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PubMed1985

The separation of phosphocreatine from creatine, and pH determination in frog muscle by natural abundance 13C-NMR.

Phosphocreatine can be separated from creatine in superfused frog muscle by natural abundance 13C-NMR, based on the difference in resonance frequency of their guanidino carbons. After taking into account the longitudinal relaxation times and nuclear Overhauser enhancement factors, the integrated peak areas of the guanidino carbons could be used for determination of the phosphocreatine-to-creatine ratio in the muscle. The pH dependence of the chemical shift of the C-2 carbon in the histidine ring of carnosine was used for estimation of the intracellular pH in the intact muscle.

Animals↗
PubMed1976

The action of phosphocreatine and fructose 1,6-diphosphate on blood in vitro.

Blood in vitro has been used to evaluate the effects of phosphocreatine and fructose 1,6-diphosphate on the adenylate cycle. These compounds, following different metabolic pathways, increased the ATP concentration, phosphocreatine through a direct action on the adenylic phosphate cycle and fructose 1,6-diphosphate mainly by it glycolytic effect.

Adenosine Diphosphate↗
PubMed1979

Apparent inhibition of pyruvate kinase by phosphocreatine and phosphoarginine.

1. Addition of a non-dialysable, heat-labile and acid-precipitable factor which was not absorbed on DEAE-cellulose column, could restore the sensitivity of the chromatographed muscle pyruvate kinase from Marphysa sanguinea towards phosphocreatine inhibition. 2. This factor, being non-specific as it acts on pyruvate kinase isozymes from different sources, demonstrated high creatine kinase activity. 3. High concentrations of ADP, creatine or replacement of ADP with IDP/UDP or high pH abolished the inhibition indicating that the inhibition was mediated through creatine kinase by depleting ADP. 4. Apparent inhibition of phosphocreatine was related to the relative activities of 3 intracellular enzymes--pyruvate kinase, creatine kinase and adenosine triphosphatase.

Animals↗
PubMed1988

The cardiac contractile failure induced by chronic creatine and phosphocreatine deficiency.

Rats were fed a diet containing beta-guanidinopropionic acid (GP), an inhibitor of creatine transport. After 6 to 8 weeks of feeding the myocardial creatine (Cr) and phosphocreatine (PCr) stores were severely depleted while ATP content was normal. Hearts of GP-treated rats perfused according to Neely's working heart model revealed clear cardiac contractile failure: the maximal work capacity at a stepwise increase in resistance as well as the maximal oxygen consumption were 32 to 40% less in the GP group. The cardiac failure in GP-treated working hearts was associated with a rise in the left ventricular diastolic pressure, which could cause a diminished cardiac output probably due to impaired LV filling. The extent of the contractile failure was found to depend on functional load and on the degree of Cr (PCr) substitution. The energy fluxes through creatine kinase measured by the 31P-NMR saturation transfer technique were diminished by a factor of two after substitution of 90% of creatine, but still exceeded the rate of ATP turnover. The results are compatible with the concept of phosphocreatine pathway for intracellular energy transport and show that PCr is an important high energy phosphate compound for cardiac contractile function.

Animals↗
PubMed1995

Adaptation to chronic hypoxia alters cardiac metabolic response to beta stimulation: novel face of phosphocreatine overshoot phenomenon.

The dynamics of the changes in myocardial phosphorylated compound contents (inorganic phosphate: Pi; phosphocreatine: PCr; ATP) induced by 10(-6)M isoprenaline administration was studied, using 31P-NMR spectroscopy, in hearts isolated from rats adapted for three weeks to normobaric hypoxia (10% of oxygen). When compared with the behaviour of control hearts, the inotropic response to Ca2+ and isoprenaline was larger in the hearts from hypoxic rats, while the oxygen consumption was similar. During administration of isoprenaline, a decrease in the myocardial contents of high energy phosphates (ATP and PCr) and an accumulation of Pi was observed in both groups. After action of isoprenaline, the hearts from hypoxic animals showed significant overshoot of PCr, that was not seen in hearts from normoxic rats. The mechanisms of these alterations are analysed and the phosphocreatine overshoot, as well as the increased rate pressure product to oxygen consumption ratio, are assumed to indicate more efficient energy conversion in the heart from animals adapted to chronic hypoxia.

Acclimatization↗
PubMed1998

Impaired aerobic glycolysis in muscle phosphofructokinase deficiency results in biphasic post-exercise phosphocreatine recovery in 31P magnetic resonance spectroscopy.

