(Circulation. 2000;101:2090.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
ATP Synthesis During Low-Flow Ischemia
Influence of Increased Glycolytic Substrate
From the Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, and the NMR Laboratory for Physiological Chemistry, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital (J.S.I., J.F.), Boston, Mass.
Correspondence to Carl S. Apstein, MD, 715 Albany St, Room X720, Boston, MA 02118. E-mail capstein{at}acs.bu.edu
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Abstract |
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Background—Our goals were to (1) simulate the degree of low-flow ischemia and mixed anaerobic and aerobic metabolism of an acutely infarcting region; (2) define changes in anaerobic glycolysis, oxidative phosphorylation, and the creatine kinase (CK) reaction velocity; and (3) determine whether and how increased glycolytic substrate alters the energetic profile, function, and recovery of the ischemic myocardium in the isolated blood-perfused rat heart.
Methods and Results—Hearts had 60 minutes of low-flow ischemia (10% of baseline coronary flow) and 30 minutes of reperfusion with either control or high glucose and insulin (G+I) as substrate. In controls, during ischemia, rate-pressure product and oxygen consumption decreased by 84%. CK velocity decreased by 64%; ATP and phosphocreatine (PCr) concentrations decreased by 51% and 63%, respectively; inorganic phosphate (Pi) concentration increased by 300%; and free [ADP] did not increase. During ischemia, relative to controls, the G+I group had similar CK velocity, oxygen consumption, and tissue acidosis but increased glycolysis, higher [ATP] and [PCr], and lower [Pi] and therefore had a greater free energy yield from ATP hydrolysis. Ischemic systolic and diastolic function and postischemic recovery were better.
Conclusions—During low-flow ischemia simulating an acute myocardial infarction region, oxidative phosphorylation accounted for 90% of ATP synthesis. The CK velocity fell by 66%, and CK did not completely use available PCr to slow ATP depletion. G+I, by increasing glycolysis, slowed ATP depletion, maintained lower [Pi], and maintained a higher free energy from ATP hydrolysis. This improved energetic profile resulted in better systolic and diastolic function during ischemia and reperfusion. These results support the clinical use of G+I in acute MI.
Key Words: creatine kinase • glucose • insulin • ischemia • metabolism
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Introduction |
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During normoxia, ATP delivery to the myofilaments and membrane ion pumps is ensured by ATP synthesis from glycolysis and oxidative phosphorylation. The creatine kinase (CK) reaction contributes to the ability of cardiac muscle to increase and sustain high levels of work, as shown during the ATP supply-demand mismatch of hypoxia1 and high cardiac work loads2 when phosphoryl transfer from phosphocreatine (PCr) to ADP slows the rate of ATP depletion. Moreover, maintaining high ATP and low ADP and inorganic phosphate (Pi) levels maximizes the free energy available from ATP hydrolysis.
The relative contributions of oxidative versus glycolytic ATP synthesis rates to total ATP synthesis; the time course and extent of changes in [ATP], [ADP], [Pi], pH, and the free energy of ATP hydrolysis; and concomitant systolic and diastolic dysfunction that occurs during the low-flow ischemia of an acute myocardial infarction (MI) region are not known. Previous work in animals has suggested that oxidative metabolism remains the major ATP source in the ischemic region immediately after coronary ligation.3 Despite its importance in supporting cardiac function under stress, changes in CK reaction velocity are also undefined during low-flow ischemia. Thus, our first goal was to define the alterations that occur in anaerobic glycolysis, oxidative phosphorylation, and CK velocity simultaneously with changes in systolic and diastolic function in isolated blood-perfused rat hearts during a degree of low-flow ischemia that exists in the acute MI region in humans.4
During low-flow ischemia, the activity of aerobic and anaerobic pathways are determined in part by the amount of residual coronary flow and available carbon substrates. Increasing glycolytic substrate with high glucose and insulin (G+I) has been reported to be beneficial in low-flow ischemia and patients with acute MI,5 6 7 8 9 but the bioenergetic consequences of G+I in this setting are unknown. G+I increases glycolysis,5 but it may also affect oxidative phosphorylation and CK velocity by increasing pyruvate delivery to the Krebs cycle, by worsening tissue acidosis, and by changing ADP and/or Pi concentrations. Therefore, our second goal was to define the effects of increased glycolytic substrate on each of these possibilities.
