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Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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During
stress, patients with coronary artery disease frequently fail to
increase coronary flow and myocardial oxygen consumption (M
O2) in response to a greater
demand for oxygen, resulting in "demand-induced" ischemia.
We tested the hypothesis that dobutamine infusion with flow restriction
stimulates nonoxidative glycolysis without a change in
MO2 or fatty acid uptake.
Measurements were made in the anterior wall of anesthetized open-chest
swine hearts (n = 7). The left anterior descending
(LAD) coronary artery flow was controlled via an extracorporeal
perfusion circuit, and substrate uptake and oxidation were measured
with radiotracers. Demand-induced ischemia was produced with
intravenous dobutamine (15 µg · kg
1 · min1) and 20%
reduction in LAD flow for 20 min. Despite no change in
MO2, there was a switch from lactate
uptake (5.9 ± 3.1) to production (74.5 ± 16.3 µmol/min),
glycogen depletion (66%), and increased glucose uptake (105%), but no
change in anterior wall power or the index of anterior wall energy
efficiency. There was no change in the rate of tracer-measured fatty
acid uptake; however, exogenous fatty acid oxidation decreased by 71%.
Thus demand-induced ischemia stimulated nonoxidative glycolysis
and lactate production, but did not effect fatty acid uptake despite a
fall in exogenous fatty acid oxidation.
angina; dobutamine; heart; energy metabolism
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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WHEN THE NORMAL HEALTHY
HEART is exposed to an increased demand for cardiac power, there
is an increase in myocardial oxygen consumption
(MO2) and glucose, lactate, and
fatty acid oxidation, (10, 14-16, 19, 24, 26).
Frequently, patients with coronary artery disease have sufficient
coronary blood flow and MO2 at rest
but will fail to have the normal increase in coronary flow in response
to a greater demand for oxygen, such as occurs with physical exercise
or adrenergic stimulation (increase in heart rate, afterload, and
contractility). Dobutamine stress echocardiography has traditionally
been used in clinical settings to identify residual viable myocardium
in patients following acute myocardial infarction or those with
suspected myocardial hibernation (35, 36) and can also be
utilized to diagnose coronary artery disease by increasing demand for
oxygen consumption and blood flow in the myocardium. In previously
published studies, an infusion of dobutamine to open-chest anesthetized
swine resulted in an increase in
MO2, heart rate, and myocardial
uptake of fatty acids, lactate, and glucose, but with no evidence of
myocardial ischemia (14-16), similar to
exercise in healthy humans (10, 19). When the increased energy demand occurs in combination with an inability to increase coronary blood flow, a mismatch occurs between oxygen demand and supply, resulting in stimulation of glycolysis and a switch to lactate
production, a condition that is referred to as "demand-induced ischemia" (31).
Little is known about the regulation of substrate metabolism during demand-induced ischemia. Pharmacological agents that partially inhibit fatty acid oxidation (ranolazine, trimetazidine, oxfenicine, and perhexiline) have been shown to reduce the symptoms of demand-induced ischemia in patients with stable angina (3, 7, 21, 40), presumably by reducing inhibition by fatty acid oxidation on pyruvate dehydrogenase, thereby increasing glucose oxidation and decreasing lactate and H+ production (20, 23, 40). Because these partial fatty oxidation inhibitors are effective during demand-induced ischemia, one would hypothesize that there is a high rate of fatty acid oxidation under these conditions. A more careful assessment of the metabolic responses during demand-induced ischemia has not been conducted.
The purpose of this study was to examine the contractile and
metabolic responses to demand-induced ischemia caused by an
inability to increase flow in response to the increased oxygen demand.
We hypothesized that demand-induced ischemia would result in no
change in free fatty acid uptake or
MO2, but would stimulate
nonoxidative glycolysis and lactate production. Studies were performed
in an open-chest swine model where flow was restricted and demand was increased with an intravenous infusion of dobutamine.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiments were performed on seven domestic pigs (mean weight, 40.5 ± 0.9 kg). Studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NIH Publication Number 85-23) and the Institutional Animal Care and Use Committee at Case Western Reserve University.
Surgical preparation.
