Glycolysis is predominant source of myocardial ATP production immediately after birth

1991 ◽  
Vol 261 (6) ◽  
pp. H1698-H1705 ◽  
Author(s):  
G. D. Lopaschuk ◽  
M. A. Spafford ◽  
D. R. Marsh
Keyword(s):  
Steady State ◽  
Fatty Acid ◽  
Glucose Oxidation ◽  
Glycolytic Flux ◽  
Lactate Oxidation ◽  
Atp Production ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
14Co2 Production ◽  
Pulmonary Arterial

Glycolytic flux, as well as glucose, fatty acid, and lactate oxidation, was determined in isolated working hearts obtained from 1- and 7-day-old rabbits. One-day-old rabbit hearts were perfused via the inferior cava against a constant aortic and pulmonary arterial afterload, whereas hearts from 7-day-old rabbits were perfused via the left atria against a constant aortic afterload. Hearts were perfused with buffer containing 100 microU/ml insulin and either 1) 11 mM [U-14C/2-3H]glucose, 0.4 mM palmitate, 2 mM lactate; 2) 11 mM glucose, 0.4 mM [1-14C]palmitate, 2 mM lactate; or 3) 11 mM glucose, 0.4 mM palmitate, 2 mM [U-14C]lactate. Glycolytic rates (measured as 3H2O production) were high in 1-day-old hearts but decreased by 7 days (from 2,730 +/- 280 to 580 +/- 80 nmol.min-1.g dry wt-1). Rates of glucose oxidation (measured as 14CO2 production) were lower in both 1- and 7-day-old hearts (59 +/- 4.4 and 23 +/- 2 nmol.min-1.g dry wt-1). Palmitate oxidation rates were low in 1-day-old hearts but dramatically increased by 7 days (22.6 +/- 5.6 and 305 +/- 33 nmol oxidized.min-1.g dry wt-1, respectively). In contrast, lactate was readily oxidized by both 1- and 7-day-old hearts (169 +/- 14 and 456 +/- 52 nmol.min-1.g dry wt-1, respectively). In 1-day-old hearts, 44% of steady-state ATP production from exogenous sources were derived from glycolysis, whereas 18, 13, and 25% were derived from glucose, palmitate, and lactate oxidation, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium regulation of glycolysis, glucose oxidation and fatty acid oxidation in the aerobic and ischemic heart

1995 ◽  
Vol 73 (11) ◽  
pp. 1632-1640 ◽  
Author(s):  
Brett Schönekess ◽  
Peter G. Brindley ◽  
Gary O. Lopaschuk
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Glucose Oxidation ◽  
Pyruvate Dehydrogenase Complex ◽  
Dry Weight ◽  
Low Flow ◽  
Acid Oxidation ◽  
Atp Production ◽  
Palmitate Oxidation ◽  
Oxidation Rates

Although Ca2+is an important regulator of energy metabolism, the effects of increasing extracellular [Ca2+] on energy substrate preference are not clear. We determined the relationship between [Ca2+], fatty acids, and ischemia on rates of glycolysis, glucose oxidation, and palmitate oxidation in isolated working rat hearts. Hearts were perfused with Krebs–Henseleit buffer containing 11 mM glucose, 100 μU/mL insulin, and either 1.25 or 2.5 mM Ca2+, in the presence or absence of 1.2 mM palmitate. Rates of glycolysis and glucose oxidation or palmitate oxidation were measured in the hearts using [5-3H,14C(U)]glucose or [1-14C]palmitate, respectively. In the absence of fatty acids, glycolysis and glucose oxidation rates were similar, regardless of whether [Ca2+] was 1.25 or 2.5 mM. Addition of 1.2 mM palmitate to the perfusate of hearts perfused with 1.25 mM Ca2+significantly decreased rates of both glycolysis (from 4623 ± 438 to 1378 ± 238 nmol∙min−1∙g−1dry weight) and glucose oxidation (from 1392 ± 219 to 114 ± 22 nmol∙min−1∙g−1dry weight). When [Ca2+] was increased from 1.25 to 2.5 mM in hearts perfused with 1.2 mM palmitate, glycolysis and glucose oxidation increased by 164 and 271%, respectively, with no change in palmitate oxidation rates. Increasing [Ca2+] from 1.25 to 2.5 mM increased the contribution of glucose to ATP production from 9.3 to 18.7%. When hearts were subjected to low-flow ischemia (by reducing coronary flow to 0.5 mL∙min−1) oxidative metabolism was essentially abolished. Under these conditions, glycolytic rates were not dependent on either [Ca2+] or the presence or absence of fatty acids. These results demonstrate that perfusate [Ca2+] is an important determinant of myocardial glucose metabolism in aerobic hearts, and that glycolysis and glucose oxidation are more responsive to changes in [Ca2+] than is fatty acid oxidation.Key words: β-oxidation, glucose oxidation, pyruvate dehydrogenase complex.

