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Anesthesiology Research Laboratory, Departments of 1 Anesthesiology and 2 Physiology, and 3 Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee 53226; 4 Department of Biomedical Engineering, Marquette University, Milwaukee 53233; 5 Research Service, Veterans Affairs Medical Center, Milwaukee, Wisconsin 53295; and 6 Department of Anesthesiology and Intensive Care Medicine, University Hospital Münster, 48129 Münster, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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NADH increases during ischemia because O2 shortage limits NADH oxidation at the electron transport chain. Ischemic (IPC) and anesthetic preconditioning (APC) attenuate cardiac reperfusion injury. We examined whether IPC and APC similarly alter NADH, i.e., mitochondrial metabolism. NADH fluorescence was measured at the left ventricular wall of 40 Langendorff-prepared guinea pig hearts. IPC was achieved by two 5-min periods of ischemia and APC by exposure to 0.5 or 1.3 mM sevoflurane for 15 min, each ending 30 min before 30 min of global ischemia. During ischemia, NADH initially increased in nonpreconditioned control hearts and then gradually declined below baseline levels. This increase in NADH was lower after APC but not after IPC. The subsequent decline was slower after IPC and APC. On reperfusion, NADH was less decreased after IPC or APC, mechanical and metabolic functions were improved, and infarct size was lower compared with controls. Our results indicate that IPC and APC cause distinctive changes in mitochondrial metabolism during ischemia and thus lead to improved function and tissue viability on reperfusion.
experimental; infarction; sevoflurane; dose dependency; mitochondrial function
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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EXPERIMENTS IN ISOLATED MYOCYTES, intact hearts, and whole animal models have shown that cardiac cell injury and mechanical dysfunction are caused by reperfusion after prolonged ischemia. Depending on the duration and magnitude of the ischemia, the injury can be reversible (stunning) or irreversible (infarction) (20). Several interrelated mechanisms are responsible: 1) cytosolic Na+ and Ca2+ overload (39) with myofibrillar hypercontracture, cytoskeletal damage, and cell disruption; 2) mitochondrial Ca2+ overload (27, 39), inefficient ATP synthesis or utilization, and NADH accumulation (39); 3) reduced maximal Ca2+-activated force and/or Ca2+ sensitivity (39); 4) impaired myocardial vascular perfusion (32); and 5) reactive oxygen species-induced damage to Na+ and Ca2+ pump proteins and membranes by lipid peroxidation (4).
Ischemic preconditioning (IPC), i.e., brief periods of ischemia before prolonged ischemia, can attenuate the subsequent damage and lead to better functional recovery and reduced infarct size (3, 11, 28). Anesthetic preconditioning (APC), i.e., exposure to a volatile anesthetic followed by its washout, does not require ischemia to achieve cardioprotection. Preconditioning with isoflurane reduced infarct size in dogs (24). We showed additionally that APC with sevoflurane, like IPC, improved vascular, mechanical, and metabolic function, reduced Ca2+ overload, and improved drug-induced endothelial nitric oxide release in isolated guinea pig hearts (3, 30).
It is difficult to understand how these divergent stimuli, brief ischemia and anesthetic exposure, can both lead to preconditioning. One mechanism common to IPC and APC is believed to be the opening of ATP-sensitive K+ (KATP) channels because KATP channel antagonists attenuated the protection by both IPC (22, 30) and APC (24, 30). Although opening mitochondrial KATP channels may be an effective way to attenuate mitochondrial damage (23), it remains unclear how this confers cardioprotection. Mitochondrial membrane depolarization caused by K+ influx could lead to partial uncoupling of oxidative phosphorylation, thus improving the efficiency of oxidative phosphorylation and minimizing respiration inefficiency during ischemia-reperfusion (37). Direct or indirect release of reactive oxygen species (5, 31, 34, 42), presumably from electron transport chain uncoupling in mitochondria, may also play a common role. However, the exact triggering mechanisms of IPC and APC before ischemia and those that elicit cardioprotection during ischemia and on reperfusion are not fully understood.