Using 31P magnetic resonance spectroscopy, energy metabolism in calf muscles of two patients with biochemically and genetically proven muscular phosphofructokinase deficiency, and an asymptomatic heterozygote was monitored during isometric foot plantarflexion performed under aerobic and anaerobic conditions and in the aerobic recovery phases. In the heterozygote only a moderate alteration from normal was found in terms of an elevated ATP demand during exercise. In the homozygote, hexose phosphates, indicated as phosphomonoesters, increased dramatically during contraction. Phosphomonoester accumulation resulted in consumption of free inorganic phosphate (P(i)). During ischemic exercise the absence of glycolytic ATP formation resulted in a linear time course of phosphocreatine breakdown and a moderate alkalinization. During the recovery, phosphocreatine resynthesis showed a biphasic time course, indicating that mitochondrial function itself was not directly affected. At first glance, the early depletion of P(i) below initial resting levels and the rate of phosphate splitting from sugar phosphates seemed to become the limiting factor for the rate of the oxidative phosphorylation and creatine kinase reaction. However, the actual concentrations of P(i) and ADP estimated at the onset of delay were too high to exclusively explain the dramatic delay in PCr resynthesis. For this reason, a reduced turnover of the citric acid cycle was assumed, which was caused by the complete absence of glycolysis in PFK deficiency patients. Furthermore, results from PFK deficiency patients were compared with previous findings from myophosphorylase deficiency patients in the literature.

Adenosine Triphosphate↗
PubMed2001

On the mechanisms of neuroprotection by creatine and phosphocreatine.

Creatine and phosphocreatine were evaluated for their ability to prevent death of cultured striatal and hippocampal neurons exposed to either glutamate or 3-nitropropionic acid (3NP) and to inhibit the mitochondrial permeability transition in CNS mitochondria. Phosphocreatine (PCr), and to a lesser extent creatine (Cr), but not (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK801), dose-dependently ameliorated 3NP toxicity when applied simultaneously with the 3NP in Mg2+-free media. Pre-treatment of PCr for 2 or 5 days and Cr for 5 days protected against glutamate excitotoxicity equivalent to that achieved by MK801 post-treatment. The combination of PCr or Cr pre-treatment and MK801 post-treatment did not provide additional protection, indicating that both prevented the toxicity attributable to secondary glutamate release. To determine if Cr or PCr directly inhibited the permeability transition, mitochondrial swelling and depolarization were assayed in isolated, purified brain mitochondria. PCr reduced the amount of swelling induced by calcium by 20%. Cr decreased mitochondrial swelling when inhibitors of creatine kinase octamer-dimer transition were present. However, in brain mitochondria prepared from rats fed a diet supplemented with 2% creatine for 2 weeks, the extent of calcium-induced mitochondrial swelling was not altered. Thus, the neuroprotective properties of PCr and Cr may reflect enhancement of cytoplasmic high-energy phosphates but not permeability transition inhibition.

Animals↗
PubMed1977

31P nuclear magnetic relaxation studies of phosphocreatine in intact muscle: determination of intracellular free magnesium.

31P nuclear magnetic relaxation rates for phosphocreatine in intact frog gastrocnemius were compared with those observed in model solutions at 4 degrees, a temperature at which muscle maintains its physiological state for at least 5 hr. Both nuclear Overhauser effect and spin-lattice relaxation rate (1/T1) experiments indicate that dipole-dipole interactions from the dominant relaxation path for 31P in intact muscle and model solutions, independent of phosphocreatine and Mg concentrations. Spin-spin relaxation rates (1/T2) measured by modified Carr-Purcell-Melboom-Gill spin-echo experiments suggest the importance of scalar coupling modulated by chemical exchange with free Mg. From these results, we estimate the free intracellular Mg in intact muscle as 4.4 mM and demonstrate that 31P T2 experiments can be used as a tool for studying free Mg levels with minimum disturbance of the intact cell.

Animals↗
PubMed1985

Phosphocreatine content and intracellular pH of calf muscle measured by phosphorus NMR spectroscopy in occlusive arterial disease of the legs.

