Division of Cardiology, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, Minnesota 55417
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ABSTRACT |
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2-Deoxy-2-[18F]fluoro-D-glucose
(FDG) may be used to predict glucose kinetics when the factor relating
differences in transport and phosphorylation between compounds remains
constant ("lumped constant"). It is not clear whether hyperemia
alters that factor. In anesthetized swine, myocardial FDG
uptake was estimated by positron emission tomography, during an
intracoronary infusion of either adenosine, ATP, or bradykinin (40 µg · kg1 · min
1,
40 µg · kg
1 · min
1,
and 2 nmol · kg
1 · min
1,
respectively; n = 6 for all groups). In controls during normal perfusion (n = 6), FDG uptake was 0.78 ± 0.32 µmol · g
1 · min
1,
whereas glucose uptake by Fick was 0.71 ± 0.25 µmol · g
1 · min
1
(r = 0.73; P < 0.05). Adenosine increased
blood flow from 1.29 ± 0.43 to 4.80 ± 2.19 ml · g
1 · min
1
(P < 0.05) and glucose uptake from 1.16 ± 1.10 to 3.35 ± 2.12 µmol · g
1 · min
1
(P < 0.05), whereas FDG uptake in the hyperemic region was
lower than remote regions (0.46 ± 0.29 and 0.95 ± 0.55 µmol · g
1 · min
1,
respectively; P < 0.05). In the ATP and bradykinin groups,
blood flow increased four- and twofold, respectively, with no net
change in glucose uptake. FDG uptake in the hyperemic region was also significantly lower than remote regions. For all animals, the ratio of
blood flow in the hyperemic region relative to remote region was
inversely proportional to the ratio of FDG uptake in the same regions
(r2=0.73; P < 0.001). Because nitric
oxide elaboration during hyperemia could potentially alter substrate
preference and FDG kinetics, six additional swine were studied during
maximal adenosine before and after intracoronary
NG-monomethyl-L-arginine (1.5 mg/kg).
Inhibition of nitric oxide had no effect on either regional myocardial
substrate uptake or FDG accumulation. In conclusion, hyperemia
decreased regional myocardial FDG uptake relative to normally perfused
regions and this effect on the lumped constant was independent of
nitric oxide.
positron emission tomography; swine; glucose metabolism; adenosine; vasodilatation; nitric oxide
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INTRODUCTION |
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REGIONAL MYOCARDIAL GLUCOSE uptake can be quantitated in vivo with dynamic scanning with positron emission tomography (PET) and the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose (FDG). The accuracy of this technique assumes that the factor relating differences in transport and phosphorylation between molecules of glucose and FDG (i.e., "lumped constant") remains fixed (23). Although 0.67 has been traditionally used for the lumped constant with in vivo heart studies (2, 16, 18), results from isolated rat heart experiments have shown that the factor may vary under certain conditions such as during altered substrate and hormone levels (6). Therefore, the interpretation of absolute glucose measurements from FDG kinetic studies may be confounded when competing substrates in the blood are altered.
Despite the inconstancy of the lumped constant during these variable metabolic conditions, the assessment of relative differences in regional myocardial FDG uptake for clinical decisions remains valid (24, 25). Although patients with diabetes mellitus could have variable insulin levels, which, in turn, could affect the lumped constant (6), that would not cause regional heterogeneity in myocardial FDG uptake. Thus far no clinical situation, including ischemia and reperfusion, has been shown to affect regional differences in the lumped constant (21). In isolated rabbit septa, however, a fourfold increase in perfusion induced a 50% reduction in the value of the lumped constant when compared with Fick measurements of glucose uptake (8). This would mean that during hyperemia, FDG kinetic studies would underestimate overall glucose uptake by ~50%. Whether the same degree of heterogeneity in myocardial perfusion can alter the lumped constant in vivo is not clear. The purpose of this study, therefore, was to determine the effects of hyperemia on regional glucose uptake by Fick and compare those results with FDG uptake by dynamic PET scanning. Adenosine, ATP, and bradykinin were used as the vasodilators because significant vasodilation is achievable with minimal effects on remote myocardium. A second aim was to determine whether nitric oxide elaborated during hyperemia could be responsible for a shift in substrate preference and altered FDG kinetics relative to glucose.
