© 1997 American Heart Association, Inc.
Articles |
Cardioprotective Effect of Diazoxide and Its Interaction With Mitochondrial ATP-Sensitive K+ Channels
Possible Mechanism of Cardioprotection
From the Department of Chemistry, Biochemistry, and Molecular Biology (K.D.G., P.P., V.Y.-Y.), Oregon Graduate Institute of Science and Technology, Portland, and the Department of Cardiovascular Biochemistry (H.N.M., R.B.D., A.J.D., N.J.L., M.A.S., G.J.G.), Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.
Correspondence to Gary J. Grover, PhD, Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000.
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Abstract Previous studies showed a poor correlation between sarcolemmal K+ currents and cardioprotection for ATP-sensitive K+ channel (KATP) openers. Diazoxide is a weak cardiac sarcolemmal KATP opener, but it is a potent opener of mitochondrial KATP, making it a useful tool for determining the importance of this mitochondrial site. In reconstituted bovine heart KATP, diazoxide opened mitochondrial KATP with a K1/2 of 0.8 µmol/L while being 1000-fold less potent at opening sarcolemmal KATP. To compare cardioprotective potency, diazoxide or cromakalim was given to isolated rat hearts subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. Diazoxide and cromakalim increased the time to onset of contracture with a similar potency (EC25, 11.0 and 8.8 µmol/L, respectively) and improved postischemic functional recovery in a glibenclamide (glyburide)-reversible manner. In addition, sodium 5-hydroxydecanoic acid completely abolished the protective effect of diazoxide. Whole-myocyte studies showed that diazoxide was significantly less potent than cromakalim in increasing sarcolemmal K+ currents. Diazoxide shortened ischemic action potential duration significantly less than cromakalim at equicardioprotective concentrations. We also determined the effects of cromakalim and diazoxide on reconstituted rat mitochondrial cardiac KATP activity. Cromakalim and diazoxide were both potent activators of K+ flux in this preparation (K1/2 values, 1.1±0.1 and 0.49±0.05 µmol/L, respectively). Both glibenclamide and sodium 5-hydroxydecanoic acid inhibited K+ flux through the diazoxide-opened mitochondrial KATP. The profile of activity of diazoxide (and perhaps KATP openers in general) suggests that they protect ischemic hearts in a manner that is consistent with an interaction with mitochondrial KATP.
Key Words: ATP-sensitive K+ channel • mitochondria • heart • myocardial ischemia
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Introduction |
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The KATP openers are a structurally diverse class of agents that, among other activities, protect ischemic myocardial tissue.1,2 These protective effects are abolished by KATP blockers such as glibenclamide (glyburide) and 5-HD. It was originally thought that KATP openers protected ischemic myocardium by shortening the APD, thereby producing a "cardioplegic" effect. Although ATP is conserved during ischemia with these agents,3,4 this protective action is not accompanied by significant cardiodepression,2 which is not consistent with a cardioplegic effect. Recent studies by Yao and Gross5 showed cardioprotection in dogs with a dose of bimakalim that did not shorten monophasic APD. We found a similar lack of correlation between monophasic APD and cardioprotection for cromakalim.6 Pyranyl cyanoguanidine analogues that retain glibenclamide-reversible cardioprotective effects have been discovered, but they are relatively devoid of APD shortening effects or the ability to enhance whole-myocyte K+ currents.7,8 These agents are also weak vasodilators, suggesting this activity to be unimportant for cardioprotection.
These data suggest the possibility of a site of action that is distinct from sarcolemmal KATP. KATP are known to be expressed in mitochondrial membranes, where they function in the control of mitochondrial volume and energetics.9,10 Interestingly, benzopyran KATP openers have been shown to open mitochondrial KATP within their cardioprotective concentration range, suggesting the possibility that mitochondrial KATP is the site of cardioprotective action.11,12
Diazoxide is an potent opener of KATP in pancreatic cells, but compared with other KATP openers, diazoxide has relatively little effect on cardiac APD.13 Recent studies from Garlid's laboratory12 showed that diazoxide opened bovine cardiac sarcolemmal KATP in the high micromolar range (K1/2, 855 µmol/L), whereas it opened mitochondrial KATP within a submicromolar range (K1/2, 0.4 µmol/L), making this agent a potentially useful tool for separating the activities of the two KATP.12 Conversely, cromakalim was a potent opener of both sarcolemmal and mitochondrial channels. The first goal of the present study was to determine whether diazoxide retains the cardioprotective activity of cromakalim, thereby implicating a role for mitochondrial KATP. With this in mind, we determined the cardioprotective potency of diazoxide (which has not previously been determined) in isolated rat hearts and compared this activity with its ability to open rat cardiac mitochondrial KATP. A second goal of the present study was to determine the effect of 5-HD, which has little effect on sarcolemmal KATP,14 on the cardioprotective action of diazoxide or on the mitochondrial KATP opening activity of diazoxide.
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Isolated Rat Heart Model of Ischemia and Reperfusion
Male Sprague-Dawley rats (400 to 500 g) were anesthetized using 100 mg/kg IP sodium pentobarbital. The trachea was intubated, and then the jugular vein was injected with heparin (1000 U/kg). While the rats were being mechanically ventilated, their hearts were perfused in situ via retrograde cannulation of the aorta. The hearts were then excised and quickly moved to a Langendorff apparatus, where they were perfused with oxygenated Krebs-Henseleit solution containing (mmol/L) NaCl 112, NaHCO3 25, KCl 5, MgSO4 1.2, KH2PO4 1, CaCl2 1.2, glucose 11.5, and pyruvate 2 at a constant perfusion pressure (85 mm Hg). A water-filled latex balloon attached to a metal cannula was then inserted into the left ventricle and connected to a Statham pressure transducer for measurement of left ventricular pressure. The hearts were allowed to equilibrate for 15 minutes, at which time EDP was adjusted to 5 mm Hg and this balloon volume was maintained for the duration of the experiment. Preischemia or predrug function, heart rate, and coronary flow (extracorporeal electromagnetic flow probe, Carolina Medical Electronics) were then measured. Contractile function was calculated by subtracting EDP from left ventricular peak systolic pressure, resulting in LVDP. Cardiac temperature was maintained throughout the experiment by submerging the hearts in 37°C buffer, which was allowed to accumulate in a stoppered heated chamber.
