scholarly journals Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium

2012 ◽  
Vol 303 (7) ◽  
pp. H844-H852 ◽  
Author(s):  
Ashwin Akki ◽  
Jason Su ◽  
Toshiyuki Yano ◽  
Ashish Gupta ◽  
Yibin Wang ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Functional Recovery ◽  
Contractile Function ◽  
Atp Synthesis ◽  
High Energy ◽  
Rate Pressure Product ◽  
Lactate Dehydrogenase Release ◽  
Biochemical Assays ◽  
Perfused Hearts ◽  
Postischemic Myocardium

Reduced myofibrillar ATP availability during prolonged myocardial ischemia may limit post-ischemic mechanical function. Because creatine kinase (CK) is the prime energy reserve reaction of the heart and because it has been difficult to augment ATP synthesis during and after ischemia, we used mice that overexpress the myofibrillar isoform of creatine kinase (CKM) in cardiac-specific, conditional fashion to test the hypothesis that CKM overexpression increases ATP delivery in ischemic-reperfused hearts and improves functional recovery. Isolated, retrograde-perfused hearts from control and CKM mice were subjected to 25 min of global, no-flow ischemia and 40 min of reperfusion while cardiac function [rate pressure product (RPP)] was monitored. A combination of 31P-nuclear magnetic resonance experiments at 11.7T and biochemical assays was used to measure the myocardial rate of ATP synthesis via CK (CK flux) and intracellular pH (pHi). Baseline CK flux was severalfold higher in CKM hearts (8.1 ± 1.0 vs. 32.9 ± 3.8, mM/s, control vs. CKM; P < 0.001) with no differences in phosphocreatine concentration [PCr] and RPP. End-ischemic pHi was higher in CKM hearts than in control hearts (6.04 ± 0.12 vs. 6.37 ± 0.04, control vs. CKM; P < 0.05) with no differences in [PCr] and [ATP] between the two groups. Post-ischemic PCr (66.2 ± 1.3 vs. 99.1 ± 8.0, %preischemic levels; P < 0.01), CK flux (3.2 ± 0.4 vs. 14.0 ± 1.2 mM/s; P < 0.001) and functional recovery (13.7 ± 3.4 vs. 64.9 ± 13.2%preischemic RPP; P < 0.01) were significantly higher and lactate dehydrogenase release was lower in CKM than in control hearts. Thus augmenting cardiac CKM expression attenuates ischemic acidosis, reduces injury, and improves not only high-energy phosphate content and the rate of CK ATP synthesis in postischemic myocardium but also recovery of contractile function.

Glycolytic buffering affects cardiac bioenergetic signaling and contractile reserve similar to creatine kinase

2003 ◽  
Vol 285 (2) ◽  
pp. H883-H890 ◽  
Author(s):  
Glenn J. Harrison ◽  
Michiel H. van Wijhe ◽  
Bas de Groot ◽  
Francina J. Dijk ◽  
Lori A. Gustafson ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Oxygen Consumption ◽  
Cardiac Myocyte ◽  
Atp Hydrolysis ◽  
Response Times ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Iodoacetic Acid ◽  
Rate Pressure Product ◽  
Contractile Reserve

Creatine kinase (CK) and glycolysis represent important energy-buffering processes in the cardiac myocyte. Although the role of compartmentalized CK in energy transfer has been investigated intensely, similar duties for intracellular glycolysis have not been demonstrated. By measuring the response time of mitochondrial oxygen consumption to dynamic workload jumps ( tmito) in isolated rabbit hearts, we studied the effect of inhibiting energetic systems (CK and/or glycolysis) on transcytosolic signal transduction that couples cytosolic ATP hydrolysis to activation of oxidative phosphorylation. Tyrode-perfused hearts were exposed to 15 min of the following: 1) 0.4 mM iodoacetamide (IA; n = 6) to block CK (CK activity <3% vs. control), 2) 0.3 mM iodoacetic acid (IAA; n = 5) to inhibit glycolysis (GAPDH activity <3% vs. control), or 3) vehicle (control, n = 7) at 37°C. Pretreatment tmito was similar across groups at 4.3 ± 0.3 s (means ± SE). No change in tmito was observed in control hearts; however, in IAA- and IA-treated hearts, tmito decreased by 15 ± 3% and 40 ± 5%, respectively ( P < 0.05 vs. control), indicating quicker energy supply-demand signaling in the absence of ADP/ATP buffering by CK or glycolysis. The faster response times in IAA and IA groups were independent of the size of the workload jump, and the increase in myocardial oxygen consumption during workload steps was unaffected by CK or glycolysis blockade. Contractile function was compromised by IAA and IA treatment versus control, with contractile reserve (defined as increase in rate-pressure product during a standard heart rate jump) reduced to 80 ± 8% and 80 ± 10% of baseline, respectively ( P < 0.05 vs. control), and significant elevations in end-diastolic pressure, suggesting raised ADP concentration. These results demonstrate that buffering of phosphate metabolites by glycolysis in the cytosol contributes appreciably to slower mitochondrial activation and may enhance contractile efficiency during increased cardiac workloads. Glycolysis may therefore play a role similar to CK in heart muscle.