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METHODS |
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Surgical preparation. This study was performed under the guidance of the Animal Care Committee at the Veterans Affairs Medical Center, which conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85-23, revised 1985). Domestic swine of either sex (31-42 kg) were sedated with ketamine hydrochloride (20 mg/kg im) and thiopental (10 mg/kg iv). They were intubated and connected to a respirator for intermittent positive pressure ventilation with a mixture of oxygen and room air. Ventilator settings were adjusted during the experiments to maintain normal arterial pH (7.35-7.45), PCO2 (35-45 mmHg), and PO2 (>100 mmHg). The left external jugular vein, internal carotid artery, and femoral artery were exposed and cannulated with 7-Fr catheters.
Anesthesia was initiated with -chloralose (150 mg/kg iv) and
maintained with a continuous infusion of thiopental (5 mg · kg
1 · h
1).
Succinylcholine (0.25 mg iv) was administered, and via midline sternotomy, the heart was suspended in a pericardial cradle. A 7-Fr
catheter was secured in the left atrium and used for administration of
radiolabeled microspheres. A 5-Fr Millar catheter was inserted into the
left ventricle (LV) through the apex and used for measurement of LV
pressure and its first derivative (LV dP/dt). A proximal portion of the left anterior descending coronary artery (LAD) was
dissected free from its adventitia and cannulated with a small silicone
catheter (0.3 mm in inner diameter and 0.6 mm in outer diameter) (15).
A 22-Fr intracatheter was then inserted into the great cardiac LAD vein
distal to the arterial infusion catheter. We have shown that during
this anesthesia, systemic hemodynamics, regional shortening, and
myocardial oxygen consumption are not altered over the time course of
the scanning protocol.
Regional myocardial blood flow. One to two million microspheres (15 µ) labeled with either 141Ce, 113Sn, 103Ru, or 95Nb were injected into the left atrium for myocardial blood flow determination. Reference arterial blood samples were withdrawn from the femoral artery catheter at a fixed rate of 10 ml/min, beginning 5 s before and for 2 min after injection of microspheres. At the conclusion of the experiment and before death, myocardium in the LAD distribution was identified by injection of blue dye into the coronary artery catheter. Hearts were fixed in 10% Formalin for at least 48 h and separated into LAD and non-LAD regions. Each was then divided into three layers of equal thickness (inner, mid, and outer) and placed in 1- to 2-g samples. Myocardial and reference blood samples were counted in a multichannel analyzer (Gamma Counter-5000; Packard Instrument), and regional blood flows were determined.
Chemical analyses. Blood gas analyses were calculated from a pH analyzer (CIBA Corning model 178) and a Triac centrifuge (Clay Adams). Lactate and glucose concentrations were determined from aliquots of 3 ml of blood that were transferred into iced-glass tubes for later analysis by enzymatic technique. Free fatty acids were determined by standard RIA kits (Sigma). The extraction of substrates was calculated by plasma arteriovenous differences expressed as a percentage of plasma arterial concentrations, and Fick estimates of consumption were computed from the product of myocardial blood flows and the arteriovenous plasma differences.
Experimental protocol. During the animal preparation and ~1 h
before the experimental protocol, 25 g of dextrose were infused intravenously in all animals. After a 30-min stabilization period, radiolabeled microspheres were injected and whole blood samples were
collected from the aorta and great cardiac LAD vein. An intracoronary infusion of either adenosine (40 µg · kg1 · min
1;
n = 6), ATP (40 µg · kg
1 · min
1;
n = 6), or bradykinin (2 nmol
kg
1 · min
1)
was begun for 10 min, and samples were repeated. Vasodilating agents
were supplied from Sigma (St. Louis, MO) and were mixed on the morning
of each experiment. For comparison, six control animals were subjected
to the same instrumentation, and glucose uptake and FDG kinetics were
determined during an intracoronary infusion of saline (2 cc/min). Blood
flow and arteriovenous sampling were repeated at the conclusion of the
PET scanning protocol.