After equilibration, the hearts were subjected to one of several treatments. Hearts were treated with vehicle (0.04% DMSO, n=7), 1 to 100 µmol/L cromakalim (n=6 per group), or 1 to 100 µmol/L diazoxide (n=6 to 8 per group). The respective drug treatments were given for 10 minutes and were included in the perfusate. At this time, the hearts were subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. Ischemia was initiated by completely shutting off perfusate flow. At the end of the reperfusion period, contractile function, coronary flow, and LDH release were measured. The respective drugs were given only before global ischemia and were not given during reperfusion. Severity of ischemic/reperfusion damage was determined from the time to the onset of contracture during global ischemia, recovery of contractile function at 30 minutes into reperfusion, and cumulative LDH release into the reperfusate. The fluid in the organ chamber originates from the coronary effluent; therefore, the effluent was collected during reperfusion to calculate LDH release. Time to contracture was defined as the time (minutes) during global ischemia in which the first 5 mm Hg increase in EDP was observed, and these data were used to calculate cardioprotective potency because of the concentration-dependent profile of this index. Cardioprotective potency was expressed as EC25, which is the concentration causing a 25% increase in time to onset of contracture relative to vehicle-treated hearts and is a reliable index of potency for pharmacological comparison of drugs.3
Another study was done to determine whether the preischemic and postischemic effects of diazoxide are abolished by the KATP blocker glibenclamide. For this study, rat hearts were isolated and prepared as described above. They were pretreated with vehicle (0.04% DMSO, n=5), 30 µmol/L diazoxide (n=5), or 30 µmol/L diazoxide+0.3 µmol/L glibenclamide (n=5), 10 µmol/L cromakalim (n=5), or 10 µmol/L cromakalim+0.3 µmol/L glibenclamide (n=5) for 10 minutes, and the hearts were rendered globally ischemic for 25 minutes and reperfused for 30 minutes. Functional and biochemical end points were determined as described above. The concentrations of diazoxide and cromakalim were chosen to be approximately equivalent in terms of cardioprotective activity.
We also determined the effect of 5-HD on the cardioprotective activity of diazoxide. Rat hearts were pretreated with vehicle (0.04% DMSO, n=5), 30 µmol/L diazoxide (n=5), or 100 µmol/L 5-HD+30 µmol/L diazoxide (n=5). Drug treatment lasted for 10 minutes, after which the hearts were rendered globally ischemic for 25 minutes and reperfused for 30 minutes. Functional and biochemical end points were measured as described above. These studies are important because of the observation that 5-HD abolishes the protective effects of KATP openers while having no effect on their APD shortening activity, showing a lack of blocking activity on cardiac sarcolemmal channels.14
Although no work has been done on the effect of diazoxide on mitochondrial KATP in species other than rats and cattle, it would be prudent to show that the protective effects of diazoxide can be seen in other species. We determined the effect of diazoxide on necrosis and recovery of function in isolated rabbit hearts subjected to global ischemia and reperfusion. Rabbit hearts were pretreated for 10 minutes with vehicle (0.04% DMSO, n=13), 30 µmol/L cromakalim (n=13), 30 µmol/L diazoxide (n=13), or 30 µmol/L diazoxide+100 µmol/L 5-HD (n=13). The hearts were then subjected to 50 minutes of total global ischemia followed by 30 minutes of reperfusion. Time to contracture, postischemic recovery of contractile function, and LDH release were measured as described above. Rabbit hearts are more resistant to global ischemia compared with rat hearts; therefore, longer periods of ischemia are required to achieve similar degrees of ischemic damage.
Electrophysiological Recording:
Whole-Cell K+ Currents
In addition to cardioprotection studies, the relative effect of
cromakalim and diazoxide on K+ currents in rat
ventricular myocytes was studied to determine whether a
dissociation between cardioprotection and sarcolemmal currents could be
observed. Rat ventricular myocytes were dissociated using
previously described methods.15 Currents were recorded
using the whole-cell configuration of the patch-clamp
technique.16 Electrodes (2 to 5 M
) were fabricated from
borosilicate glass. Voltage-clamp protocols were generated, and data
were acquired using Pulse software (HEKA) in conjunction with a HEKA
EPC9 amplifier (Lambrecht). Voltage ramps from -100 to 40 mV were
applied from a holding potential of -40 mV (to inactivate
Na+ current). Resultant currents were filtered at 3 KHz
using an analog four-pole Bessel filter. The bath solution contained
(mmol/L) NaCl 140, KCl 4, MgCl2 1, CaCl2
2, glucose 10, and HEPES 5, pH 7.4. Nisoldipine (1
µmol/L) was added to the bath solution to inhibit L-type
Ca2+ current. The pipette solution contained
(mmol/L) KCl 125, MgCl2 2, CaCl2 2, NaCl
10, EGTA 10, HEPES 5, glucose 10, and ATP 1, pH 7.2 with KOH. All
experiments were performed at 33°C to 34.5°C. Stock solutions of
diazoxide and cromakalim (0.1 mol/L) were prepared using DMSO
and then diluted in bath solution as required.
Isolated Rat Heart Model for APD Determination
Whereas a separation between cromakalim and diazoxide was
observed for whole-myocyte K+ currents, it was also
important to determine the effects of these agents on K+
currents in ischemic tissue. To accomplish this, rats were
anesthetized, and their hearts removed and perfused as
described above. The hearts were instrumented to record the ECG and
epicardial MAPs (Franz epicardial Langendorff probe, EP Technologies)
throughout the experiment. ECG and MAP signals were routed to a chart
recorder (TA4000, Gould) and an oscilloscope (DL1200, Yokogawa).
The ambient temperature around the preparation was maintained by a
heated vessel (37±0.2°C, FE 2, Haake). A cannula was placed inside
the right atria to allow superfusion of the tissue during subsequent
global ischemia in an effort to maintain electrical activity.
Platinum leads were also placed on the heart to pace the ventricles
once the atrial superfusion failed to afford adequate rate control.
When atrial superfusion failed to maintain proper sinoatrial nodal
activity, ventricular pacing was initiated at 5 Hz.
A total of 33 hearts were used for the present studies. Each heart was given 10 minutes of equilibration time. After equilibration, ECG and action potentials were recorded on chart paper run at 200 mm/s, and coronary flow was noted. Hearts were then given vehicle (0.1% DMSO, n=13), cromakalim (10 µmol/L, n=10), or diazoxide (30 µmol/L, n=10). At the end of 10 minutes of respective compound administration, data were again collected. The hearts were then rendered globally ischemic by stopping flow through the perfusion cannula. Atrial superfusion was immediately initiated with drug-free buffer (37°C) at a flow rate of 10 to 20 mL/min to maintain intrinsic heart rate. Data were collected every minute or until (1) tachyarrhythmias were initiated, which precluded data collection, (2) hearts were no longer able to be ventricularly paced, or (3) action potentials became of extremely low amplitude or were sufficiently deformed and irregularly shaped to preclude a valid measurement.