Energy metabolism of calf muscle was assessed non-invasively by phosphorus (31P) NMR spectroscopy in eleven patients with symptomatic arterial occlusion and in seven matched controls. Phosphocreatine (PCr) content and pH values decreased during non-ischaemic foot exercise to lower values in severely afflicted patients but in all patients, as a group, they were not significantly decreased compared to controls. In contrast, recovery from ischaemic exercise (arterial occlusion by a tourniquet) demonstrated significant differences between patients and controls. Intracellular pH and PCr recovered more slowly in patients than in controls; PCr recovery proceeded exponentially with a recovery half-time of 203 +/- 74 s in patients compared to 36.7 +/- 5.5 s in controls (P less than 0.02). Phosphocreatine (PCr) recovery after ischaemic exercise correlated significantly with the degree of arterial stenoses as assessed by Doppler ultrasound (r = 0.739, P = 0.019) and by angiography (r = 0.885, P = 0.005), suggesting that the degree of large vessel stenoses limits the postischaemic increase in mitochondrial oxidative phosphorylation. Reactive blood flow after ischaemia failed to correlate with PCr recovery or with the degree of arterial stenoses. Phosphorus (31P) NMR spectroscopy provides, therefore, quantitative parameters of muscle energy metabolism in patients with peripheral arterial occlusions.

Arterial Occlusive Diseases↗
PubMed2000

Linear relation between cerebral phosphocreatine concentration and memory capacities during permanent brain vessel occlusions in rats.

The present study investigates the interrelation between cerebral energy state and memory capacities in a rat model of stepwise cerebral vessel occlusions. After acute and subchronic permanent vessel occlusions, cortical energy metabolites (ATP, phosphocreatine, ADP, AMP) were detected by high-pressure liquid chromatography (HPLC) analysis, and the effects on learning, memory, and cognitive behavior were evaluated using a hole-board test. The results of the study demonstrated a drastic decrease in energy-rich phosphates by 33% for phosphocreatine and by 44% for ATP after acute vessel occlusions. In addition, rat working and reference memories were strikingly decreased to about 5% of controls. In contrast, two weeks after four-vessel occlusion, the energy state was almost completely restored to control levels. However, a significant decrease in memory capacities was observed in subchronic state. In summary, this study has demonstrated a close linear relationship (p < 0.001) between an impaired cerebral energy state and brain memory dysfunction after acute and permanent cerebral four-vessel occlusion. Thus, this animal model of stepwise reduction of the cerebral blood supply may reflect some clinically relevant processes occurring during cerebrovascular and neurodegenerative diseases.

Adenosine Diphosphate↗
PubMed1996

Changes in ATP, phosphocreatine, and 16 metabolites in muscle stimulated for up to 96 hours.

Rabbit tibialis anterior muscles were stimulated continuously at 10 Hz for periods ranging from 2 min to 96 h and were analyzed for energy reserves and metabolic intermediates. Glycogen, ATP and phosphocreatine fell rapidly during the first 5 min of stimulation. Glycogen continued to fall to very low levels, whereas ATP and phosphocreatine rose, reaching 70% of control by 1 h, despite ongoing stimulation. After 2 h, glycogen also increased, regaining control levels in 4 days. Glucose rose to 4.5 times control in 30 min and still exceeded 2.5 times control at 24 h. In the first 2 min, glycolytic intermediates, glucose 6-phosphate (G-6-P), fructose 1,6-bisphosphate, lactate, and pyruvate more than doubled and then returned to control levels or below. Malate and 3-glycerophosphate rose 600 and 200%, respectively. Both of these compounds participate in shuttling reducing equivalents from cytoplasm into mitochondria. Citrate and alpha-ketoglutarate underwent much more modest changes. Glucose 1,6-bisphosphate (G-1,6-P2) fell to one-third of control by 2 h and then rose dramatically at 4 h. At 4 days it was still twice control. The 6-phosphogluconate (6PG) doubled at 2 min, then rose to 12 times control at 2 h, fell somewhat, and peaked at 16 times control at 24 h. Aspartate and alanine both exhibited a biphasic rise in concentration, whereas glutamate fell to 30% in 15 min and rose slowly after 4 h. The rise in glucose was interpreted to be the consequence of rapid glycogenolysis together with inhibition of hexokinase by G-1,6-P2 and elevated G-6-P. Paradoxically, glycogen resynthesis apparently occurred when the glycogen synthase stimulator, G-6-P, was very low, and the glycolysis stimulator, G-1,6-P2, was high. Although G-1,6-P2 is an inhibitor of 6PG dehydrogenase, the timing of the changes in G-1,6-P2 and 6PG levels suggests that the accumulation of 6PG was initiated by some other influence.