To achieve these goals, 31P NMR spectroscopy and magnetization transfer (MT) measurements were performed in isolated blood-perfused hearts subjected to a clinically relevant degree of low-flow ischemia (10% of baseline coronary flow) and provided with either normal levels of insulin and the major physiological substrates (glucose, free fatty acid, and lactate) (the control group) or to the control levels of free fatty acid and lactate but with increased levels of glucose and insulin (the G+I group).
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Methods |
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Heart Preparation
Isovolumic LV and coronary perfusion pressures were recorded5 10 in RBC-perfused rat hearts (balloon in LV) isolated from fasted male Wistar rats (300 to 350 g). For experiments using NMR spectroscopy, the heart was placed in a 20-mm glass NMR tube in an NMR spectrometer and perfused with phosphate-free Krebs-Henseleit buffer containing bovine RBCs at a hematocrit of 40% as described.10 Animal care was in accord with the protocol of the Boston University School of Medicine and Harvard Medical School Institutional Animal Care and Use Committees.
Experimental Protocols
After 60 minutes of baseline normoxic perfusion at a constant
coronary flow rate (coronary perfusion pressure 80
mm Hg), hearts underwent 60 minutes of low-flow ischemia
(constant coronary flow at 10% of baseline), were reperfused
for 30 minutes at the baseline coronary flow rate, and then
were freeze-clamped. In control hearts (n=12), the initial
concentrations of 5.5 mmol/L glucose and 15 µU/mL insulin were
maintained throughout the protocol. In the G+I group (n=12), from 5
minutes before the onset of low-flow ischemia until the end of
reperfusion, high glucose and insulin were infused into the aortic
cannula; final concentrations were 19.5 mmol/L glucose and 250
µU/mL insulin. Half of the experiments (n=6 per group) were performed
without NMR spectroscopy to permit the collection of venous effluent
for measurement of M
O2 and
lactate.
31P NMR Measurements
Standard 1-pulse 31P NMR spectra (Figure 1
) obtained at 161.94 MHz as previously described11
were acquired over 2 minutes by signal-averaging 52 scans of 60° (27
µs) read pulses separated by an interscan delay of 2.3 seconds
immediately before and after each MT experiment and each change in
coronary flow. Four MT experiments (Figure 2)
were carried out: 1 before ischemia, 1 after 10 minutes and
again after 38 minutes of ischemia (early and late
ischemia, respectively), and 1 after 10 minutes of
reperfusion.
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Metabolite Contents and Conversion to Concentrations
Integrated signal intensities in 31P NMR
spectra corresponding to the ATP, phosphocreatine (PCr), and
Pi contents of the heart were measured by NMR1
curve-fitting routine (New Methods Research Inc). Signal intensities of
the [ß-P]ATP resonance peaks during baseline perfusion were
indistinguishable for the glucose and insulin and the control groups
and were assigned a concentration value of 10.8 mmol/L,
independently determined by high-pressure liquid
chromatography,12 to convert content to
concentration. Other metabolite concentrations were determined from the
ratio of their signal intensities (corrected for differential
relaxation) relative to that of [ß-P]ATP during the stabilization
period multiplied by 10.8 mmol/L. Intracellular pH was determined
by comparing the chemical shift difference between the
Pi and PCr resonances with values obtained from a
external standard curve.
[ADP] was calculated by 2 methods. The first makes the assumption that the CK reaction was at or near equilibrium throughout the protocol: Keq=[ATP][free creatine]/[ADP][PCr][H+], where Keq was set to 1.66x109 per mole at pH 713 for baseline and reperfusion periods, and 1.47x109 per mole at pH 6.2 for ischemia.14 The second method assumes that the CK reaction is at equilibrium only during the baseline period. The pseudo–first-order rate constant of the CK reaction, kfor, measured by MT is the product of the second-order rate constant, k', and free [ADP]. We calculated the second-order rate constant at baseline (by dividing kfor by [ADP]) and assumed it remained constant. [ADP] for ischemia and reperfusion was estimated by dividing kfor (measured by MT) by k', referred to as [ADP]'. This second method of [ADP]' calculation recognizes that k' may vary during the experimental protocol. Total tissue creatine measured in a subset of hearts15 was not different between groups and was unaffected by ischemia and reperfusion (22 to 23 mmol/L).
