Cardiovascular Research Group, Departments of Pediatrics and Pharmacology, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2
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ABSTRACT |
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Clinical studies have demonstrated improved
myocardial recovery after severe ischemia in response to acute
triiodothyronine (T3) treatment.
We determined whether T3 improves
the recovery of ischemic hearts by improving energy substrate
metabolism. Isolated working rat hearts were perfused with 5.5 mM
glucose and 1.2 mM palmitate and were subjected to 30 min of no-flow
ischemia. Glycolysis, glucose oxidation, and palmitate
oxidation were measured during aerobic reperfusion by adding
[5-3H]glucose,
[U-14C]glucose, or
[9,10-3H]palmitate to
the perfusate, respectively. During reperfusion, cardiac work in
untreated hearts recovered to a lesser extent than myocardial
O2 consumption
(MO2), resulting
in a decreased recovery of cardiac efficiency, which recovered to only
25% of preischemic values. Treatment of hearts with
T3 (10 nM) before ischemia
increased glucose oxidation during reperfusion, which was associated
with a significant increase in pyruvate dehydrogenase (PDH) activity,
the rate-limiting enzyme for glucose oxidation. In contrast,
T3 had no effect on
M
O2, glycolysis, or
palmitate oxidation. This resulted in a significant decrease in
H+ production from glycolysis
uncoupled from glucose oxidation (2.7 ± 0.3 and 1.9 ± 0.3 µmol · g dry
wt
1
· min
1
in control and T3-treated hearts,
respectively, P < 0.05), as well as
a 3.2-fold improvement in cardiac work and a 2.3-fold increase in
cardiac efficiency compared with untreated postischemic hearts
(P < 0.05). These data suggest that
T3 can exert acute effects that
improve the coupling of glycolysis to glucose oxidation, thereby
decreasing H+ production and
increasing cardiac efficiency as well as contractile function during
reperfusion of the postischemic heart.
glycolysis; glucose oxidation; fatty acid oxidation; hydrogen production
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INTRODUCTION |
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IT IS WELL-KNOWN that thyroid hormone regulates metabolic and physiological functions in cardiac tissue. The direct effects of 3,5,3'-triiodo-L-thyronine (T3), the biologically active form of the hormone, on cardiac cells can be nuclear or extranuclear in nature (see Ref. 8 for review). Nuclear effects are delayed in onset and are brought about by binding of thyroid hormone to nuclear thyroid hormone receptors. In vivo, hyperthyroidism can cause increases in heart rate, contractility, and cardiac output, thus raising the inotropic state of the heart, which is accompanied by a high level of energy substrate metabolism, especially glucose utilization (25, 29). Although these effects of thyroid hormone are thought to be the result of changes in myocardial gene expression, attention has recently focused on acute, nonnuclear-mediated actions of T3 (see Ref. 16 for review).
Extranuclear effects of thyroid hormone are rapid in onset, are not altered by inhibition of protein synthesis, and are mediated by thyroid hormone binding to plasma membrane receptors (see Refs. 16 and 20 for review). Various lines of evidence have documented that T3 can act as a vasodilator and positive inotrope in vitro (15, 16). The recognition of these effects has resulted in treatment strategies using T3 that target specific clinical conditions associated with impaired cardiovascular performance and low serum T3 concentration, including heart failure, cardiac surgery, and acute myocardial infarction (8, 11, 16, 35). In clinical as well as experimental trials, improved myocardial recovery in response to acute T3 supplementation has been demonstrated after myocardial ischemia and cardiopulmonary bypass (13, 28, 35). The mechanisms responsible for the cardioprotective effects of T3 have yet to be defined.
