Mechanism of impaired energy metabolism during acidosis: role of oxidative metabolism

1992 ◽  
Vol 262 (6) ◽  
pp. H1818-H1822 ◽  
Author(s):  
G. Suleymanlar ◽  
H. Z. Zhou ◽  
M. McCormack ◽  
N. Elkins ◽  
R. Kucera ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Energy Metabolism ◽  
Respiratory Control ◽  
High Energy ◽  
Metabolic Effects ◽  
High Energy Phosphates ◽  
Perfused Heart ◽  
Rat Hearts ◽  
Perfused Rat Hearts

Isolated perfused rat hearts were used to study the effects of metabolic acidosis on energy metabolism. Hearts perfused with different substrates (glucose, pyruvate, and succinate) were subjected to metabolic acidosis. With all substrates, there were comparable decrements in oxygen consumption (approximately 35%), cardiac function (decrease in first derivative of pressure of 65%), and similar changes in high-energy phosphates (approximately 150% increases in inorganic phosphate and 25% decreases in phosphocreatine concentrations) with metabolic acidosis. To further investigate the metabolic effects of acidosis, isolated cardiac mitochondria were exposed to different incubation media pH conditions and given simple metabolites (glutamate/malate, succinate, or pyruvate) or fatty acids (octanoate). Reduction of incubation media pH to 6.0 did not significantly affect either coupled respiration rate or the respiratory control ratio (RCR) with any substrate. These data suggest that metabolic acidosis induces decreases in energy production in the isolated perfused heart by inhibiting mitochondrial substrate utilization and not by impairing glycolysis. However, this impairment of mitochondrial function is not a direct effect of acidosis itself but appears to occur secondarily to some other effects of acidosis which are, as yet, incompletely understood.

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.

Cardioprotective Effects of Propofol and Sevoflurane in Ischemic and Reperfused Rat Hearts 

1999 ◽  
Vol 91 (5) ◽  
pp. 1349-1349 ◽  
Author(s):  
Sanjiv Mathur ◽  
Parviz Farhangkhgoee ◽  
Morris Karmazyn
Keyword(s):  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphates ◽  
Constant Flow Rate ◽  
Rat Hearts ◽  
Reperfusion Period ◽  
Coronary Syndromes ◽  
Cardioprotective Effects ◽  
Developed Pressure

Background Sodium ion-hydrogen ion (Na(+)-H(+)) exchange inhibitors are effective cardioprotective agents. The N(+)-H(+) exchange inhibitor HOE 642 (cariporide) has undergone clinical trials in acute coronary syndromes, including bypass surgery. Propofol and sevoflurane are also cardioprotective via unknown mechanisms. The authors investigated the interaction between propofol and HOE 642 in the ischemic reperfused rat heart and studied the role of adenosine triphosphate-sensitive potassium (K(ATP)) channels in the myocardial protection associated with propofol and sevoflurane. Methods Isolated rat hearts were perfused by the Langendorff method at a constant flow rate, and left ventricular function and coronary pressures were assessed using standard methods. Energy metabolites were also determined. To assess the role of K(ATP) channels, hearts were pretreated with the K(ATP) blocker glyburide (10 microM). Hearts were then exposed to either control buffer or buffer containing HOE 642 (5 microM), propofol (35 microM), sevoflurane (2.15 vol%), the K(ATP) opener pinacidil (1 microM), or the combination of propofol and HOE 642. Each heart was then subjected to 1 h of global ischemia followed by 1 h of reperfusion. Results Hearts treated with propofol, sevoflurane, pinacidil, or HOE 642 showed significantly higher recovery of left ventricular developed pressure and reduced end-diastolic pressures compared with controls. The combination of propofol and HOE 642 provided superior protection toward the end of the reperfusion period. Propofol, sevoflurane, and HOE 642 also attenuated the onset and magnitude of ischemic contracture and preserved high-energy phosphates (HEPs) compared with controls. Glyburide attenuated the cardioprotective effects of sevoflurane and abolished the protection observed with pinacidil. In contrast, glyburide had no effect on the cardioprotection associated with propofol treatment. Conclusion HOE 642, propofol, and sevoflurane provide cardioprotection via different mechanisms. These distinct mechanisms may allow for the additive and superior protection observed with the combination of these anesthetics and HOE 642.

