scholarly journals HOE-642 (cariporide) alters pHi and diastolic function after ischemia during reperfusion in pig hearts in situ

2001 ◽  
Vol 280 (2) ◽  
pp. H830-H834 ◽  
Author(s):  
Michael A. Portman ◽  
Anthony L. Panos ◽  
Yun Xiao ◽  
David L. Anderson ◽  
Xue-Han Ning
Keyword(s):  
Diastolic Function ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Exchange Inhibitor ◽  
Diastolic Stiffness ◽  
Ischemic And Reperfusion Injury ◽  
Intracellular Alkalinization

The specific Na+/H+ exchange inhibitor HOE-642 prevents ischemic and reperfusion injury in the myocardium. Although this inhibitor alters H+ ion flux during reperfusion in vitro, this action has not been confirmed during complex conditions in situ. Myocardial intracellular pH (pHi) and high-energy phosphates were monitored using 31P magnetic resonance spectroscopy in open-chest pigs supported by cardiopulmonary bypass during 10 min of ischemia and reperfusion. Intravenous HOE-642 (2 mg/kg; n = 8) administered before ischemia prevented the increases in diastolic stiffness noted in control pigs ( n = 8), although it did not alter the postischemic peak-elastance or pressure-rate product measured using a distensible balloon within the left ventricle. HOE-642 induced no change in pHi during ischemia but caused significant delays in intracellular realkalinization during reperfusion. HOE-642 did not alter phosphocreatine depletion and repletion but did improve ATP preservation. Na+/H+ exchange inhibition through HOE-642 delays intracellular alkalinization in the myocardium in situ during reperfusion in association with improved diastolic function and high-energy phosphate preservation.

ATP utilization and provision in fast-twitch skeletal muscle during tetanic contractions

1989 ◽  
Vol 257 (4) ◽  
pp. E595-E605 ◽  
Author(s):  
L. L. Spriet
Keyword(s):  
Average Energy ◽  
High Energy ◽  
Energy Costs ◽  
High Energy Phosphates ◽  
Phosphorylase Activity ◽  
Train Duration ◽  
Fast Twitch Muscle ◽  
Fast Twitch

Rat fast-twitch muscles were tetanically stimulated in situ with an occluded circulation to examine ATP utilization and provision during isometric tension production. Plantaris (PL) and gastrocnemius (G) muscles were stimulated for 60 s in four conditions: A) 1.0-Hz train rate, 200-ms train duration at 80 Hz, B) 1.0 Hz (100 ms, 80 Hz), C) 0.5 Hz (100 ms, 80 Hz), and D) 1.0 Hz (200 ms, 40 Hz). Muscles were sampled pre- and post-stimulation for pH, high-energy phosphates, and glycolytic intermediates. Contributions to total ATP utilization (all muscles and conditions) were 64-67% glycolysis, 24-28% phosphocreatine, and 8-9% endogenous ATP. Glycogenolysis and glycolysis were greatest in white G (WG), 40% lower in red G (RG), and intermediate in PL muscles. Average energy costs in conditions A and D were approximately 0.60 mumol ATP/(N.s). Decreasing the train duration to 100 ms in B and the number of tetani to 30 in C increased energy costs to 0.93 +/- 0.05 and 1.26 +/- 0.07 mumol ATP/(N.s). Despite a lower pH, WG glycogenolytic (phosphorylase) activity was constant during condition A, whereas RG activity decreased in the final 30 contractions. Larger accumulations of Pi and inosine monophosphate may account for the maintained phosphorylase activity. Glycolytic (phosphofructokinase, PFK) activity was highest in WG and associated with higher fructose 6-phosphate concentration, greater depletion of ATP and, in later contractions, a higher NH4+ concentration. During tetanic in situ stimulation of fast-twitch muscle, the H+ profiles of phosphorylase and PFK are extended beyond in vitro predictions via the accumulation of positive modulators. This permits significant anaerobic ATP production via the glycolytic pathway despite increasing [H+]. The findings also suggest that lengthening the duration of tetani, generating lower peak tensions, and prolonging relaxation time all contribute to lower energy costs in fast-twitch muscle.

