Effects of hyperventilation on phosphocreatine kinetics and muscle deoxygenation during moderate-intensity plantar flexion exercise.

The effects of controlled voluntary hyperventilation (Hyp) on phosphocreatine (PCr) kinetics and muscle deoxygenation were examined during moderate-intensity plantar flexion exercise. Male subjects (n = 7) performed trials consisting of 20-min rest, 6-min exercise, and 10-min recovery in control [Con; end-tidal Pco(2) (Pet(CO(2))) approximately 33 mmHg] and Hyp (Pet(CO(2)) approximately 17 mmHg) conditions. Phosphorus-31 magnetic resonance and near-infrared spectroscopy were used simultaneously to monitor intramuscular acid-base status, high-energy phosphates, and muscle oxygenation. Resting intracellular hydrogen ion concentration ([H(+)](i)) was lower (P < 0.05) in Hyp [90 nM (SD 3)] than Con [96 nM (SD 4)]; however, at end exercise, [H(+)](i) was greater (P < 0.05) in Hyp [128 nM (SD 19)] than Con [120 nM (SD 17)]. At rest, [PCr] was not different between Con [36 mM (SD 2)] and Hyp [36 mM (SD 1)]. The time constant (tau) of PCr breakdown during transition from rest to exercise was greater (P < 0.05) in Hyp [39 s (SD 22)] than Con [32 s (SD 22)], and the PCr amplitude was greater (P < 0.05) in Hyp [26% (SD 4)] than Con [22% (SD 6)]. The deoxyhemoglobin and/or deoxymyoglobin (HHb) tau was similar between Hyp [13 s (SD 8)] and Con [10 s (SD 3)]; however, the amplitude was increased (P < 0.05) in Hyp [40 arbitrary units (au) (SD 23)] compared with Con [26 au (SD 17)]. In conclusion, our results indicate that Hyp-induced hypocapnia enhanced substrate-level phosphorylation during moderate-intensity exercise. In addition, the increased amplitude of the HHb response suggests a reduced local muscle perfusion in Hyp compared with Con.

Insulin protects against hepatic bioenergetic deterioration induced by cancer cachexia: an in vivo 31P magnetic resonance spectroscopy study.

The bioenergetic effects of cancer cachexia on the livers of male Fischer rats inoculated with a methylcholanthrene-induced sarcoma were assessed using serial in vivo 31P magnetic resonance spectroscopy. Rats were randomized into three groups: tumor-bearing controls (n = 7); an insulin-treated group receiving 2 units/100 g body weight/day starting 21 days after implantation (n = 8); and a chronic insulin-treated group receiving insulin every day after implantation (n = 3). During the 32-day study, serial measurements of food intake, body weight, and tumor volume were taken, and 31P magnetic resonance spectroscopy analyses of the livers were conducted every 7 days after tumor implantation. Neither the short-term nor the chronic insulin treatment regimens stimulated the progress of tumor growth. However, both treatments prevented body weight loss, and the short-term insulin treatment prevented tumor-induced decrease in food intake relative to the control group. Liver bioenergetic deterioration was evaluated from the increase in the ratio of Pi to ATP obtained from the hepatic 31P magnetic resonance spectra. At day 28 postimplantation, control rats exhibited appreciable hepatic bioenergetic deterioration, i.e., a Pi/ATP ratio of 1.41 +/- 0.35 (SE), significantly higher (P < 0.05) than the Pi/ATP ratio for short-term or chronic insulin treatment groups (Pi/ATP 0.92 +/- 0.22 and 0.84 +/- 0.22, respectively) or rats before tumor implantation (Pi/ATP 0.76 +/- 0.14). This insulin-induced bioenergetic protection occurred at any given tumor burden up to at least 10%. Thus, both short-term insulin given just prior to the frank manifestations of cancer cachexia and chronic insulin treatment given throughout tumor growth ameliorated host hepatic bioenergetic deterioration without significantly stimulating tumor growth. Insulin may act by altering the host metabolism (stimulation of liver glucose uptake and utilization, decreased energy-requiring gluconeogenesis, and general protein-sparing action) at the expense of the tumor.

Effect of cancer on the in vivo energy state of rat liver and skeletal muscle.