The free-energy release from ATP hydrolysis was calculated from the
equation 
G~P=G°+RT
ln[ATP]/[ADP][Pi], where G° (30.5
kJ/mol) is the value of ATP hydrolysis under standard conditions of
molarity, temperature, pH, and [Mg2+], R is the
gas constant (8.314 J · mol-1 ·
K-1), and T is temperature in kelvin. Input
values for ATP and Pi were obtained from
31P NMR measurements, [ADP], and [ADP]' were
calculated as described above, and the 2 [ADP] values were used to
calculate G and G', respectively. Free energies are
presented as absolute values.
Lactate concentration was measured in coronary
arterial and venous sample supernatants after digestion
with perchloric acid. Lactate production rates (µmol ·
g dry wt-1 ·
min-1) were calculated from the coronary
flow rate and heart weight. Total lactate production was
determined from the area under the curve of lactate production
rate versus time during ischemia and the first 90 seconds of
reperfusion. Tissue lactate and glycogen were measured in the hearts
frozen at the end of reperfusion.5
MO2 was calculated from the
arteriovenous O2 content differences derived from
O2 saturation curves for the Krebs-RBC
perfusate over the experimental range of pH and
PO2. Lactate production and
MO2 are reported as (mmol/L)/s
by using measured wet/dry heart weight ratios and a value of 0.5 mL
intracellular water per gram wet weight.16 Dry/wet weight
is constant during low-flow ischemia and decreases by only 6%
after reperfusion.5
CK Reaction Velocity
The CK reaction is
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[
-P]ATP) were analyzed according to the 2-site
chemical exchange model yielding the pseudo–first-order rate constant,
kfor.11 Multiplying
kfor by [PCr] yields the measured
reaction velocity,
Vfor=kfor[PCr]. CK
velocity can also be calculated from the rate
equation15 :
Vcalc=Vmax[ADP][PCr]/(1+D)KaKib.
Measured input values are 55 (mmol/L)/s for Vmax
(total CK activity under saturating conditions at 37°C), the
cytosolic concentrations of PCr and ADP for each heart and kinetic
constants from Reference 1717 .
Statistical Analysis
Data acquired sequentially in individual hearts were tested by a
2-way ANOVA for repeated measures. When 2-way ANOVA gave a significant
(P<0.05) difference either among the sequential
measures or between the 2 groups, the data were further
analyzed: (1) 1-factor ANOVA and 2-tailed paired Student’s
t tests were used to test for statistical significance among
the sequential experimental periods (stabilization, early
ischemia, late ischemia, and reperfusion). (2) Either a
2-tailed unpaired Student’s t test or a Mann-Whitney rank
sum test comparing control and G+I–treated hearts was used to test for
statistical significance between the 2 groups. All calculations were
aided by Statview 512+ (Brain Power Inc). All data are
presented as mean±SEM.
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Results |
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Hemodynamics
During ischemia, systolic function (and also developed pressure and rate-pressure product) decreased to
20%
of baseline (Table 1 and Figure 3). G+I slightly increased
systolic function during late ischemia and
substantially increased it during early reperfusion (Figure 3).
G+I exerted a highly protective effect on diastolic
function, markedly blunting the increase in diastolic
pressure during both ischemia and reperfusion. G+I also
decreased coronary resistance (coronary perfusion
pressure at constant coronary flow) during ischemia and
reperfusion.
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) and G+I hearts (•). Data are shown during
preischemic perfusion (0 to 60 minutes), low-flow
ischemia (60 to 120 minutes), and reperfusion (120 to 150
minutes). n=12 per group. *P<0.05 vs equivalent control
values.
Metabolite Concentrations
Control [ATP] and [PCr] decreased early and progressively
during ischemia and did not recover during reperfusion (Figures 1
and 4 and
Table 2). In contrast, for the G+I group,
[ATP] did not decrease during early ischemia, [ATP] and
[PCr] were higher than in controls at late ischemia, and
neither increased during reperfusion. [ADP] calculated by 2 methods
(see Methods) did not increase in either group during ischemia
but tended to be lower in the G+I group. Pi
increased 3-fold by end ischemia in controls but did not change
with G+I. There were no differences in resonance areas for
monophosphate esters between the 2 groups during ischemia or
reperfusion. Intracellular pH decreased to 6.2 in both groups during
ischemia.