Adenosine modification of energy substrate use in isolated hearts perfused with fatty acids

1992 ◽  
Vol 262 (5) ◽  
pp. H1501-H1507 ◽  
Author(s):  
B. A. Finegan ◽  
A. S. Clanachan ◽  
C. S. Coulson ◽  
G. D. Lopaschuk
Keyword(s):  
Steady State ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Isolated Hearts ◽  
Oxidation Rates ◽  
Rat Hearts ◽  
Myocardial Substrate ◽  
14Co2 Production ◽  
Oxidation Ratio

The objective of this study was to determine the effect of adenosine on overall myocardial substrate utilization and mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer containing 11 mM glucose (no fat) or with 11 mM glucose and 0.4 mM palmitate (normal fat). Steady-state rates of glycolysis, glucose oxidation, and fatty acid oxidation were measured by determination of quantitative 3H2O and 14CO2 production from radiolabeled substrates. The ratio of glycolysis (6.07 +/- 0.57 mumol.min-1.g dry wt-1) to glucose oxidation (3.12 +/- 0.28 mumol.min-1.g dry wt-1) under no fat conditions was 2:1. The addition of palmitate per se decreased glucose oxidation (to 0.81 +/- 0.09 mumol.min-1.g dry wt-1) and increased the glycolysis-to-glucose oxidation ratio to 6:1. Adenosine (100 microM) reduced this ratio to 3:1 by decreasing glycolysis (to 3.75 +/- 0.32 mumol.min-1.g dry wt-1) and increasing glucose oxidation (to 1.28 +/- 0.18 mumol.min-1.g dry wt-1) in the presence of palmitate. Steady-state palmitate oxidation rates were not altered by adenosine. Adenosine increased efficiency (work performed per unit O2 consumed) of spontaneously beating hearts but had no effect in paced hearts. These effects of adenosine on glucose metabolism may explain the beneficial actions of adenosine during reperfusion post ischemia.

Triacylglycerol turnover in isolated working hearts of acutely diabetic rats

1994 ◽  
Vol 72 (10) ◽  
pp. 1110-1119 ◽  
Author(s):  
Maruf Saddik ◽  
Gary D. Lopaschuk
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Acid Oxidation ◽  
Atp Production ◽  
Oxidation Rates ◽  
Rat Hearts

Although myocardial triacylglycerol may be a potentially important source of fatty acids for β-oxidation in diabetes, few studies have measured triacylglycerol turnover directly in hearts from diabetic animals. In this study, myocardial triacylglycerol turnover was directly measured in isolated working hearts from streptozotocin-induced acutely diabetic rats. Hearts were initially perfused in the presence of 1.2 mM [14C]palmitate and 11 mM glucose for 1 h (pulse) to label the endogenous lipid pools, followed by a 10-min washout perfusion. Hearts were then perfused for another hour (chase) with buffer containing 11 mM glucose ± 1.2 mM [3H]palmitate. During the chase, both 14CO2 and 3H2O production (measures of endogenous and exogenous fatty acid oxidation, respectively) were determined. A second series of hearts were perfused using the same protocol, except that unlabeled palmitate was used during the pulse and 11 mM [14C(U),5-3H]glucose ± unlabeled palmitate was present during the chase. Both glycolysis (3H2O production) and glucose oxidation (14CO2 production) rates were measured in this series. Myocardial triacylglycerol levels were significantly higher in the diabetic rat hearts (77.5 ± 4.6 vs. 33.7 ± 4.1 μmol fatty acid/g dry mass in control hearts). In diabetic rat hearts chased with 1.2 mM palmitate, triacylglycerol lipolysis was increased, although endogenous [14C]palmitate oxidation rates were similar to control hearts and contributed 10.1% of overall ATP production. The majority of fatty acids derived from triacylglycerol lipolysis were released into the perfusate. In the absence of palmitate, both triacylglycerol lipolysis and endogenous [14C]palmitate oxidation rates were significantly increased in diabetic rat hearts, compared with control. Under these conditions, triacylglycerol fatty acid oxidation contributed 70% of steady-state ATP production in diabetic rat hearts, compared with 34% in control hearts. These results demonstrate that in diabetic rat hearts myocardial triacylglycerol lipolysis is significantly increased and can readily be used as a source of fatty acids for mitochondrial β-oxidation.Key words: heart, triacylglycerols, fatty acid oxidation, glucose oxidation, glycolysis.

