., 1998).
Functional Expression of KATP Channels and
Electrophysiology.
Human embryonic kidney cells were plated at a
density of 1 × 105 cells per 35-mm dish
with glass coverslips in Dulbecco's modified Eagle's medium
supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. Plasmid DNA (3 µg) containing both the Kir
(6.1 or 6.2) and SUR (1, 2A, or 2B) cDNA was transfected using Lipofectamine Plus (Life Technologies, Gaithersburg, MD) 18 h after splitting the cells. Mouse Kir6.1 [a kind gift of Dr. Y. Kurachi (Yamada et al., 1997)] and rabbit Kir6.2 (Hu et al., 1999) were cloned into vector pGFP-IRES (Johns et al., 1997). Hamster SUR1
[a kind gift from Dr. Bryan (Aguilar-Bryan et al., 1995)] was cloned
into expression vector pCDNA3.1 (Invitrogen). Rat SUR2A [kindly
provided by Dr. Seino (Inagaki et al., 1996)] was cloned into
mammalian expression vector pCMV6. Mouse SUR2B was cloned into
expression vector pCDNA3 and was a kind gift of Dr. Kurachi (Yamada et
al., 1997).
100 mV to +50 mV were applied
over 400 ms every 2 s, from a holding potential of 20 mV. The
currents at 0 mV and 70 mV were measured to assay KATP channel activity and seal stability,
respectively. Experiments were performed at room temperature
(
22°C).
Three KATP channel openers (diazoxide, pinacidil,
and P-1075) and three KATP channel blockers
(glybenclamide, 5HD, and HMR-1098) were used to probe the
pharmacological characteristics of six (Kir6.1/SUR1, Kir6.1/SUR2A,
Kir6.1/SUR2B, Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B)
heterologously expressed KATP channels and native mitoKATP channels in rabbit ventricular myocytes.
The pharmacological profiles for each opener or blocker of the six
heterologously expressed KATP channels were then
compared with those of native mitoKATP channels.
The data are presented as mean ± S.E.M.
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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Pharmacology of Heterologously Expressed KATP
Channels.
Fig. 1 summarizes the
KATP current densities (measured at 0 mV during
the ramp) activated by diazoxide (100 µM), pinacidil (100 µM), or
P-1075 (100 µM) and after glybenclamide (10 µM), 5HD (200 µM),
and HMR-1098 (10 µM). All combinations of Kir6.x and SUR were opened
by 100 µM pinacidil and blocked by 10 µM glybenclamide. Kir6.1
combinations with SUR1 or 2B were opened by diazoxide; of the Kir6.2
combinations, however, only the Kir6.2/SUR1 (-cell type
sKATP channels) was sensitive to this compound.
Blockade by 5HD was associated with SUR1 expression partnered with
either Kir subunit, whereas blockade by HMR-1098 seemed to be selective for Kir6.2 coexpressed with either SUR1 or SUR2A (cardiac
sKATP channels), but not SUR2B [vascular
KATP channels (Yamada et al., 1997)]. P-1075
(100 µM) activated all the KATP channels,
except the construct with Kir6.1/SUR1.
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Pharmacological Comparison of mitoKATP Channels to
Heterologously Expressed KATP Channels.
Table
1 compares the pharmacology of
heterologously expressed KATP channels from this
study with the previously-described responses of
mitoKATP channels to the same openers and
blockers. For this, we used mitochondrial flavoprotein fluorescence as
an indirect index of mitoKATP channel opening in
rabbit ventricular myocytes. Diazoxide selectively opens
mitoKATP channels but has no effect on cardiac
sKATP channels, whereas pinacidil nonselectively opens both mitoKATP and
sKATP channels (Liu et al., 1998). P-1075 opens cardiac sKATP but has no effect on
mitoKATP channels (Sato et al., 2000). On the
other hand, glybenclamide (Jaburek et al., 1998) blocks both
mitoKATP and sKATP
channels, whereas 5HD selectively blocks mitoKATP
channels in ventricular myocytes (Sato et al., 1998). Recent evidence
from our laboratory also shows that HMR-1098 is a selective
sKATP channel blocker which does not block
mitoKATP channels (Sato et al., 2000). From Table
1, it is clear that only the coexpression of Kir6.1/SUR1 constructs has
a pharmacological profile similar to that of
mitoKATP channels in rabbit ventricular myocytes.
|
) and
mitoKATP channels with an
EC50 value of 27 µM (Fig. 3, 
). The latter
value is based on measurements of mitochondrial oxidation in intact
cells; diazoxide is more potent in activating potassium flux in
isolated mitochondria, as shown in the inset of Fig. 3 [re-plotted
from Garlid et al. (1996)]. Thus, the potency with which diazoxide
activates Kir6.1/SUR1 membrane current falls well within the range
reported for activation of mitoKATP channels. P-1075 opens all the heterologously expressed
KATP channels as shown in Fig.