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G~P was similar and high in the
control and G+I groups for preischemia and early
ischemia. During late ischemia,
G~P (calculated with either set of
[ADP] values) decreased by 2 to 4 kJ/mol for the control group but
stayed high in the G+I group.
Oxidative Phosphorylation
O2 consumption
(MO2), used as the index of
oxidative phosphorylation, was comparable in the 2
groups, declining to 18% of baseline during ischemia and
recovering to 72% to 95%. Thus, increasing the supply of glucose did
not increase MO2.
Glycolysis
Glycolysis, assessed from ischemic lactate
production (µmol · g dry
wt-1 · min-1), was
increased in the G+I hearts. In controls, lactate production
peaked at 20 minutes (1.66±0.62) and thereafter gradually declined to
1.02±0.38 at end ischemia. In contrast, in G+I hearts, lactate
production progressively increased to 40 minutes (2.93±0.38)
and remained high (2.44±0.3) (P<0.01 versus controls at
end ischemia). Total ischemic lactate
production was 166±32 µmol/g dry wt for controls and
273±22 µmol/g dry wt for G+I hearts (P<0.05).
At end reperfusion, tissue lactate (10.6±1.2 versus 11.6±1.9 µmol/g dry wt, P=NS) and tissue glycogen (39.9±10.6 versus 23.9±7.3 µmol glucose equivalent/g dry wt, P=NS) were similar for the control and G+I groups.
Creatine Kinase
During preischemia, the measured pseudo–first-order
rate constant of the CK reaction (kfor) and
CK velocity (Vfor) were similar for the 2 groups
(Figure 2 and Table 2). During
ischemia, measured CK velocity decreased similarly in both
groups, to 36% to 49% of baseline, and remained depressed (41% to
42%) during reperfusion. Predicted CK velocity
(Vcalc) was calculated by use of input values for
both [ADP] and [ADP]'. The rate equation predicted that during
preischemia, Vcalc would be equal for
the control and G+I groups, and during ischemia,
Vcalc would decrease similarly in both groups;
both were observed. V'calc values were also
depressed during ischemia but somewhat less than
Vcalc. Thus, both measured and calculated
estimates of CK velocity during ischemia showed a moderate
inhibition and no influence of the G+I substrate. During reperfusion,
the rate equation predicted higher velocities than those measured by MT
for both groups.
Washout of CK Activity
Coronary venous effluent was collected and assayed for CK
activity, and the cumulative CK leakage was calculated. G+I did not
affect CK leakage during ischemia (2.6 IU/g wet wt) or
reperfusion (32 IU/g wet wt). Thus, leakage was only 0.2% of total
tissue CK (1100 IU/g) during ischemia and only 3% during
reperfusion.
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Discussion |
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Model of Ischemia
In this study, red blood cell (RBC)–perfused hearts with a normal hematocrit were hypoperfused at a coronary flow rate that approximated myocardial perfusion levels that have been measured in acute MI in patients. Under these conditions, the coronary flow level and normal hemoglobin content provided enough oxygen delivery that oxidative phosphorylation was still the major source of ATP production and accounted for
90% of ATP
synthesis despite the ischemic state. To simulate acute MI perfusion conditions, we imposed an ischemic coronary flow rate of 10% of normal. This value is representative of perfusion levels immediately after a coronary occlusion in humans4 and dogs.3 However, an acute MI region undoubtedly contains a gradation of perfusion levels. In regions of relatively more severe ischemia, both glycolysis and oxidative phosphorylation would be relatively more inhibited; with less severe ischemia, oxidative phosphorylation would probably contribute a relatively greater fraction of ATP synthesis.
Many characteristics of this model differ from either total (zero-flow)
ischemia or high-flow hypoxia.12
With normal substrate availability, and like both total
ischemia and hypoxia, ATP and PCr levels decreased
while Pi accumulated. This was the case despite
decreases of left ventricular (LV) developed pressure and
rate-pressure product of 85% from baseline, which would be
expected to proportionally decrease ATP utilization. Unlike total
ischemia, in which, to slow the rate of ATP depletion, PCr
falls within minutes to undetectable levels, [PCr] was still nearly
40% of preischemic values at 30 minutes of low-flow
ischemia, a time at which ATP had decreased by 25%.