One important marker of mitochondrial function is mitochondrial NADH. Hypoxia and ischemia lead to excess accumulation of NADH (19, 39) and suggest uncoupled oxidative phosphorylation. Because APC and IPC may trigger mechanisms that induce metabolic protection during ischemia, we hypothesized that APC and IPC cause similar changes in mitochondrial function before, during, and after ischemia as evidenced by online recordings of NADH fluorescence.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Langendorff heart preparation.
The investigation conformed to the Guide for the Care and Use of
Laboratory Animals [National Institutes of Health (NIH) No. 85-23, Revised 1996]. Approval was obtained from the Medical College of Wisconsin animal studies committee. Our Langendorff heart method has
been described previously (2, 3, 30, 39). Guinea pig
hearts (n = 40) were perfused with an oxygenated
Krebs-Ringer (KR) solution of the following composition (in mM): 138 Na+, 4.5 K+, 1.2 Mg2+, 2.5 Ca2+, 134 Cl
, 14.5 HCO
O2)
was calculated as coronary inflow per
weight · (PaO2 
PvO2) · 24 µl O2/ml at 760 mmHg,
and cardiac efficiency as
(LVPsys-dia) · HR/MO2.
All effluent was collected over the first 10 min of reperfusion, and a
sample of the accumulated effluent was frozen for later analysis of
creatine kinase (CK; Creatine Kinase Flex reagent cartridge, Dade
Behring Dimension; Newark, DE; sensitivity >10 U/l) and troponin I
(Tpn I; ng/ml by immunoassay). CK and Tpn I values were expressed as
their release per heart weight (CK:
mU · g1 · min1 and Tpn I:
ng · g1 · min1).
One of two different concentrations of sevoflurane (Abbott; Chicago,
IL) was bubbled into the perfusate using an agent-specific vaporizer
(Vapor 2000, Dräger Medizintechnik; Lübeck, Germany) placed
in the O2-CO2 gas mixture line. Samples of
coronary perfusate were collected from a port in the aortic cannula to
measure sevoflurane concentrations by gas chromatography. Measured
inflow sevoflurane concentrations were 0.5 ± 0.0 and 1.3 ± 0.1 mmol/l, equivalent to 3.7 ± 0.1 and 8.9 ± 0.7% atm at
37°C, respectively. The high concentration was chosen to determine
whether preconditioning was dependent on anesthetic concentration.
Although this concentration is too high to maintain long-term general
anesthesia, the inspired concentration is used temporarily during mask
induction to speed the onset of anesthesia (17,
40).
If ventricular fibrillation occurred on reperfusion, a bolus of 250 µg lidocaine was given immediately. All data were collected from
hearts in sinus rhythm. At the end of 120 min reperfusion, hearts were
removed and cut into six to seven transverse sections of 3-mm
thickness. The sections were immediately stained with 1%
2,3,5-triphenyltetrazolium chloride (TTC) in 0.1 M
KH2PO4 buffer (pH 7.4, 38°C) for 5 min. TTC
stains viable tissue red, indicating the presence of a formazan
precipitate that results from the reduction of TTC by dehydrogenase
enzymes present in viable tissue (1). All slices were
digitally imaged by a photoscanner, and the infarcted areas were
measured in a blinded fashion by planimetry using NIH software (Image
1.62). Infarcted areas of individual slices were averaged on the basis
of their weight to calculate the total infarct size (%IS) of each
heart in percent. Reproducibility of this method is approximately ±5%
based on the blinded studies of ex situ but nonperfused
Langendorff-prepared hearts (M. L. Riess, laboratory observations).
Measurement of NADH in intact hearts. Tissue autofluorescence is a widely used and accepted method to measure NADH in isolated hearts and myocardial tissue (8, 10, 33).