Inhibition of fatty acid metabolism alters myocardial high-energy phosphates in vivo

1994 ◽  
Vol 267 (1) ◽  
pp. H224-H231 ◽  
Author(s):  
G. G. Schwartz ◽  
C. Greyson ◽  
J. A. Wisneski ◽  
J. Garcia
Keyword(s):  
Fatty Acid ◽  
Acid Metabolism ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Ffa Metabolism ◽  
Carnitine Palmitoyltransferase I ◽  
Stimulation Of

We previously observed that isoproterenol (ISO) stimulation of the in situ porcine right ventricle (RV) increases the ratio of phosphocreatine (PCr) to ATP, accompanied by marked augmentation of myocardial free fatty acid (FFA) uptake. We hypothesized that increased FFA uptake and utilization cause the increase in PCr/ATP and that inhibition of FFA metabolism during ISO would prevent such an increase. In open-chest pigs, myocardial oxygen consumption (MVO2) of the RV free wall was increased with ISO (0.15 microgram.kg-1.min-1 iv) in the absence (n = 6) and presence (n = 6) of oxfenicine (65 mg/kg iv), an inhibitor of carnitine palmitoyltransferase I. ISO caused twofold increases in MVO2 and arterial FFA concentration. In the absence of oxfenicine, ISO increased RV FFA uptake from a control of 0.01 +/- 0.01 to 0.11 +/- 0.02 (SE) mumol.g-1.min-1. The PCr/ATP, measured by 31P-nuclear magnetic resonance spectroscopy, rose from 1.75 +/- 0.05 to 2.22 +/- 0.10 (P < 0.05). In the presence of oxfenicine, FFA uptake did not increase with ISO, despite elevated arterial FFA concentration. PCr/ATP fell from 1.65 +/- 0.05 to 1.53 +/- 0.07 (P < 0.01 vs. response without oxfenicine). In four additional pigs, arterial FFA concentration was increased in the absence of ISO by infusion of Intralipid and heparin sodium. PCr/ATP increased in each pig. When oxfenicine was administered with Intralipid, PCr/ATP decreased in each pig. We conclude that increased utilization of FFA raises the RV PCr/ATP ratio in vivo. Inhibition of FFA metabolism prevents the rise in PCr/ATP otherwise observed with ISO or with high arterial FFA.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Intracellular energetics and critical Po2 in resting ischemic human skeletal muscle in vivo

2010 ◽  
Vol 299 (5) ◽  
pp. R1415-R1422 ◽  
Author(s):  
Ian R. Lanza ◽  
Michael A. Tevald ◽  
Douglas E. Befroy ◽  
Jane A. Kent-Braun
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Ex Vivo ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Atp Production ◽  
Resting Muscle

During ischemia and some types of muscular contractions, oxygen tension (Po2) declines to the point that mitochondrial ATP synthesis becomes limited by oxygen availability. Although this critical Po2 has been determined in animal tissue in vitro and in situ, there remains controversy concerning potential disparities between values measured in vivo and ex vivo. To address this issue, we used concurrent heteronuclear magnetic resonance spectroscopy (MRS) to determine the critical intracellular Po2 in resting human skeletal muscle in vivo. We interleaved measurements of deoxymyoglobin using 1H-MRS with measures of high-energy phosphates and pH using 31P-MRS, during 15 min of ischemia in the tibialis anterior muscles of 6 young men. ATP production and intramyocellular Po2 were quantified throughout ischemia. Critical Po2, determined as the Po2 corresponding to the point where PCr begins to decline (PCrip) in resting muscle during ischemia, was 0.35 ± 0.20 Torr, means ± SD. This in vivo value is consistent with reported values ex vivo and does not support the notion that critical Po2 in resting muscle is higher when measured in vivo. Furthermore, we observed a 4.5-fold range of critical Po2 values among the individuals studied. Regression analyses revealed that time to PCrip was associated with critical Po2 and the rate of myoglobin desaturation ( r = 0.83, P = 0.04) but not the rate of ATP consumption during ischemia. The apparent dissociation between ATP demand and myoglobin deoxygenation during ischemia suggests that some degree of uncoupling between intracellular energetics and oxygenation is a potentially important factor that influences critical Po2 in vivo.

Magnetic resonance spectroscopy of high-energy phosphates and lactate immediately after coronary artery bypass surgery

Perfusion ◽  
1998 ◽  
Vol 13 (5) ◽  
pp. 328-333 ◽  
Author(s):  
D NF Harris ◽  
J A Wilson ◽  
S D Taylor-Robinson ◽  
K M Taylor
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Cerebral Ischaemia ◽  
Artery Bypass ◽  
High Energy ◽  
Jugular Bulb ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Intracellular Acidosis ◽  
High Incidence

Hypothermic cardiopulmonary bypass (CPB) is associated with a high incidence of neuropsychological defects, marked cerebral swelling immediately after surgery and jugular bulb desaturation during rewarming. This suggests cerebral ischaemia may occur, but evidence is indirect. We studied four patients with 31P magnetic resonance spectroscopy (MRS) and four with 1H MRS before and immediately after coronary surgery. There was no visible lactate in 1H MR spectra. In 31P MR spectra, the ratio of phosphocreatine to adenosine triphosphate was maintained (before: 2.13 ± 0.86 vs after: 2.57 ± 1.31; mean ± 1 SD) and there was no intracellular acidosis (intracellular pH: 7.1 ± 0.04 vs 7.16 ± 0.08), while phosphocreatine/inorganic phosphate was increased immediately after the operation (2.92 ± 0.37 vs 6.39 ± 2.67, p = 0.03). This suggests rebound replacement of energy stores following recovery from temporary cerebral ischaemia during CPB: intra-operative studies would be needed to test this hypothesis further.