In most clinical situations of reperfusion after ischemia,
heart muscle is exposed to high levels of fatty acids (see Ref. 21 for
review). When hearts are aerobically reperfused after ischemia,
glucose oxidation is suppressed because of high rates of fatty acid
-oxidation. This results in a marked imbalance between rates of
glycolysis and glucose oxidation (19, 22). In severely ischemic
myocardium, production of protons from the hydrolysis of glycolytically
derived ATP is a major contributor to acidosis (9, 29). Clearance of
H+ via the
Na+/H+
exchanger in aerobically perfused hearts subjected to an intracellular acid load leads to a significant decrease in cardiac efficiency (14,
20). This is due to the exchange of
H+ with extracellular
Na+ via the
Na+/H+
exchanger. The intracellular Na+
can then decrease the efflux of
Ca2+ via the
Na+/Ca2+
exchanger during reperfusion, resulting in
Ca2+ overload and cell death. Our
previous studies have shown that reducing the source of protons by
stimulation of glucose oxidation or inhibition of excessive rates of
glycolysis improves cardiac efficiency (2, 10, 20, 26). As a result,
modifying glucose metabolism is one potential mechanism by which
T3 could potentially exert its
cardioprotective effects. Previous studies have suggested that
T3 can modify both glycolysis and
glucose oxidation in the heart (3, 32). Whether the cardioprotective
effects of T3 are attributable to
changes in glucose metabolism or a switch in energy substrate
preference has not been determined.
In this study we determined whether acute T3 treatment could improve mechanical function and cardiac efficiency during reperfusion of ischemic hearts by modulation of glucose metabolism. Isolated working rat hearts perfused with high levels of fatty acids were subjected to a 30-min period of global no-flow ischemia, followed by 40 min of aerobic reperfusion. The effects of T3 on the recovery of cardiac work, O2 consumption, glycolysis, and oxidative metabolism of glucose and fatty acid were measured. Our results demonstrate that by reducing the production of H+ from glucose metabolism, T3 significantly improves the recovery of mechanical function and cardiac efficiency in the postischemic heart.
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MATERIALS AND METHODS |
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Heart perfusions. Rat hearts were cannulated for isolated working heart perfusions as described previously (22). Briefly, male Sprague-Dawley rats (250-300 g) were anesthetized with pentobarbital sodium (60 mg/kg ip), and hearts were quickly excised, the aorta was cannulated, and a retrograde perfusion at 37°C was initiated at a hydrostatic pressure of 60 mmHg. Hearts were trimmed of excess tissue, and the pulmonary artery and the opening to the left atrium were then cannulated. After 15 min of Langendorff perfusion, hearts were switched to the working mode by clamping the aortic inflow line from the Langendorff reservoir and opening the left atrial inflow line. The perfusate was delivered from an oxygenator into the left atrium at a constant preload pressure of 11.5 mmHg. Perfusate was ejected from spontaneously beating hearts into a compliance chamber (containing 1 ml of air) and into the aortic outflow line. The afterload was set at a hydrostatic pressure of 80 mmHg. All working hearts were perfused with Krebs-Henseleit solution containing 2.5 mM free Ca2+, 5.5 mM glucose, and 1.2 mM palmitate prebound to 3% bovine serum albumin (fraction V, Boehringer Mannheim).
Spontaneously beating hearts were used in all studies. Heart rate and aortic pressure were measured with a Gould P21 pressure transducer connected to the aortic outflow line. Cardiac output and aortic flow were measured with Transonic T206 ultrasonic flow probes in the preload and afterload lines, respectively. Coronary flow was calculated as the difference between cardiac output and aortic flow. The O2 contents of the perfusate entering and leaving the heart were measured using Yellow Springs Instrument micro oxygen electrodes placed in the preload and pulmonary arterial lines, respectively. Myocardial O2 consumption (MExperimental protocol. Working hearts were initially perfused for a 30-min period under aerobic conditions. Global no-flow ischemia was then introduced by clamping both the left atrial inflow and aortic outflow lines. After 30 min of no-flow ischemia, the left atrial and aortic flows were restored and the hearts were reperfused for a further 40-min period under aerobic conditions. T3 (Sigma) was added at the onset of the 30-min aerobic working heart perfusion at a final concentration of 10 nM. T3 was diluted in 1 N NaOH immediately before use, and the same amount of NaOH was added to the control group.