To assess changes in NADH fluorescence, each experiment was carried out in a light-blocking Faraday cage. The distal end of a bifurcated fiber-optic cable (6.8 mm2 per bundle) was placed gently against the LV anterior wall. Netting was applied around the heart for optimal contact with the fiber- optic tip. This maneuver did not affect LVP. The two proximal ends of the fiber-optic cable were connected to a modified spectrophotometer (Photon Technology International, PTI; London, Canada). Tissue autofluorescence was excited with light from a xenon arc lamp at 75 W: the light was filtered through a 350-nm monochromator (Delta RAM, PTI), and the beam was focused onto the in-going fibers of the optic bundle. The arc lamp shutter was opened only for 2.5-s recording intervals to prevent photobleaching. Fluorescence emissions were collected by fibers of the second limb of the cable. This light was separated by a dichroic beamsplitter at 430 nm and filtered by interference filters (Chroma Technology; Brattleboro, VT) at 405 ± 15 and 460 ± 10 nm. Intensities were measured by photomultipliers (Photomultiplier Detection System 814, PTI). Although fluorescence at 460 nm could also arise from unknown intracellular constituents or cytosolic NADH, the majority comes from mitochondrial NADH (16, 33). Possible motion artifacts in the NADH fluorescence at 460 nm are diminished by using a second reference wavelength, e.g., 405 nm, which is less sensitive to changes in NADH; thus, the ratio of the intensities at 460 and at 405 nm is interpreted as a measure of NADH (8). The use of these two tissue light isobestic wavelengths also accounts for possible alterations in myoglobin light absorption, e.g., by hypoxia (8). We did not calibrate NADH fluorescence in these experiments; therefore, the values obtained are more conservative estimates of changes in NADH (7). NADH is given in arbitrary fluorescence units. In a nonischemic time control group (not displayed) NAOH varied < 5% over 195 min. All analog signals were digitized (PowerLab/16 SP, ADInstruments; Castle Hill, Australia) and recorded at 200 Hz (Chart & Scope version 3.6.3, ADInstruments) on Power Macintosh Computer G3 (Apple; Cupertino, CA) for later analysis using MATLAB (The MathWorks; Natick, MA) and Microsoft Excel (Microsoft; Redmond, WA) software. All variables were averaged over the sampling period of 2.5 s.Protocol. Each experiment lasted 195 min beginning after 30 min of equilibration. There were four ischemic groups: an untreated ischemic control group (CON, n = 10) was not subjected to preconditioning; one group was subject to two 5-min periods of ischemia, each 5 min apart (IPC, n = 10); and two other groups were exposed to 0.5 mM sevoflurane (APC-1, n = 10) or 1.3 mM sevoflurane (APC-2, n = 10) for 15 min. Preconditioning was followed by a 30-min washout period. All hearts then underwent 30 min of ischemia and 120 min of reperfusion. Sevoflurane was undetectable in the effluent during the initial equilibration period as well as during ischemia and reperfusion. Initial control measurements for each heart were obtained at the end of the equilibration period.
Statistical analysis.
All data were expressed as means ± SE. Among the group data, CON,
APC-1, APC-2, and IPC were compared by analysis of variance to
determine significance (Super ANOVA 1.11 software for Macintosh from
Abacus Concepts; Berkeley, CA) at the following selected time points:
before (at 0 min), during (at 15 min), and after (at 45 min) the
preconditioning stimulus; during ischemia (at 50 and 75 min);
and during reperfusion (at 80, 135, and 195 min). If F
values (P < 0.05) were significant, post hoc
comparisons of means tests (Student-Newman-Keuls) were utilized to
compare the four groups. Differences among means were considered
statistically significant when P < 0.05. Statistical
symbols used are the following: aAPC-1 vs. CON,
bAPC-2 vs. CON, cIPC vs. CON,
dAPC-1 vs. APC-2, eAPC-1 vs. IPC, and
fAPC-2 vs. IPC. The relationships between the rate of NADH
decline during ischemia (dNADHI/dt) and
infarct size (%IS), and the deviation in NADH from baseline (~0.54
arbitrary fluorescence units) at 120 min reperfusion
(
NADHRP) and %IS were determined by the Pearson correlation.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Changes in cardiac NADH fluorescence by IPC and APC.