scholarly journals Direct evidence for a role of intramitochondrial Ca2+ in the regulation of oxidative phosphorylation in the stimulated rat heart. Studies using31P n.m.r. and ruthenium red

1989 ◽  
Vol 262 (1) ◽  
pp. 293-301 ◽  
Author(s):  
J F Unitt ◽  
J G McCormack ◽  
D Reid ◽  
L K MacLachlan ◽  
P J England
Keyword(s):  
Oxidative Phosphorylation ◽  
Direct Evidence ◽  
Respiratory Control ◽  
Ruthenium Red ◽  
Phosphorylation Potential ◽  
Mitochondrial Inner Membrane ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Inotropic Stimulation

1. The concentrations of free ATP, phosphocreatine (PCr), Pi, H+ and ADP (calculated) were monitored in perfused rat hearts by 31P n.m.r. before and during positive inotropic stimulation. Data were accumulated in 20 s blocks. 2. Administration of 0.1 microM-(-)-isoprenaline resulted in no significant changes in ATP, transient decreases in PCr, and transient increases in ADP and Pi. However, the concentrations of all of these metabolites returned to pre-stimulated values within 1 min, whereas cardiac work and O2 uptake remained elevated. 3. In contrast, in hearts perfused continuously with Ruthenium Red (2.5 micrograms/ml), a potent inhibitor of mitochondrial Ca2+ uptake, administration of isoprenaline caused significant decreases in ATP, and also much larger and more prolonged changes in the concentrations of ADP, PCr and Pi. In this instance values did not fully return to pre-stimulated concentrations. Administration of Ruthenium Red alone to unstimulated hearts had minor effects. 4. It is proposed that, in the absence of Ruthenium Red, the transmission of changes in cytoplasmic Ca2+ across the mitochondrial inner membrane is able to maintain the phosphorylation potential of the heart during positive inotropic stimulation, through activation of the Ca2+-sensitive intramitochondrial dehydrogenases (pyruvate, NAD+-isocitrate and 2-oxoglutarate dehydrogenases) leading to enhanced NADH production. 5. This mechanism is unavailable in the presence of Ruthenium Red, and oxidative phosphorylation must be stimulated primarily by a fall in phosphorylation potential, in accordance with the classical concept of respiratory control. However, the full oxidative response of the heart to stimulation may not be achievable under such circumstances.

Factors influencing myocardial response to metabolic acidosis in isolated rat hearts

1987 ◽  
Vol 253 (5) ◽  
pp. H1261-H1270 ◽  
Author(s):  
T. A. Watters ◽  
M. F. Wendland ◽  
W. W. Parmley ◽  
T. L. James ◽  
E. H. Botvinick ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Coronary Flow ◽  
Work Load ◽  
High Energy ◽  
High Energy Phosphates ◽  
Factors Influencing ◽  
Rat Hearts ◽  
Developed Pressure ◽  
High Work Load ◽  
High Work

We assessed the effects of metabolic acidosis in Langendorff rat hearts to identify factors influencing myocardial response to metabolic acidosis. Intracellular pH (pHi), beta-ATP, phosphocreatine, and inorganic phosphate (Pi) content were measured by 31P nuclear magnetic resonance spectroscopy along with simultaneous measurements of coronary flow and developed pressure during 30 min of perfusion at pH = 6.8, followed by 15 min of reequilibration at pH = 7.4. Under high work-load conditions, pHi, high-energy phosphates, coronary flow, and developed pressure were severely reduced during metabolic acidosis. Each of these hearts exhibited a progressive decline in developed pressure and stopped beating during reequilibration. Lowering work load prevented severe biochemical or mechanical deterioration, allowing complete recovery during reequilibration. In the presence of high work load, factors found to improve myocardial tolerance to metabolic acidosis included maintaining base-line or higher levels of coronary flow with vasodilators or substitution of pyruvate for glucose as the energy-producing substrate. Raising perfusate osmolality did not prevent severe decreases in coronary flow and developed pressure during acidosis, but did allow a dramatic recovery during reequilibration. Recovery of biochemical and mechanical performance after 30 min of metabolic acidosis was directly related to 1) ln[ATP]/[ADP]f[Pi] greater than or equal to 4.1, where [ADP]f is the concentration of free ADP; 2) pHi greater than 6.40; and 3) ATP level greater than or equal to 75% of control.