Effect of Diazoxide on Rat Cardiac Mitochondrial
KATP
Purification of Inner Membrane Vesicles From Rat Heart
Mitochondria
Rat heart mitochondria were prepared according to Matlib et
al17 and inner membrane vesicles were prepared as described
by McEnery et al.18 In brief, mitochondria were suspended
at 20 mg protein/mL in 220 mmol/L D-mannitol,
70 mmol/L sucrose, 0.5 mg/mL bovine serum
albumin, and 20 mmol/L potassium HEPES, pH 7.4. The
suspension was sonicated for 20 seconds at 55 W and then cooled on ice
for 2 minutes. After eight sonication/cooling cycles, the suspension
was centrifuged at 10 000g for 15 minutes at 4°C,
and the supernatant was centrifuged at 120 000g for
30 minutes at 4°C. The resulting pellet was washed in 150
mmol/L potassium phosphate, 25 mmol/L potassium
EDTA, pH 7.9, 1 mmol/L ATP, 0.5 mmol/L
dithiothreitol, and 5% ethylene glycol (PA buffer). Vesicles were
incubated in PA buffer containing 3 mol/L guanidine-HCl to
remove F1-ATPase and other membrane-bound proteins. Treated
vesicles were centrifuged at 140 000g for 30
minutes at 4°C, and the pellet was resuspended in PA buffer. This
wash cycle was repeated twice. The final membrane pellet was
resuspended to 10 mg protein/mL in 250 mmol/L sucrose,
1 mmol/L TEA+-EDTA, and 50 mmol/L
Tris-HCl, pH 7.2, and stored at -70°C until needed.
Purification, Reconstitution, and Assay of Rat Heart
Mitochondrial KATP
Purification and reconstitution followed protocols described
previously.19,20 Inner mitochondrial membrane proteins were
solubilized in 3% Triton X-100, 20% glycerol, 0.1%
ß-mercaptoethanol, 0.2 mmol/L TEA+-EGTA,
1 mmol/L MgCl2, and 50 mmol/L
Tris-HCl, pH 7.2. After incubation for 60 minutes at 4°C, the mixture
was centrifuged at 120 000g for 30 minutes. One
milliliter of the supernatant containing 2 mg of extracted proteins was
loaded onto a 1-mL DEAE-cellulose column that had been equilibrated
with column buffer containing 1% Triton X-100, 0.1%
ß-mercaptoethanol, 1 mmol/L TEA+-EDTA, and
50 mmol/L Tris-HCl, pH 7.2. The active fraction was eluted
at 300 mmol/L KCl, was desalted by passing it through a
Sephadex G-250 to 300 column (1:20 [vol/vol] ratio), and was
concentrated by filtration.
The purified mitochondrial KATP fraction was added to a
10:1 mixture of L-
-lecithin (Avanti) and cardiolipin in
a buffer containing 10% octylpentaoxyethylene, 300
µmol/L PBFI, 100 mmol/L
TEA+-SO4, 0.14 mmol/L KCl, 1
mmol/L TEA+-EDTA, and 25 mmol/L
TEA+-HEPES, pH 6.8. This mixture was loaded onto a
Bio-Beads SM-2 column (Bio-Rad) (1:4 [vol/vol] ratio),
incubated for 40 minutes at 4°C, and then centrifuged at
800g for 2 minutes. Eluted sample was loaded onto a new
Bio-Beads SM-2 column, incubated, and centrifuged as described
before, and an eluted sample was passed twice through Sephadex
G-25–300 columns (1:10 [vol/vol] ratio). The resulting stock
of proteoliposomes was stored on ice during the experiment.
Stock proteoliposomes (15 µL) were added to 2 mL of external medium containing 150 mmol/L KCl, 1 mmol/L TEA+-EDTA, and 25 mmol/L TEA+-HEPES, pH 7.4. In the assay, electrophoretic K+ flux was initiated by 1 µmol/L FCCP to provide charge compensation via H+ flux. K+ flux into proteoliposomes was determined by linear regression of the initial rate of K+ uptake, and K+-dependent fluorescence of intraliposomal PBFI was calibrated for each preparation.9,19
Assays of K+ Flux in Proteoliposomes Containing
Reconstituted KATP Isolated From Bovine Heart Mitochondria
and Sarcolemma
The purpose of this part of the study was to confirm the
relative mitochondrial selectivity of diazoxide. This was done in
bovine hearts because rat hearts provide insufficient material with
which to prepare reconstituted sarcolemmal channels. Inner
mitochondrial membrane proteins were solubilized in 3% Triton X-100
and fractionated on DEAE cellulose. KATP, which eluted with
250 mmol/L KCl, was reconstituted into proteoliposomes
exactly as previously described.9,19 Sarcolemmal
KATP was solubilized, purified, and reconstituted into
proteoliposomes using the same protocols, except that its activity was
found in the 100 mmol/L KCl fraction.20
Internal medium contained 300 µmol/L PBFI, 0.14
mmol/L KCl, 1 mmol/L TEA+-EDTA, 25
mmol/L TEA+-HEPES, and 100 mmol/L
TEA+-SO4 (pH 6.8). Vesicles were added (in a
final concentration of 0.38 mg lipid/mL) to external medium containing
150 mmol/L KCl, 3 mmol/L MgCl2,
0.5 mmol/L ATP, and 25 mmol/L
TEA+-HEPES (pH 7.4) at 25°C. Sarcolemmal vesicles were
prepared from the left ventricular muscle of fresh bovine
heart according to a modification21 of the method of
Jones.22 Internal and external media were as described for
mitochondrial KATP, except that choline was substituted for
TEA+ ion, which inhibits K+ flux through cell
KATP. In the assay, electrophoretic K+ flux was
initiated by 1 µmol/L FCCP, which catalyzes proton flux
to provide charge compensation. K+ flux was determined by
linear regression of the initial changes in the
K+-dependent fluorescence of intraliposomal PBFI,
which was calibrated for each preparation.
Chemicals and Drugs
PBFI was purchased from Molecular Probes Inc. Cromakalim was
synthesized in the Department of Chemistry at Bristol-Myers Squibb. All
other compounds were obtained from Sigma Chemical Co.
Statistics
Differences with respect to time and treatment were discerned
using a factorial ANOVA. A Newman-Keuls, Dunnett's, or Tukey's post
hoc test was used for comparisons. All data are presented as
the mean±SEM, and significant differences were determined at the
P<.05 level.
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Effect of Diazoxide on Severity of Ischemic/Reperfusion Damage in Rat Hearts
The effect of diazoxide on preischemic and postischemic contractile function and coronary flow is shown in Table 1
. Diazoxide had little
effect on heart rate or LVDP before ischemia. Diazoxide
significantly increased coronary flow at 30 and 100
µmol/L. During reperfusion, significant bradycardia and
contractile dysfunction were observed in vehicle-treated hearts,
suggesting severe ischemic/reperfusion injury. Diazoxide
attenuated the reperfusion bradycardia and significantly enhanced the
recovery of contractile function in a concentration-dependent manner.
Coronary reflow was significantly reduced in vehicle-treated
hearts. Reflow was only slightly improved by diazoxide. The effect of
diazoxide or cromakalim on the time to onset of contracture is shown in
Fig 1. Diazoxide increased the time to
contracture in a concentration-dependent manner, with an
EC25 of 11.0 µmol/L (n=6 to 8 per group).