Importantly, PCr levels decreased only slightly between 30 and 60
minutes of low-flow ischemia, even though ATP levels continued
to fall. This pattern is like high-flow hypoxia. But unlike
high-flow hypoxia, in which intracellular pH fell by only
0.1 pH unit, intracellular pH decreased during low-flow
ischemia by nearly 1 pH unit (from 7.1 to 6.2). Thus, the
low-flow ischemia used in the present study is like
high-flow hypoxia with regard to the fall in [ATP] and
[PCr] but like total ischemia with regard to accumulation of
protons.
Inhibition of CK
Our results for both measured and calculated CK velocity show that
CK reaction velocity is lower during low-flow ischemia. This is
also demonstrated by the failure of CK to use more of the available PCr
to slow the rate of ATP depletion. This result was unexpected and
suggests that, in contrast to minimal perturbation of CK velocity
observed under conditions of mild underperfusion,18 CK is
substantially inhibited in the metabolic milieu of an acute
infarct region. Recently, Ponticos and colleagues19
presented evidence that CK can be inhibited by as much as 60%
by phosphorylation by AMP kinase under conditions in
which PCr/creatine and ATP/ADP levels fall. We suggest that inhibition
of CK by this mechanism is likely to occur under the conditions of our
study.
ATP Synthesis With Normal Substrates
At baseline, ATP synthesis rate from oxidative
phosphorylation (estimated from
MO2) and from
glycolysis20 were 1.0 and 0.01 mmol/L of cell
water/s, respectively. During low-flow ischemia, these rates
were 0.2 and 0.02 (mmol/L)/s, respectively (assuming 1 net mole
of glycolytic ATP produced per mole of lactate produced). Comparing
low-flow ischemia to baseline, the ATP synthesis rate from
oxidative phosphorylation decreased to 20%, while
glycolytic ATP production doubled. The ratio of
glycolytic/oxidative ATP synthesis increased 10-fold, from 0.01/1.0
(1%) at baseline to 0.02/0.2 (10%). Nonetheless, 90% of ATP
synthesis in this simulated acute MI milieu was via oxidative
phosphorylation.
ATP Synthesis With Increased G+I
A major result of the present study is that G+I increased
[ATP] during low-flow ischemia primarily by increased
glycolysis and not by increasing oxidative
phosphorylation assessed by O2
utilization. G+I did not stimulate oxidative
phosphorylation by increasing [ADP] or
[Pi], because neither was increased by G+I. The
increased [ATP] in the G+I group may be partly due to a slight
increase in the P:O ratio due to a shift in substrate oxidation from
free fatty acid to pyruvate. Finally, our results show that the
increase in [ATP] in the G+I group was not the result of increased
PCr utilization or of any mechanisms secondary to increased
acidosis.
What was the fate of the ATP that resulted from G+I–mediated increase
of glycolytic synthesis during ischemia? The amount of
glycolytic ATP synthesis during the entire 60-minute ischemic
period (estimated from lactate production) was 61 and 104
mmol glycolytic ATP/L cell water in the control and G+I groups,
respectively (or 30 and 52 µmol per heart, respectively).
Therefore, the differential rate of ischemic glycolytic ATP
synthesis attributable to the G+I was 0.37 µmol ·
heart-1 · min-1,
or 0.7 mmol/L cell water/min. This would have increased [ATP]
markedly above the controls, by 42 mmol/L, at end
ischemia if no increase in ATP utilization had occurred in the
G+I group. The observation that there was only a 6.8 mmol/L
differential in high-energy phosphate concentration between groups at
end ischemia suggests that the major portion of the "extra"
glycolytic ATP resulting from the G+I substrate was used to support the
better systolic and diastolic function of the G+I
group. Only a small fraction was used to preserve a higher level of
high-energy phosphates during ischemia.
Despite the increase in glycolytic flux, the G+I substrate did not cause more severe tissue acidosis during low-flow ischemia. There are at least 2 explanations for this. First, the presence of even a very low flow provides substantial washout of lactate and protons; tissue lactate does not accumulate significantly unless perfusion is <5% of control.21 Second, intracellular pH also depends on ATP hydrolysis (a proton-generating reaction),22 which was less with G+I.
Higher G~p With G+I
Another major finding is that G+I markedly increased the free
energy release from ATP hydrolysis, G~p .