In six swine, the effect of adenosine on regional substrate uptake was determined before and after inhibition of nitric oxide with intracoronary NG-monomethyl-L-arginine (1.5 mg/kg over 10 min). This agent was chosen for these studies because at this dose it has a significant effect on blunting nitric oxide production without altering maximal adenosine blood flow (7). FDG kinetics with PET was then studied in two of those animals during an intracoronary infusion of adenosine. In two additional swine, FDG uptake was determined 50 min after a 10-min infusion of adenosine, to ensure that any altered FDG kinetics was not related to adenosine receptor stimulation independent of blood flow changes.
PET scanning procedures. Animals were moved into the scanning room where dynamic PET images were obtained with an ECAT 953B/31 (CTI/Siemens, Knoxville, TN). The camera consists of 16 contiguous rings of bismuth germinate detectors allowing acquisition of 31 cross-sectional images of the heart simultaneously recorded in a 10.8-cm axial field of view. In a transaxial plane, a resolution of 5.8 mm full width at half maximum would be expected at the center of the field of view. Emission images were reconstructed with a Hanning filter with a cutoff frequency of 0.4 of maximum (0-0.5 scale). The effective transaxial resolution of the reconstructed images is 10 mm. The animal preparations were placed onto the table, and with the use of a laser light detector, they were positioned so that the heart was in the center of the field of view. Measurement of attenuation due to tissue density was accomplished by a 10-min transmission scan with an internal source of radiation. After the transmission scan, myocardial blood flow images were obtained with either 15O-water (40 mCi) or 13N-ammonia (15 mCi) during the constant infusion of the vasodilator. These perfusion images were collected to confirm that regions of interest were placed in the hyperemic LAD territory. After five half-lives of the blood flow tracer, the intracoronary infusion was restarted and FDG (6 mCi) was infused intravenously over 20 s. Dynamic scans were acquired over the next 40 min with a scanning protocol consisting of twelve 10-s, six 30-s, four 60-s, three 120-s, and three 300-s frames and one 600-s frame.
Data analysis. Circular regions of interest (ROI) were chosen
from ~10-12 transverse planes from the myocardial blood flow image. Eight-to-ten ROI were obtained from the hyperemic LAD region, and an equivalent number were also obtained from the normally perfused
remote territory. A circular ROI was also obtained from the largest
portion of the LV cavity (input function). FDG uptake was determined
from Patlak plots of the time-activity curves obtained from the LV and
each myocardial ROI. Values were averaged for LAD and non-LAD regions.
The model has been previously described and validated and is based on a
three-compartment model. In brief, the Patlak plot defines a constant
(K), which incorporates the forward (k1)
and reverse (k2) rate constants from plasma to
tissue as well as the phosphorylation (k3)
constant. The formula is expressed as: [K =
(k1 × k2)/(k2 + k3)]. The dephosphorylation
constant (k4) is assumed to be zero. The model
includes a spillover correction and has been previously validated in
our laboratory (14). Partial volume effects were corrected by assuming
that 100% recovery would be expected in objects 15 mm and that the
average myocardial wall thickness was 10 mm.
Statistics. Results are expressed as means ± SD. For repeated measures, changes were tested for significance at the P < 0.05 level by paired Student's t-test. During the intracoronary infusions, a comparison was made between FDG uptake in the LAD region normalized to remote regions vs. myocardial blood flow by microspheres in the LAD region, normalized to remote regions. The relationship was tested for all experimental groups with a linear regression model.