At the end of reperfusion, hearts were quickly frozen with Wollenberger clamps cooled to the temperature of liquid N2. The atrial tissue was dried in an oven for 12 h at 100°C and weighed. The frozen ventricular tissue was weighed and powdered in a mortar and pestle cooled to the temperature of liquid N2. A portion of the powdered tissue was used to determine the dry weight-to-wet weight ratio. The dried atrial weight, frozen ventricular weight, and ventricular dry weight-to-wet weight ratio were then used to determine the total dry weight of the heart.Measurement of glycolysis, glucose oxidation, and palmitate
oxidation.
Glycolysis and glucose oxidation were measured simultaneously by
perfusing hearts with
[5-3H/U-14C]glucose
(22). Fatty acid oxidation rates were measured with perfusate
containing
[1-14C]palmitate (19).
Total myocardial
3H2O
production and
14CO2
production were determined at 10-min intervals during both the initial
aerobic perfusion period and the 40-min period of reperfusion. To
measure the rates of glycolysis,
3H2O
in perfusate samples was separated from
[3H]glucose and
[14C]glucose with
Dowex columns (22). Fatty acid and glucose oxidation rates were
determined by quantitative measurement of
14CO2
production, including
14CO2
released as a gas in the oxygenation chamber and
14CO2
dissolved as HCO3 in perfusate. The
gaseous 14CO2
was trapped in hyamine hydroxide solution through an exhaust line in
the perfusion system. The
14CO2
dissolved as HCO
3 was released and
trapped on filter paper saturated with hyamine hydroxide in the central well of 25-ml stoppered flasks after perfusate samples had been acidified by the addition of 9 N
H2SO4.
Measurement of pyruvate dehydrogenase activity. Frozen powdered ventricular tissue was divided into two samples (of ~30 mg/sample). One sample was used to determine the active state of pyruvate dehydrogenase (PDHa); the other sample was used for determination of the total activity of PDH (PDHt). Tissues were homogenized and used to measure the rate of acetyl-CoA formation from pyruvate, as described by Constantin-Teodosiu et al. (6). The acetyl-CoA was determined as [14C]citrate after condensation with [14C]oxalacetate by citrate synthase (6). PDHa was measured in homogenates containing NaF and dichloroacetate, and PDHt was measured after preincubation of homogenates with Ca2+, Mg2+, dichloroacetate, glucose, and hexokinase (to completely dephosphorylate PDH) (6, 7).
Calculation of H+ production from glucose utilization. If glucose passes through glycolysis to lactate and the ATP so formed is hydrolyzed, a net production of 2 H+ per molecule of glucose occurs (20, 22). In contrast, if glycolysis is coupled to glucose oxidation, the net production of H+ is zero. Therefore, the overall rate of H+ production derived from glucose utilization was determined by subtracting the rate of glucose oxidation from the rate of glycolysis and multiplying by two.
Calculation of tricarboxylic acid cycle rates. The rate of acetyl-CoA production for the tricarboxylic acid (TCA) cycle was calculated on the basis of 2 and 8 mol of acetyl-CoA being produced from glucose and palmitate oxidation, respectively (19, 20).
Statistical analysis. All data are presented as the means ± SE. Data were intially analyzed with the statistical program Instat 2.01 with the Student's t-test. When data sets were unevenly distributed, the Mann-Whitney and Wilcoxon nonparametric tests were used to determine the difference between preischemic and postischemic values (when used, this is indicated in the individual tables). Two-way ANOVA was used to compare the preischemic and postischemic values among groups.
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RESULTS |
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Effects of T3 on cardiac mechanical
function of isolated working hearts subjected to 30 min of global
no-flow ischemia.
Figure
1A shows
the effects of treatment with 10 nM
T3 on the recovery of cardiac work
in hearts subjected to 30 min of global ischemia. After severe
ischemia, the recovery of cardiac work was depressed in control
hearts, returning to only 11% of preischemic values after 40 min of
reperfusion. During reperfusion, heart rate, systolic pressure,
developed pressure, cardiac output, and coronary flow were all
significantly depressed compared with preischemic values.