Cromakalim increased the time to contracture, with an EC25
of 8.8 µmol/L (n=6 or 7 per group), which is similar in
cardioprotective potency to diazoxide. The effect of diazoxide on
reperfusion EDP and LDH release is shown in Fig 2. Reperfusion EDP and LDH release were
elevated in vehicle-treated hearts. Diazoxide significantly reduced
reperfusion EDP and LDH starting at 1 and 3 µmol/L,
respectively, and they were reduced in a concentration-dependent
manner. The functional and LDH data for cromakalim are not shown, but
similar data have been published in detail previously.2 For
these parameters, cromakalim was slightly more potent as a
cardioprotectant compared with diazoxide, as was seen for time to
contracture.
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We also determined the effect of glibenclamide on the
preischemic and postischemic cardioprotective
activity of diazoxide (Fig 3, Table 2). At 30 µmol/L, diazoxide
significantly increased preischemic coronary flow.
Glibenclamide completely abolished this effect. Diazoxide significantly
reduced LDH release during reperfusion, and this protective effect was
completely abolished by glibenclamide. Diazoxide also significantly
enhanced postischemic functional recovery, and
glibenclamide completely abolished this protective effect (Table 2).
Cromakalim at 10 µmol/L improved postischemic
contractile function and reduced cumulative LDH release to a degree
similar to that observed for 30 µmol/L diazoxide. The
cardioprotective effect of cromakalim was completely abolished by
glibenclamide.
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The effect of the more selective KATP blocker, 5-HD,
on the cardioprotective activity of diazoxide is shown in Table 3 and Fig 4. Diazoxide exerted a significant
protective effect, as measured by functional recovery and a reduced LDH
release. 5-HD completely abolished this cardioprotective effect. The
preischemic coronary dilator effect of diazoxide
was not attenuated by 5-HD, which is consistent with the
selective nature of its KATP blockade. Previous studies
have shown both 5-HD and glibenclamide alone (at the concentrations
used in the present study) have no effect on severity of
ischemic/reperfusion damage in our isolated rat heart
model.2,14,23,24
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A small study was conducted to show whether diazoxide could also
protect ischemic tissue in another species. We chose rabbits
because their hearts can be readily used for Langendorff preparations
and clear determinations of ischemic severity can be made. As
shown in Table 4, diazoxide was
protective in rabbit hearts, as measured by an enhanced recovery of
postischemic contractile function and reduced LDH release.
Diazoxide significantly increased preischemic
coronary flow and had no effect on cardiac function at this
time. A similar response was noted for cromakalim. In addition to the
protective effects on reperfusion function and necrosis, diazoxide
significantly (P<.05) increased the time to contracture
during ischemia from 42.9±0.9 minutes in vehicle-treated
hearts to 49.5±0.3 minutes in diazoxide-treated hearts. Cromakalim
increased the time to contracture (47.9±0.7 minutes) to a degree
similar to that found with diazoxide at the 30 µmol/L
concentration. At 100 µmol/L, 5-HD completely abolished
the cardioprotective effects of diazoxide (Table 4). 5-HD completely
abolished the increase in time to contracture (42.7±0.8 min) observed
with diazoxide alone.
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Effect of Diazoxide and Cromakalim on Whole-Cell Currents
Consistent with previous studies,25
stimulation of isolated voltage-clamped rat ventricular
myocytes with a slow voltage ramp evoked an N-shaped current response
(Fig 5). Exposure of the cells to
100 µmol/L diazoxide had little affect on the
current-voltage relationship; current measured at +40 mV was 0.56±0.09
nA in control and 0.59±0.09 nA in the presence of diazoxide (n=6, Fig 5). Addition of 300 µmol/L diazoxide produced a robust
increase in current at voltages positive to 
-85 mV in 8 of 18 cells
tested. At 1000 µmol/L, diazoxide evoked a large response
in 6 of 8 cells tested (Fig 5A and 5B). The activated current
was reversible on washout. Interestingly, the higher concentrations of
diazoxide, especially 1000 µmol/L, partially inhibited
the control currents (Fig 5A).
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The reversal potential of the activated current indicates that
diazoxide evoked a K+ current. Moreover, the
current-voltage relationship observed in the presence of diazoxide is
similar to that previously reported for the K+ channel
activator rimakalim in rat cardiac myocytes.20
Currents activated by diazoxide (1000 µmol/L)
were fully blocked by the subsequent addition of glibenclamide (3
µmol/L, n=6, Fig 5A
) but refractory to inhibition by 5-HD
(100 µmol/L, n=4). Cromakalim was found to be
considerably more potent than diazoxide, producing a small increase in
current at 10 µmol/L in 5 of 8 cells tested, and a robust
response at 30 µmol/L in all cells tested (n=7, Fig 5B).
A comparison of the concentration-response curves indicates that
diazoxide was 50-fold less potent than cromakalim as a
K+ channel activator in isolated rat
ventricular cells.
Effect of Diazoxide on Normal and Ischemic APD in Rat
Hearts
Since 10 µmol/L cromakalim and 30
µmol/L diazoxide were found to be equivalent in terms of their
ability to protect ischemic rat hearts, we compared the effect
of these concentrations on APD in normal and ischemic rat
hearts. Vehicle-treated hearts displayed an early ischemic APD
lengthening before shortening to 25±6% at 6 minutes after occlusion
(Fig 6). The only statistically
significant shortening occurred at 5 and 6 minutes after
ischemia in the vehicle-treated hearts. In the 8 hearts that
showed tachyarrhythmias, the mean time to onset was
406±64 seconds. The remaining preparations were discontinued for
reasons stated above (loss of reliable action potential measurements
and inability to pace); therefore, the n value for all time periods may
not be the same. No effect was seen on preischemic APD
values after 10 minutes of exposure to 30 µmol/L
diazoxide. Although diazoxide-treated hearts maintained the early
portion of the APD lengthening (1-minute data) seen in the vehicle
group, at 2 and 3 minutes after occlusion diazoxide did slightly
shorten APD relative to vehicle. At later time points (4 to 6 minutes),
diazoxide did not significantly reduce APD relative to vehicle-treated
hearts. Mean onset time to tachyarrhythmias was 265±40
seconds in diazoxide-treated hearts. Cromakalim caused a 7±3%
shortening of preischemic APD, but this was not
statistically significant. On occlusion, cromakalim caused an abolition
of the early lengthening seen with vehicle and diazoxide, and APD
shortening reached a nadir that was 67±10% less than its control
value at 5 minutes of ischemia. All points collected after
occlusion were significantly different from corresponding control,
diazoxide, or vehicle values. A mean duration of 146±10 seconds was
noted for the onset to tachyarrhythmias for cromakalim,
and most preparations invariably showed fibrillatory activity
early in the protocol. It is important to note that the
arrhythmias noted in the vehicle- and diazoxide-treated groups
were mostly tachycardic, and at no time was the cycle length
statistically different among groups, irrespective of the need for
pacing. Basic cycle lengths were 220±9, 215±9, and 213±8
milliseconds for vehicle, diazoxide, and cromakalim, respectively.
These data taken together show that there is little relationship
between APD shortening and cardioprotection for diazoxide and
cromakalim.