Cardiac performance and creatine kinase flux during inhibition of ATP synthesis in the perfused rat heart

1999 ◽  
Vol 277 (1) ◽  
pp. H308-H317 ◽  
Author(s):  
P. Mateo ◽  
V. Stepanov ◽  
B. Gillet ◽  
J.-C. Beloeil ◽  
J. A. Hoerter
Keyword(s):  
Creatine Kinase ◽  
Rat Heart ◽  
Mechanical Performance ◽  
Diastolic Pressure ◽  
Atp Synthesis ◽  
Cardiac Performance ◽  
Rate Pressure Product ◽  
Saturation Transfer ◽  
Perfused Rat Heart ◽  
Performance Rate

To study the relation among mitochondrial energy supply, cardiac performance, and energy transfer through creatine kinase (CK), two acute models of inhibition of ATP synthesis were compared in the isovolumic acetate-perfused rat heart. Similar impairments of mechanical performance (rate-pressure product, RPP) were achieved by various stepwise decreases in O2 supply ([Formula: see text] down to 20% of control) or by infusing CN (0.15–0.25 mM). The forward CK flux measured by saturation-transfer 31P NMR spectroscopy was 6.1 ± 0.4 mM/s in control hearts. Only after severe hypoxia ([Formula: see text] < 40% of control) did CK flux drop (to 1.9 ± 0.2 mM/s at[Formula: see text] = 25% of control) together with impaired systolic activity and a rise in end-diastolic pressure. In contrast, in mild hypoxia CK flux remained constant and similar to control (5.3 ± 0.5 mM/s, not significant) despite a twofold reduction in systolic activity. Similarly in all CN groups, constant CK flux was maintained for a threefold reduction in RPP, showing the absence of a relation between cardiac performance and global NMR-measured CK flux during mild ATP synthesis inhibition.

CK inhibition accelerates transcytosolic energy signaling during rapid workload steps in isolated rabbit hearts

1999 ◽  
Vol 276 (1) ◽  
pp. H134-H140 ◽  
Author(s):  
Glenn J. Harrison ◽  
Michiel H. van Wijhe ◽  
Bas de Groot ◽  
Francina J. Dijk ◽  
Johannes H. G. M. van Beek
Keyword(s):  
Response Times ◽  
Contractile Function ◽  
Creatine Phosphate ◽  
Oxidative Capacity ◽  
Rate Pressure Product ◽  
Contractile Reserve ◽  
Speed Up ◽  
Whole Heart ◽  
Perfused Hearts

The effect of graded creatine kinase (CK) inhibition on the response time of mitochondrial O2 consumption to dynamic workload jumps ( t mito) was studied in isolated rabbit hearts. Tyrode-perfused hearts ( n = 7/group) were exposed to 15 min of 0, 0.1, 0.2, or 0.4 mM iodoacetamide (IA) (CK activity = 100, 14, 6, and 3%, respectively). Pretreatment t mito was similar across groups at 6.5 ± 0.5 s (mean ± SE). The increase observed over time in control hearts (33 ± 8%) was progressively reversed to 16 ± 6, −20 ± 6 ( P< 0.01 vs. control), and −46 ± 6 ( P < 0.01 vs. control) % in the 0.1, 0.2 and 0.4 mM IA groups, respectively. The faster response times occurred without reductions in mitochondrial oxidative capacity (assessed in vitro) or myocardial O2 consumption of the whole heart during workload steps. Isovolumic contractile function assessed as rate-pressure product (RPP) and contractile reserve (increase in RPP during heart rate steps) were significantly reduced by IA. We conclude that CK in the myofibrils and/or cytosol does not speed up transfer of the energy-related signal to the mitochondria but rather acts as an energetic buffer, effectively slowing the stimulus between myofibrils/ion pumps and oxidative phosphorylation. This argues against the existence of an obligatory creatine phosphate energy shuttle, because CK is effectively bypassed.