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RESULTS |
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Systemic hemodynamics and myocardial blood flows. Systemic
hemodynamics are shown for each group in Table
1. Myocardial blood flows in the LAD and
non-LAD regions of the control group were 0.84 ± 0.22 and 0.92 ± 0.22 ml · g1 · min
1,
respectively. These were slightly lower than baseline blood flows in
the adenosine group, which probably reflect the intergroup differences
in heart rate and blood pressure. In the adenosine and ATP groups,
myocardial blood flow in the LAD region increased nearly fourfold,
whereas the increment in the bradykinin group was about twofold.
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Plasma substrates and myocardial glucose uptake. Plasma
substrates are shown in Table 1. In the control group, myocardial glucose uptake by Fick analysis was 0.71 ± 0.25 µmol · g1 · min
1
(Fig. 1). In the adenosine group,
myocardial glucose uptake by Fick increased from 1.16 ± 1.10 at
baseline to 3.35 ± 2.12 µmol · g
1 · min
1 (P < 0.05) without a net
change in lactate uptake (0.51 ± 0.10 at baseline vs. 0.37 ± 0.08 µmol · g
1 · min
1
during adenosine; nonsignificant). Myocardial glucose uptake in the ATP
group was 0.50 ± 0.53 at baseline and 0.68 ± 0.55 µmol · g
1 · min
1
during the infusion (nonsignificant), whereas in the bradykinin group,
it was 0.41 ± 0.49 at baseline and 0.77 ± 0.56 µmol · kg
1 · min
1 during the infusion
(nonsignificant). Except for the adenosine group, vasodilation with
either ATP or bradykinin resulted in no net change in regional
myocardial glucose uptake by Fick (Fig. 1).
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FDG uptake in LAD and remote regions. Myocardial glucose uptake
as determined by FDG kinetics is shown for all four groups in Fig.
2. In the control group, regional
myocardial FDG uptake in the LAD region was 0.78 ± 0.32 µmol · g1 · min
1,
which correlated well with estimates of glucose uptake by Fick (r
= 0.73; P < 0.05). This demonstrates that tracer kinetics
with FDG predict myocardial glucose uptake under steady-state
conditions. As shown from Fig. 2, minimal differences in FDG uptake
between LAD and remote regions were noted in the control group. In the adenosine, ATP, and bradykinin groups, however, FDG uptake in the
hyperemic LAD region was lower than in the non-LAD regions. The remote
regions of each of the hyperemic groups were not significantly dissimilar from the control group. Figure 3
is a representative animal during vasodilation and demonstrates
decreased FDG uptake in the hyperperfused LAD region.
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To ensure that adenosine receptor stimulation did not alter FDG
kinetics independent of perfusion, myocardial FDG uptake was determined
50 min after a 10-min infusion of adenosine in two additional animals.
After the adenosine infusion but during normal perfusion, the metabolic
rate of FDG uptake in the LAD and remote regions was 0.26 ± 0.11 and
0.28 ± 0.14 µmol · g1 · min
1,
respectively. This demonstrates that after the adenosine infusion homogeneous tracer uptake is observed and that a sustained regional alteration in the lumped constant does not occur.
For each of the animals in the four groups, the relative change in FDG
uptake in the LAD region was then compared with the relative change in
blood flow in the same regions during the infusions. Figure
4 shows the relationship between FDG uptake
in the LAD region normalized to remote regions vs. myocardial blood
flow with microspheres in the LAD region, normalized to the non-LAD territory. By linear regression, a significant relationship existed between the relative degree of hyperemia and relative decrease in FDG
uptake [f(x) = 1.155075E
1(x) + 1.0008085E + 0; SE = 0.139; r2 = 0.73; P < 0.001].
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Nitric oxide inhibition and the effects on substrate uptake.