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Effects of Diazoxide on Reconstituted Bovine Heart Mitochondrial
and Sarcolemmal KATP Activity
Fig 7 contains the diazoxide (Fig 7A) and cromakalim (Fig 7B) concentration-response curves for
stimulation of K+ flux in vesicles reconstituted with
KATP purified from bovine heart mitochondria (solid
circles, Fig 7) and sarcolemma (open circles, Fig 7). Cromakalim was a
potent activator of K+ flux in both
preparations (Fig 7B). Observed K1/2 values for cromakalim
were 1.6±0.1 µmol/L (n=5) for mitochondrial
KATP and 18±2 µmol/L (n=3) for sarcolemmal
KATP. The reconstituted KATP from the two
sources responded differently to diazoxide. Observed K1/2
values for diazoxide were 0.80±0.03 µmol/L (n=4) for
mitochondrial KATP and 840±25 µmol/L (n=3)
for sarcolemmal KATP. In both preparations,
KATP openers activated K+ flux only
when it was inhibited by ATP. Therefore, mitochondrial KATP
is 1000-fold more sensitive to diazoxide than sarcolemmal channels.
These data confirm previously published work from this
laboratory.12 Also, compared with cromakalim, diazoxide is
50-fold less potent at activating sarcolemmal KATP,
which is consistent with the findings seen with whole-cell
currents.
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J/
) and sarcolemmal
KATP channels (
) in response to diazoxide (panel A) or
cromakalim (panel B).
Effect of Diazoxide and Cromakalim on Rat Heart Mitochondrial
KATP: Effect of KATP Blockade
Since the ischemia studies were performed in isolated rat
hearts, we also determined the effect of diazoxide on rat cardiac
mitochondrial KATP. As shown in Fig 8A, diazoxide and cromakalim are potent
activators of the ATP-inhibited mitochondrial
KATP from rat heart. Observed K1/2 values were
0.49±0.05 µmol/L for diazoxide (n=3) and 1.1±0.1
µmol/L for cromakalim (n=3). These values are similar to those
previously obtained with reconstituted mitochondrial KATP
from rat liver and bovine heart.12
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To mimic the in situ pharmacological experiments, we included MgATP,
diazoxide (10 µmol/L), and glibenclamide or 5-HD in the
assay medium and varied the inhibitor concentration. As
demonstrated in Fig 8B, K+ flux through the
diazoxide-opened channel was inhibited by low concentrations of
glibenclamide (K1/2, 56 nmol/L) and 5-HD
(K1/2, 83 µmol/L). Similar results were
obtained in two experiments using 10 µmol/L cromakalim,
with glibenclamide inhibiting with K1/2 of 92 nmol/L
and 5-HD inhibiting with K1/2 of 31 µmol/L.
In the absence of ATP and K+ channel openers, glibenclamide
inhibited K+ flux with K1/2 of 40
nmol/L, whereas 5-HD had no effect up to 500
µmol/L, the highest concentration tested.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Structurally diverse KATP openers exert cardioprotective effects in various animal models of ischemia.2 These protective effects are exerted directly on ischemic myocytes and are independent of vasodilatory activity. The cardioprotective effects of KATP openers are universally abolished by KATP blockers such as glibenclamide. The ability of glibenclamide to abolish cardioprotective effects is selective for KATP openers.23 KATP openers may mimic an endogenous cardioprotective mechanism, since many laboratories have shown cardiac preconditioning to be abolished by KATP blockers.26–28
It was tempting to conclude that the cardioprotective effects of KATP openers were due to APD shortening and the consequent reduction of Ca2+ entry into myocytes. KATP openers do conserve ATP during ischemia, which is at least consistent with a cardioplegic effect for KATP openers.3,4 Data from Gross's laboratory5 as well as our own6 suggested a lack of correlation for ischemic APD shortening and cardioprotection. Monophasic APD measurements were used in these studies; therefore, regional changes in APD could have gone undetected. Subsequently, we performed studies showing a lack of correlation between intracellular APD measurements and glibenclamide-reversible cardioprotection for the pyranyl cyanoguanidine BMS-180448.7 This compound is interesting because it is less potent as a vasodilator compared with cromakalim but is identical as a cardioprotectant.27 Interestingly, BMS-180448 is poor at opening single KATP in cardiomyocytes, and the mechanism for the glibenclamide reversibility of its cardioprotective action is not clear. We hypothesized that an intracellular KATP could be mediating cardioprotection.
A KATP that appears to be opened by benzopyran
KATP openers such as cromakalim is expressed in
mitochondrial membranes.9–12 This channel was clearly
shown to be inhibited by glibenclamide.9 This channel was
also shown to be inhibited by ATP and ADP and to be dependent on
[K+]o, and there appeared to be little
dependence of pH on channel function.9 The function of
mitochondrial KATP is to regulate mitochondrial volume,
which, in turn, is thought to regulate electron
transport.12 Recent results from Garlid's
laboratory12 have also shown that diazoxide opens liver
mitochondrial KATP in the low micromolar range. Diazoxide
is an interesting compound because it is potent at opening pancreatic
KATP but is relatively weak at shortening cardiac
APD.1,13 Results shown in the present study also
demonstrated diazoxide to be 2000-fold more potent than sarcolemmal
KATP at opening mitochondrial KATP. This makes
diazoxide a potentially important tool for dissecting the role of
mitchondrial KATP in heart. With this in mind, we
determined the effect of diazoxide in a rat model of ischemia
and reperfusion. Potent cardioprotective effects exerted by diazoxide
would strongly implicate a role for mitochondrial KATP.
Diazoxide protected ischemic/reperfused rat hearts with a
potency in the low micromolar range. This protection was concentration
dependent and was similar in profile to other KATP openers
tested in this model, although it is slightly less potent than agents
such as cromakalim and aprikalim.2,24 The protective
effects of a high concentration of diazoxide were completely abolished
by glibenclamide; however, they were not clearly correlated with APD
shortening either before or during ischemia. Diazoxide had no
effect on APD before ischemia and was significantly less potent
than cromakalim during ischemia. Ischemic APD
shortening was slightly enhanced by diazoxide early into
ischemia; however, the ultimate amount of shortening was
similar to vehicle. Diazoxide (30 µmol/L) was found to be
comparable to 10 µmol/L cromakalim in the degree of
cardioprotection. Historical EC25 values for cromakalim
(time to contracture) are 5 to 9 µmol/L,2,8
which are comparable to the values found for diazoxide. The potency of
these two agents for opening mitochondrial KATP was also
similar. Therefore, diazoxide and cromakalim differ markedly in their
effects on APD as well as on the opening of reconstituted sarcolemmal
KATP, and the common thread is that both open cardiac
mitochondrial KATP with high potency. These studies were
important in documenting a separation of sarcolemmal KATP
opening from cardioprotection in which an index of such opening (APD)
was measured during ischemia. A similar separation was seen for
whole-cell myocyte currents. Diazoxide activated
IKATP but was 50 times less potent than
cromakalim. Moreover, the diazoxide-activated current was
refractory to block by 5-HD (100 µmol/L). Similar results
were previously reported for cromakalim-activated
IKATP in guinea pig myocytes, where the
activated currents were also fully blocked by glibenclamide but
insensitive to 5-HD.14 Thus, sarcolemmal KATP
is sensitive to block by glibenclamide but not 5-HD.