NMR-visible ATP and Pi in normoxic and reperfused rat hearts: a quantitative study

1991 ◽  
Vol 260 (1) ◽  
pp. H6-H12 ◽  
Author(s):  
S. M. Humphrey ◽  
P. B. Garlick
Keyword(s):  
Chemical Analysis ◽  
31P Nmr ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
High Energy Phosphates ◽  
Rat Hearts ◽  
External Standard ◽  
Perfused Rat Hearts ◽  
Krebs Buffer ◽  
Isolated Perfused Rat Hearts

Nuclear magnetic resonance (NMR) spectroscopy detects only free, unbound metabolites. We have therefore compared the free high-energy phosphate content of isolated perfused rat hearts (determined by 31P-NMR) with the total high-energy phosphates of the same hearts (determined by chemical analysis) to determine the fractions, if any, that are NMR invisible. Aerobic perfusion (40 min at 37 degrees C, Pi-free Krebs buffer) was followed by 10, 14, or 18 min total global ischemia and 30 min reperfusion (n = 6 in each group). Fully relaxed 31P-NMR spectra (40 scans using 90 degrees pulses at 15-s intervals) were collected at various times throughout the protocol, and the signal intensities of the beta-phosphate of ATP, phosphocreatine (PCr), and Pi were quantified using methylenediphosphonate as an external standard. Hearts were freeze clamped either before ischemia or at the end of reperfusion and were chemically assayed for ATP, PCr, and Pi. After 40 min of normoxia, the ATP and PCr contents determined by NMR were almost identical to the values determined by chemical analysis. However, only 39 +/- 8% of the total Pi was NMR visible. After reperfusion, after 14 or 18 min of ischemia, the proportion of NMR-visible ATP had decreased to 64 +/- 9% (P less than 0.005). After reperfusion after 18 min ischemia, the proportion of NMR-visible Pi had increased to 76 +/- 10% (P less than 0.05). In conclusion, whereas the total cellular content of PCr is always NMR visible, ischemia-reperfusion can alter the fraction of NMR-visible ATP and Pi.

Complete inhibition of creatine kinase in isolated perfused rat hearts

1987 ◽  
Vol 252 (1) ◽  
pp. E124-E129 ◽  
Author(s):  
E. T. Fossel ◽  
H. Hoefeler
Keyword(s):  
Creatine Kinase ◽  
Systolic Pressure ◽  
Creatine Phosphate ◽  
High Energy ◽  
Complete Inhibition ◽  
High Energy Phosphates ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Low Levels ◽  
Developed Pressure

Transient exposure of an isolated isovolumic perfused rat heart to low concentrations (0.5 mM) of perfusate-born iodoacetamide resulted in complete inhibition of creatine kinase and partial inhibition of glyceraldehyde-3-phosphate dehydrogenase in the heart. At low levels of developed pressure, hearts maintained mechanical function, ATP, and creatine phosphate levels at control values. However, iodoacetamide-inhibited hearts were unable to maintain control values of end diastolic pressure or peak systolic pressure as work load increased. Global ischemia resulted in loss of all ATP without loss of creatine phosphate, indicating lack of active creatine kinase. These results indicate that isovolumic perfused rat hearts are able to maintain normal function and normal levels of high-energy phosphates without active creatine kinase at low levels of developed pressure.

Substrate dependence of metabolic state and coronary flow in perfused rat heart

1985 ◽  
Vol 249 (4) ◽  
pp. H799-H806 ◽  
Author(s):  
J. W. Starnes ◽  
D. F. Wilson ◽  
M. Erecinska
Keyword(s):  
Energy Metabolism ◽  
Coronary Flow ◽  
Work Load ◽  
Creatine Phosphate ◽  
High Energy ◽  
Cardiac Cells ◽  
O2 Consumption ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Perfused Hearts

The effect of substrate source on the regulation of energy metabolism and coronary flow was studied in isolated perfused rat hearts. Compared with glucose-perfused hearts, those perfused at the same work load with palmitate or acetate demonstrated increases (P less than 0.01) in O2 consumption of 16 and 18%, respectively, and increases (P less than 0.01) in coronary flow of 30 and 32%, respectively. Parallel substrate-related changes occurred in the levels of high-energy phosphate compounds: tissue creatine, ADP free, and inorganic phosphate (Pi) were significantly decreased, leading to increases (P less than 0.01) in [creatine phosphate]/[creatine] and [ATP]free/[ADP]free[Pi]. These changes were accompanied by increased reduction of intramitochondrial pyridine nucleotides. Omitting orthophosphate from perfusate lowered intracellular Pi and modified cardiac function, but substrate-related differences were similar to those in Pi containing media. Differences in intracellular pH among substrates were observed, which may contribute in some instances to differences in energy metabolism and coronary flow. When work load was altered in glucose- and acetate-perfused hearts, both O2 consumption and coronary flow were linearly related to cytosolic [ATP]free/[ADP]free[Pi], and slopes of regression lines were similar for both substrates. These correlations support the view that [ATP]free/[ADP]free[Pi] is a major determinant of O2 consumption by cardiac cells and of coronary flow.