Regional arteriovenous extraction of substrates was determined at
baseline and during maximal adenosine, both before and after inhibition
of nitric oxide synthase. Under basal conditions, arterial glucose and
lactate concentrations were 5.6 ± 2.5 and 1.3 ± 0.6 µmol/ml,
respectively, whereas fatty acid concentrations were 309 ± 166 nmol/ml. Arterial concentrations remained constant over the sampling
period. As shown by Table 2, the inhibition
of NO production induced no differences in relative substrate uptake during vasodilation with adenosine. In two animals, FDG uptake was
determined during the adenosine infusion in the presence of the NO
inhibitor. The metabolic rate of FDG uptake in the hyperemic LAD region
was 0.14 ± 0.02 µmol · g1 · min
1
and was much lower than the corresponding remote region (0.20 ± 0.03 µmol · g
1 · min
1).
That difference in metabolic rates of FDG uptake is similar to that
observed in the animals without the inhibitor. The findings demonstrate
that elaboration of nitric oxide during hyperemia is not responsible
for the decreased FDG uptake in the hyperemic regions.
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DISCUSSION |
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The principal finding of this study is that adenosine in maximal vasodilator doses increased Fick estimates of glucose uptake but lowered FDG retention when compared with remote myocardium. This disparity between PET and Fick estimates of glucose uptake resulted from an underestimation in PET-derived glucose measurements during supramaximal increments in perfusion. During an intracoronary infusion of either ATP or bradykinin, no changes were noted in Fick estimates of glucose uptake but FDG uptake was also lower than remote regions. These observations support the contention that maximal increments in regional blood flow alter the factor relating differences in transport and phosphorylation between molecules of FDG and glucose (i.e., lumped constant).
Variability of the lumped constant. The Sokoloff model of
deoxyglucose kinetics for predicting glucose uptake was adapted for the
brain and is reliable when differences in transport and phosphorylation
between the two molecules are constant (23). This factor has been
termed the lumped constant and is comprised of six individual
components, defined by the after equation
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Recently, however, it has become apparent that FDG kinetic studies may have inherent limitations in predicting absolute measurements of glucose metabolism under various circumstances. In extracorporeally perfused pig hearts, the accumulation of 14C-labeled deoxyglucose was insensitive to changes in glucose utilization as measured by 3H-labeled glucose when overall glucose flux was low (12). Likewise, changes in deoxyglucose levels may not predict large changes in glucose uptake if the lumped constant becomes altered, such as during variable substrate levels. In isolated rat hearts perfused with increasing concentrations of either insulin, fatty acids, or lactate, the lumped constant was lowered causing deoxyglucose kinetics to underestimate overall glucose uptake (6). Although these studies are important for interpreting global estimates of myocardial glucose uptake, they are less relevant to clinical PET studies in which FDG uptake from one region is compared with remote territories (24, 25).
Perfusion and the lumped constant. The present study identifies
a situation in which FDG uptake within two regions of the same
myocardium might not be comparable due to regional differences in the
lumped constant. The fourfold difference in perfusion between LAD and
non-LAD regions during the intracoronary infusion of adenosine was
responsible for the observed decrease in the lumped constant. In
isolated rat hearts, a twofold increase in myocardial blood flow did
not alter the lumped constant during three levels of glucose-insulin
concentrations (17), suggesting that FDG kinetic studies are unaffected
by modest changes in blood flow. With larger changes in perfusion such
as during maximal vasodilation, however, the reliability of FDG kinetic
studies in estimating glucose uptake may be affected. For instance, in
isolated perfused rabbit septa, a 50% reduction in the lumped constant
occurred when perfusion was increased from 0.5 to 4.5 ml · g1 · min
1
(8). This resulted in a 50% underestimation in glucose uptake relative
to Fick measures of glucose uptake. These data are compatible with the
present findings in which the magnitude of the flow increment with
adenosine was fourfold and the estimates of glucose uptake in the
involved regions were ~50% less than that of remote territories. The
effects of hyperemic flows on the lumped constant may relate to
differential changes in the transport coefficient between molecules of
FDG and glucose
(K
/K1).