After an overnight fast, animals were sedated with 6 mg/kg Telazol
(im), masked down with isoflurane (5%), intubated via a tracheotomy,
and ventilated to maintain blood gases in the normal range
(PO2 > 100 mmHg,
PCO2 35-45 mmHg, and pH 7.35-7.45)
(39). Anesthesia was maintained with isoflurane
(0.75-1.5%). The heart was exposed via a midline sternotomy with
left-side rib resection (30). Heparin was infused to
prevent clotting and thrombus formation (200 U/kg bolus, followed by
100 U · kg1 · h1 iv), and a
20% triglyceride emulsion was infused (Intralipid 20%, 0.3 ml · kg1 · h1 iv) to
increase plasma free fatty acids to ~0.6 mM (39). Left anterior descending coronary artery (LAD) blood flow was controlled by
an extracorporeal perfusion circuit via a roller pump with blood
supplied from the femoral artery, as previously described in detail
(27, 30, 39). Arterial blood samples were obtained from a
constant flow (10 ml/min) withdrawal loop from the LAD perfusion
circuit so that blood sampling would not disturb coronary artery blood
flow. A 7-Fr Milar Mikrotip dual-transducer catheter was used to assess
left ventricular (LV) pressure. A polyethylene cannula was placed in
the anterior interventricular vein and was used to collect venous blood
samples from the perfusion zone of the LAD. Studies by Renstrom et al.
(33, 34), using a constant infusion of indocyanide green
dye, have shown that the anterior interventricular vein in domestic
swine receives 91 ± 1% of its blood from the LAD; however, we
measured this factor in each animal with a constant infusion of green
dye (0.3 mg/min into the LAD perfusion line) under normal conditions
and during demand-induced ischemia. Regional segment length was
measured in the anterior free wall (LAD bed) using sonomicrometry as
previously described (Triton Technologies, San Diego, CA) (16,
27). The crystal pair was positioned at approximately midwall
depth. This preparation allowed us to subject the LAD perfusion bed to
demand-induced ischemia by decreasing LAD flow by 20% while
infusing dobutamine. Regional myocardial contractile dysfunction was
assessed during demand-induced ischemia from the decrease in
the LV pressure-segment length loop area from normal conditions to
demand-induced ischemia conditions in the anterior wall. The
right main and circumflex coronary artery blood flows were not
restricted, thus their perfusion beds could increase myocardial blood
flow in response to the increased demand as previously described
(15, 16).
Experimental protocol.
After completion of the instrumentation, a continuous infusion of
[U-14C]glucose (0.2 µCi/min) and [9,
10-3H]oleate (0.2 µCi/min) was introduced into the
proximal end of the coronary perfusion line at a rate of 0.1 ml/min
(see Fig. 1). By infusing tracer directly
into the coronary perfusion circuit, the radioactivity dose was greatly
reduced, as was the extent of secondary labeling of
14CO2 and 3H2O, which
increases the precision of the measurement of oleate and glucose
oxidation by the myocardium. After 40 min of tracer infusion, three
pairs of arterial and interventricular venous samples were drawn 10 min
apart (40, 50, and 60 min after tracer infusion). Sixty minutes after
the tracer infusion was initiated, demand-induced ischemia was
initiated with an infusion of dobutamine (15 µg · kg1 · min1) to
increase myocardial oxygen demand and by reducing LAD blood flow by
20% for a period of 20 min. The LAD perfuses approximately one-third
of the LV mass, thus during dobutamine infusion the LV mass subjected
to demand-induced ischemia was limited to the LAD bed, and the
mass perfused by the right main and circumflex coronary arteries
presumably experienced the normal dobutamine-induced increase in
myocardial blood flow and oxygen consumption (15, 16).