Figure 1 shows changes in NADH
fluorescence at the LV free wall for each of the four study groups
before, during, and after ischemia. IPC caused a completely
reversible increase in NADH during the preconditioning stimuli. The
high, but not the low, concentration of sevoflurane also caused a
reversible, although lower, increase in NADH. During ischemia,
NADH initially increased and peaked at 5 min in nonpreconditioned
hearts, followed by a gradual decline below baseline levels. IPC hearts
exhibited the same increase but a slower decline in NADH
(P < 0.05) during ischemia. There was a lower
initial increase in NADH during ischemia in APC hearts than in
IPC or CON hearts. As in IPC hearts, the gradual decline in NADH was
slower in APC-1 (P < 0.05) and APC-2 hearts (P < 0.01) than in CON hearts. Throughout reperfusion,
the deviation in NADH fluorescence from baseline levels was markedly
smaller in IPC and APC hearts than in nonpreconditioned hearts.
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Changes in mechanical function by IPC and APC.
Figure 2, A and B,
shows changes in LVP and dLVP/dtmax
(contractility) and dLVP/dtmin (relaxation) for
each of the four groups before, during, and after ischemia.
Sevoflurane exposure caused concentration-dependent decreases in
LVPsys, which were completely reversible on washout before
ischemia. After a few minutes of ischemia,
LVPsys equaled LVPdia, which increased
gradually and similarly in each group throughout ischemia. On
reperfusion, IPC and APC-2 hearts had a better recovery of
LVPsys, and there was an insignificant trend in each
preconditioned group for a lower LVPdia compared with CON
hearts. Developed LVPsys-dia (not shown) was improved
throughout reperfusion in APC-2 and IPC groups compared with APC-1 or
CON (P < 0.05).
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Changes in metabolic function by IPC and APC.
Table 1 displays effects of cardiac
preconditioning on three additional variables before ischemia
and on reperfusion. MO2 and coronary
inflow were decreased during exposure to 1.3 mM but not to 0.5 mM
sevoflurane; cardiac efficiency
[HR · (LVPsys-dia)/MO2] was decreased by both concentrations. These effects were completely reversed by washout of sevoflurane before ischemia. At 5 min
reperfusion after 30 min ischemia, coronary inflow was higher
in IPC and APC-2 hearts compared with APC-1 and CON hearts;
MO2 and cardiac efficiency did not
differ among groups at 5 min reperfusion. At 120 min reperfusion, MO2 was higher in the IPC and the
APC-2 groups than in the APC-1 or CON groups. Cardiac efficiency was
not significantly different among groups at 60 and 120 min reperfusion.
coronary inflow at 60 and 120 min reperfusion was higher in the IPC and
APC-2 groups than in the APC-1 or CON groups.
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Reduced CK and Tpn I release and infarct size after IPC and APC.
Figure 3, A and B,
shows the accumulative CK
(mU · g1 · min1) and Tpn I
release (ng · g1 · min1)
after 10 min reperfusion. Both were lower in preconditioned hearts than
in control hearts. %IS was smaller after IPC and APC and was
concentration dependent for APC, as shown in Fig. 3C. There
were highly significant correlations 1) between %IS at 120 min reperfusion and the slope of the NADH decline
(NADHI/dt in arbitrary fluorescence units/25
min) between 5 and 30 min ischemia (n = 40;
r = 0.66; P < 0.01), and 2)
between %IS and the deviation of NADH (NADHRP in
arbitrary fluorescence units) from baseline values (~0.54 arbitrary
fluorescence units) at 120 min reperfusion (n = 40;
r = 0.63; P < 0.01). The
relationship between %IS and dNADHI/dt was
%IS = 221 · dNADHI/dt + 18;
the relationship between %IS and NADHRP was %IS = 138 · NADHRP + 20 (y = mx + b, where m = slope and
b = y-intercept).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Both IPC and APC have been shown to attenuate cardiac ischemia-reperfusion injury in several different models. However, the exact sequence of intracellular events during and after short periods of ischemia or temporary exposure to a volatile anesthetic and during and after the subsequent prolonged ischemia is not fully understood. This is the first study to show that mitochondrial energetics are altered during ischemia and reperfusion after preconditioning stimuli in the isolated heart.