4, except KATP
channels formed by Kir6.1/SUR1. Interestingly, P-1075 also has no
effect on the native mitoKATP channel, as shown in Fig. 4 and by Sato et al. (Sato et al., 2000).
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). We
found that HMR1098 potently blocks Kir6.2/SUR2A
(IC50 of 1.5 µM) but has no appreciable effect
to 30 µM on Kir6.1/SUR1 or Kir6.2/SUR2B (IC50 = 100 µM) (Fig. 6). HMR-1098 also blocks
Kir6.2/SUR1 with an IC50 of 5 µM. HMR-1098 at
30 µM has no effect on native mitoKATP channels, and has only 20% inhibition at 100 µM.
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Discussion |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Recent evidence has strongly implicated
mitoKATP channels as the effectors of IPC and
pharmacological cardioprotection (Liu et al., 1999; Szewczyk and
Marban, 1999). MitoKATP channel opening has also
been shown to reduce neuronal injury (Domoki et al., 1999).
KATP channels are formed as an octomeric complex
of four pore-forming Kir6.x and four sulfonylurea receptors
(Aguilar-Bryan et al., 1998). Two subfamilies of Kir (Kir6.1 and
Kir6.2) and three subfamilies of SUR (SUR1, SUR2A, and SUR2B) have been
identified. Although the exact molecular structure of
mitoKATP has not been identified, much is known
about its pharmacology. By patch-clamping mitoplasts from rat liver
mitochondria, Inoue and coworkers were the first to demonstrate the
existence of a mitochondrial potassium channel that is reversibly
inactivated by ATP and inhibited by glybenclamide (Inoue et al., 1991).
Later, a fraction containing mitoKATP channel
activity was purified from the inner membranes of rat liver and beef
heart mitochondria (Paucek et al., 1992). Using reconstituted
mitochondrial vesicles or isolated mitochondria and measuring potassium
flux, Garlid et al. demonstrated that heart and liver
mitoKATP channels share some pharmacological
properties with the channels found in sarcolemma. However,
mitochondrial channels have higher sensitivity to opening by diazoxide,
exceeding the sensitivity of sarcolemmal channels by 2000-fold (Garlid
et al., 1996). We later confirmed this selectivity to diazoxide in intact rabbit ventricular myocytes using mitochondrial oxidation as an
index of mitoKATP channel opening (Liu et al.,
1998). We further found that pinacidil is a nonselective
KATP channel opener, and P-1075 is a selective
cardiac sKATP channel opener (it does not open
mitoKATP channels) in ventricular myocytes (Liu
et al., 1998; Sato et al., 2000). We also have shown that 5HD and
HMR-1098 selectively block mitoKATP and
sKATP channels, respectively, in ventricular
myocytes (Sato et al., 1998, 2000). The mitoKATP
channel has not been cloned, although several observations suggest that mitoKATP channels contain both the Kir6.x subunit
(Suzuki et al., 1997) and the SUR subunit (because of its sensitivity
to glybenclamide). We thus studied the pharmacology of all six known
types of KATP channels heterologously expressed
in HEK293 cells and compared it with that of
mitoKATP channels.
Comparison of Sensitivity to KATP Channel Openers.
Pinacidil at 100 µM opens all six types of KATP
channels (Kir6.1/SUR1, Kir6.2/SUR1, Kir6.1/SUR2A, Kir6.2/SUR2B,
Kir6.1/SUR2B, and Kir6.2/SUR2B). Consistent with our previous study on
intact rabbit ventricular myocytes (Liu et al., 1998), diazoxide did not open Kir6.2/SUR2A cardiac-type sKATP
channels. Diazoxide at 100 µM also failed to activate Kir6.2/SUR2B,
one of the proposed vascular KATP channels
(Isomoto et al., 1996). But, at a higher concentration (200 µM),
diazoxide does open this channel (Fig. 3), consistent with a previous
study in cell-attached patches (Isomoto et al., 1996). Diazoxide has
been shown to be slightly more potent in opening this channel in
excised patches (Schwanstecher et al., 1998) (at 100 µM, diazoxide
elicited 75% of maximal channel activity), but this difference may
have been caused by the excised patch versus intact cell in our study.