In the rat brain, this transport coefficient for FDG was found to be
1.67, which implies that the transport carrier system favors FDG over
glucose (3). When transport exceeds phosphorylation rates, as occurs
during hyperemic states, the lumped constant would be expected to
approach the phosphorylation coefficient of FDG-glucose. Under those
circumstances, a decreased lumped constant is observed.
Adenosine and glucose uptake. Adenosine regulates regional myocardial blood flow and, in addition, may play a critical role in modulating metabolism. In anesthetized dogs, an intracoronary adenosine infusion increased glucose uptake at least fourfold in the presence of insulin (10, 11), which is consistent with the findings in the present study. Because the effects of adenosine on glucose uptake were minimal without insulin, the authors proposed a mechanism involving postinsulin receptors (10). This is at variance with studies from normoxic rat hearts, however, which have shown that the effects on glucose uptake by adenosine and insulin are additive but via independent mechanisms (1). This also differs from studies of isolated rat hearts, which have shown that adenosine inhibits glucose metabolism, particularly when glucose is the sole substrate (4, 5).
It is unlikely that the effects of adenosine on glucose uptake are flow mediated. Hyperemic flow responses with nitroprusside in both in vivo and in vitro preparations had minimal effects on glucose uptake, whereas similar increments in flow with adenosine caused substantial increases in glucose uptake (11, 13). The magnitude of the change in glucose uptake in those in vivo studies is similar to the nearly fourfold increase in Fick measures of glucose uptake by adenosine observed in the present study. It is conceivable that exogenous adenosine could also alter the lumped constant by virtue of the insulin-like actions of A1-receptor stimulation (27). Insulin has been shown to reduce the lumped constant in isolated rat hearts presumably by the migration of hexokinase from the cytoplasm to the mitochondria where it preferentially binds glucose over deoxyglucose (20). Against this as the mechanism, however, is the observation that ATP and bradykinin also increased myocardial blood flow and like adenosine lowered FDG uptake within the hyperperfused regions. In two animals, we observed that during normal blood flows, myocardial FDG uptake was homogeneous after the hyperemic period. Therefore, it is unlikely that a transient infusion of adenosine could affect a persistent effect on FDG kinetics, independent of perfusion.
Although the vasodilators used in the present series involved both endothelium-dependent and -independent mechanisms, the elaboration of nitric oxide via endothelium-dependent flow-induced dilation could elaborate nitric oxide (9) and alter regional myocardial substrate uptake (19). In a separate group of animals, we determined regional myocardial substrate uptake during adenosine, both before and after inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine. This dose has been shown to inhibit nitric oxide without affecting maximal adenosine flows (7). The results showed that the effect of adenosine on regional myocardial substrate uptake or FDG kinetics was not altered by nitric oxide synthase inhibition. Therefore, the effects of hyperemia on the lumped constant are not a nonspecific effect of nitric oxide elaboration during maximal vasodilation.
Limitations. A limitation of the study is the use of Fick measures of glucose uptake to assess changes in glucose uptake. To accurately judge the limitations of FDG kinetics, alternate tracers such as [14C]glucose and [13C]lactate may provide more specific information about intermediate metabolites and be more sensitive, particularly during low rates of glucose consumption (22).
In summary, quantitative PET measurements of regional FDG uptake may underestimate myocardial glucose uptake when perfusion is increased maximally. This effect seems independent of the agent used to induce maximal vasodilation and is consistent with the contention that supramaximal increases in myocardial blood flow alter the factor relating differences in transport and phosphorylation between molecules of glucose and deoxyglucose (lumped constant). Because the range of flow increments in the present study is far greater than might be encountered during clinical PET studies, it is doubtful that the results would alter the interpretation of FDG uptake within heterogeneously perfused myocardial regions in patients. However, future studies should address how modest changes in regional perfusion might alter FDG kinetics.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-52157 to E. O. McFalls.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: E. O. McFalls, Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN 55417 (E-mail: mcfal001{at}tc.umn.edu).