Arterial and anterior interventricular venous blood samples were then
taken at 63, 66, 70, and 80 min of tracer infusion (3, 6, 10, and 20 min of demand-induced ischemia). Blood samples were analyzed
for the concentrations of oxygen, lactate, and glucose in blood and
plasma free fatty acids. In addition, samples were analyzed for
[14C]glucose, 14CO2,
[3H]oleate, and 3H2O; this
information was used to calculate the rates of exogenous glucose and
oleate oxidation, as described below. Cardiovascular measurements were
recorded immediately before each arterial and venous blood sample
collection. Heart rate, left ventricular pressure (LVP), peak positive
and negative first derivative of LV pressure (dP/dt), and
segment length were continuously recorded using a commercial on-line
data acquisition system (Crystal Biotech model CBI8000 with Biopaq
software). Small myocardial biopsies (10-20 mg) were taken from
the anterior LV free wall with a 14-gauge biopsy needle 5 min before
initiating demand-induced ischemia and at 8 and 18 min of
demand-induced ischemia. All biopsies were immediately
freeze-clamped (3-5 s) on aluminum blocks precooled in liquid
nitrogen and stored at 
80°C for subsequent analysis. Tissue
ATP and lactate were assayed in these samples. After 20 min of
demand-induced ischemia, two large (~3 g) punch biopsies were
rapidly obtained from the anterior and posterior LV free wall and
freeze-clamped in large steel tongs precooled in liquid nitrogen; these
samples were assayed for concentrations of tissue glycogen and
triglycerides.
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Analytic methods. Arterial and venous pH, PCO2, and PO2 were determined on a blood gas analyzer (NOVA Profile Stat 3, NOVA Biomedical; Waltham, MA), and hemoglobin concentration and saturation were determined on a hemoximeter (Avoximeter; San Antonio, TX). Blood samples for glucose, lactate, and [14C]glucose were deproteinized in ice-cold 1 M perchloric acid (1:2 vol/vol) and analyzed for glucose and lactate using enzymatic spectrophotometric assays on a 96-well plate reader as previously described (13, 45). Blood samples for [14C]glucose and [14C]lactate measurements were neutralized with K2CO3, and the neutral eluate was run through ion-exchange resin columns (Bio-Rad AG 50W-X8 Resin and Bio-Rad AG1-X8 Formate Resin) to separate [14C]glucose as previously described (10, 43). Total glucose concentration and 14C activity were then measured in the eluate to calculate [14C]glucose specific activity. Plasma [3H]oleate concentration was measured by extracting the fatty acids from 0.5 ml of plasma in 3 ml of heptane-isopropanol (3:7) and counting the organic phase as previously described (44). 3H2O concentration was measured by distilling 0.5 ml of plasma in custom-made, modified Hickman stills (Kontes Glass, Custom Shop). Blood 14CO2 concentration was measured by expelling 14CO2 with the addition of concentrated lactic acid and trapping it in hyamine hydroxide as previously described (9, 45). Plasma free fatty acids were measured using a commercially available enzymatic spectrophotometric kit (Wako Chemicals; Richmond, VA).
Tissue concentrations of ATP and ADP were measured using the ATP Bioluminescent Assay Kit (Sigma-Aldrich). Tissue lactate concentrations were measured using an enzymatic spectrofluorometric assay. Tissue glycogen was assayed on perchloric acid extracts using the amyloglucosidase method as described by Passoneau and Lauderdale (32). Tissue triglycerides were extracted in ice-cold chloroform-methanol (2:1 vol/vol), and triglyceride content was measured using an enzymatic spectrophotometric assay (Triglyceride E kit, Wako Chemicals).Calculations.
The net uptake (µmol/min) for glucose and free fatty acids were
calculated as the product of the arterial and coronary venous substrate
concentration difference and myocardial blood flow. The rate of
exogenous glucose and fatty acid oxidation (µmol/min) were calculated
as the product of myocardial blood flow (ml/min) and the release of
either 14CO2 or 3H2O
(dpm/ml) into the coronary vein, divided by the arterial specific radioactivity of glucose or free fatty acids (dpm/µmol)
(43). The interventricular venous concentrations of
14CO2 and 3H2O were
corrected for dilution of blood derived from coronary arteries other
than the LAD by multiplying the measured values by the concentration of
green dye in venous plasma divided by the concentration in arterial
plasma (33, 34). Myocardial blood flow (ml/min) was
measured from the calibrated pump flow of the coronary perfusion line.
MO2 was calculated as the product of
the arterial and venous oxygen concentration difference times the
myocardial blood flow.
O2 in µmol/s times 6 ATP/O2 consumed, plus the lactate production (µmol/s)
times 1 ATP/lactate.
Statistical analysis.
