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1045
Fasting In Vivo Delays Myocardial Cell
Damage After Brief Periods of Ischemia in
the Isolated Working Rat Heart
Christian A. Schneider and Heinrich Taegtmeyer
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To assess the effects of fasting on recovery of function and exogenous glucose metabolism after
15 minutes of total ischemia, we perfused isolated working rat hearts from fed and fasted
animals. Hearts were perfused in a recirculating system with bicarbonate buffer containing
glucose (10 mM). Mechanical performance, release of marker proteins for ischemic membrane
damage (lactate dehydrogenase, myoglobin, citrate synthase), and the concentrations of lactate
and glucose in the perfusion medium were measured serially. Tissue metabolites were also
measured. Fasting raised the myocardial glycogen content by 25%. Cardiac performance of
perfused hearts from fed and fasted animals was the same during the preischemic and the postischemic period. The time of return of function to preischemic values was significantly less in
hearts from fasted rats (2.3 versus 7.8 minutes, p<0.025). The release of cytosolic and
mitochondrial marker proteins was significantly lower in hearts from fasted rats than in hearts
from fed rats. Glucose metabolic rates during control and reperfusion were unchanged for
hearts from fasted rats, but decreased for hearts from fed rats during reperfusion. Conversely,
lactate utilization was significantly increased in hearts from fed rats during reperfusion. The
adenine nucleotide content at the end of ischemia was higher in hearts from fasted animals
than in hearts from fed animals. We conclude that increasing glycogen levels prior to ischemia
improves recovery of function, lessens membrane damage, and prevents loss of adenine
nucleotides. (Circulation Research 1991;68:1045-1050)
V ery little is known about the effects of fasting
on the resistance of the myocardium against
ischemic stress. Among the many hormonal
and metabolic changes in the fasting organism,1
changes in endogenous substrate supply are of particular interest for the ischemic heart.
Fasting is known to increase the myocardial glycogen content in rats through inhibition of the glycolytic pathway by enhanced oxidation of fatty acids.2
Although data by Neely et a13 suggest that lactate
from glycogen breakdown during ischemia has deleterious effects on the postischemic cardiac performance and that lowering of the myocardial glycogen
content protects the rat heart during ischemia, data
From the Department of Internal Medicine, Division of Cardiology, University of Texas Medical School at Houston, Houston,
Tex.
C.A.S. has been supported by a research fellowship of the
Boehringer Ingelheim Fonds Stiftung fuer Grundlagenforschung,
Stuttgart, FRG. The work has been supported in part by a
grant-in-aid from the American Heart Association National Center and by private funds.
Address for correspondence: H. Taegtmeyer, MD, DPhil, University of Texas Medical School at Houston, Division of Cardiology, 6431 Fannin, MSB 1.246, Houston, TX 77030.
Received August 23, 1990; accepted December 10, 1990.
by Scheuer and Stezoski4 and by others5,6 have suggested that an increased myocardial glycogen content
protects the heart during periods of oxygen deprivation. Moreover, we have recently reported that reducing the myocardial glycogen content before ischemia had no protective effect after hypothermic
ischemic arrest in the isolated perfused rabbit heart.7
In the present study we examined the effects of
endogenous substrates, chiefly glycogen, on myocardial function and metabolism after brief periods of
total ischemia. We focused on glycogen, because it is
the major endogenous substrate that the heart can
utilize for energy production during ischemia, since it
has been previously demonstrated that even after 90
minutes of global ischemia the total tissue content of
triacylglycerols and phospholipids remains unchanged in rat heart.8
To assess beneficial or harmful effects of fasting on
the ischemic myocardium, we compared perfused
hearts from rats that had free access to food and
water with rats that were fasted for 16 hours. We
found that fasting of animals in vivo improves postischemic function of rat hearts in vitro as assessed by
contractile and biochemical parameters, but that this
improvement is not due to enhanced glycogenolysis
during ischemia.
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Circulation Research Vol 68, No 4 April 1991
Materials and Methods
Materials
All chemicals were obtained from Fisher Scientific,
Lexington, Mass., or Sigma Chemical Co., St. Louis.
Enzymes and cofactors were obtained from Boehringer Mannheim, Indianapolis, Ind., unless indicated otherwise.
Animals
Male Sprague-Dawley rats (300-350 g) were obtained from Sasco Corp., Houston, and were either
fed ad libitum or fasted overnight (for 16 hours) with
free access to water.