MO2 in control hearts
recovered to a greater extent during reperfusion than did cardiac work
(Fig. 1B), resulting in a
significant decrease in cardiac efficiency throughout the entire 40-min
reperfusion period (Fig. 1C).
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Effects of T3 on glycolysis, glucose oxidation, and palmitate oxidation during reperfusion of hearts after ischemia. Figure 2 shows cumulative glycolysis (A), glucose oxidation (B), and palmitate oxidation (C). T3 did not have any significant effects on glycolysis (Fig. 2A) and palmitate oxidation (Fig. 2C) but did result in a significant increase in glucose oxidation during the reperfusion period (Fig. 2B). PDH activity (the rate-limiting enzyme for glucose oxidation) was also measured in hearts frozen at the end of the reperfusion period. T3 treatment significantly stimulated PDHa activity without affecting PDHt in postischemic hearts (Table 2). Although T3 treatment stimulated glucose oxidation in the reperfusion period, no effect of T3 on glucose oxidation was observed during the initial aerobic perfusion.
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Effects of T3 on H+ production from glucose metabolism. Figure 3 shows the cumulative H+ production from glucose metabolism during reperfusion of ischemic hearts, calculated from rates of glycolysis and glucose oxidation presented in Fig. 2. Over the course of the 40 min of reperfusion, more than 200 µmol/g dry wt of H+ was produced from glucose metabolism in control hearts. A significant decrease in H+ production was seen in T3-treated hearts compared with control hearts. Steady-state H+ production in aerobic and reperfused ischemic hearts is shown in Table 3. By selectively increasing glucose oxidation rates, T3 improved the coupling between glycolysis and glucose oxidation, resulting in a significant decrease in H+ production during reperfusion.
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Effects of T3 on rates of TCA cycle activity. To investigate TCA cycle activity during reperfusion, the rate of acetyl-CoA production from glucose oxidation and palmitate oxidation was calculated. As shown in Table 4, the total rate of TCA acetyl-CoA production in control hearts was significantly decreased during reperfusion compared with the preischemic value. This was consistent with the poor recovery of cardiac work. Treatment with T3 did not alter overall acetyl-CoA production from glucose and palmitate oxidation. However, during reperfusion, T3 increased acetyl-CoA production from glucose.
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DISCUSSION |
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Acute treatment with physiological or supraphysiological concentrations of T3 has been shown to have cardioprotective actions in experimental models of ischemia and reperfusion, as well as in the rescue of myocardial function after human cardiopulmonary bypass operations (13, 17, 28, 35). Our data also show that acute T3 can significantly improve the recovery of contractile function of isolated rat hearts subjected to a severe episode of no-flow ischemia. These effects of T3 were associated with an improvement in the coupling of glycolysis to glucose oxidation, thereby decreasing H+ production and increasing cardiac efficiency during reperfusion of the postischemic heart.
T3 effects on cardiac energy metabolism. Few studies have determined directly the effects of acute T3 treatment on energy metabolism in the heart. A study by Segal (32) showed that physiological concentrations of T3 (1 pM to 10 nM) significantly stimulate 2-deoxyglucose uptake in rat heart slices after as little as 10 min posttreatment. However, in both aerobic and postischemic hearts, we observed that T3 treatment was not associated with any significant effects on glycolysis. Therefore, we suggest that the cardioprotective effects of T3 are not associated with an increase in glucose uptake and metabolism by glycolysis. Possible reasons for the differences between our study and that performed in rat heart slices are that 1) relevant levels of fatty acids were present in our perfusate and not in the rat heart slice studies, and 2) hearts in our study were subjected to physiological workloads. Because circulating fatty acid levels are elevated both during and after clinically relevant conditions of ischemia, and because fatty acids have dramatic effects on glucose metabolism, we felt it necessary to perform our studies in the presence of high levels of fatty acids. In addition, because rates of glucose metabolism are related to workload, all experiments were performed in hearts perfused in the working mode.