Cellular response to reperfused oxygen in the postischemic myocardium

1996 ◽  
Vol 271 (2) ◽  
pp. H687-H695 ◽  
Author(s):  
Y. Chung ◽  
T. Jue
Keyword(s):  
Cellular Response ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Formation Rate ◽  
Lactate Concentration ◽  
High Energy ◽  
O2 Consumption ◽  
1H Nuclear Magnetic Resonance ◽  
Lactate Formation ◽  
Postischemic Myocardium

Perfused rat heart experiments focused on determining the critical O2 level in postischemic myocardium. After a 20-min global ischemia, reperfusion began with O2-saturated saline buffer reflowing at different rates (0.5-12 ml/min). The 1H nuclear magnetic resonance (NMR) signal of the Val E11 myoglobin (Mb) gave an index of the intracellular oxygenation, whereas the 31P-NMR spectra reflected the high-energy phosphate and pH status. At the same time, physiological monitors recorded both contractile function and O2 consumption. Biochemical analysis determined the lactate concentration. Within 6-12 min of reperfusion, the O2 reached a new steady state, which depended directly on the flow rate. Below 12 ml/min reflow, the postischemic O2 level was consistently lower than the corresponding control values. Phosphocreatine, P(i), pH, myocardial O2 consumption, and lactate formation rate exhibited a similar linear relationship with MbO2 saturation in both the control and postischemic myocardium. It appears that neither the cellular energy production nor the steep intracellular O2 gradient has changed substantially in the postischemic myocardium.

Contractile and metabolic effects of increased creatine kinase activity in mouse skeletal muscle

1996 ◽  
Vol 270 (4) ◽  
pp. C1236-C1245 ◽  
Author(s):  
B. B. Roman ◽  
J. M. Foley ◽  
R. A. Meyer ◽  
A. P. Koretsky
Keyword(s):  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Kinase Activity ◽  
Contractile Function ◽  
Contractile Activity ◽  
High Energy ◽  
Metabolic Effects ◽  
High Energy Phosphates ◽  
Lactate Dehydrogenase Activity ◽  
B Subunit

The effects of increased expression of creatine kinase (CK) in skeletal muscle were studied in control and transgenic animals homozygous for expression of the B subunit of CK. CK activity was 47% higher in transgenic gastrocnemius muscle. The CK activity was distributed as follows: 45 +/- 1% MM dinner, 31 +/- 4% MB dimer, and 22 +/- 5% BB dimer. No significant differences in metabolic or contractile proteins were detected except for a 22% decrease in lactate dehydrogenase activity and a 9% decrease in adenylate kinase activity. The only significant effect in contractile activity was that the rise time of a 5-s isometric contraction was 28% faster in the transgenic muscle. 31P nuclear magnetic resonance (NMR) spectra were obtained from control and transgenic muscles during mechanical activation, and there were no NMR measurable differences detected. These results indicate that a 50% increase in CK activity due to expression of the B subunit does not have large effects on skeletal muscle metabolism or contractile function. Therefore, control muscle has sufficient CK activity to keep up with changes in cellular high-energy phosphates except during the early phase of intense contractile activity.

scholarly journals Effect of Photic Stimulation on Human Visual Cortex Lactate and Phosphates Using 1H and 31P Magnetic Resonance Spectroscopy

1992 ◽  
Vol 12 (4) ◽  
pp. 584-592 ◽  
Author(s):  
D. Sappey-Marinier ◽  
G. Calabrese ◽  
G. Fein ◽  
J. W. Hugg ◽  
C. Biggins ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Visual Cortex ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Brain Activity ◽  
Atp Synthesis ◽  
High Energy ◽  
Significant Rise ◽  
Photic Stimulation ◽  
Resonance Spectroscopy

Previous animal and human studies showed that photic stimulation (PS) increased cerebral blood flow and glucose uptake much more than oxygen consumption, suggesting selective activation of anaerobic glycolysis. In the present studies, image-guided 1H and 31P magnetic resonance spectroscopy (MRS) was used to monitor the changes in lactate and high-energy phosphate concentrations produced by PS of visual cortex in six normal volunteers. PS initially produced a significant rise (to 250% of control, p < 0.01) in visual cortex lactate during the first 6.4 min of PS, followed by a significant decline ( p = 0.01) as PS continued. The PCr/Pi ratios decreased significantly from control values during the first 12.8 min of PS ( p < 0.05), and the pH was slightly increased. The positive P100 deflection of the visual evoked potential recorded between 100 and 172 ms after the strobe was significantly decreased from control at 12.8 min of PS ( p < 0.05). The finding that PS caused decreased PCr/Pi is consistent with the view that increased brain activity stimulated ATPase, causing a rise in ADP that shifted the creatine kinase reaction in the direction of ATP synthesis. The rise in lactate together with an increase in pH suggest that intracellular alkalosis, caused by the shift of creatine kinase, selectively stimulated glycolysis.