The key findings of this study are the distinct changes in NADH before, during, and after ischemia in IPC and APC hearts compared with nonpreconditioned control hearts. First, during brief periods of ischemia (IPC) and, to a lesser degree, during exposure to the higher concentration of sevoflurane, NADH increased reversibly. Second, during ischemia, NADH accumulated in each group but peaked similarly and more so in control and IPC groups than in APC groups and then declined more slowly in each preconditioned group compared with the control group. Third, on reperfusion, the IPC and both APC groups exhibited a closer return to preischemia baseline NADH values than the control group. Finally, changes in NADH during ischemia could be correlated to the subsequent infarct size.
NADH, mitochondrial function, and ischemia.
Mitochondria may play a central role in the protective effects induced
by preconditioning against ischemia-reperfusion injury (6, 15, 21). Primary mitochondrial functions are the
generation of ATP and Ca2+ homeostasis. ATP synthesis by
the F1Fo-ATP synthetic complex (complex
V) is driven by the electrochemical proton gradient (µH) in the
inner mitochondrial membrane. µH is generated by the transfer of
electrons from NADH (and FADH2) to O2
(9). With adequate substrate and O2, this
system is in equilibrium to maintain the inner mitochondrial membrane
potential at about 200 mV at a pH of ~8.2. Oxidation of NADH to
NAD+ and phosphorylation of ADP to ATP are normally matched.
-oxidation of fatty acids (36). Dehydrogenases
generate NADH from NAD+ during glycolysis. Steady-state
NADH levels are therefore determined by the balance between NADH
generation and oxidation, making it a parameter of mitochondrial function.
During ischemia, the supply of O2 to accept
electrons diminishes, electron flux through the electron transport
chain falters, and NADH accumulates (19, 39). Excess NADH
inhibits the dehydrogenases, so entry of pyruvate into the TCA cycle is
blocked and oxidative phosphorylation ceases (41).
Cytosolic ATP is generated by glycolysis and may be used in reverse
fashion by F1Fo-ATPase to attempt to maintain a
physiological µH (13a).
Anesthetic exposure and NADH. Studies by Cohen and colleagues (12, 29) in the 1970s and others demonstrated that volatile anesthetics reversibly reduced NADH dehydrogenase activity and mildly depressed oxidative phosphorylation. It was suggested that anesthetics increase energy stores by decreasing mitochondrial O2 uptake and so protect against hypoxia. Kissin et al. (25) showed in isolated rat hearts that NADH fluorescence increased by about 8% per minimal alveolar concentration compared with anoxia (100% increase in NADH) and suggested the reduced oxidation-reduction state is related to an inhibition of electron transport chain by anesthetics.
In line with these findings, the present study demonstrates that temporary exposure to the higher concentration of sevoflurane (APC-2) reversibly increased NADH fluorescence. During both types of preconditioning stimuli, exposure to volatile anesthetics and brief periods of ischemia, there was a variable, but reversible, decrease in mechanical and metabolic function. Better preservation of function and tissue viability on reperfusion was evidenced in both IPC and APC-2 groups compared with the APC-1 group that failed to exhibit this initial increase in NADH. It is unclear if depression of myocardial function and by inference mitochondrial energetics is required to initiate preconditioning. There are several cardiac depressant drugs that do not appear to trigger preconditioning (13). Also, giving a KATP antagonist with a volatile anesthetic reduced the preconditioning effects despite a similar temporary depression of function in both groups (24). On the other hand, a temporary increase in extracellular calcium, which induces a positive inotropic effect, has been shown to precondition hearts (26). In contrast, brief exposure to a volatile anesthetic decreased intracellular Ca2+ transients (35). It is even less clear if a rise in NADH is a prerequisite for preconditioning. Both volatile anesthetics and brief periods of ischemia reduced function and metabolism before ischemia; this suggests a metabolic trigger that ultimately protects the heart during ischemia and reperfusion. This increase in NADH during the preconditioning stimuli, however, may have different causes. The increases in NADH during brief ischemia and exposure to a volatile anesthetic indicate altered mitochondrial energy balance. Sevoflurane could reduce NADH oxidation due to reduced electron transport (12, 29). This could in part account for the negative inotropic