Diazoxide does activate Kir6.1/SUR2B, another vascular
KATP channel that responds to
KATP channel openers and glybenclamide but is
insensitive to ATP (Yamada et al., 1997). As shown in Fig. 4, P-1075 is
a potent opener for the smooth muscle KATP
channels (Kir6.1/SUR2B and Kir6.2/SUR2B), with an
EC50 value of 0.16 µM. P-1075 also activates
Kir6.1/SUR2A, Kir6.2/SUR1 (pancreatic -cell), and Kir6.2/SUR2A.
Interestingly, P-1075 had no effect on either Kir6.1/SUR1 or native
mitoKATP channels.
Comparison of Sensitivity to KATP Channel
Blockers.
Glybenclamide is a potent and nonselective
KATP channel blocker; 10 µM blocked all six
types of the reconstituted KATP channels. Although we could not evaluate the effects of glybenclamide on native
mitoKATP channels in rabbit ventricular myocytes
using flavoprotein fluorescence as an indirect index [because of an apparent uncoupling effect (Szewczyk et al., 1997)] (Sato et al., 1998), Jaburek et al. (1998) demonstrated, using potassium flux measurement in isolated mitochondria, that glybenclamide blocks mitoKATP channels with a
K1/2 value of 1 to 6 µM (Jaburek et al., 1998). Interestingly, 5HD (at 200 µM) blocks only the
KATP channels formed by Kir6.1/SUR1 and
Kir6.2/SUR1. It does not block cardiac-type sKATP
(Kir6.2/SUR2A), consistent with results in cardiac ventricular myocytes
(Sato et al., 1998). Our results with HMR-1098 on heterologously expressed KATP channels are also consistent with
its reported pharmacology in native cells. HMR-1098 blocked
Kir6.2/SUR2A in this study, whereas it blocks
sKATP in rabbit ventricular myocytes (Sato et
al., 2000). HMR-1883, a lipophilic derivative of HMR-1098, also
completely blocked sKATP channels in guinea pig
ventricular myocytes (Gogelein et al., 1998). HMR-1098 did not block
Kir6.2/SUR2B (a vascular KATP channel) in this
study: consistent with this finding, much higher concentrations of
HM-1883 are required to inhibit coronary vasodilation induced by
hypoxia in the guinea pig (Gogelein et al., 1998). HMR-1098 up to 10 µM also had no inhibitory effect on Kir6.1/SUR2B, another
KATP channel found in vascular smooth muscle
cells (Yamada et al., 1997). An intermediate concentration of HMR-1098
is required to inhibit Kir6.2/SUR1, a pancreatic -cell type
KATP channel, also consistent with the study of
HMR-1883 in native pancreatic cells (Gogelein et al., 1998).
Pharmacological Similarities of KATP Channels Formed by Kir6.1/SUR1 to mitoKATP Channels. Based on the data summarized in Table 1, it is clear that channels formed by Kir6.1/SUR1 coexpression pharmacologically resemble mitoKATP channels. This similarity is further illustrated by the following comparisons.
Diazoxide activates Kir6.1/SUR1 channels with an EC50 value of 10 µM and native mitoKATP channels in rabbit ventricular myocytes with an EC50 value of 27 µM (Fig. 3). The EC50 value of 10 µM to activate Kir6.1/SUR1 is close to the value that is reported on isolated mitochondria [K1/2, 2.3 µM (Garlid et al., 1996)]. This value is also not inconsistent with the 27 µM to half-maximal activation of mitoKATP channels in intact
myocytes (Fig. 3), considering the diffusion barriers between
extracellularly applied diazoxide and the mitochondria in intact
myocytes and other differences in the experimental conditions. Although
P-1075 activates most of the heterologously expressed
KATP channels, it has no effect on Kir6.1/SUR1 or
native mitoKATP channels up to 100 µM.
Furthermore, channels formed by Kir6.1/SUR1 have very similar profiles
to pharmacological blockade as well. 5HD blocks Kir6.1/SUR1 channels
and mitoKATP channels with similar potency (Fig.
4). 5HD has been reported to block mitoKATP
channels reconstituted in liposomes and in isolated mitochondria with a
K1/2 value of 58 to 85 µM (Jaburek et
al., 1998). Sato et al. have reported that HMR-1098 at 30 µM
completely inhibits cardiac sKATP channels, but
does not block the native mitoKATP channel in
rabbit ventricular myocytes (Sato et al., 2000). At 10 µM, HMR-1098
does not significantly inhibit Kir6.1/SUR1 channels, and it causes only
about 50% inhibition at 100 µM. However, HMR-1098 potently inhibits
Kir6.2/SUR2A, and the potency (IC50 = 1.5 µM)
is very similar to that of HMR-1883 (a lipophilic derivative of
HMR-1098) on inhibition of sKATP channels in
guinea pig ventricular myocytes (IC50 = 0.8 µM)
(Gogelein et al., 1998).