All hemodynamic parameters; rates of free fatty acid, glucose,
and lactate uptakes; rates of free fatty acid and glucose oxidation; concentrations of tissue ATP, lactate, triglyceride, and glycogen; and
regional anterior wall work and power index were compared between
normal conditions and demand-induced ischemia using paired t-tests. Lactate production and
MO2 over time were analyzed using a
one-way repeated measure analysis of variance. Arterial and venous
concentrations and differences were compared using a two-way,
repeated-measure analysis of variance, using a Student-Newman-Keuls test for post hoc comparisons. All significance tests were performed at
the 0.05 level of significance. All values are reported as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamics.
Hemodynamic variables are listed in Table
1. Demand-induced ischemia
resulted in significant increases in heart rate (48 ± 8%), LV
peak positive (85 ± 9%) and negative dP/dt (29 ± 9%), and rate pressure product (44 ± 7%). There was no
increase in MO2 in the LAD perfusion
bed during the period of demand-induced ischemia (Table 1 and
Fig. 2).
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Substrate metabolism.
The arterial concentrations of lactate and glucose did not
change significantly during the experiment (Fig.
3). Arterial concentration of free fatty
acid was unchanged until the final 20 min of demand-induced ischemia when arterial free fatty acid was slightly higher than all other time points; this was matched by a similar rise in venous free fatty acid, resulting in no change in arteriovenous difference for
free fatty acid. However, the arteriovenous difference increased for
glucose and the uptake of lactate converted to production (Fig. 3).
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O2
(Fig. 2). Demand-induced ischemia caused a ~2.7-fold increase
in myocardial tissue lactate content, a ~22% reduction in ATP
content, and a ~25% fall in the ATP/ADP ratio (P < 0.05) (Table 2), with no change in tissue ADP content (data not shown).
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Regional left ventricular wall work and power.
Sonomicrometry was used to assess anterior wall work and power index as
calculated from the segment length-LVP loop area. Figure
5 presents an example of segment
length-LVP loops generated during both the normal conditions and during
demand-induced ischemia from a representative animal. Anterior
wall work index was significantly decreased by 38 ± 10%
(169 ± 35 vs. 109 ± 28 mmHg · mm; P < 0.05) during demand-induced ischemia (Fig.
6). Anterior wall power index was
unchanged during this period (299 ± 47 vs. 309 ± 86 mmHg · mm · s1). The estimated rate of
total ATP production (11.5 ± 1.2 and 12.1 ± 1.3 µmol/s)
was constant; however, there was a switch to lactate production during
demand-induced ischemia, which contributed 1.2 ± 0.3 µmol ATP/s, which accounted for 10 ± 2% of the total energy
expenditure during demand-induced ischemia. Because there were
no changes in either the anterior wall power index or the estimated
total ATP production, the anterior wall energy efficiency index was
unchanged during the demand-induced ischemia period (Table 1).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present investigation is the first to show that demand-induced
ischemia resulting from dobutamine infusion with flow
restriction activates nonoxidative glycolysis, but does not change
MO2, anterior wall power, or the
myocardial energy efficiency index. Whereas there was no change in the
rate of tracer-measured free fatty acid uptake, exogenous free fatty
acid oxidation was decreased. Thus demand-induced ischemia
stimulated glycolysis and lactate production, but did not effect fatty
acid uptake despite a paradoxical fall in exogenous fatty acid oxidation.
Previous studies in patients with coronary artery disease demonstrated stimulation of lactate production when the heart was stressed by atrial pacing (31, 42). In the present investigation there was a dramatic switch to lactate production when dobutamine infusion was accompanied by a 20% reduction in LAD flow. Similarly, Parker et al. (31) demonstrated a significant increase in lactate production during angina induced by atrial pacing in patients with coronary artery disease. The switch to net lactate production corresponded with the onset of chest pain and the depression of the S-T segment during progressive atrial pacing. Another group of patients who experience exertional angina but have normal coronary arteries have been found to have limited coronary flow reserve due to a dysfunction of small coronary arteries (5). These patients have been reported to have a limited ability to increase coronary blood flow (6) and abnormal lactate metabolism in response to atrial pacing (4). Wisneski et al. (43) reported similar increases in lactate production during atrial pacing both in patients who experienced mild chest pain as well as in patients who did not experience clinical symptoms of ischemia. Thus the present investigation demonstrates that there is increased net glycogen breakdown, glucose uptake, and tissue lactate accumulation and a fall in ATP content during demand-induced ischemia, illustrating the activation of nonoxidative glycolysis under these conditions.