Further evidence for a role for mitochondrial KATP in mediating the cardioprotective effects of diazoxide was seen in the 5-HD studies. Previous studies showed that 5-HD does not abolish the APD shortening or vasodilator effects of KATP openers but completely abolishes their cardioprotective effects.14 As further confirmation of the importance of mitochondrial KATP, we determined the effect of 5-HD on the pharmacological actions of diazoxide. 5-HD completely abolished the cardioprotective effects of diazoxide but did not affect its coronary dilator activity, which is consistent with its effects on other KATP openers.14 5-HD also significantly inhibited the ability of diazoxide to open reconstituted mitochondrial KATP. These data strongly suggest an important role for mitochondrial KATP in mediating the cardioprotective effects of KATP openers. The purity of mitochondrial pellets and sarcolemmal membranes was verified as described previously.9
The data in the present study, as well as previously reported work, suggest the possibility that differences between KATP may be not only at the level of cell type but also at the level of organelles. The data collected in the present study are consistent with the idea that the relevant cardioprotective site for KATP openers is mitochondrial KATP. Pyranyl cyanoguanidine analogues that protect ischemic myocardium without affecting sarcolemmal K+ currents have been found. These agents protect hearts in a glibenclamide-reversible manner, suggesting an involvement with KATP. Interestingly, agents such as BMS-180448 are less potent as vasodilators compared with cromakalim, while being equipotent as cardioprotectants. Diazoxide is a potent pancreatic KATP opener, unlike BMS-180448 and cromakalim.29–32 Interestingly, diazoxide does not appear to be potent at reducing cardiac APD,13 although results have been variable and have not been measured in ischemic myocardium.33 These results suggest multiple subtypes of KATP or receptors (if not of KATP itself).
Although these data are consistent with the mitochondrion as a potential site of cardioprotective activity, it is still unclear how the opening of mitochondrial KATP can exert protective effects. Agents such as diazoxide are protective in isolated rat heart models of total global ischemia, in which oxidative phosphorylation is essentially inhibited. Nevertheless, KATP openers such as cromakalim significantly conserve ATP and inhibit accumulation of AMP during global ischemia, suggesting reduced ATP hydrolysis. Mitochondrial KATP are thought to be involved with mitochondrial volume control and energetics. Therefore, it is likely that mitochondrial KATP activation may act to inhibit ATP wastage.34 There may be an interaction between mitochondrial KATP and inefficient ATP wastage by mitochondrial ATP hydrolase activity. This plausible mechanism, which remains to be investigated, would be consistent with the ability of KATP openers to conserve ATP without major effects on cardiac function. Published data from our laboratories showed that BMS-180448 preserved mitochondrial ultrastructural integrity as well as the efficiency of oxygen utilization, further suggesting mitochondrial protection.35 Interestingly, the histological necrosis data in that study35 were well correlated with the surrogate marker of LDH release, and later studies36 further validated these findings.
|
Selected Abbreviations and Acronyms |
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|
Acknowledgments |
|---|
This study was supported in part by grant GM-31086 (Dr Garlid) from the National Institutes of Health.
Received March 24, 1997; accepted September 23, 1997.
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 L. Tritapepe, V. De Santis, D. Vitale, M. Santulli, A. Morelli, I. Nofroni, P. E. Puddu, M. Singer, and P. Pietropaoli Preconditioning effects of levosimendan in coronary artery bypass grafting--a pilot study Br. J. Anaesth., June 1, 2006; 96(6): 694 - 700. [Abstract] [Full Text] [PDF]
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 T. Takeda, M. Akao, M. Matsumoto-Ida, M. Kato, H. Takenaka, Y. Kihara, T. Kume, A. Akaike, and T. Kita Serofendic Acid, a Novel Substance Extracted From Fetal Calf Serum, Protects Against Oxidative Stress in Neonatal Rat Cardiac Myocytes J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1882 - 1890. [Abstract] [Full Text] [PDF]
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 L. Wang, C. Kinnear, J. M. Hammel, W. Zhu, Z. Hua, W. Mi, and C. A. Caldarone Preservation of Mitochondrial Structure and Function After Cardioplegic Arrest in the Neonate Using a Selective Mitochondrial K(ATP) Channel Opener. Ann. Thorac. Surg., May 1, 2006; 81(5): 1817 - 1823. [Abstract] [Full Text] [PDF]
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G. J. Grover Mitochondrial ATP-sensitive potassium channels and mitochondrial protein kinase C: sometimes it's good to have a close neighbor Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1752 - H1753. [Full Text] [PDF]
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 G. Roseborough, D. Gao, L. Chen, M. A. Trush, S. Zhou, G. M. Williams, and C. Wei The Mitochondrial K-ATP Channel Opener, Diazoxide, Prevents Ischemia-Reperfusion Injury in the Rabbit Spinal Cord Am. J. Pathol., May 1, 2006; 168(5): 1443 - 1451. [Abstract] [Full Text] [PDF]
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D. V. Cuong, N. Kim, J. B. Youm, H. Joo, M. Warda, J.-W. Lee, W. S. Park, T. Kim, S. Kang, H. Kim, et al. Nitric oxide-cGMP-protein kinase G signaling pathway induces anoxic preconditioning through activation of ATP-sensitive K+ channels in rat hearts Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1808 - H1817. [Abstract] [Full Text] [PDF]
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M. T. Jiang, M. Ljubkovic, Y. Nakae, Y. Shi, W.-M. Kwok, D. F. Stowe, and Z. J. Bosnjak Characterization of human cardiac mitochondrial ATP-sensitive potassium channel and its regulation by phorbol ester in vitro Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1770 - H1776. [Abstract] [Full Text] [PDF]
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F. Di Lisa and P. Bernardi Mitochondria and ischemia-reperfusion injury of the heart: Fixing a hole Cardiovasc Res, May 1, 2006; 70(2): 191 - 199. [Abstract] [Full Text] [PDF]
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K. Inagaki, E. Churchill, and D. Mochly-Rosen Epsilon protein kinase C as a potential therapeutic target for the ischemic heart Cardiovasc Res, May 1, 2006; 70(2): 222 - 230. [Abstract] [Full Text] [PDF]
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A. Hassouna, M. Loubani, B. M. Matata, A. Fowler, N. B. Standen, and M. Galinanes Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium Cardiovasc Res, February 1, 2006; 69(2): 450 - 458. [Abstract] [Full Text] [PDF]
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T. Sato, A. D. T. Costa, T. Saito, T. Ogura, H. Ishida, K. D. Garlid, and H. Nakaya Bepridil, an Antiarrhythmic Drug, Opens Mitochondrial KATP Channels, Blocks Sarcolemmal KATP Channels, and Confers Cardioprotection J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 182 - 188. [Abstract] [Full Text] [PDF]