Taken together, we have demonstrated that the
KATP channel formed by the coexpression of Kir6.1
and SUR1 has a pharmacological profile similar to that of native
mitoKATP channels. However, this does not
necessarily imply that Kir6.1/SUR1 represents the mitoKATP channel. Kir6.1 gene has a ubiquitous
expression profile with higher levels in the heart (Inagaki et al.,
1995; Akao et al., 1997). In addition, immunogold staining has
localized Kir6.1 to the inner mitochondrial membrane in skeletal muscle
(Suzuki et al., 1997). Nevertheless, using a viral gene transfer
technique, we did not observe any significant suppression of
diazoxide-induced mitoKATP channel opening by a
dominant-negative Kir6.1 construct in rabbit ventricular myocytes, and
Kir6.1 antibody staining was not colocalized with mitochondria in
isolated cardiac myocytes (Seharaseyon et al., 2000). Furthermore, the
sizes of the mitochondrial Kir and SUR purified from isolated
mitochondria are not consistent with the conventional
KATP channel subunits (Paucek et al., 1999). Despite these negative findings, mitoKATP
channels may contain structural motifs involved in drug binding similar
to that of Kir6.1/SUR1, perhaps providing a clue to the ultimate
resolution of the structure of this channel. Although more studies are
needed to identify the molecular structure of the
mitoKATP channels, the present findings are the
first step in defining the molecular correlates of drug sensitivity for
mitoKATP channels and can be used as a guide for
future structure-function analyses.
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Footnotes |
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Supported by National Institutes of Health Grants R37-HL36957 (to E.M.) and T32-HL09586 (to J.S.). E.M. holds the Michel Mirowski, M.D., Professorship of Cardiology of the Johns Hopkins University.
Send reprint requests to: Eduardo Marbán, M.D., Ph.D., Institute of Molecular Cardiobiology, Johns Hopkins University, 844 Ross Building, 720 Rutland Ave., Baltimore, MD 21205. E-mail: marban{at}jhmi.edu
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Abbreviations |
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IPC, ischemic preconditioning; KATP, ATP-sensitive potassium channel; mitoKATP, mitochondrial ATP-sensitive potassium channel; sKATP, surface membrane ATP-sensitive potassium channel; Kir, inward rectifying potassium channel; SUR, sulfonylurea receptor; HEK, human embryonic kidney; 5HD, 5-hydroxydecanoic acid sodium.
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References |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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-cells.
J Pharmacol Exp Ther
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 A. Tsuchida, T. Miura, M. Tanno, J. Sakamoto, T. Miki, A. Kuno, T. Matsumoto, Y. Ohnuma, Y. Ichikawa, and K. Shimamoto Infarct size limitation by nicorandil: Roles of mitochondrial KATP channels, sarcolemmal KATP channels, and protein kinase C J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1523 - 1530. [Abstract] [Full Text] [PDF]
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A. Hambrock, R. Preisig-Muller, U. Russ, A. Piehl, P. J. Hanley, J. Ray, J. Daut, U. Quast, and C. Derst Four novel splice variants of sulfonylurea receptor 1 Am J Physiol Cell Physiol, August 1, 2002; 283(2): C587 - C598. [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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 J. P. Giblin, Y. Cui, L. H. Clapp, and A. Tinker Assembly Limits the Pharmacological Complexity of ATP-sensitive Potassium Channels J. Biol. Chem., April 12, 2002; 277(16): 13717 - 13723. [Abstract] [Full Text] [PDF]
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C.-H. Tsai, S.-F. Su, T.-F. Chou, and T.-M. Lee Differential Effects of Sarcolemmal and Mitochondrial KATP Channels Activated by 17beta -Estradiol on Reperfusion Arrhythmias and Infarct Sizes in Canine Hearts J. Pharmacol. Exp. Ther., April 1, 2002; 301(1): 234 - 240. [Abstract] [Full Text] [PDF]
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 P. S. Pagel, J. G. Krolikowski, F. Kehl, B. Mraovic, J. R. Kersten, and D. C. Warltier The Role of Mitochondrial and Sarcolemmal KATP Channels in Canine Ethanol-Induced Preconditioning In Vivo Anesth. Analg., April 1, 2002; 94(4): 841 - 848. [Abstract] [Full Text] [PDF]
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