The cardiac cycle: regulation and energy oscillations

1983 ◽  
Vol 245 (2) ◽  
pp. H354-H362 ◽  
Author(s):  
J. Wikman-Coffelt ◽  
R. Sievers ◽  
R. J. Coffelt ◽  
W. W. Parmley
Keyword(s):  
Cardiac Cycle ◽  
Atp Hydrolysis ◽  
High Energy ◽  
High Energy Phosphates ◽  
Perfused Heart ◽  
Time To Peak ◽  
Rat Hearts ◽  
High Concentrations ◽  
Slow Transport ◽  
Cycle Regulation

Cyclical changes in energy-related metabolites were observed in glucose-perfused but not pyruvate-perfused isolated working rat hearts. A chronological study of various phases of the cardiac cycle indicated maximum changes in metabolites occurred at half time to peak pressure (dF/dtmax). The high-energy phosphates ATP and phosphocreatine, as well as the glycolytic metabolites, glucose 6-phosphate and pyruvate, reached minimum values immediately prior to peak systole and maximum values during late diastole. The products of high-energy phosphate hydrolysis, ADP, inorganic phosphate, and creatine, as well as the regulator, adenosine 3',5'-cyclic monophosphate, showed the phase alternate. It was necessary to study cyclical changes in a maximally stressed glucose-perfused heart because the cyclical changes were small and appeared to be the result of rate-limiting steps in glycolysis and the slow transport of NADH into the mitochondria. For stressing the heart, thereby increasing ATP utilization and augmenting cyclical changes, the afterload chamber was set at 110 mmHg, and the perfusate contained high concentrations of calcium (3.5 mM, free) and isoproterenol (5 X 10(-9) M). When correction was made for binding and compartmentation of metabolites, data indicated that the free energy of ATP hydrolysis was preserved during the contraction process by a continuous binding and recycling of ADP.

Fasudil prevents KATP channel-induced improvement in postischemic functional recovery

2005 ◽  
Vol 288 (6) ◽  
pp. H3011-H3015 ◽  
Author(s):  
Kenya Nishizawa ◽  
Paul E. Wolkowicz ◽  
Tadashi Yamagishi ◽  
Ling-Ling Guo ◽  
Martin M. Pike
Keyword(s):  
Diastolic Pressure ◽  
Rho Kinase ◽  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphate ◽  
Cellular Processes ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Rock Activity ◽  
Mechanical Recovery

Whereas activation of ATP-dependent potassium (KATP) channels greatly improves postischemic myocardial recovery, the final effector mechanism for KATP channel-induced cardioprotection remains elusive. RhoA is a GTPase that regulates a variety of cellular processes known to be involved with KATP channel cardioprotection. Our goal was to determine whether the activity of a key rhoA effector, rho kinase (ROCK), is required for KATP channel-induced cardioprotection. Four groups of perfused rat hearts were subjected to 36 min of zero-flow ischemia and 44 min of reperfusion with continuous measurements of mechanical function and 31P NMR high-energy phosphate data: 1) untreated, 2) pinacidil (10 μM) to activate KATP channels, 3) fasudil (15 μM) to inhibit ROCK, and 4) both fasudil and pinacidil. Pinacidil significantly improved postischemic mechanical recovery [39 ± 16 vs. 108 ± 4 mmHg left ventricular diastolic pressure (LVDP), untreated and pinacidil, respectively]. Fasudil did not affect reperfusion LVDP (41 ± 13 mmHg) but completely blocked the marked improvement in mechanical recovery that occurred with pinacidil treatment (54 ± 15 mmHg). Substantial attenuation of the postischemic energetic recovery was also observed. These data support the hypothesis that ROCK activity plays a role in KATP channel-induced cardioprotection.

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