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Perfusion Apparatus
We used the isolated working heart perfusion
apparatus of Neely et a19 as modified by Taegtmeyer
et al10 and measured the physiological performance
of the heart (heart rate, aortic systolic and diastolic
pressure, and cardiac output), assessed glucose and
lactate metabolic rates, and estimated the release of
marker proteins from the myocardium.
Working Heart Preparation
The working heart preparation has been described
in detail earlier.10 Briefly, rats were anesthetized with
sodium pentobarbital (10 mg/100 g body wt i.p.).
After injection of heparin (200 IU) into the inferior
vena cava, the heart was rapidly removed and
mounted on the aortic cannula. A brief period of
retrograde perfusion (approximately 5 minutes) was
necessary to wash out any blood from the heart and
to perform the left atrial cannulation. Hearts were
then perfused at 37°C with recirculating KrebsHenseleit bicarbonate buffer (200 ml) containing
glucose (10 mM) as a substrate. The perfusion medium was gassed with 95% 02-5% CO2.
All experiments were carried out with an afterload
of 100 cm H2O and a preload of 15 cm H2O. Aortic
flow and coronary flow were measured every 10
minutes. Cardiac output was calculated as the sum of
aortic and coronary flow. Heart rate and systolic and
diastolic pressure were continuously measured with a
Hewlett-Packard transducer and recording system.
Perfusion Protocol
The perfusion protocol consisted of three parts.
Hearts were perfused under normoxic conditions for
30 minutes. This initial perfusion period was followed
by 15 minutes of total global ischemia and then by
reperfusion for another 30 minutes. Ischemia was
induced by clamping both the aortic and the atrial
lines, and reperfusion was accomplished by opening
the same. At the end of the experiments, hearts were
frozen with a pair of aluminum tongs cooled to the
temperature of liquid nitrogen.10 In selected experiments, hearts were freeze-clamped at the end of the
ischemic period. The frozen tissue was stored at
-70°C until extraction of the tissue metabolites.
Biochemical Methods
Perfusate samples. At specified times during the
experiment, small (1 ml) samples of the coronary
effluent and the perfusion medium were withdrawn
to measure glucose and lactate as well as lactate
dehydrogenase, myoglobin, and citrate synthase,
which we considered cellular marker proteins of
sarcolemmal and mitochondrial ischemic damage.
Glucose and lactate assays. Glucose and lactate
were measured with a glucose/lactate analyzer (2300
STAT, YSI Inc., Yellow Springs, Ohio). Rates of
glucose utilization and lactate production and utilization were calculated by disappearance or appearance of glucose or lactate in the perfusion medium as
described earlier.10
Assays of lactate dehydrogenase, myoglobin, and
citrate synthase. Lactate dehydrogenase was determined spectrophotometrically using a kit purchased
from Sigma Diagnostics, St. Louis. Results are expressed as units per gram dry weight.
Myoglobin was determined by measuring the absorbance of myoglobin at 410 nm1" at 25°C. Crystallized horse heart myoglobin (Sigma) served as standard. Results are expressed as milliunits per gram dry
weight.
Citrate synthase was assayed by the method of
Srere12 using 5,5'-dithiobis-(2-nitro-benzoate). The
results are expressed as milliunits per gram dry
weight.
All readings were made on a Gilford Spectrophotometer Model 2600 (Gilford Instruments, Oberlin,
Ohio). Areas under the curve were calculated as the
integral of each enzyme-activity curve using a BASIC
program (areas under the curve, without units). Peak
activity of the proteins is the maximum of activity
during reperfusion.
Tissue extraction and metabolite assays. Tissue was
extracted with 6% perchloric acid as described earlier.'3 ATP, ADP, AMP, phosphocreatine, glucose
6-phosphate, pyruvate, alanine, and citrate were
measured as described in Bergmeyer.14 Glycogen was
determined by the method of Walaas and Walaas15
using amyloglucosidase. Triacylglycerols were extracted with chloroform/ethanol (2:1, vol/vol)'6 and
determined by the method of Eggstein et al.17
A small portion of the pulverized tissue was used
to obtain the wet weight/dry weight ratio. Tissue was
weighed (wet weight) and dried in an oven (60°C) for
at least 36 hours and weighed again (dry weight).
Tissue metabolites data are presented as micromoles
per gram dry weight, glycogen as micromoles glucose
per gram dry weight.
Statistical Analysis
All data are presented as mean+SEM. A twotailed t test (paired and unpaired) was used to
compare the preischemic and postischemic period
from hearts of fed and fasted rats. Differences were
considered statistically significant when p<0.05.