Muscle metabolic responses to exercise above and below the “critical power” assessed using 31P-MRS

2008 ◽  
Vol 294 (2) ◽  
pp. R585-R593 ◽  
Author(s):  
Andrew M. Jones ◽  
Daryl P. Wilkerson ◽  
Fred DiMenna ◽  
Jonathan Fulford ◽  
David C. Poole
Keyword(s):  
Critical Power ◽  
Quadriceps Muscle ◽  
High Energy ◽  
Knee Extension ◽  
Work Rate ◽  
Metabolic Responses ◽  
Time To Exhaustion ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Constant Work Rate

We tested the hypothesis that the asymptote of the hyperbolic relationship between work rate and time to exhaustion during muscular exercise, the “critical power” (CP), represents the highest constant work rate that can be sustained without a progressive loss of homeostasis [as assessed using 31P magnetic resonance spectroscopy (MRS) measurements of muscle metabolites]. Six healthy male subjects initially completed single-leg knee-extension exercise at three to four different constant work rates to the limit of tolerance (range 3–18 min) for estimation of the CP (mean ± SD, 20 ± 2 W). Subsequently, the subjects exercised at work rates 10% below CP (<CP) for 20 min and 10% above CP (>CP) for as long as possible, while the metabolic responses in the contracting quadriceps muscle, i.e., phosphorylcreatine concentration ([PCr]), Pi concentration ([Pi]), and pH, were estimated using 31P-MRS. All subjects completed 20 min of <CP exercise without duress, whereas the limit of tolerance during >CP exercise was 14.7 ± 7.1 min. During <CP exercise, stable values for [PCr], [Pi], and pH were attained within 3 min after the onset of exercise, and there were no further significant changes in these variables (end-exercise values = 68 ± 11% of baseline [PCr], 314 ± 216% of baseline [Pi], and pH 7.01 ± 0.03). During >CP exercise, however, [PCr] continued to fall to the point of exhaustion and [Pi] and pH changed precipitously to values that are typically observed at the termination of high-intensity exhaustive exercise (end-exercise values = 26 ± 16% of baseline [PCr], 564 ± 167% of baseline [Pi], and pH 6.87 ± 0.10, all P < 0.05 vs. <CP exercise). These data support the hypothesis that the CP represents the highest constant work rate that can be sustained without a progressive depletion of muscle high-energy phosphates and a rapid accumulation of metabolites (i.e., H+ concentration and [Pi]), which have been associated with the fatigue process.

Anaerobic energy provision in aged skeletal muscle during tetanic stimulation

1991 ◽  
Vol 70 (4) ◽  
pp. 1787-1795 ◽  
Author(s):  
C. B. Campbell ◽  
D. R. Marsh ◽  
L. L. Spriet
Keyword(s):  
Skeletal Muscle ◽  
Energy Demand ◽  
Energy Charge ◽  
High Energy ◽  
High Energy Phosphates ◽  
Fischer 344 ◽  
Charge Potential ◽  
Anaerobic Energy ◽  
Gastrocnemius Muscles

The effect of age on skeletal muscle anaerobic energy metabolism was investigated in adult (11 mo) and aged (25 mo) Fischer 344 rats. Hindlimb skeletal muscles innervated by the sciatic nerve were stimulated to contract with trains of supramaximal impulses (100 ms, 80 Hz) at a train rate of 1 Hz for 60 s, with an occluded circulation. Soleus, plantaris, and red and white gastrocnemius (WG) were sampled from control and stimulated limbs. All muscle masses were reduced with age (9-13%). Peak isometric tensions, normalized per gram of wet muscle, were lower throughout the stimulation in the aged animals (28%). The potential for anaerobic ATP provision was unaltered with age in all muscles, because resting high-energy phosphates and glycogen contents were similar to adult values. Anaerobic ATP provision during stimulation was unaltered by aging in soleus, plantaris, and red gastrocnemius muscles. In the WG, containing mainly fast glycolytic (FG) fibers, ATP and phosphocreatine contents were depleted less in aged muscle. In situ glycogenolysis and glycolysis were 90.0 +/- 4.8 and 69.3 +/- 2.6 mumol/g dry muscle (dm) in adult WG and reduced to 62.3 +/- 6.9 and 51.5 +/- 5.5 mumol/g dm, respectively, in aged WG. Consequently, total anaerobic ATP provision was lower in aged WG (224.5 +/- 20.9 mumol/g dm) vs. adult (292.6 +/- 7.6 mumol/g dm) WG muscle. In summary, the decreased tetanic tension production in aged animals was associated with a decreased anaerobic energy production in FG fibers. Reduced high-energy phosphate use and a greater energy charge potential after stimulation suggested that the energy demand was reduced in aged FG fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of intracellular acidosis on contractile function in the working rat heart