Free energy release from ATP hydrolysis is not constant but rather
depends on the concentrations of ATP, ADP, and
Pi. With G+I, [ATP] was higher, [ADP] was
relatively unchanged, and [Pi] was lower than
for controls. We calculated
G~p . and
G'~p . using values
of [ADP] and [ADP]'. Regardless of which estimate of [ADP] was
used, at late ischemia, greater free energy (4.0 to 4.4 kJ/mol)
was available for all cellular ATPase reactions for the G+I group.
Study Limitations
Our protocol was designed to simulate, as closely as possible, the
myocardial metabolic milieu present in an acutely
infarcting region in humans. However, because the G+I was started 5
minutes before the onset of ischemia, our protocol does not
mimic the timing of drug administration of an acute MI. Because global
ischemia was imposed, the entire LV of the isolated heart
served as a model of the acute MI region. Despite the imposition of
global coronary flow reduction, heterogeneous
ischemia most likely exists in this model, as it does in acute
clinical MI.4 Our NMR spectra report average tissue values
for the entire heart and do not report any intracellular or regional
variations and/or gradients; such average values may belie the extent
of metabolite and free energy changes in different regions. Because it
is impossible to measure free [ADP] directly, we calculated its value
by 2 independent methods. Although there were some differences in
estimates for [ADP] according to the method of calculation, both
methods resulted in the same overall conclusions regarding the
bioenergetic benefits of the G+I substrate.
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Acknowledgments |
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This work was supported by grants from the NHLBI (HL-48715 to Dr Apstein, HL-52350 to Dr Ingwall, and K08-HL-03574 to Dr Eberli), and from the American Heart Association, National and Massachusetts Affiliate to Drs Eberli, Cave, and Friedrich. We acknowledge the assistance of Jonathan Rose, Soeun Ngoy, and Adam Silverman.
Received June 24, 1999; revision received November 2, 1999; accepted November 29, 1999.
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L. Wexler and J. S. Ingwall Carl S. Apstein, MD: 1941-2005 Circulation, August 22, 2006; 114(8): 867 - 868. [Full Text] [PDF]
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 F. C. Chen and O. Ogut Decline of contractility during ischemia-reperfusion injury: actin glutathionylation and its effect on allosteric interaction with tropomyosin Am J Physiol Cell Physiol, March 1, 2006; 290(3): C719 - C727. [Abstract] [Full Text] [PDF]
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A. C. Hinken and K. S. McDonald {beta}-Myosin heavy chain myocytes are more resistant to changes in power output induced by ischemic conditions Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H869 - H877. [Abstract] [Full Text] [PDF]
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 J. R. Libonati, Z. V. Kendrick, and S. R. Houser Sprint training improves postischemic, left ventricular diastolic performance J Appl Physiol, December 1, 2005; 99(6): 2121 - 2127. [Abstract] [Full Text] [PDF]
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 R. Lautamaki, K.E. J. Airaksinen, M. Seppanen, J. Toikka, M. Luotolahti, E. Ball, R. Borra, R. Harkonen, P. Iozzo, M. Stewart, et al. Rosiglitazone Improves Myocardial Glucose Uptake in Patients With Type 2 Diabetes and Coronary Artery Disease: A 16-Week Randomized, Double-Blind, Placebo-Controlled Study Diabetes, September 1, 2005; 54(9): 2787 - 2794. [Abstract] [Full Text] [PDF]
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 J. K. Koskenkari, P. K. Kaukoranta, K. T. Kiviluoma, M.J. P. Raatikainen, P. P. Ohtonen, and T. I. Ala-Kokko Metabolic and Hemodynamic Effects of High-Dose Insulin Treatment in Aortic Valve and Coronary Surgery Ann. Thorac. Surg., August 1, 2005; 80(2): 511 - 517. [Abstract] [Full Text] [PDF]
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H. Wiggers, H. Norrelund, S. S. Nielsen, N. H. Andersen, J. E. Nielsen-Kudsk, J. S. Christiansen, T. T. Nielsen, N. Moller, and H. E. Botker Influence of insulin and free fatty acids on contractile function in patients with chronically stunned and hibernating myocardium Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H938 - H946. [Abstract] [Full Text] [PDF]
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 C. S. Apstein and L. H. Opie A challenge to the metabolic approach to myocardial ischaemia Eur. Heart J., May 2, 2005; 26(10): 956 - 959. [Abstract] [Full Text] [PDF]
