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.

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)

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.

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)

Reduced high-energy phosphate levels in rat hearts. I. Effects of alloxan diabetes

1976 ◽  
Vol 230 (6) ◽  
pp. 1744-1750 ◽  
Author(s):  
TB Allison ◽  
SP Bruttig ◽  
Crass MF ◽  
RS Eliot ◽  
JC Shipp
Keyword(s):  
Oxidative Metabolism ◽  
Oxygen Delivery ◽  
Rat Heart ◽  
High Energy ◽  
Diabetic Rat ◽  
High Energy Phosphate ◽  
Atp Production ◽  
Rat Hearts

Significant alterations in heart carbohydrate and lipid metabolism are present 48 h after intravenous injection of alloxan (60 mg/kg) in rats. It has been suggested that uncoupling of oxidative phosphorylation occurs in the alloxanized rat heart in vivo, whereas normal oxidative metabolism has been demonstrated in alloxan-diabetic rat hearts perfused in vitro under conditions of adequate oxygen delivery. We examined the hypothesis that high-energy phosphate metabolism might be adversely affected in the alloxan-diabetic rat heart in vivo. Phosphocreatine and ATP were reduced by 58 and 45%, respectively (P is less than 0.001). Also, oxygen-dissociation curves were shifted to the left by 4 mmHg, and the rate of oxygen release from blood was reduced by 21% (P is less than 0.01). Insulin administration normalized heart high-energy phosphate compounds. ATP production was accelerated in diabetic hearts perfused in vitro with a well-oxygenated buffer. These studies support the hypothesis that oxidative ATP production in the alloxan-diabetic rat heart is reduced and suggest that decreased oxygen delivery may have a regulatory role in the oxidative metabolism of the diabetic rat heart.

Increased myocardial lactate oxidation in lambs with aortopulmonary shunts at rest and during exercise

1998 ◽  
Vol 275 (5) ◽  
pp. H1503-H1512 ◽  
Author(s):  
Gertie C. M. Beaufort-Krol ◽  
Janny Takens ◽  
Marieke C. Molenkamp ◽  
Gioia B. Smid ◽  
Koos J. Meuzelaar ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Myocardial Hypertrophy ◽  
Conscious State ◽  
Exercise Group ◽  
Lactate Oxidation ◽  
Lactate Release ◽  
Exogenous Glucose ◽  
Lactate Uptake ◽  
And Control ◽  
Myocardial Oxidative Metabolism

Free fatty acids are the major fuels for the myocardium, but during a higher load carbohydrates are preferred. Previously, we demonstrated that myocardial net lactate uptake was higher in lambs with aortopulmonary shunts than in control lambs. To determine whether this was caused by an increased lactate uptake and oxidation or by a decreased lactate release, we studied myocardial lactate and glucose metabolism with13C-labeled substrates in 36 lambs in a fasting, conscious state. The lambs were assigned to two groups: a resting group consisting of 8 shunt and 9 control lambs, and an exercise group (50% of peak O2consumption) consisting of 9 shunt and 10 control lambs. Myocardial lactate oxidation was higher in shunt than in control lambs (mean ± SE, rest: 10.33 ± 2.61 vs. 0.17 ± 0.82, exercise: 38.05 ± 8.87 vs. 16.89 ± 4.78 μmol ⋅ min−1⋅ 100 g−1; P < 0.05). There was no difference in myocardial lactate release between shunt and control lambs. Oxidation of exogenous glucose, which was approximately zero at rest, increased during exercise in shunt and control lambs. The contribution of glucose and lactate to myocardial oxidative metabolism increased during exercise compared with at rest in both shunt and control lambs. We conclude that myocardial lactate oxidation is higher in shunt than in control lambs, both at rest and during exercise, and that the contribution of carbohydrates in myocardial oxidative metabolism in shunt lambs is higher than in control lambs. Thus it appears that this higher contribution of carbohydrates occurs not only in the case of pressure-overloaded hearts but also in myocardial hypertrophy due to volume overloading.

Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts

1999 ◽  
Vol 276 (6) ◽  
pp. H1861-H1867 ◽  
Author(s):  
Peter Ferdinandy ◽  
Donna Panas ◽  
Richard Schulz
Keyword(s):  
Protein Synthesis ◽  
Oxygen Consumption ◽  
Contractile Function ◽  
Tca Cycle ◽  
Protein Synthesis Inhibitor ◽  
Mechanical Function ◽  
Cardiac Work ◽  
Synthesis Inhibitor ◽  
Atp Production ◽  
Rat Hearts