Our data show that the primary effect of T3 on myocardial glucose metabolism is a stimulation of glucose oxidation during reperfusion. A previous study using rat cardiac myocytes also suggested that acute treatment of T3 directly stimulates glucose oxidation (3). The effects of T3 on glucose oxidation are unlikely to be due to a generalized increase in oxidative metabolism, because the increase in glucose oxidation seen in T3-treated hearts was not accompanied by an increase in fatty acid oxidation. Of interest is that the effects of T3 on glucose oxidation were observed only during reperfusion of ischemic hearts and not under aerobic preischemic conditions. T3 treatment significantly increased nonphosphorylated PDHa activity in postischemic hearts. Because PDHa plays an important role in regulation of glucose oxidation (4), our data strongly suggest that T3 stimulates glucose oxidation and improves coupling of glycolysis to glucose oxidation secondary to a stimulation of PDHa activity. In rat hearts, ischemia or reperfusion has previously been shown to lead to an inactivation of PDHa under conditions similar to those used in the present study (18, 31). Ischemia is likely to increase intramitochondrial NADH/NAD+ and acetyl-CoA/CoA ratios, which would lead to inactivation of PDH; however, the reduced ATP/ADP would balance this to some extent by favoring activation (18). It has been reported that acute T3 treatment can reduce intramitochondrial ATP/ADP (33, 34), which may contribute to the observed activation of PDHa. However, the detailed mechanism of how T3 regulates PDH activity is still unclear. Future studies are needed to clarify whether acute T3 treatment has any effect on PDH kinase or phosphatase, both of which also play an important role in regulating PDH activity (6, 7). PDH activity has also been shown to be stimulated by hyperthyroidism (30), although this is probably due to transcriptional regulation. Because acute treatment of T3 is unlikely to upregulate protein synthesis, and PDHt was not altered, the observed effects of T3 on PDHa in our study were likely the result of changes in the phosphorylated state of PDH.Recovery of contractile function, energy metabolism, and cardiac efficiency in the postischemic heart. During reperfusion of the severely ischemic control hearts, a significant decrease in the recovery of cardiac function occurred that was associated with a decrease in cardiac efficiency (Fig. 1). This decrease in cardiac efficiency has also been observed in previous studies (19, 20). However, unlike these previous studies, we did not observe a complete recovery of fatty acid oxidation in control hearts during reperfusion. This difference in the recovery of fatty acid oxidation may be related to the severity of ischemic injury observed in the present study. As shown in Fig. 1, cardiac work recovered to 11% of preischemic rates in control hearts compared with 30-40% in our previous studies (19, 20). However, it should be recognized that, despite this poor recovery of cardiac work, fatty acid oxidation in control hearts recovered to >50% of preischemic levels, resulting in a marked increase in fatty acid oxidation per unit work, a finding consistent with our previous studies. Regardless of the degree of recovery of fatty acid oxidation in this study, our data suggest that the beneficial effects of T3 are unlikely to be due to any direct effects on fatty acid oxidation.
It is well-known that long-term hyperthyroidism is associated with high levels of MCoupling of glycolysis to glucose oxidation in the postischemic heart. The production of H+ from glucose metabolism is an important contributor to the impaired recovery of mechanism function and to the decrease in cardiac efficiency seen after a severe ischemic episode (19, 20, 22). During reperfusion, treatment with T3 dramatically stimulated glucose oxidation, with no effect on glycolysis. Each molecule of glucose that passes through glycolysis that is not subsequently oxidized results in the production of 2 H+ from the hydrolysis of glycolytically derived ATP (19, 20). In the presence of high levels of fatty acids, glucose oxidation rates are 5-fold to 10-fold lower than glycolytic rates (19, 22, 23). Selective stimulation of glucose oxidation improves the coupling of glycolysis to glucose oxidation, leading to a reduction in H+ production. We have suggested that an increase in H+ accumulation during the critical period of reperfusion may contribute to cardiac inefficiency (21) and the well-documented Ca2+ overload in the postischemic heart that results from an increase in Na+/H+ exchange activity coupled with Na+/Ca2+ exchange (14). Because T3 reduced the H+ production from glucose utilization during reperfusion, the driving force for the Na+/H+ exchange is decreased, and Na+/Ca2+ exchange activity would thus be expected to be reduced during reperfusion. Decreased activity of this exchanger may be responsible for the significant improvement in cardiac efficiency observed during reperfusion.