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 The CREATE-ECLA Trial Group Investigators* Effect of Glucose-Insulin-Potassium Infusion on Mortality in Patients With Acute ST-Segment Elevation Myocardial Infarction: The CREATE-ECLA Randomized Controlled Trial JAMA, January 26, 2005; 293(4): 437 - 446. [Abstract] [Full Text] [PDF]
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 R. G. Weiss, G. Gerstenblith, and P. A. Bottomley ATP flux through creatine kinase in the normal, stressed, and failing human heart PNAS, January 18, 2005; 102(3): 808 - 813. [Abstract] [Full Text] [PDF]
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 F. R Eberli Stunned myocardium--an unfinished puzzle Cardiovasc Res, August 1, 2004; 63(2): 189 - 191. [Full Text] [PDF]
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 R. A. Kloner and S. H. Rezkalla Cardiac protection during acute myocardial infarction: Where do we stand in 2004? J. Am. Coll. Cardiol., July 21, 2004; 44(2): 276 - 286. [Abstract] [Full Text] [PDF]
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L. Lee, J. Horowitz, and M. Frenneaux Metabolic manipulation in ischaemic heart disease, a novel approach to treatment Eur. Heart J., April 2, 2004; 25(8): 634 - 641. [Abstract] [Full Text] [PDF]
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Y. Nishino, T. Miura, T. Miki, J. Sakamoto, Y. Nakamura, Y. Ikeda, H. Kobayashi, and K. Shimamoto Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection Cardiovasc Res, February 15, 2004; 61(3): 610 - 619. [Abstract] [Full Text] [PDF]
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 S. Clement, S. S. Braithwaite, M. F. Magee, A. Ahmann, E. P. Smith, R. G. Schafer, and I. B. Hirsch Management of Diabetes and Hyperglycemia in Hospitals Diabetes Care, February 1, 2004; 27(2): 553 - 591. [Full Text] [PDF]
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L. H. Opie Preconditioning and metabolic anti-ischaemic agents Eur. Heart J., October 2, 2003; 24(20): 1854 - 1856. [Abstract] [Full Text] [PDF]
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I. C. C. van der Horst, F. Zijlstra, A. W. J. van't Hof, C. J. M. Doggen, M.-J. de Boer, H. Suryapranata, J. C. A. Hoorntje, J.-H. E. Dambrink, R. O. B. Gans, H. J. G. Bilo, et al. Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: The glucose-insulin-potassium study: a randomized trial J. Am. Coll. Cardiol., September 3, 2003; 42(5): 784 - 791. [Abstract] [Full Text] [PDF]
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C. S. Apstein The benefits of glucose-insulin-potassium for acute myocardial infarction (and some concerns) J. Am. Coll. Cardiol., September 3, 2003; 42(5): 792 - 795. [Full Text] [PDF]
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O. Ogut and F. V. Brozovich Creatine Phosphate Consumption and the Actomyosin Crossbridge Cycle in Cardiac Muscles Circ. Res., July 11, 2003; 93(1): 54 - 60. [Abstract] [Full Text] [PDF]
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N. Varma, J. P. Morgan, and C. S. Apstein Mechanisms underlying ischemic diastolic dysfunction: relation between rigor, calcium homeostasis, and relaxation rate Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H758 - H771. [Abstract] [Full Text] [PDF]
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J. Sundell and J. Knuuti Insulin and myocardial blood flow Cardiovasc Res, February 1, 2003; 57(2): 312 - 319. [Abstract] [Full Text] [PDF]
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G. Li, X. Wang, F. Du, Y. Ren, G. Drzewiecki, J. K.-J Li, and J. Kedem Effects of partial ischaemia and volume loading on myocardial efficiency and cardiac performance in dogs Cardiovasc Res, July 1, 2002; 55(1): 122 - 130. [Abstract] [Full Text] [PDF]
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N. Varma, F. R. Eberli, and C. S. Apstein Left ventricular diastolic dysfunction during demand ischemia: rigor underlies increased stiffness without calcium-mediated tension. Amelioration by glycolytic substrate J. Am. Coll. Cardiol., June 15, 2001; 37(8): 2144 - 2153. [Abstract] [Full Text] [PDF]
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A. K. Jonassen, M. N. Sack, O. D. Mjos, and D. M. Yellon Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling Circ. Res., December 7, 2001; 89(12): 1191 - 1198. [Abstract] [Full Text] [PDF]
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