Received 24 March 1999; accepted in final form 1 September 1999.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Angello, D.,
R. Berne,
and
N. Coddington.
Adenosine and insulin mediate glucose uptake in normoxic rat hearts by different mechanisms.
Am. J. Physiol. Heart Circ. Physiol.
265:
H880-H885,
1993
2.
Buxton, D.,
and
H. Schelbert.
Measurement of regional glucose metabolic rates in reperfused myocardium.
Am. J. Physiol. Heart Circ. Physiol.
261:
H2058-H2068,
1991
3.
Crane, P.,
W. Pardridge,
L. Braun,
and
W. Oldendorf.
Kinetics of transport and phosphorylation of 2-fluoro-deoxy-D-glucose in rat brain.
J. Neurochem.
40:
160-167,
1983[ISI][Medline].
4.
Dale, W.,
C. Hale,
H. Kim,
and
M. Rovetto.
Myocardial glucose utilization: failure of adenosine to alter it and inhibition by the adenosine analogue N2-(L-2-phenylisopropyl) adenosine.
Circ. Res.
69:
791-799,
1991[Abstract].
5.
Finegan, B.,
A. Clanachan,
C. Coulson,
and
G. Lopaschuk.
Adenosine modification of energy substrate use in isolated hearts perfused with fatty acids.
Am. J. Physiol. Heart Circ. Physiol.
262:
H1501-H1507,
1992
6.
Hariharan, R.,
M. Bray,
R. Ganim,
T. Doenst,
C. Med,
G. Goodwin,
and
H. Taegtmeyer.
Fundamental limitations of [18F]2-deoxy-2-fluoro-D-glucose for assessing myocardial glucose uptake.
Circulation
91:
2435-2444,
1995
7.
Kirkeboen, K.,
P. Naess,
J. Offstad,
and
A. Ilebekk.
Effects of regional inhibition of nitric oxide sythesis in intact porcine hearts.
Am. J. Physiol. Heart Circ. Physiol.
266:
H1516-H1527,
1994
8.
Krivokapich, J.,
H. Sung-Cheng,
C. Selin,
and
M. Phelps.
Fluorodeoxyglucose rate constants, lumped constant and glucose metabolic rate in rabbit heart.
Am. J. Physiol. Heart Circ. Physiol.
252:
H777-H787,
1987
9.
Kuo, L.,
M. Davis,
and
W. Chilian.
Endothelium-dependent, flow-induced dilatation of isolated coronary arterioles.
Am. J. Physiol. Heart Circ. Physiol.
259:
H1063-H1070,
1990
10.
Law, W.,
and
M. McLane.
Adenosine enhances myocardial glucose uptake only in the presence of insulin.
Metabolism
40:
947-952,
1991[ISI][Medline].
11.
Law, W.,
and
R. Raymond.
Adenosine potentiates insulin-stimulated myocardial glucose uptake in vivo.
Am. J. Physiol. Heart Circ. Physiol.
254:
H970-H975,
1988
12.
Liedtke, A.,
B. Renstrom,
and
S. Nellis.
Correlation between (5-3H) glucose and (U-14C) deoxyglucose as markers of glycolysis in reperfused myocardium.
Circ. Res.
71:
689-700,
1992[Abstract].
13.
Mainwaring, R.,
R. Lasley,
R. Rubio,
D. Wyatt,
and
R. Mentzer, Jr.
Adenosine stimulates glucose uptake in the isolated rat heart.
Surgery
103:
445-449,
1988[ISI][Medline].
14.
McFalls, E.,
D. Duncker,
R. Krams,
L. Sassen,
A. Hoogendoorn,
and
P. Verdouw.
Recruitment of myocardial work and metabolism in regionally stunned porcine myocardium.
Am. J. Physiol. Heart Circ. Physiol.
263:
H1724-H1731,
1992
15.
McFalls, E.,
D. Duncker,
H. Ward,
and
P. Fashingbauer.
Impaired endothelium-dependent vasodilation of coronary resistance vessels in severely stunned porcine myocardium.