We examined the mechanism of the time- and protein synthesis-dependent decline in cardiac mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer for 120 min in the presence or absence of the protein synthesis inhibitor cycloheximide (CX; 10 μM). Cardiac work remained stable for 60 min and then spontaneously decreased during 60–120 min of perfusion. This was accompanied by an increase in myocardial inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO) activities and enhanced dityrosine formation in the perfusate, an indicator of peroxynitrite generation. CX markedly attenuated the loss in contractile function and prevented the increase in iNOS and XO activities and dityrosine level. Despite the decline in cardiac work in control hearts, the coupling between tricarboxylic acid (TCA) cycle activity and oxygen consumption remained constant in both groups. ATP, creatine phosphate, and glycogen levels were not different between control and CX groups and did not differ over 120 min of perfusion. We concluded that the delayed and spontaneous loss in myocardial mechanical function in isolated working rat hearts is 1) attenuated by CX treatment, 2) accompanied by a concomitant increase in both iNOS and XO activities and peroxynitrite generation in the heart, and 3) not dependent on a direct impairment in myocardial ATP production, myocardial oxygen consumption, or TCA cycle acetyl-CoA production but may be due to an inefficiency of the heart to utilize ATP for contractile work.

Dichloroacetate improves cardiac efficiency after ischemia independent of changes in mitochondrial proton leak

2001 ◽  
Vol 280 (4) ◽  
pp. H1762-H1769 ◽  
Author(s):  
Masayuki Taniguchi ◽  
Craig Wilson ◽  
Charlene A. Hunter ◽  
Daniel J. Pehowich ◽  
Alexander S. Clanachan ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Glucose Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Mitochondrial Membrane ◽  
Glucose Oxidation ◽  
Proton Leak ◽  
Cardiac Efficiency ◽  
Cardiac Work ◽  
Atp Production ◽  
Rat Hearts

Dichloroacetate (DCA) is a pyruvate dehydrogenase activator that increases cardiac efficiency during reperfusion of ischemic hearts. We determined whether DCA increases efficiency of mitochondrial ATP production by measuring proton leak in mitochondria from isolated working rat hearts subjected to 30 min of ischemia and 60 min of reperfusion. In untreated hearts, cardiac work and efficiency decreased during reperfusion to 26% and 40% of preischemic values, respectively. Membrane potential was significantly lower in mitochondria from reperfused (175.6 ± 2.2 mV) versus aerobic (185.8 ± 3.1 mV) hearts. DCA (1 mM added at reperfusion) improved recovery of cardiac work (1.9-fold) and efficiency (1.5-fold) but had no effect on mitochondrial membrane potential (170.6 ± 2.9 mV). At the maximal attainable membrane potential, O2consumption (nmol O2 · mg−1 · min−1) did not differ between untreated or DCA-treated hearts (128.3 ± 7.5 and 120.6 ± 7.6, respectively) but was significantly greater than aerobic hearts (76.6 ± 7.6). During reperfusion, DCA increased glucose oxidation 2.5-fold and decreased H+production from glucose metabolism to 53% of untreated hearts. Because H+ production decreases cardiac efficiency, we suggest that DCA increases cardiac efficiency during reperfusion of ischemic hearts by increasing the efficiency of ATP use and not by increasing the efficiency of ATP production.

Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts

1990 ◽  
Vol 259 (4) ◽  
pp. H1079-H1085 ◽  
Author(s):  
J. J. McVeigh ◽  
G. D. Lopaschuk
Keyword(s):  
Fatty Acid ◽  
Glucose Oxidation ◽  
Acid Inhibition ◽  
Mechanical Function ◽  
Oxidation Rates ◽  
Rat Hearts ◽  
High Concentrations ◽  
Fatty Acid Inhibition ◽  
Mechanical Recovery ◽  
Stimulation Of

We have previously shown that high concentrations of fatty acids depress reperfusion recovery of ischemic rat hearts as a result of a fatty acid inhibition of glucose oxidation. In this study, we determined whether dichloroacetate, an activator of pyruvate dehydrogenase, could overcome fatty acid inhibition of glucose oxidation and thereby improve mechanical recovery of hearts reperfused after a period of transient global ischemia. Isolated working rat hearts, perfused with 11 mM glucose, 1.2 mM palmitate, and 500 microU/ml insulin, were subjected to a 30-min period of no flow ischemia, followed by a 30-min period of reperfusion. Under these conditions, control hearts recovered 37% of preischemic function. The addition of 1 mM dichloroacetate to the perfusate at reperfusion resulted in a significant improvement in recovery of mechanical function (to 73% of preischemic function). When dichloroacetate was added before the onset of ischemia, however, this protective effect was lost, and a significant increase in myocardial lactate accumulation during ischemia was observed. The effects of dichloroacetate on glucose oxidation rates in both nonischemic and reperfused ischemic hearts was determined by perfusing hearts with 11 mM [U-14C]glucose and 1.2 mM palmitate and quantitatively collecting 14CO2 produced by the heart. In nonischemic hearts, 1 mM dichloroacetate increased steady-state glucose oxidation rates from 298 +/- 69 to 1,223 +/- 135 nmol.g dry wt-1.min-1. The addition of dichloroacetate to hearts reperfused after a 25-min period of ischemia also increased glucose oxidation rates from (112 +/- 25 to 561 +/- 83 nmol.g dry wt-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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