The effect of increasing tumor burden on host liver and skeletal muscle energy status was studied using P-31 nuclear magnetic resonance spectroscopy (NMR), in rats inoculated with a nonmetastasizing methylcholanthrene-induced sarcoma (TB), and compared to nontumor bearing (NTB) and pair-fed (PF) rats. During the 28-day study, serial measurements of body weight, food intake, and tumor volume were obtained. Using a 0.9-cm double-turn surface coil, weekly NMR measurements were obtained from liver and skeletal muscle. An increasing ratio of [Pi]/[ATP] was used as one measure of intracellular energy depletion. [Pi]/[ATP] in NTB rats remained constant over time at 0.78 +/- 0.10 in liver, and 0.30 +/- 0.10 in skeletal muscle. In TB rats, the [Pi]/[ATP] ratio increased significantly in liver (P = 0.00002) and skeletal muscle (P = 0.04) with increasing tumor burden. In PF rats, no significant change occurred in [Pi]/[ATP] in liver or skeletal muscle, indicating that declining food intake was not responsible for the change in [Pi]/[ATP] seen in TB rats. Surface-coil spectroscopy of liver and skeletal muscle permits serial measurement of visceral energy stores. Increasing tumor burden results in early, ongoing depletion of energy stores as reflected by increasing [Pi]/[ATP] in these organs.

An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy.

BACKGROUND: In this study, phospholipid metabolism of cell membranes, high-energy phosphate metabolism, and intracellular free magnesium concentration in the prefrontal cortex of first-episode drug-naive schizophrenic patients and medicated schizophrenic patients at different stages of illness were compared with those of controls. METHODS: Localized in vivo phosphorus 31 magnetic resonance spectra of the left dorsolateral prefrontal cortex of 11 drug-native, eight newly diagnosed medicated, and 10 chronic medicated patients with schizophrenia were compared with controls of similar gender, education, parental education, and handedness. RESULTS: Significantly decreased levels of phosphomonoesters in drug-native, newly diagnosed medicated, and chronic medicated patients and significantly increased levels of phosphodiesters in drug-native patients were observed when compared with controls. There were no significant differences in the levels of high-energy phosphate metabolites between the groups except for a significant decrease in the inorganic orthophosphate levels of newly diagnosed medicated patients. A significant increase in the intracellular free magnesium concentration was observed in drug-naive, newly diagnosed medicated, and chronic medicated patients compared with controls. There were no correlations between the patients' negative and positive symptoms and the observed phosphorus-containing metabolites. CONCLUSIONS: A reduction in precursors of membrane phospholipid are observed during the early and chronic stages of the schizophrenia illness, and breakdown products of membrane phospholipids are increased at the early stage of illness before medication treatment.

Hypophosphatemia and respiratory failure: prolonged abnormal energy metabolism demonstrated by nuclear magnetic resonance spectroscopy.

Hypophosphatemia has been shown to cause acute respiratory failure. The mechanism is believed to be due to decreased high-energy substrate availability at the cellular level leading to respiratory muscle dysfunction. However, direct measurement of these substrates has not been previously studied. A patient with hypophosphatemic respiratory failure is described in whom phosphocreatine and pH were continuously monitored using nuclear magnetic resonance spectroscopy. This revealed a defect in muscle metabolism that required several weeks to recover despite prompt correction of the serum phosphate level.

Membrane phospholipid metabolism and schizophrenia: an in vivo 31P-MR spectroscopy study.

Membrane phospholipid metabolism was studied with 31P magnetic resonance spectroscopy in the left dorsal prefrontal cortex of 19 male, medicated, schizophrenic patients and compared to 18 normal male controls matched in age, education and parental education level. The schizophrenic patients had significantly decreased phosphomonoester levels (PMEs, metabolites predominantly involved in the synthesis of membrane phospholipids). Phosphodiester levels (PDEs, breakdown products of membrane phospholipids) were not statistically different in schizophrenic patients compared to controls. However, a significant increase in the PDE levels was observed in the newly diagnosed patient subgroup. This observed pattern of the PMEs and PDEs would be consistent with the presence of an abnormal neurodevelopment early in the illness of schizophrenia.

Effects of exercise on muscle transverse relaxation determined by MR imaging and in vivo relaxometry.