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D. F. Stowe, M. Aldakkak, A. K. S. Camara, M. L. Riess, A. Heinen, S. G. Varadarajan, and M.-T. Jiang Cardiac mitochondrial preconditioning by Big Ca2+-sensitive K+ channel opening requires superoxide radical generation Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H434 - H440. [Abstract] [Full Text] [PDF]
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A. D. T. Costa, C. L. Quinlan, A. Andrukhiv, I. C. West, M. Jaburek, and K. D. Garlid The direct physiological effects of mitoKATP opening on heart mitochondria Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H406 - H415. [Abstract] [Full Text] [PDF]
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M. Fujii and D. J. Chambers Myocardial protection with intermittent cross-clamp fibrillation: does preconditioning play a role? Eur. J. Cardiothorac. Surg., December 1, 2005; 28(6): 821 - 831. [Abstract] [Full Text] [PDF]
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D. Obal, S. Dettwiler, C. Favoccia, H. Scharbatke, B. Preckel, and W. Schlack The Influence of Mitochondrial KATP-Channels in the Cardioprotection of Preconditioning and Postconditioning by Sevoflurane in the Rat In Vivo Anesth. Analg., November 1, 2005; 101(5): 1252 - 1260. [Abstract] [Full Text] [PDF]
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J. E. Davies, S. B. Digerness, C. R. Killingsworth, C. Zaragoza, C. R. Katholi, R. K. Justice, S. P. Goldberg, and W. L. Holman Multiple Treatment Approach to Limit Cardiac Ischemia-Reperfusion Injury Ann. Thorac. Surg., October 1, 2005; 80(4): 1408 - 1416. [Abstract] [Full Text] [PDF]
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P. Korge, H. M. Honda, and J. N. Weiss K+-dependent regulation of matrix volume improves mitochondrial function under conditions mimicking ischemia-reperfusion Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H66 - H77. [Abstract] [Full Text] [PDF]
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M. Juhaszova, C. Rabuel, D. B. Zorov, E. G. Lakatta, and S. J. Sollott Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res, May 1, 2005; 66(2): 233 - 244. [Abstract] [Full Text] [PDF]
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 R. J. Edwards, S. R. Redwood, P. D. Lambiase, and M. S. Marber The effect of an angiotensin-converting enzyme inhibitor and a K+ATP channel opener on warm up angina Eur. Heart J., March 2, 2005; 26(6): 598 - 606. [Abstract] [Full Text] [PDF]
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B. C. Blunt, Y. Chen, J. D. Potter, and P. A. Hofmann Modest actomyosin energy conservation increases myocardial postischemic function Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1088 - H1096. [Abstract] [Full Text] [PDF]
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 G. J. Gross Sildenafil and Endothelial Dysfunction in Humans Circulation, February 15, 2005; 111(6): 721 - 723. [Full Text] [PDF]
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C.-M. Cao, Q. Xia, Q. Gao, M. Chen, and T.-M. Wong Calcium-Activated Potassium Channel Triggers Cardioprotection of Ischemic Preconditioning J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 644 - 650. [Abstract] [Full Text] [PDF]
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F. Er, G. Michels, N. Gassanov, F. Rivero, and U. C. Hoppe Testosterone Induces Cytoprotection by Activating ATP-Sensitive K+ Channels in the Cardiac Mitochondrial Inner Membrane Circulation, November 9, 2004; 110(19): 3100 - 3107. [Abstract] [Full Text] [PDF]
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H. Barthel, D. Ebel, J. Mullenheim, D. Obal, B. Preckel, and W. Schlack Effect of lidocaine on ischaemic preconditioning in isolated rat heart Br. J. Anaesth., November 1, 2004; 93(5): 698 - 704. [Abstract] [Full Text] [PDF]
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S. Kohro, Q. H. Hogan, D. C. Warltier, and Z. J. Bosnjak Protein Kinase C Inhibitors Produce Mitochondrial Flavoprotein Oxidation in Cardiac Myocytes Anesth. Analg., November 1, 2004; 99(5): 1316 - 1322. [Abstract] [Full Text] [PDF]
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 A. Hassouna, B. M. Matata, and M. Galinanes PKC-{epsilon} is upstream and PKC-{alpha} is downstream of mitoKATP channels in the signal transduction pathway of ischemic preconditioning of human myocardium Am J Physiol Cell Physiol, November 1, 2004; 287(5): C1418 - C1425. [Abstract] [Full Text] [PDF]
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A. J. Rousou, M. Ericsson, M. Federman, S. Levitsky, and J. D. McCully Opening of mitochondrial KATP channels enhances cardioprotection through the modulation of mitochondrial matrix volume, calcium accumulation, and respiration Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1967 - H1976. [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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G. C. Sparagna, C. E. Jones, and D. L. M. Hickson-Bick Attenuation of fatty acid-induced apoptosis by low-dose alcohol in neonatal rat cardiomyocytes Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2209 - H2215. [Abstract] [Full Text] [PDF]
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M.W. Broadhead, R.K. Kharbanda, M.J. Peters, and R.J. MacAllister KATP Channel Activation Induces Ischemic Preconditioning of the Endothelium in Humans In Vivo Circulation, October 12, 2004; 110(15): 2077 - 2082. [Abstract] [Full Text] [PDF]
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 H. Ardehali, Z. Chen, Y. Ko, R. Mejia-Alvarez, and E. Marban Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity PNAS, August 10, 2004; 101(32): 11880 - 11885. [Abstract] [Full Text] [PDF]
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A. K. S. Camara, Q. Chen, S. S. Rhodes, M. L. Riess, and D. F. Stowe Negative inotropic drugs alter indexes of cytosolic [Ca2+]-left ventricular pressure relationships after ischemia Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H667 - H680. [Abstract] [Full Text] [PDF]
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D. J. Hausenloy, D. M. Yellon, S. Mani-Babu, and M. R. Duchen Preconditioning protects by inhibiting the mitochondrial permeability transition Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H841 - H849. [Abstract] [Full Text] [PDF]
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 G. D. Mironova, A. E. Negoda, B. S. Marinov, P. Paucek, A. D. T. Costa, S. M. Grigoriev, Y. Yu. Skarga, and K. D. Garlid Functional Distinctions between the Mitochondrial ATP-dependent K+ Channel (mitoKATP) and Its Inward Rectifier Subunit (mitoKIR) J. Biol. Chem., July 30, 2004; 279(31): 32562 - 32568. [Abstract] [Full Text] [PDF]
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M. Zaugg, M. C. Schaub, and P. Foex Myocardial injury and its prevention in the perioperative setting Br. J. Anaesth., July 1, 2004; 93(1): 21 - 33. [Abstract] [Full Text] [PDF]
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R. D. Rainbow, D. Lodwick, D. Hudman, N. W. Davies, R. I. Norman, and N. B. Standen SUR2A C-terminal fragments reduce KATP currents and ischaemic tolerance of rat cardiac myocytes J. Physiol., June 15, 2004; 557(3): 785 - 794. [Abstract] [Full Text] [PDF]