Myocardial creatine kinase kinetics in hearts with postinfarction left ventricular remodeling

1999 ◽  
Vol 276 (3) ◽  
pp. H892-H900 ◽  
Author(s):  
Yo Murakami ◽  
Jianyi Zhang ◽  
Marcel H. J. Eijgelshoven ◽  
Wei Chen ◽  
Wenda C. Carlyle ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
High Energy ◽  
Left Ventricular ◽  
Forward Rate ◽  
Rate Pressure Product ◽  
Resonance Spectroscopy ◽  
Coronary Artery Ligation ◽  
Artery Ligation

This study examined whether alterations in myocardial creatine kinase (CK) kinetics and high-energy phosphate (HEP) levels occur in postinfarction left ventricular remodeling (LVR). Myocardial HEP and CK kinetics were examined in 19 pigs 6 wk after myocardial infarction was produced by left circumflex coronary artery ligation, and the results were compared with those from 9 normal pigs. Blood flow (microspheres), oxygen consumption (MV˙o2), HEP levels [31P magnetic resonance spectroscopy (MRS)], and CK kinetics (31P MRS) were measured in myocardium remote from the infarct under basal conditions and during dobutamine infusion (20 μg ⋅ kg−1⋅ min−1iv). Six of the pigs with LVR had overt congestive heart failure (CHF) at the time of study. Under basal conditions, creatine phosphate (CrP)-to-ATP ratios were lower in all transmural layers of hearts with CHF and in the subendocardium of LVR hearts than in normal hearts ( P < 0.05). Myocardial ATP (biopsy) was significantly decreased in hearts with CHF. The CK forward rate constant was lower ( P < 0.05) in the CHF group (0.21 ± 0.03 s−1) than in LVR (0.38 ± 0.04 s−1) or normal groups (0.41 ± 0.03 s−1); CK forward flux rates in CHF, LVR, and normal groups were 6.4 ± 2.3, 14.3 ± 2.1, and 20.3 ± 2.4 μmol ⋅ g−1⋅ s−1, respectively ( P < 0.05, CHF vs. LVR and LVR vs. normal). Dobutamine caused doubling of the rate-pressure product in the LVR and normal groups, whereas CHF hearts failed to respond to dobutamine. CK flux rates did not change during dobutamine in any group. The ratios of CK flux to ATP synthesis (from MV˙o2) under baseline conditions were 10.9 ± 1.2, 8.03 ± 0.9, and 3.86 ± 0.5 for normal, LVR, and CHF hearts, respectively (each P < 0.05); during dobutamine, this ratio decreased to 3.73 ± 0.5, 2.58 ± 0.4, and 2.78 ± 0.5, respectively ( P = not significant among groups). These data demonstrate that CK flux rates are decreased in hearts with postinfarction LVR, but this change does not limit the response to dobutamine. In hearts with end-stage CHF, the changes in HEP and CK flux are more marked. These changes could contribute to the decreased responsiveness of these hearts to dobutamine.

scholarly journals Preconditioning in rat hearts is independent of mitochondrial F1F0ATPase inhibition

1998 ◽  
Vol 274 (1) ◽  
pp. H90-H97 ◽  
Author(s):  
David W. Green ◽  
Holt N. Murray ◽  
Paul G. Sleph ◽  
Feng-Lai Wang ◽  
Anne J. Baird ◽  
...  
Keyword(s):  
Atp Hydrolysis ◽  
Contractile Function ◽  
Atp Synthesis ◽  
Isolated Rat Heart ◽  
Global Ischemia ◽  
Mitochondrial Atpase ◽  
Atpase Inhibitor ◽  
Lactate Dehydrogenase Release ◽  
Rat Hearts ◽  
Isolated Rat