Control of oxidative metabolism in volume-overloaded rat hearts: effect of propionyl-L-carnitine

1997 ◽  
Vol 272 (4) ◽  
pp. H1615-H1624 ◽  
Author(s):  
Z. El Alaoui-Talibi ◽  
A. Guendouz ◽  
M. Moravec ◽  
J. Moravec
Keyword(s):  
Steady State ◽  
Mechanical Performance ◽  
Mechanical Activity ◽  
Energy Turnover ◽  
Acetyl Coa ◽  
Experimental Conditions ◽  
Atp Production ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Rat Hearts

The objective of the present work was the assessment of metabolic events responsible for the improvement of hemodynamic function of volume-overloaded hearts from rats receiving propionyl-L-carnitine. A severe cardiac hypertrophy was induced in 2-mo-old rats by surgical opening of an aortocaval communication. Three months later, during in vitro perfusions with 1.2 mM palmitate, 11 mM glucose, and 10 IU/l insulin, the mechanical performance and overall energy turnover (myocardial O2 consumption) of hypertrophied rat hearts were significantly decreased under conditions of moderate and high workloads. These changes in cardiac energetics paralleled the decrease in total tissue carnitine content and alterations in exogenous palmitate oxidation. The oxidative utilization of glucose was also slightly depressed in volume-overloaded hearts while steady-state glycolysis rates increased, especially in hearts subjected to high mechanical loads. This slowing of metabolic pathways involved in acetyl-CoA generation resulted in decreased NADH availability and in an apparent substrate limitation of oxidative phosphorylation suggested by a failure of cytosolic unbound ADP to drive respiration. Long-term administration of propionyl-L-carnitine normalized the degree of reduction of mitochondrial pyridine nucleotides and improved the kinetics of mitochondrial ATP production in volume-overloaded hearts. The resulting acceleration of energy turnover was essentially related to improved oxidative utilization of glucose, but steady-state palmitate oxidation rates also increased in severely hypertrophied hearts. This concomitant acceleration of glucose and palmitate oxidation may be related to the particular experimental conditions (high exogenous palmitate concentrations, elevated workloads) used in this study. We assume that the increase in intracellular carnitine, together with a stimulation of acetyl-CoA demands related to high workloads, creates conditions that are compatible with the simultaneous relief of pyruvate dehydrogenase and carnitine palmitoyltransferase I. The resulting increase in the rate of steady-state ATP production improves, in turn, the mechanical activity of volume-overloaded hearts.

Energy substrate utilization by isolated working hearts from newborn rabbits

1990 ◽  
Vol 258 (5) ◽  
pp. H1274-H1280 ◽  
Author(s):  
G. D. Lopaschuk ◽  
M. A. Spafford
Keyword(s):  
Fatty Acids ◽  
Vena Cava ◽  
Energy Substrate ◽  
Atp Production ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Pulmonary Arterial ◽  
Working Heart ◽  
Krebs Henseleit Buffer ◽  
Exogenous Substrates

The ability of newborn rabbit hearts to utilize fatty acids as an energy substrate was determined. Isolated working hearts from 1- or 7-day-old rabbits were perfused with Krebs-Henseleit buffer containing either 11 mM glucose or 0.4 mM palmitate as carbon substrates. One-day-old rabbit hearts were perfused at a 11.5-mmHg filling pressure via the inferior vena cava and at a combined aortic and pulmonary arterial hydrostatic afterload of 20 mmHg. In these hearts, addition of insulin was necessary to maintain mechanical function. Function was maintained in the presence of glucose or glucose plus palmitate but not in the presence of palmitate alone. Measurement of glucose and palmitate oxidation rates in hearts perfused with glucose, palmitate, and insulin showed that 57% of ATP production from exogenous substrates was provided by glucose. Substrate use was also measured in 7-day-old rabbit hearts perfused in the Neely working heart mode at a 7.5-mmHg preload and 30-mmHg afterload. In these hearts, function could be maintained in the presence of either glucose alone or palmitate alone. Insulin addition was not necessary to maintain function. Measurement of glucose and palmitate oxidation in 7-day-old rabbit hearts perfused with glucose, palmitate, and insulin showed that only 10% of ATP production from exogenous substrates was provided by glucose. These data demonstrate that between 1 and 7 days of life in the rabbit the heart switches to using predominantly fatty acids as an energy substrate.