A number of other pharmacological agents also stimulate glucose oxidation and have a beneficial effect on the recovery of mechanical function during reperfusion of the postischemic heart (2, 23). One of these agents is dichloroacetate, a potent PDH activator that also improves the coupling between glycolysis and glucose oxidation. This also results in a significant decrease in H+ production from glucose metabolism during reperfusion, resulting in a significant increase in cardiac efficiency.Summary. We demonstrate a significant improvement of recovery in postischemic cardiac function and efficiency in isolated rat hearts by use of moderately supraphysiological amounts of T3. The cardioprotective effect of T3 may be due to its stimulation of glucose oxidation secondary to an increase in PDHa activity, and therefore a reduction in the production of H+ by coupling glycolysis with glucose oxidation.
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ACKNOWLEDGEMENTS |
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This study was supported by a grant from the Medical Research Council (MRC) of Canada. G. D. Lopaschuk is an MRC of Canada Scientist and an Alberta Heritage Foundation for Medical Research Senior Scholar. Q. Liu is an MRC of Canada Graduate Student.
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FOOTNOTES |
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Address for reprint requests: G. D. Lopaschuk, 423 Heritage Medical Research Bldg., The Univ. of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Received 31 December 1997; accepted in final form 12 May 1998.
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REFERENCES |
---|
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---|
1.
Brand, M. D.,
L. F. Chien,
G. K. Ainscon,
D. F. S. Rolfe,
and
R. K. Porter.
The cause and function of mitochondrial proton leak.
Biochim. Biophys. Acta
1187:
132-139,
1994[Medline].
2.
Broderick, T. L.,
H. A. Quinney,
C. C. Barker,
and
G. D. Lopaschuk.
Beneficial effect of carnitine on mechanical recovery of rat hearts reperfused after a transient period of global ischemia is accompanied by a stimulation of glucose oxidation.
Circulation
87:
972-981,
1993[Abstract].
3.
Burns, A. H.,
and
W. J. Reddy.
Direct effects of thyroid hormones on glucose oxidation by isolated rat cardiac myocytes.
J. Mol. Cell. Cardiol.
7:
553-561,
1975[Medline].
4.
Clarke, B.,
M. Spedding,
L. Patmore,
and
J. G. McCormack.
Protective effects of ranolazine in guinea-pig hearts during low-flow ischemia and their association with increases in active pyruvate dehydrogenase.
Br. J. Pharmacol.
109:
748-750,
1993[Abstract].
5.
Collins-Nakai, R. L.,
D. Noseworthy,
and
G. D. Lopaschuk.
Epinephrine increases ATP production in hearts by preferentially increasing glucose metabolism.
Am. J. Physiol.
267 (Heart Circ. Physiol. 36):
H1862-H1871,
1994
6.
Constantin-Teodosiu, D.,
G. Cederblad,
and
E. Hultman.
A sensitive radioisotopic assay of pyruvate dehydrogenase complex in human muscle tissue.
Anal. Biochem.
198:
347-351,
1991[Medline].
7.
Constantin-Teodosiu, D.,
G. Cederblad,
and
E. Hultman.
PDC activity and acetyl group accumulation in skeletal muscle during prolonged exercise.
J. Appl. Physiol.
73:
2403-2407,
1992
8.
Davis, P. J.,
and
F. B. Davis.
Acute cellular actions of thyroid hormone and myocardial function.