1987 ◽  
Vol 253 (6) ◽  
pp. H1499-H1505 ◽  
Author(s):  
F. M. Jeffrey ◽  
C. R. Malloy ◽  
G. K. Radda
Keyword(s):  
Stroke Volume ◽  
Intracellular Ph ◽  
Rat Heart ◽  
Contractile Function ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
High Energy Phosphates ◽  
Intracellular Acidosis ◽  
Tension Development ◽  
O2 Delivery

The decrease in myocardial contractility during ischemia, hypoxia, and extracellular acidosis has been attributed to intracellular acidosis. Previous studies of the relationship between pH and contractile state have utilized respiratory or metabolic acidosis to alter intracellular pH. We developed a model in the working perfused rat heart to study the effects of intracellular acidosis with normal external pH and optimal O2 delivery. Intracellular pH and high-energy phosphates were monitored by 31P nuclear magnetic resonance spectroscopy. Hearts were perfused to a steady state with a medium containing 10 mM NH4Cl (extracellular pH, 7.4). The subsequent washout of NH3 from the cytosol generated a slight acidosis (from intracellular pH 7.0 to 6.8) which was associated with little change in the determinants of O2 consumption (rate-pressure product) and O2 delivery (coronary flow). Acidosis induced a substantial decrease in aortic flow and stroke volume which was associated with little change in peak systolic pressure. Results were qualitatively similar at different external [Ca2+] (1.75, 2.5, 3.15 mM) and preload (12 or 21 cmH2O) but were most prominent at the lowest external [Ca2+] and left atrial pressure. In contrast to this model of isolated intracellular acidosis, hearts subject to a respiratory (extracellular plus intracellular) acidosis showed a marked reduction in pressure development. It was concluded that 1) for the same intracellular acidosis the influence on tension development was more pronounced with a combined extra- and intracellular acidosis than with an isolated intracellular acidosis, and 2) stroke volume at constant preload was impaired by intracellular acidosis even though changes in developed pressure were minimal. These observations suggest that isolated intracellular acidosis has adverse effects on diastolic compliance and/or relaxation.

scholarly journals Reductions in mitochondrial O2 consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium

2009 ◽  
Vol 297 (1) ◽  
pp. H223-H232 ◽  
Author(s):  
Qingsong Hu ◽  
Gen Suzuki ◽  
Rebeccah F. Young ◽  
Brian J. Page ◽  
James A. Fallavollita ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Adenine Nucleotides ◽  
Creatine Phosphate ◽  
High Energy ◽  
Atp Depletion ◽  
Hibernating Myocardium ◽  
Wall Thickening ◽  
High Energy Phosphates ◽  
Simulated Ischemia

We performed the present study to determine whether hibernating myocardium is chronically protected from ischemia. Myocardial tissue was rapidly excised from hibernating left anterior descending coronary regions (systolic wall thickening = 2.8 ± 0.2 vs. 5.4 ± 0.3 mm in remote myocardium), and high-energy phosphates were quantified by HPLC during simulated ischemia in vitro (37°C). At baseline, ATP (20.1 ± 1.0 vs. 26.7 ± 2.1 μmol/g dry wt, P < 0.05), ADP (8.1 ± 0.4 vs. 10.3 ± 0.8 μmol/g, P < 0.05), and total adenine nucleotides (31.2 ± 1.3 vs. 40.1 ± 2.9 μmol/g, P < 0.05) were depressed compared with normal myocardium, whereas total creatine, creatine phosphate, and ATP-to-ADP ratios were unchanged. During simulated ischemia, there was a marked attenuation of ATP depletion (5.6 ± 0.9 vs. 13.7 ± 1.7 μmol/g at 20 min in control, P < 0.05) and mitochondrial respiration [145 ± 13 vs. 187 ± 11 ng atoms O2·mg protein−1·min−1 in control (state 3), P < 0.05], whereas lactate accumulation was unaffected. These in vitro changes were accompanied by protection of the hibernating heart from acute stunning during demand-induced ischemia. Thus, despite contractile dysfunction at rest, hibernating myocardium is ischemia tolerant, with reduced mitochondrial respiration and slowing of ATP depletion during simulated ischemia, which may maintain myocyte viability.

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