Effects of ranolazine on oxidative substrate preference in epitrochlearis muscle

1996 ◽  
Vol 81 (2) ◽  
pp. 905-910 ◽  
Author(s):  
J. G. McCormack ◽  
V. E. Baracos ◽  
R. Barr ◽  
G. D. Lopaschuk
Keyword(s):  
Skeletal Muscle ◽  
Glucose Oxidation ◽  
Amino Acid Mixture ◽  
Substrate Preference ◽  
Acid Mixture ◽  
Lactate Oxidation ◽  
Atp Production ◽  
Palmitate Oxidation ◽  
Antianginal Agent

Ranolazine is an novel investigational antianginal agent that stimulates glucose oxidation in isolated rat hearts. This study determined its effects on metabolic substrate and O2 utilization in an in vitro skeletal muscle preparation, the rat epitrochlearis muscle. Muscles were superfused with Krebs-Henseleit buffer containing 3% albumin, 0.4 mM palmitate, 5.5 mM glucose, 0.5 mM lactate, and a physiological amino acid mixture. Perfusate also contained either 1) [U-14C]glucose for measurement of glucose oxidation or 2) [9,10–3H]palmitate and [U-14C]lactate for measurement of palmitate and lactate oxidation. Addition of ranolazine (10 microM) significantly stimulated glucose oxidation and decreased palmitate oxidation but had no effect on lactate oxidation. Overall, the calculated relative contribution of glucose oxidation to aerobic ATP production increased from 12 to 33%, whereas from palmitate it decreased from 55 to 26%. Ranolazine did not alter tissue malonyl-CoA contents, making it unlikely that the decrease in palmitate oxidation caused by ranolazine is due to a decrease in the activity of acetyl-CoA carboxylase. These data demonstrate that ranolazine can shift energy substrate preference in skeletal muscle, which could potentially prove useful in ischemic disorders of skeletal muscle.

Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts

1994 ◽  
Vol 267 (2) ◽  
pp. H742-H750 ◽  
Author(s):  
M. F. Allard ◽  
B. O. Schonekess ◽  
S. L. Henning ◽  
D. R. English ◽  
G. D. Lopaschuk
Keyword(s):  
Oxidative Metabolism ◽  
Work Conditions ◽  
Primary Energy ◽  
Acid Oxidation ◽  
Lactate Oxidation ◽  
Atp Production ◽  
Palmitate Oxidation ◽  
Rat Hearts ◽  
14Co2 Production ◽  
And Control

The contribution of glycolysis and oxidative metabolism to ATP production was determined in isolated working hypertrophied hearts perfused with Krebs-Henseleit buffer containing 3% albumin, 0.4 mM palmitate, 0.5 mM lactate, and 11 mM glucose. Glycolysis and glucose oxidation were directly measured by perfusing hearts with [5–3H/U-14C]glucose and by measuring 3H2O and 14CO2 production, respectively. Palmitate and lactate oxidation were determined by simultaneous measurement of 3H2O and 14CO2 in hearts perfused with [9,10–3H]palmitate and [U-14C]lactate. At low workloads (60 mmHg aortic after-load), rates of palmitate oxidation were 47% lower in hypertrophied hearts than in control hearts, but palmitate oxidation remained the primary energy source in both groups, accounting for 55 and 69% of total ATP production, respectively. The contribution of glycolysis to ATP production was significantly higher in hypertrophied hearts (19%) than in control hearts (7%), whereas that of glucose and lactate oxidation did not differ between groups. During conditions of high work (120 mmHg aortic afterload), the extra ATP production required for mechanical function was obtained primarily from an increase in the oxidation of glucose and lactate in both groups. The contribution of palmitate oxidation to overall ATP production decreased in hypertrophied and control hearts (to 40 and 55% of overall ATP production, respectively) and was no longer significantly depressed in hypertrophied hearts. Glycolysis, on the other hand, was accelerated in control hearts to rates seen in the hypertrophied hearts. Thus a reduced contribution of fatty acid oxidation to energy production in hypertrophied rat hearts is accompanied by a compensatory increase in glycolysis during low work conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery of glycolysis and oxidative metabolism during postischemic reperfusion of hypertrophied rat hearts