The primary source of glycolytic substrate for lactate production
during demand-induced ischemia was endogenous glycogen stores (~84%), with a lesser contribution from exogenous glucose (16%). The total net lactate production in the LAD bed during demand-induced ischemia was measured, and the approximate lactate production was calculated from the conversion of exogenous glucose to lactate and
the glycogen breakdown that was converted to lactate. The measured
lactate production during the demand-induced ischemia period
was 1,407 µmoles, and the mean expected lactate production from
exogenous glucose and glycogen breakdown was 1,602 µmoles. These
calculations were based on the following assumptions; 2 lactate
molecules were produced for every glucose and/or glycosyl unit broken
down, and the mean LAD bed weight was 42.0 g. The predobutamine
glycogen concentration was assumed to be 31.1 µmol/g wet wt in the
LAD bed [i.e., the same value as in the CFX bed at the end of the
protocol, as previously found in nonischemic unstressed
myocardium (38), thus the total glycogen breakdown during
demand-induced ischemia was 1,789 µmoles (31.1 µmol/g 9.8 µmol/g × 42 g × 2 lactates/glycosyl
unit)]. From the assumption that ~25% of glycolytic flux
was subsequently oxidized and 75% was converted to lactate, 1,342 µmoles of lactate were produced from glycogen during the 20 min of
demand-induced ischemia. The lactate that was produced from
exogenous glucose [260 µmoles (13 µmols/min × 20 min)] was
then added, resulting in a mean expected total of 1,602 µmoles of
lactate production during demand-induced ischemia. This value
was in the same range as the integral of the net lactate production,
which was calculated as 1,113 µmoles released from the myocardium
(venous-arterial lactate difference times blood flow; Fig. 2) and 294 µmoles of lactate that accumulated in the tissue [(10.9
µmol/g 4.1 µmol/g) × 42 g], for a total of 1,407 µmoles. Thus there was good agreement between the estimated lactate production from glycogen breakdown and glucose conversion to
lactate and the total of lactate production.
It is important to note that the high rate of nonoxidative glycolysis during demand-induced ischemia accounts for only 10% of the total energy expenditure, but it clearly reflects a dramatic disruption to normal myocardial metabolism as seen in the marked lactate efflux and accumulation in the tissue. It has been suggested that lactate and H+ accumulation and efflux during ischemia have negative effects on the ability of cardiac muscle to maintain Ca2+ homeostasis and to use the energy released from the breakdown of ATP to perform contractile work (8, 29, 37). Drugs that decrease the rate of nonoxidative glycolysis by partial inhibition of fatty acid oxidation, such as trimetazidine (20) or ranolazine (28), improve the symptoms of patients with exercise-induced angina, possibly by increasing pyruvate oxidation in the mitochondria, thus reducing lactate accumulation and efflux. This mechanism remains to be demonstrated under clinically relevant in vivo conditions.
We observed that the amount of anterior wall work for each heartbeat was decreased by 38% from control conditions to demand-induced ischemia (Fig. 6, left). Because the heart rate increased by 47% during demand-induced ischemia, anterior wall power (taken as anterior wall work × heart rate) remained constant (Fig. 6, right). Moreover, the estimated rate of total ATP production was constant, thus because the anterior wall power index and the estimated total ATP production were constant, the anterior wall energy efficiency index was unaffected by demand-induced ischemia (Table 1). To our knowledge, this is the first demonstration that under conditions of high nonoxidative glycolysis, ATP depletion, and lactate accumulation, the myocardium does not become energetically less efficient.