Adenosine Triphosphate↗
PubMed1993

Physical training attenuates phosphocreatine and long-chain acyl-CoA alterations in diabetic rat heart.

This study was designed to assess the effect of physical training on high-energy phosphate levels in the heart of diabetic rats. Diabetes was induced with streptozocin (50 mg/kg), and exercise training was carried out on a treadmill with a progressive 10-wk program. Plasma glucose levels at the end of the training program showed only a small improvement of the diabetic state in trained animals (21.7 +/- 1.3 vs. 24.4 +/- 0.8 mmol/l; P < 0.05). The lower heart rate observed in sedentary diabetic rats (279 +/- 6 vs. 356 +/- 5 beats/min; P < 0.001) was improved by physical training (301 +/- 8 beats/min; P < 0.05 vs. sedentary diabetics). Significantly lower phosphocreatine levels were found in sedentary diabetic rats (12.0 +/- 0.7 mumol/g dry wt) than in sedentary control rats (15.0 +/- 0.9 mumol/g dry wt; P < 0.05) but not in trained diabetic rats (13.7 +/- 0.7 mumol/g dry wt). ATP levels were not affected by diabetes but were increased by training. The increased long-chain acyl-CoA levels in sedentary diabetic rats (146 +/- 7 vs. 119 +/- 8 mumol/g dry wt in sedentary control rats; P < 0.05) were improved by training (138 +/- 6 mumol/g dry wt; P > 0.05 vs. sedentary control rats). These data indicate that the diminution in phosphocreatine levels observed in the heart tissue of chronically diabetic rats can be attenuated by an exercise training program.

Acyl Coenzyme A↗
PubMed1998

Phosphocreatine hydrolysis during submaximal exercise: the effect of FIO2.

There is evidence that the concentration of the high-energy phosphate metabolites may be altered during steady-state submaximal exercise by the breathing of different fractions of inspired O2 (FIO2). Whereas it has been suggested that these changes may be the result of differences in time taken to achieve steady-state O2 uptake (V(O2)) at different FIO2 values, we postulated that they are due to a direct effect of O2 tension. We used 31P-magnetic resonance spectroscopy during constant-load, steady-state submaximal exercise to determine 1) whether changes in high-energy phosphates do occur at the same V(O2) with varied FIO2 and 2) that these changes are not due to differences in V(O2) onset kinetics. Six male subjects performed steady-state submaximal plantar flexion exercise [7.2 +/- 0.6 (SE) W] for 10 min while lying supine in a 1.5-T clinical scanner. Magnetic resonance spectroscopy data were collected continuously for 2 min before exercise, 10 min during exercise, and 6 min during recovery. Subjects performed three different exercise bouts at constant load with the FIO2 switched after 5 min of the 10-min exercise bout. The three exercise treatments were 1) FIO2 of 0.1 switched to 0.21, 2) FIO2 of 0.1 switched to 1.00, and 3) FIO2 of 1.00 switched to 0.1. For all three treatments, the FIO2 switch significantly (P </= 0.05) altered phosphocreatine: 1) 55.5 +/- 4.8 to 67.8 +/- 4.9% (%rest); 2) 59.0 +/- 4.3 to 72.3 +/- 5.1%; and 3) 72.6 +/- 3.1 to 64.2 +/- 3.4%, respectively. There were no significant differences in intracellular pH for the three treatments. The results demonstrate that the differences in phosphocreatine concentration with varied FIO2 are not the result of different V(O2) onset kinetics, as this was eliminated by the experimental design. These data also demonstrate that changes in intracellular oxygenation, at the same work intensity, result in significant changes in cell homeostasis and thereby suggest a role for metabolic control by O2 even during submaximal exercise.

Adult↗
PubMed1992

Early time course of N-acetylaspartate, creatine and phosphocreatine, and compounds containing choline in the brain after acute stroke. A proton magnetic resonance spectroscopy study.