Schneider and Taegtmeyer Myocardial Glycogen, Ischemia, and Reperfusion
1047
7
10+
E =Fed
M =Fasted
8+
E 6-
p(O.025
4.1
I
2±
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
0-
FIGURE 1. Mean time to return offunction after 15 minutes
of total ischemia in hearts from fed and fasted rats. Values are
mean +SEM of 10 (fed) and five (fasted) rats.
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Results
Glycogen Content In Vivo, Performance In Vitro, and
Time to Recovety of Function
Before perfusion (in vivo), the glycogen content of
hearts from fed rats was significantly lower than of
hearts from fasted rats (89+5 versus 125+±5 ,umol/g
dry wt, p<0.002). The triacylglycerol content in vivo
also increased with fasting (from 109±14 versus
151±+10 1,mol/g dry,p<0.05).
While the time to full recovery of preischemic
function (heart rate, cardiac output, and systolic and
diastolic pressure) after ischemia was significantly
longer in hearts from fed rats than in hearts from
fasted rats (Figure 1), steady-state cardiac performance during the preischemic and postischemic period was the same in hearts from fed and fasted rats
(range, 222-249 ml/min g dry wt, not significant; data
not shown). It should be noted that we did not
observe any prolonged myocardial dysfunction
("stunning") after 15 minutes of ischemia.
Glucose and Lactate Metabolic Rates
We also measured rates of glucose utilization and
lactate metabolism before and after ischemia. The
results are presented in Table 1. In the preischemic
TABLE 1. Metabolic Rates for Glucose and Lactate of Hearts
From 10 Fed and Five Fasted Rats Before and After 15 Minutes of
Total Ischemia
Preischemic
n
Glucose metabolic rate
Fed
Fasted
Lactate metabolic rate
Fed
Fasted
Values are mean±SEM.
Postischemic
(,umol/g dry/hr)
-978±283
10
5
-784± 135
-305+38*
-637±57t
10
5
278±135
112±85
-976±219t
- 160±186§
*p<0.035 vs. preischemic fed.
tp<0.05 vs. postischemic fed.
tp<0.01 vs. preischemic fed.
§p<0.01 vs. postischemic fed.
mln
FIGURE 2. Lactate dehydrogenase release from the myocardium into the coronary effluent of hearts from fed and fasted
rats before and after 15 minutes of total ischemia. Note the
significantly higher postischemic release of lactate dehydrogenase by hearts from fed rats. Values are mean ±SEM of 10
(fed) and five (fasted) experiments at each time point.
*p<O005.
period, hearts from both groups used exogenous glucose as substrate and produced lactate. During the
postischemic period, glucose utilization by hearts from
fed animals was markedly reduced (from -978 to -305
,umol/g dry/hr) with simultaneous increased lactate
utilization (from +278 to -976 ,umol/g dry/hr). In
hearts from fasted animals, no change in glucose utilization was seen. The lactate utilization was less and the
glucose utilization significantly greater than in hearts
from fed animals (Table 2). These data have been
published earlier18 and are included here for clarity.
Markers of the Ischemic Cell Damage
Figure 2 shows release of lactate dehydrogenase
(MW 140,000) from the perfused hearts. In both
groups a small but consistent amount of enzyme was
released during the preischemic period. Hearts from
fed animals demonstrated a significant release of
lactate dehydrogenase in the early postischemic period, while hearts from fasted animals did not show
any difference in the release of enzyme between the
preischemic and postischemic period. To compare
the total amount of lactate dehydrogenase released
we also analyzed areas under the curve during the
preischemic and postischemic period in hearts from
fed and fasted animals (Table 2). While there were
no significant differences during the control period,
total release of lactate dehydrogenase was significantly greater during the postischemic period in
hearts from fed than from fasted animals. Even more
important, there was no significant difference of the
lactate dehydrogenase release between the preischemic and postischemic period in hearts of fasted
animals.
We also examined the release of myoglobin, a
helical protein (MW 17,500) that has been used as a
marker for myocardial cell damage." Results for
peak release and total release (areas under the
curve) are summarized in Table 3. There was signif-
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Circulation Research Vol 68, No 4 April 1991
TABLE 2. Peak Activity and Areas Under the Curve for
Lactate Dehydrogenase
TABLE 4. Peak Activity and Areas Under the Curve for
Citrate Synthase
n
Preischemic
Postischemic
Peak
10
...
Fed
20.1+6.9
5
...
3.4+1.8*
Fasted
AUC
10
76.5±+20.4
Fed
116±25.2t
5
35.2±14.5
40.8±16.41
Fasted
Values are mean+SEM. Peak, unit/g dry wt; AUC, areas under
the curve.