During demand-induced ischemia, tracer-measured free fatty acid
uptake was unchanged, but there was a fall in exogenous free fatty acid
oxidation. These results suggest that labeled free fatty acids that are
taken up during demand-induced ischemia are primarily stored as
intracellular triglycerides. This concept is supported by studies in
isolated myocytes that found an 81% increase in incorporation of
[14C]palmitate into intracardiac triglycerides following
exposure to 5 µM epinephrine (41). It is likely that
there is also an increase in the breakdown of intracardiac triglyceride
stores during demand-induced ischemia. The early study by
Kreisberg (22) showed that when the isolated rat heart was
perfused with [14C]oleate, epinephrine resulted in a 20%
decrease in oleate oxidation and a doubling in the rate of oleate
storage as triglyceride (from 9% to 22% of the oleate uptake). In
addition, the rate of glycerol release doubled, reflecting greater
intracellular triglyceride breakdown. These findings suggest that under
normal unstimulated conditions, there is a slow turnover of the
intracellular triglyceride pool; however, when the heart is stimulated
with a 
-adrenergic agonist, there is an increase in the rate of
triglyceride synthesis and breakdown (12, 25). Recent work
from Goodwin and Taegtmeyer (11, 12) in the isolated
buffer-perfused rat heart showed that stimulation of
MO2 and contractile function with 1 µM epinephrine stimulates both lipolysis and triglyceride synthesis,
and thus greater turnover of the intracellular triglyceride pool.
Clearly, further work is necessary before the effects of demand-induced ischemia on the metabolism of intracardiac triglycerides are
understood. However, we speculate that both endogenous triglycerides
and newly synthesized triglycerides from exogenous fatty acids could
contribute to total energy production during demand-induced
ischemia, and thus our measure of exogenous fatty acid
oxidation underestimates the true contribution of fatty acids during
demand-induced ischemia.
Study limitations. The present investigation did not assess the well-described transmural gradient in myocardial blood flow that occurs with a reduction in coronary flow at rest (17, 38) or in response to demand-induced ischemia (1, 2). Reductions in coronary artery flow by ~60% results in a large decrease in the subendocardial-to-subepicardial flow ratio, and greater glucose extraction (38), lactate production (13), and glycogen breakdown (18, 38) in the subendocardium relative to the subepicardium. The studies by Bache and co-workers (1, 2) demonstrate a transmural gradient in flow during demand-induced ischemia in exercising dogs with coronary flow restriction, thus suggesting that in our swine model there are gradients in both flow and nonoxidative metabolism during demand-induced ischemia. Future studies with microsphere-measured myocardial flow and transmural assessment of metabolism need to be performed to address this issue. An additional limitation in this study is that serial measurements of myocardial triglyceride and glycogen content were not performed. Glycogen breakdown likely occurred at a higher rate during the initial minute of demand-induced ischemia, as noted previously in dogs following coronary ligation (18). It is also important to understand the time course of the changes in intracardiac triglyceride content.
We believe that the fatty acid oxidation results are complex due to the fact that we did not measure either the oxidation of endogenous triglycerides or the incorporation of tritiated oleate into intracellular triglyceride stores, thus the oxidation of endogenous fatty acids (from the breakdown of intracellular triglyceride stores) has not been taken into account. It is very possible that demand-induced ischemia results in a greater oxidation of intracardiac triglyceride; however, this will need to be addressed in future studies where the triglyceride stores are "prelabeled" with radioactive oleate. In summary, despite no change in MO2, there was a switch from lactate
uptake to production, glycogen depletion, and increased glucose uptake,
but no change in anterior wall power or the index of anterior wall
energy efficiency. Furthermore, there was no change in the rate of
tracer-measured free fatty acid uptake, yet exogenous fatty acid
oxidation was decreased. Thus demand-induced ischemia
stimulated nonoxidative glycolysis and lactate production, but did not
effect fatty acid uptake despite a paradoxical fall in exogenous fatty
acid oxidation.
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ACKNOWLEDGEMENTS |
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The authors thank Jennifer Salem and Kyle Salem for expertise in developing a Matlab program for the analysis of the pressure volume-segment length loops. We also thank Brigitte Roth, David Urbanek, and Sumeet Gadgil for assistance in the conduct of this study.
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FOOTNOTES |
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This study was supported by the National Heart, Lung, and Blood Institute Grant HL-58653 and by the American Heart Association, Ohio Valley Affiliate, Postdoctoral Fellowship 0020315B.
Address for reprint requests and other correspondence: W. C. Stanley, Dept. of Physiology and Biophysics, School of Medicine, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106-4970 (E-mail: wcs4{at}po.cwru.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 January 17, 2002;10.1152/ajpheart.00976.2001
Received 8 November 2001; accepted in final form 15 January 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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