BACKGROUND AND PURPOSE: The early time course after acute stroke of cerebral N-acetylaspartate, creatine and phosphocreatine, and compounds containing choline was studied in vivo by means of localized water-suppressed proton magnetic resonance spectroscopy. METHODS: Eight patients with acute stroke were studied serially in the acute phase, 1 week after, and 2-4 weeks after the onset of clinical symptoms. Ten healthy volunteers served as controls. A stimulated echo (STEAM) sequence was used for measurement of the brain metabolites in a volume of interest located within the infarcted area as visualized by magnetic resonance imaging. For quantification, the unsaturated water signal was used as the internal standard. Regional cerebral blood flow in the infarcted area was measured relative to a symmetrically located unaffected area by means of single-photon emission computed tomographic scanning, using 99mTc-labeled d,l-hexamethylenepropyleneamine oxime as the flow tracer. RESULTS: Relative regional cerebral blood flow was considerably reduced in the infarcted area in the acute phase. After 1 week, hyperemia was seen in all but one patient. The N-acetylaspartate content was significantly reduced, with the loss appearing to occur between 6 and 24 hours after the stroke incident. The reduction in N-acetylaspartate content was greater in the central part than in the peripheral part of the infarcted area. Creatine and phosphocreatine were also reduced in the infarcted area, whereas no significant change was seen in the choline content. CONCLUSIONS: Assuming that N-acetylaspartate content reflects neuronal survival or loss, our results may suggest that treatment procedures with restoration of blood flow to severely ischemic areas should be initiated within the first 6 hours after stroke onset.

Acute Disease↗
PubMed1996

Nongenomic effects of aldosterone on phosphocreatine levels in human calf muscle during recovery from exercise.

Nongenomic in vitro effects of aldosterone on the sodium-proton antiport and intracellular second messengers have been described in human mononuclear leukocytes, vascular smooth muscle cells, and endothelial cells. To test the potential physiological relevance of these effects, an in vivo 31P magnetic resonance spectroscopy study on the human calf at rest and during exercise was performed in 10 healthy volunteers receiving either 1 mg aldosterone or placebo iv in a double blind, randomized, cross-over trial. Spectra were analyzed for phosphocreatine, ATP, phosphomonoesters, inorganic intracellular phosphate, and intracellular pH. Resting values remained unchanged by aldosterone. After isometric contraction of the calf (50% body weight for 3 min), phosphocreatine recovered to significantly higher levels after application of aldosterone compared with placebo. Other parameters were not significantly changed by aldosterone. Effects appeared immediately after isometric contraction and, thus, occurred within 8 min of aldosterone administration. They are, therefore, likely to represent the first contemporary evidence of nongenomic in vivo effects of aldosterone in man. These findings also point to an involvement of aldosteron in the acute stress adaptation of cellular oxidative metabolism in human muscle physiology.

Adult↗
PubMed2001

[Determination of phosphocreatine in muscular tissues by high performance liquid chromatography].

The quantitation of energy stores(phosphocreatine, PCr) is of paramount importance in the study of living-tissues metabolism. This is more so in the heart, which depends to a very great extent on an uninterrupted aerobic metabolism to maintain its normal function. Availability of data on myocardial energy stores is, therefore, indispensable for assessing the responses of heart to drugs or stresses such as ischemia and hypoxemia. A simple and rapid method for the determination of phosphocreatine in muscular tissues by RP-HPLC has been developed. The chromatographic conditions were as follows: Zorbax XDB-C18 column(150 mm x 4.6 mm i.d., 5 microns), V(20 mmol/L KH2PO4 and 2 mmol/L tetrabutyl ammonium phosphate): V(acetonitrile) = 96:4(pH 5.8) mobile phase and UV detector at 215 nm. PCr in muscular tissues was extracted with 0.4 mol/L HClO4. The calibration curve showed a good linearity in 5 mg/L-100 mg/L(r = 0.9992). The average recovery was 99.34%. The limit of detection was 2 mg/L. The verified results demonstrated that this method is precise, accurate and can be used for determination of PCr in muscular tissue.

Animals↗
PubMed1976

Pharmacological analysis of regulation of phosphocreatine and ATP metabolism in resting skeletal muscle.

Phosphocreatine and ATP metabolism in the gastrocnemius muscle of rats was studied using 32P. Infusion of acetylcholine decreased utilization of energy in the resting muscle, probably as a result of lowered tonus of the resting muscle in analogy to the changes following muscle relaxation with tubocurarine or denervation. Isoprenaline, adrenaline and noradrenaline accelerated incorporation of 32P in phosphocreatine and ATP and depleted their reserves, and phenylephrine had an opposite effect. Ligation of the adrenals slowed the rate of this metabolism. Presumably regulation of energetic metabolism and energy consumption in resting skeletal muscle is dependent on two mechanisms, one of which is connected witly with liberation of adrenaline and its access to the muscle.

Acetylcholine↗