Ann. Thorac. Surg.
56:
S16-S23,
1993[Medline].
9.
Dennis, S. C.,
W. Gevers,
and
L. H. Opie.
Protons in ischemia: where do they come from; where do they go to?
J. Mol. Cell. Cardiol.
23:
1077-1086,
1991[Medline].
10.
Finegan, B. A.,
G. D. Lopaschuk,
S. C. Coulson,
and
A. S. Clanachan.
Adenosine alters glucose use during ischemia and reperfusion in isolated rat hearts.
Circulation
87:
900-908,
1993[Abstract].
11.
Hamilton, M. A.
Prevalence and clinical implication of abnormal thyroid hormone metabolism in advanced heart failure.
Ann. Thorac. Surg.
56:
S48-S53,
1993[Medline].
12.
Hardy, D. L.,
and
J. Mowbray.
Direct thyroid hormone signalling via ADP-ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter.
FEBS Lett.
394:
61-65,
1996[Medline].
13.
Kadletz, M.,
P. G. Mullen,
M. Ding,
L. G. Wolf,
and
A. S. Wechsler.
Effect of triiodothyronine on postischemic myocardial function in the isolated heart.
Ann. Thorac. Surg.
57:
657-662,
1994[Abstract].
14.
Karmazyn, M.,
and
M. P. Moffat.
Role of Na+/H+ exchange in cardiac ischemia and reperfusion injury by the pH paradox.
Cardiovasc. Res.
27:
915-924,
1993[Medline].
15.
Klein, I.
Thyroid hormone and the cardiovascular system.
Am. J. Med.
88:
631-637,
1990[Medline].
16.
Klemperer, J. D.,
K. Ojamaa,
and
I. Klein.
Thyroid hormone therapy in cardiovascular disease.
Prog. Cardiovasc. Dis.
4:
329-336,
1996.
17.
Klemperer, J. D.,
J. Zelano,
R. E. Helm,
K. Berman,
K. Ojamaa,
I. Klein,
O. W. Isom,
and
K. Krieger.
Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia.
J. Thorac. Cardiovasc. Surg.
109:
457-465,
1995
18.
Kobayashi, K.,
and
J. R. Neely.
Effects of ischemia and reperfusion on pyruvate dehydrogenase activity in isolated rat hearts.
J. Mol. Cell. Cardiol.
15:
359-367,
1983[Medline].
19.
Liu, B.,
Z. Alaoui-Talibi,
A. S. Clanachan,
R. Schulz,
and
G. D. Lopaschuk.
Uncoupling of contractile function from mitochondrial TCA cycle activity and MO2 during reperfusion of ischemic hearts.
Am. J. Physiol.
270 (Heart Circ. Physiol. 39):
H72-H80,
1996
20.
Liu, B.,
A. S. Clanachan,
R. Schulz,
and
G. D. Lopaschuk.
Cardiac efficiency is improved after ischemia by altering both the source and fate of protons.
Circ. Res.
79:
940-948,
1996
21.
Lopaschuk, G. D.,
D. D. Belke,
J. Gamble,
I. Itoi,
and
B. O. Schonekess.
Regulation of fatty acid oxidation in the mammalian heart in health and disease.
Biochim. Biophys. Acta
1213:
263-276,
1994[Medline].
22.
Lopaschuk, G. D.,
R. B. Wambolt,
and
R. L. Barr.
An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts.
J. Pharmacol. Exp. Ther.
264:
135-144,
1993[Abstract].
23.
McCormack, J. G.,
R. L. Barr,
A. A. Wolff,
and
G. D. Lopaschuk.
Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts.
Circulation
93:
135-142,
1996
24.
Meng, H.-P.,
T. G. Maddaford,
and
G. N. Pierce.
Effect of amiloride and selected analogues on postischemic recovery of cardiac contractile function.
Am. J. Physiol.
264 (Heart Circ. Physiol. 33):
H1831-H1835,
1993
25.