1996 ◽  
Vol 271 (2) ◽  
pp. H798-H805 ◽  
Author(s):  
B. O. Schonekess ◽  
M. F. Allard ◽  
G. D. Lopaschuk
Keyword(s):  
Oxidative Metabolism ◽  
Glucose Oxidation ◽  
Mechanical Function ◽  
Lactate Oxidation ◽  
Atp Production ◽  
Postischemic Reperfusion ◽  
Palmitate Oxidation ◽  
Abdominal Aortic ◽  
Rat Hearts ◽  
And Control

We investigated the source and extent of recovery of ATP production during postischemic reperfusion of isolated working hearts from abdominal aortic-banded rats. Rates of glycolysis, glucose oxidation, lactate oxidation, and palmitate oxidation were measured in hypertrophied and control hearts [perfused with (in mM) 11 glucose, 0.5 lactate, and 1.2 palmitate] during and after 30 min of no-flow ischemia. In the initial aerobic period glycolytic rates were 1.87-fold higher in hypertrophied hearts compared with control hearts (P < 0.05), with rates of carbohydrate and palmitate oxidation being similar. During reperfusion, hypertrophied hearts recovered 40% of preischemic function compared with 71% in control hearts. Rates of glycolysis during reperfusion of hypertrophied hearts remained accelerated compared with control hearts (2.01-fold higher, P < 0.05), whereas oxidative metabolism returned to preischemic values in both groups. The efficiency of converting ATP production into mechanical work decreased to 29% of preischemic values in hypertrophied hearts during the postischemic reperfusion compared with a decrease to only 59% of preischemic values in control hearts. This suggests that the recovery of glycolysis and oxidative metabolism in the hypertrophied heart during postischemic reperfusion is not impaired, but rather the efficiency of converting ATP produced into mechanical function decreases.

Fatty acid metabolism in hearts containing elevated levels of CoA

1986 ◽  
Vol 250 (3) ◽  
pp. H351-H359 ◽  
Author(s):  
G. D. Lopaschuk ◽  
C. A. Hansen ◽  
J. R. Neely
Keyword(s):  
Fatty Acid ◽  
Specific Activity ◽  
Pantothenic Acid ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Triacylglycerol Hydrolysis ◽  
Chain Acyl ◽  
Apparent Decrease ◽  
Apparent Reduction ◽  
14Co2 Production

Palmitate metabolism was determined in isolated perfused hearts containing elevated levels of coenzyme A (CoA). CoA levels were elevated by perfusing hearts with Krebs-Henseleit buffer containing 0.1 mM cysteine, 0.2 mM dithiothreitol, 15 microM pantothenic acid, and no energy substrate. After 45 min, CoA levels had increased from 537 +/- 14 to 818 +/- 44 nmol/g dry wt. When these hearts containing high CoA were subsequently perfused as working hearts with buffer containing 11 mM glucose and 1.2 mM palmitate, long chain acyl CoA levels increased (94 +/- 5-305 +/- 6 nmol/g dry wt). Oxidation of exogenous palmitate (as measured by 14CO2 production from [U-14C]palmitate) was significantly depressed in hearts containing elevated CoA levels. This apparent reduction in fatty acid oxidation was not due to increased glucose or glycogen utilization. When the concentration of palmitate was decreased to 0.4 mM, acyl CoA levels increased much less, and the apparent rate of [14C]palmitate oxidation was unaffected by elevated CoA. Hearts containing high CoA also incorporated [14C]palmitate into triacylglycerols to a greater extent than did control hearts. To determine whether the apparent decrease in exogenous palmitate oxidation resulted from an increased utilization of unlabeled endogenous triacylglycerol fatty acid, [14C]palmitate specific activity was measured in myocardial acylcarnitine. The specific activity of this pool of fatty acid was similar in both control hearts and hearts containing elevated CoA. Thus dilution of the total cellular [14C]acyl carnitine by triacylglycerol hydrolysis was not sufficient to account for the decrease in [U-14C]palmitate oxidation. The possibility that a small pool of rapidly turning over acyl carnitine becomes dilated is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

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