*p<0.02 vs. fed.
tp<0.05 vs. preischemic fed.
tp<O.05 vs. postischemic fed.
n
Preischemic
Postischemic
Peak
Fed
6
...
10.5±+-2.4
Fasted
5
...
4.8+1.1*
AUC
Fed
6
123+13
195±64
Fasted
5
130±82
64+15t
Values are mean±SEM. Peak, milliunits/g dry wt; AUC, areas
under the curve.
*p<0.05 vs. postischemic fed.
tp<0.05 vs. preischemic fed.
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icantly less myoglobin release in hearts from fasted
rats during the postischemic period.
The total release of the marker enzyme for the
inner mitochondrial membrane, citrate synthase
(MW 98,000), was also significantly less in hearts
from fasted rats. The data are presented in Table 4.
Tissue metabolites. To determine whether the energy state of the myocardium at the end of ischemia
differed between hearts from fed and fasted animals,
we also measured tissue metabolites at the end of
ischemia (Table 5). Compared with hearts from fed
animals, hearts from fasted animals contained significantly higher amounts of ADP, total adenine nucleotides, glycogen, glucose 6-phosphate, and citrate,
while the contents of ATP, AMP, pyruvate, and
alanine were not different.
Discussion
The present study demonstrates that fasting and
alterations of endogenous substrate supply in rat
hearts by glycogen loading preserve the adenine
nucleotide content during ischemia, shorten recovery
time, normalize postischemic glucose utilization, and
lessen ischemic membrane damage after brief periods of ischemia. These findings are somewhat surprising in the context of reports on accelerated
glycogen breakdown and the resultant lactate production during ischemia, exerting deleterious effects
on the function of both ischemic and postischemic
myocardium.3 The findings are, however, consistent
with other earlier observations of a protective effect
TABLE 3. Peak Activity and Areas Under the Curve for Myoglobin
n
Preischemic
Postischemic
Peak
Fed
6
...
5±1
...
Fasted
5
0.8±0.4*
AUC
Fed
6
75±+ 17
92+16
Fasted
5
34±15
19±5t
Values are mean+SEM. Peak, mg/g dry wt; AUC, areas under
the curve.
*p<0.004 vs. postischemic fed.
tp<0.01 vs. postischemic fed.
of glycogen loading in rabbit hearts subjected to
hypothermic ischemic arrest for up to 12 hours.19 In
these experiments, glycogen loading was achieved by
the simultaneous injection of glucose and insulin.
The present results now seem to suggest that the
nutritional state of the animal before ischemia (and
not the amount of glycogen broken down during
ischemia) is an important determinant for the outcome of the postischemic myocardium: hearts from
fed and fasted rats used approximately the same
amount of glycogen during ischemia and also produced approximately the same amount of lactate
(Table 5). Enhanced glycogenolysis during ischemia
can therefore not explain the beneficial effects of
fasting. These findings are similar to earlier findings
by Kilgour et a120 and Tani and Neely,21 who also
found no difference in tissue lactate content between
glycogen-rich diabetic rat hearts and control hearts
after ischemia.
A surprising finding was that the net loss of
adenine nucleotides in heart muscle, a well-known
phenomenon already observed after very brief periods of ischemia,2223 was retarded in glycogen-rich
hearts of fasted rats. The significantly higher ADP
content at the end of ischemia in hearts from fasted
rats may provide a readily available substrate for
rephosphorylation during reperfusion and hence may
be an important contributor to the faster return of
function. In contrast, hearts from fed rats would be
required to replenish some of their adenine nucleotides by de novo synthesis. Since de novo synthesis of
adenine nucleotides is a very slow process compared
with the de novo synthesis of other intermediary
metabolites,23 it is unlikely that hearts of fed animals
replenished their adenine nucleotide stores during 30
minutes of reperfusion. Thus, it is reasonable to
assume that intracellular ADP concentration fulfills
an important role in the rate of recovery of function
on reoxygenation of reversibly ischemic myocardium.