Moller, N.,
S. Nielsen,
B. Nyholm,
N. Porksen,
K. G. Alberti,
and
J. Weeke.
Glucose turnover, fuel oxidation and forearm substrate exchange in patients with thyrotoxicosis before and after medical treatment.
Clin. Endocrinol.
4:
453-459,
1996.
26.
Neely, J. R.,
and
H. E. Morgan.
Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle.
Annu. Rev. Physiol.
36:
413-459,
1974.
27.
Nelson, B. D.
Thyroid hormone regulation of mitochondrial function. Comments on the mechanism of signal transduction.
Biochim. Biophys. Acta
1018:
275-277,
1990[Medline].
28.
Novitzky, D.,
P. A. Human,
and
D. K. C. Cooper.
Inotropic effect of triiodothyronine following myocardial ischemia and cardiopulmonary bypass: an experimental study in pigs.
Ann. Thorac. Surg.
45:
50-55,
1988[Abstract].
29.
Opie, L. H.
Myocardial ischemiametabolic pathways and implications of increased glycolysis.
Cardiovasc. Drugs Ther.
4:
777-790,
1990[Medline].
30.
Orfali, K. A.,
G. D. L. Fryer,
M. J. Holness,
and
M. C. Sugden.
Interactive effects of insulin and triiodothyronine on pyruvate dehydrogenase kinase activity in cardiac myocytes.
J. Mol. Cell. Cardiol.
27:
901-908,
1995[Medline].
31.
Patel, T. B.,
and
M. S. Olson.
Regulation of pyruvate dehydrogenase complex in ischemic rat heart.
Am. J. Physiol.
246 (Heart Circ. Physiol. 15):
H858-H864,
1984[Medline].
32.
Segal, J.
Acute effect of thyroid hormone on the heart: an extranuclear increase in sugar uptake.
J. Mol. Cell. Cardiol.
21:
323-334,
1989[Medline].
33.
Seitz, H. J.,
M. J. Muller,
and
S. Soboll.
Rapid thyroid-hormone effect on mitochondrial and cytosolic ATP/ADP ratios in the intact liver cell.
Biochem. J.
227:
149-153,
1985[Medline].
34.
Siess, E. A.,
and
O. H. Wieland.
Regulation of pyruvate dehydrogenase interconversion in isolated hepatocytes by the mitochondria ATP/ADP ratio.
FEBS Lett.
52:
226-230,
1975[Medline].
35.
Sinci, V.,
H. Soncul,
S. Gunaydin,
V. Halit,
L. Gokgoz,
O. Tatlican,
A. Yener,
A. Bilgehan,
and
A. Ersoz.
The effects of thyroid hormones on the heart following global ischemia: a clinical and experimental study.
Jpn. Heart J.
35:
443-454,
1994[Medline].
36.
Sterling, K.
Direct thyroid hormone activation of mitochondria: identification of adenine nucleotide translocase (AdNT) as the hormone receptor.
Transaction Assoc. Am. Physicians
100:
284-293,
1987.
37.
Sterling, K.
Direct triiodothyronine (T3) action by a primary mitochondrial pathway.
Endocr. Res.
15:
683-715,
1989[Medline].
38.
Sterling, K.,
and
M. A. Brenner.
Thyroid hormone action: effect of triiodothyronine on mitochondrial adenine nucleotide translocase in vivo and in vitro.
Metabolism
44:
193-199,
1995[Medline].
39.
Sugden, M. C.,
M. J. Holness,
Y. L. Liu,
D. M. Smith,
L. G. Fryer,
and
Y. T. Krusznska.
Mechanisms regulating cardiac fuel selection in hyperthyroidism.
Biochem. J.
286:
513-517,
1992[Medline].
40.
Walker, J. D.,
F. A. Crawford,
and
F. G. Spinale.
Pretreatment with 3,5,3'-triiodo-L-thyronine (T3): effects on myocyte contractile function after hypothermic cardioplegic arrest and rewarming.
J. Thorac. Cardiovasc. Surg.
110:
315-327,
1995