Basic Res. Cardiol.
90:
498-506,
1995[ISI][Medline].
16.
McFalls, E.,
H. Ward,
P. Fashingbauer,
and
B. Palmer.
Effects of dobutamine stimulation on regional myocardial glucose uptake poststunning as measured by positron emission tomography.
Cardiovasc. Res.
28:
1030-1035,
1994[ISI][Medline].
17.
Ng, C.,
J. Holden,
T. DeGrado,
D. Raffel,
M. Kornguth,
and
S. Gatley.
Sensitivity of myocardial fluorodeoxyglucose lumped constant to glucose and insulin.
Am. J. Physiol. Heart Circ. Physiol.
260:
H593-H603,
1991
18.
Ratib, O.,
M. Phelps,
and
S. Huang.
Positron tomography with deoxyglucose for estimating local myocardial glucose metabolism.
J. Nucl. Med.
23:
577-586,
1982[Abstract].
19.
Recchia, F.,
P. McConnell,
X. Xu,
and
T. Hintze.
Changes in cardiac metabolism produced by acute inhibition of NO synthase can be reversed by a long-acting NO donor (Abstract).
Circulation
98:
I212,
1998.
20.
Russell, R., III,
J. Mrus,
J. Mommessin,
and
H. Taegtmeyer.
Compartmentation of hexokinase in rat heart: a critical factor for tracer kinetic analysis of myocardial glucose metabolism.
J. Clin. Invest.
90:
1972-1977,
1992[ISI][Medline].
21.
Schneider, C.,
V. T. Nguyen,
and
H. Taegtmeyer.
Feeding and fasting determine postischemic glucose utilization in isolated working rat hearts.
Am. J. Physiol. Heart Circ. Physiol.
260:
H542-H548,
1991
22.
Schwaiger, M.,
R. Neese,
L. Araujo,
W. Wyns,
J. Wisneski,
H. Sochor,
S. Swank,
D. Kulber,
C. Selin,
M. Phelps,
and
H. Schelbert.
Sustained nonoxidative glucose utilization and depletion of glycogen in reperfused canine myocardium.
J. Am. Coll. Cardiol.
13:
745-754,
1989[ISI][Medline].
23.
Sokoloff, L.,
M. Reivich,
C. Kennedy,
M. Des Rosiers,
S. Patlak,
K. Pettigrew,
O. Sakurada,
and
M. Shinohara.
The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat.
J. Neurochem.
28:
897-916,
1977[ISI][Medline].
24.
Tamaki, N.,
Y. Yonekura,
K. Yamashita,
H. Saji,
Y. Magata,
M. Sends,
Y. Konishi,
K. Hirata,
T. Ban,
and
J. Konishi.
Positron emission tomography using fluorine-18 deoxyglucose in evaluation of coronary artery bypass grafting.
Am. J. Cardiol.
64:
860-865,
1989[ISI][Medline].
25.
Tillisch, J.,
R. Brunken,
R. Marshall,
M. Schwaiger,
M. Mandelkern,
M. Phelps,
and
H. Schelbert.
Reversibility of cardiac wall-motion abnormalities predicted by positron tomography.
N. Engl. J. Med.
314:
884-888,
1986[Abstract].
26.
Van, T.,
B. Nguyen,
K. Mossberg,
T. Tewson,
W. Wong,
W. Rowe,
G. Coleman,
and
H. Taegtmeyer.
Temporal analysis of myocardial glucose metabolism by 2-[18F]fluoro-deoxy-D- glucose.
Am. J. Physiol. Heart Circ. Physiol.
259:
H1022-H1031,
1990
27.
Wyatt, D.,
M. Edmunds,
R. Rubio,
R. Berne,
R. Lasley,
and
R. Mentzer, Jr.
Adenosine stimulates glycolytic flux in isolated perfused rat hearts by A1-adenosine receptors.
Am. J. Physiol. Heart Circ. Physiol.
257:
H1952-H1957,
1989