Furthermore, the breakdown of adenine nucleotides
generates protons24 and is ultimately linked to the
production of oxygen-derived free radicals,25 which
may initiate peroxidation of membranes,26 may lead
to changes in membrane fluidity, and opens ion
channels like the calcium channel.27 The acidification
of the cell during ischemia and the rise in intracellu-
Schneider and Taegtmeyer Myocardial Glycogen, Ischemia, and Reperfusion
TABLE 5. Tissue Metabolites at the End of Ischemia of Hearts From Fed and Fasted Rats
Pyruvate
G-6-P
Glycogen
PCr
TAN
AMP
ADP
ATP
5.7±1.7 39±19
0.88±0.4
1.7±0.5
12±2
2.5±1.1
4.7±1.6 4.3±1.1
Fed
(n=6)
Fasted 12.7±4.9
8.7±0.8*
2.6±1.1
24-5t
12.6±4.3
66±18t
4.6±1.4t
2.6+1.0
1049
Lactate
Alanine
Citrate
75±11
7.9±3.6
3±0.6
62±9
7.0±0.8
6.9±1.5§
(n=5)
All data are mean±SEM; number of experiments are given in parentheses. All values are micromoles per gram dry weight. The data
reported were obtained after 15 minutes of total ischemia. TAN, total adenine nucleotides; PCr, phosphocreatine; G-6-P, glucose
6-phosphate.
*p<0.015, tp<0.045, tp<0.01, §p<0.025 vs. fed.
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lar calcium can activate phopholipases and proteases,28 which in turn may lead to an increase in
membrane permeability as suggested in our experiments by the loss of marker proteins. Thus, according
to this hypothesis, brief periods of ischemia are
priming the myocardium for the deleterious effects of
reperfusion. We wish to propose now that fasting and
glycogen loading modify this "priming process" and
protect the myocardium against reperfusion injury by
yet unknown mechanisms.
A third unexpected finding of our study was the
decreased glucose utilization on reperfusion of
hearts from fed rats. A possible explanation may be
that hearts from fed rats with a lower adenine
nucleotide content were not able to phosphorylate
enough glucose to glucose 6-phosphate to keep up
with the increased postischemic ATP demand and
switched to lactate as the preferred substrate for
energy production. The decrease in glucose utilization was not only associated with an increased lactate
utilization but correlated also with a significantly
greater release of marker proteins and a delay in the
time to recovery of function. These observations are
in principal agreement with earlier findings by Bricknell and Opie,29 who showed that hearts perfused
with pyruvate as substrate lost significantly more
lactate dehydrogenase during reperfusion than
hearts perfused with glucose. It has been proposed
that ATP derived from the Embden-Meyerhof pathway is preferentially used for ion pumps and membrane functions.30'31 The small difference between
the amount of ATP derived from glucose (fasted
hearts) and preferentially from lactate/pyruvate (fed
hearts) may be crucial for defense and clearance
mechanisms in the early reperfusion period after
ischemia.
A possible reason for the protective effect of
fasting could be found in a physiological role for
glycogen, as it relates to cell homeostasis; glycogen is
stored in the cardiac cell close to the sarcoplasmic
reticulum and a glycogen-sarcoplasmic reticulum
complex has been described by Entman et al.32 The
central role that the sarcoplasmic reticulum plays in
Ca2+ metabolism and contractile coupling and the
close connection between glycogen and sarcoplasmic
reticulum makes it likely that an increased glycogen
content protects the sarcoplasmic reticulum directly,
although there is no direct proof for this hypothesis.
Such a protective effect could also help to explain the
unexpected findings reported by Tani et a121 that
diabetic, glycogen-rich hearts preserve their ability to
maintain intracellular [Ca2] better than control
hearts during ischemia. However, we cannot exclude
that other metabolic and hormonal changes contribute
to the protective effect in hearts of fasted animals.
Even after short periods of fasting the plasma-insulin
levels fall, plasma fatty acid levels increase, and the
tissue content not only of glycogen but also of citrate,
glucose 6-phosphate, coenzyme A, and triacylglycerols
increases.' Although the total tissue content of triacylglycerols and phospholipids remains largely unchanged during ischemia and reperfusion, it has been
demonstrated that the ATP-consuming triacylglycerol-nonesterified fatty acid cycle is activated during
ischemia.8 The decreased adenine nucleotide content
in hearts of fed rats might therefore lead to impaired
reesterification of nonesterified fatty acids, which have
as amphiphiles deleterious effects on the ischemic and
reperfused myocardium.33
Although we are aware that most of the above
scenario is still speculative, we have provided evidence
for the beneficial effects of fasting on the ischemic
myocardium. It is most likely that the increased myocardial glycogen content after fasting protects the heart,
although the mechanisms are still unknown.
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KEY WORDS * glycogen * reperfusion injury * adenine
nucleotides * marker proteins
Fasting in vivo delays myocardial cell damage after brief periods of ischemia in the
isolated working rat heart.
C A Schneider and H Taegtmeyer
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Circ Res. 1991;68:1045-1050
doi: 10.1161/01.RES.68.4.1045
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1991 American Heart Association, Inc. All rights reserved.
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