effects and decreased O2 consumption. Moreover, our study is consistent with our preliminary findings that bracketing of both APC and IPC with reactive oxygen species scavengers abolishes the protective effects of preconditioning (31).NADH during ischemia and reperfusion after preconditioning. As expected, the sudden decrease in cellular O2 during the onset of ischemia led to a rapid imbalance between NADH generation and oxidation (39). NADH increased and peaked in all groups at 5 min ischemia. Thereafter, the gradual decline in NADH in each group may be interpreted as a relatively less NADH generation than NADH oxidation during prolonged ischemia. More specifically, the finding that preconditioned hearts showed a slower decline in NADH than untreated hearts could reflect either a slower remaining rate of oxidative phosphorylation and/or a better preservation of dehydrogenase activity and/or substrate stores compared with nonpreconditioned hearts. In any case, production and demand appear to be better matched after preconditioning stimuli. This is consistent with higher mitochondrial ATP activity during reperfusion after IPC (22). In fact, our study suggests that subsequent tissue salvage can be predicted by the rate of NADH decline after 5 min of ischemia as shown by the highly significant correlation of rate of NADH decline and infarct size in individual hearts.
Despite these similarities between IPC and APC, there is at least one fundamental difference between the two preconditioning stimuli: prior anesthetic exposure led to a lower initial accumulation of NADH during ischemia. This indicates an altered metabolic state during ischemia that may be due to a different level of balance between NADH generation and oxidation among the groups immediately before ischemia, although NADH levels were the same. A subsequent shortage of O2 during ischemia may then result in a lesser imbalance between NADH generation and oxidation. The NADH fluorescence signal measured in this study is a product of average NADH per cell and the number of viable cells within the observed tissue. The marked and irreversible decline in NADH fluorescence on reperfusion likely represents a greater cell death on reperfusion (14) rather than just decreased NADH per cell. In contrast, the relative normalization of NADH on reperfusion in IPC and APC hearts may represent greater cell salvage. The highly significant correlation between infarct size and this deviation in NADH fluorescence from baseline 120 min after reperfusion supports this conclusion. In summary, the reversible increase in NADH during brief ischemic periods and exposure to the higher and more protective concentration of sevoflurane is indicative of an induced alteration of mitochondrial energy balance that suggests an important role of altered NADH in the triggering mechanisms of IPC and APC. The decreased NADH accumulation during the onset of ischemia after APC and the decreased rate of NADH decline during prolonged ischemia after APC and IPC likely underlie an improved mitochondrial energy balance before reperfusion. These events help to explain the improvements in metabolic and mechanical function as well as the reduction of infarct size on reperfusion. It will be important to understand the relationship of changes in NADH with formation of reactive O2 species, mitochondrial KATP channels, and mitochondrial Ca2+ levels as contributors to both preconditioning mechanisms.| |
ACKNOWLEDGEMENTS |
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The authors thank Dr. Gopu Varadarajan, Dr. Ming Tao Jiang, James Heisner, Anita Tredeau, Mary Ziebell, and Steve Contney for valuable contributions to this study.
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FOOTNOTES |
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The research was supported in part by National Heart, Lung, and Blood Institute Grants R01-HL-58691 and R01-5T32 GM-08377, and by the Innovative Medizinische Forschung, Westfälische Wilhelms-Universität Münster, Germany (RI 610005).
Portions of this work have appeared in abstract form: M. L. Riess, S. S. Rhodes, E. Novalija, Q. Chen, A. K. S. Camara, and D. F. Stowe. Anesth Analg 94: S37, 2002.
Address for reprint requests and other correspondence: D. F. Stowe, M4280, 8701 Watertown Plank Rd., Medical College of Wisconsin, Milwaukee, WI 53226 (E-mail: dfstowe{at}mcw.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published March 14, 2002;10.1152/ajpheart.01057.2001
Received 3 December 2001; accepted in final form 8 March 2002.
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METHODS
RESULTS
DISCUSSION
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