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P. S. Fischbach, A. White, T. D. Barrett, and B. R. Lucchesi Risk of Ventricular Proarrhythmia with Selective Opening of the Myocardial Sarcolemmal versus Mitochondrial ATP-Gated Potassium Channel J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 554 - 559. [Abstract] [Full Text] [PDF]
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D. Hausenloy, A. Wynne, M. Duchen, and D. Yellon Transient Mitochondrial Permeability Transition Pore Opening Mediates Preconditioning-Induced Protection Circulation, April 13, 2004; 109(14): 1714 - 1717. [Abstract] [Full Text] [PDF]
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T. Steensrud, D. Nordhaug, K. V. Husnes, E. Aghajani, and D. G. Sorlie Replacing potassium with nicorandil in cold St. Thomas' Hospital cardioplegia improves preservation of energetics and function in pig hearts Ann. Thorac. Surg., April 1, 2004; 77(4): 1391 - 1397. [Abstract] [Full Text] [PDF]
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C.J Zuurbier, O Eerbeek, P.T Goedhart, E.A Struys, N.M Verhoeven, C Jakobs, and C Ince Inhibition of the pentose phosphate pathway decreases ischemia-reperfusion-induced creatine kinase release in the heart Cardiovasc Res, April 1, 2004; 62(1): 145 - 153. [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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B. N. Eigel, H. Gursahani, and R. W. Hadley ROS are required for rapid reactivation of Na+/Ca2+ exchanger in hypoxic reoxygenated guinea pig ventricular myocytes Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H955 - H963. [Abstract] [Full Text] [PDF]
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M. Galinanes and A. G Fowler Role of clinical pathologies in myocardial injury following ischaemia and reperfusion Cardiovasc Res, February 15, 2004; 61(3): 512 - 521. [Abstract] [Full Text] [PDF]
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G. C Rodrigo, N. W Davies, and N. B Standen Diazoxide causes early activation of cardiac sarcolemmal KATP channels during metabolic inhibition by an indirect mechanism Cardiovasc Res, February 15, 2004; 61(3): 570 - 579. [Abstract] [Full Text] [PDF]
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D. J. Granville, B. Tashakkor, C. Takeuchi, A. B. Gustafsson, C. Huang, M. R. Sayen, P. Wentworth Jr., M. Yeager, and R. A. Gottlieb Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors PNAS, February 3, 2004; 101(5): 1321 - 1326. [Abstract] [Full Text] [PDF]
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E. Murphy Primary and Secondary Signaling Pathways in Early Preconditioning That Converge on the Mitochondria to Produce Cardioprotection Circ. Res., January 9, 2004; 94(1): 7 - 16. [Abstract] [Full Text] [PDF]
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M. A. Deja, K. S. Golba, M. Kolowca, K. Widenka, J. Biernat, and S. Wos Diazoxide provides protection to human myocardium in vitro that is concentration dependent Ann. Thorac. Surg., January 1, 2004; 77(1): 226 - 232. [Abstract] [Full Text] [PDF]
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D. V. Cancherini, L. G. Trabuco, N. A. Reboucas, and A. J. Kowaltowski ATP-sensitive K+ channels in renal mitochondria Am J Physiol Renal Physiol, December 1, 2003; 285(6): F1291 - F1296. [Abstract] [Full Text]
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Y. Teshima, M. Akao, S. P. Jones, and E. Marban Cariporide (HOE642), a Selective Na+-H+ Exchange Inhibitor, Inhibits the Mitochondrial Death Pathway Circulation, November 4, 2003; 108(18): 2275 - 2281. [Abstract] [Full Text] [PDF]
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A. Schneider, N. Ad, U. Izhar, I. Khaliulin, J. B. Borman, and H. Schwalb Protection of myocardium by cyclosporin A and insulin: in vitro simulated ischemia study in human myocardium Ann. Thorac. Surg., October 1, 2003; 76(4): 1240 - 1245. [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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Y. Nakae, S. Kohro, Q. H. Hogan, and Z. J. Bosnjak Intracellular Mechanism of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channel Activation with Isoflurane Anesth. Analg., October 1, 2003; 97(4): 1025 - 1032. [Abstract] [Full Text] [PDF]
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Y. Teshima, M. Akao, S. P. Jones, and E. Marban Uncoupling Protein-2 Overexpression Inhibits Mitochondrial Death Pathway in Cardiomyocytes Circ. Res., August 8, 2003; 93(3): 192 - 200. [Abstract] [Full Text] [PDF]
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G. J. Gross and J. N. Peart KATP channels and myocardial preconditioning: an update Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H921 - H930. [Abstract] [Full Text] [PDF]
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 Y. Teshima, M. Akao, R. A. Li, T. H. Chong, W. A. Baumgartner, M. V. Johnston, and E. Marban Mitochondrial ATP-Sensitive Potassium Channel Activation Protects Cerebellar Granule Neurons From Apoptosis Induced by Oxidative Stress Stroke, July 1, 2003; 34(7): 1796 - 1802. [Abstract] [Full Text] [PDF]
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J. Minners, C. J. McLeod, and M. N. Sack Mitochondrial plasticity in classical ischemic preconditioning--moving beyond the mitochondrial KATP channel Cardiovasc Res, July 1, 2003; 59(1): 1 - 6. [Abstract] [Full Text] [PDF]
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M. M. da Silva, A. Sartori, E. Belisle, and A. J. Kowaltowski Ischemic preconditioning inhibits mitochondrial respiration, increases H2O2 release, and enhances K+ transport Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H154 - H162. [Abstract] [Full Text] [PDF]
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 T. Yamauchi, S. Kashii, H. Yasuyoshi, S. Zhang, Y. Honda, and A. Akaike Mitochondrial ATP-Sensitive Potassium Channel: A Novel Site for Neuroprotection Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2750 - 2756. [Abstract] [Full Text] [PDF]
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K. Y. Kim, Y. W. Shin, S.-O. Kim, H. Lim, S.-E. Yoo, and K. W. Hong Antiangiogenic Effect of KR-31372 by Apoptosis via Mediation of Mitochondrial KATP Channel Opening and the Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1142 - 1149. [Abstract] [Full Text] [PDF]
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M. Ichinose, H. Yonemochi, T. Sato, and T. Saikawa Diazoxide triggers cardioprotection against apoptosis induced by oxidative stress Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2235 - H2241. [Abstract] [Full Text] [PDF]
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C. P. Baines, C.-X. Song, Y.-T. Zheng, G.-W. Wang, J. Zhang, O.-L. Wang, Y. Guo, R. Bolli, E. M. Cardwell, and P. Ping Protein Kinase C{epsilon} Interacts With and Inhibits the Permeability Transition Pore in Cardiac Mitochondria Circ. Res., May 2, 2003; 92(8): 873 - 880. [Abstract] [Full Text] [PDF]
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