Mitochondrial F1F0adenosinetriphosphatase (ATPase) is responsible for the majority of ATP synthesis during normoxic conditions, but under ischemic conditions it accounts for significant ATP hydrolysis. A previous study showed that preconditioning in isolated rat hearts is mediated by inhibition of this ATPase during ischemia. We tested this hypothesis in our isolated rat heart model of preconditioning. Preconditioning was accomplished by three 5-min periods of global ischemia separated by 5 min of reperfusion. This was followed by 20 min of global ischemia and 30 min of reperfusion. Preconditioning significantly enhanced reperfusion contractile function and reduced lactate dehydrogenase release but paradoxically reduced the time to onset of contracture during global ischemia. Myocardial ATP was depleted at a faster rate during the prolonged ischemia in preconditioned than in sham-treated hearts, which is consistent with the reduced time to contracture. ATP during reperfusion was repleted more rapidly in preconditioned hearts, which is consistent with their enhanced contractile function. Preconditioning significantly reduced lactate accumulation during the prolonged ischemia. We were not able to demonstrate that mitochondrial F1F0ATPase (measured in submitochondrial particles) was inhibited by preconditioning before or during the prolonged ischemia. The mitochondrial ATPase inhibitor oligomycin significantly conserved ATP during ischemia and increased the time to the onset of contracture, which is consistent with inhibition of the mitochondrial ATPase. Our results show that preconditioning in rat hearts can be independent of mitochondrial ATPase inhibition as well as ATP conservation.

31P-NMR of high-energy phosphates in perfused rat heart during metabolic acidosis

1992 ◽  
Vol 263 (3) ◽  
pp. H903-H909
Author(s):  
L. A. Jelicks ◽  
R. Gupta
Keyword(s):  
Metabolic Acidosis ◽  
Atp Synthesis ◽  
High Energy ◽  
Magnesium Concentration ◽  
High Energy Phosphates ◽  
Solution Ph ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Creatine Kinase Equilibrium ◽  
Perfused Hearts

Intracellular pH (pHi), intracellular free magnesium concentration ([Mg2+]i), and high-energy phosphates in Langendorff perfused rat hearts were evaluated by 31P-nuclear magnetic resonance (NMR) during metabolic acidosis. During acidosis, cardiac pHi approached that of the perfusing solution (pH approximately 6.7) and [Mg2+]i increased. In hearts perfused with glucose as the sole carbon source, the ratio of [phosphocreatine] to [ATP] decreased during acidosis. In contrast, in hearts supplemented with pyruvate (either 2.8 or 10 mM) this ratio increased during acidosis. Oxygen consumption decreased in hearts perfused with glucose only and with pyruvate-glucose. Using the creatine kinase equilibrium constant, we find that [MgADP] is significantly decreased in pyruvate-perfused hearts but is not significantly altered in glucose-perfused hearts during metabolic acidosis. These data indicate that [MgADP] may be the regulator of cardiac oxidative phosphorylation in the presence of excess pyruvate; however, during metabolic acidosis in hearts perfused with glucose only, ATP synthesis appears limited by the availability of pyruvate via glycolysis.

Influence of peroxynitrite on energy metabolism and cardiac function in a rat ischemia-reperfusion model

2003 ◽  
Vol 285 (4) ◽  
pp. H1385-H1395 ◽  
Author(s):  
Warren H. Lee ◽  
John S. Gounarides ◽  
Eric S. Roos ◽  
Michael S. Wolin
Keyword(s):  
Creatine Kinase ◽  
Kinase Activity ◽  
Ischemia Reperfusion ◽  
Creatine Phosphate ◽  
High Energy ◽  
Left Ventricular ◽  
Creatine Kinase Activity ◽  
Rate Pressure Product ◽  
Partial Recovery ◽  
Developed Pressure

Ischemia-reperfusion generates peroxynitrite (ONOO–), which interacts with many of the systems altered by ischemia-reperfusion. This study examines the influence of endogenously produced ONOO– on cardiac metabolism and function. Nitro-l-arginine (an inhibitor of ONOO– biosynthesis) and urate (a scavenger of ONOO–) were utilized to investigate potential pathophysiological roles for ONOO– in a rat Langendorff heart model perfused with glucose-containing saline at constant pressure and exposed to 30 min of ischemia followed by 60 min of reperfusion. In this model, ischemia-reperfusion decreased contractile function (e.g., left ventricular developed pressure), cardiac work (rate-pressure product), efficiency of O2 utilization, membrane-bound creatine kinase activity, and NMR-detectable ATP and creatine phosphate without significantly altering the recovery of coronary flow, heart rate, lactate release, and muscle pH. Treatment with urate and nitro-l-arginine produced a substantial recovery of left ventricular developed pressure, rate-pressure product, efficiency of O2 utilization, creatine kinase activity, and NMR-detectable creatine phosphate and a partial recovery of ATP. The pattern of effects observed in this study and in previously published work with similar models suggests that ONOO– may alter key steps in the efficiency of mitochondrial high-energy phosphate generation.

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