The purpose of this study was to determine the effects of intense exercise on the proton transverse (T(2)) relaxation of human skeletal muscle. The flexor digitorium profundus muscles of 12 male subjects were studied by using magnetic resonance imaging (MRI; 6 echoes, 18-ms echo time) and in vivo magnetic resonance relaxometry (1,000 echoes, 1.2-ms echo time), before and after an intense handgrip exercise. MRI of resting muscle produced a single T(2) value of 32 ms that increased by 19% (P < 0.05) with exercise. In vivo relaxometry showed at least three T(2) components (>5 ms) for all subjects with mean values of 21, 40, and 137 ms and respective magnitudes of 34, 49, and 14% of the total magnetic resonance signal. These component magnitudes changed with exercise by -44% (P < 0.05), +52% (P < 0.05), and +23% (P < 0.05), respectively. These results demonstrate that intense exercise has a profound effect on the multicomponent T(2) relaxation of muscle. Changes in the magnitudes of all the T(2) components synergistically increase MRI T(2), but changes in the two shortest T(2) components predominate.

Transient changes in muscle high-energy phosphates during moderate exercise.

The purpose of this study was to use 31P-nuclear magnetic resonance spectroscopy to examine changes in wrist flexor muscle metabolism during the transitions from rest to steady-state exercise (on-transient) and back to rest (off-transient). Five healthy young males (mean age 25 +/- 2 yr) performed a series of square-wave exercise tests, each consisting of 5 min of moderate-intensity work followed by a 5-min recovery period. The subjects repeated this protocol six times, and each individual's results were pooled before analysis. ATP and intracellular pH did not change significantly during exercise or recovery. Phosphocreatine (PCr) declined progressively at the onset of exercise, reaching a plateau after approximately 2 min. A reciprocal increase in Pi occurred during the onset of exercise. During the recovery period PCr was resynthesized, whereas Pi returned to resting levels. The data were plotted as a function of time and fit with both first- and second-order exponential growth or decay models; however, the second-order model did not significantly improve the fit of the data. Time constants for the first-order model of the on- and off-transient responses for both PCr and Pi were approximately 30 s. These values are nearly identical to the time constants for oxygen consumption during submaximal exercise that have been reported previously by several authors. The results of this study show that the metabolism of muscle PCr during steady-state exercise and recovery can be accurately described by a monoexponential model and, further, suggest that a first-order proportionality exists between metabolic substrate utilization and oxygen consumption.

Coincident thresholds in intracellular phosphorylation potential and pH during progressive exercise.

Dynamic changes in intracellular phosphocreatine (PCr), inorganic phosphate (Pi), and pH in human forearm muscle were studied from rest through heavy exercise by means of a ramp exercise protocol and 31P nuclear magnetic resonance spectroscopy. Eighteen healthy volunteers performed an isotonic wrist flexion exercise of repeated contractions at a frequency of 0.5 Hz. Work rate was increased continuously (ramped) at approximately 0.13 W each minute from 0.34 to 1.5 W or until fatigue. Pi/PCr was used as an estimate of the cellular phosphorylation potential of the muscle. Exercise caused a progressive increase in Pi/PCr with an initial slow and later fast component. The transition between these components was distinct and corresponded to the onset of pH decline in all subjects. These changes in Pi/PCr and pH were best fit (P less than 0.05) by a piecewise linear regression model with a break point or threshold. Repeated ramp testing of six subjects showed that the threshold was reproducible (r = 0.98). The results of this study demonstrate the existence of an intracellular metabolic threshold and suggest that indirect threshold measures (lactate and ventilatory thresholds) may reflect events at the cellular level.

Kinetics of pulmonary oxygen uptake and muscle phosphates during moderate-intensity calf exercise.

The purpose of this study is to directly compare the dynamic responses of phosphocreatine (PCr) and P(i) to those oxygen uptake (VO2) measured at the lung during transitions to and from moderate-intensity exercise. Changes in PCr and P(i) were measured by 31P-nuclear magnetic resonance spectroscopy, and changes in VO2 were measured breath by breath by mass spectroscopy during transitions to and from moderate-intensity square-wave ankle plantar flexion exercise in 11 subjects (7 men and 4 women; mean age 27 yr). Three repeated transitions were averaged for improvement in signal-to-noise ratio of phosphate data, and 12 transitions were averaged for VO2 measurements. Averaged transitions were fit with a monoexponential curve for determination of the time constant (tau) of the responses. Mean tau values for on transients of PCr, P(i), and phrase 2 VO2 were 47.0, 57.7, and 44.5 s, respectively, whereas means tau values for off transients were 44.8, 42.1, and 33.4 s, respectively. There were no significant differences between tau values for phosphate- and VO2-measured transients or on and off transients. The similarity of on and off kinetics supports linear first-order respiratory control models. Measurement of phase 2 pulmonary VO2 kinetics to and from moderate-intensity small-muscle-mass exercise reflect muscle phosphate kinetics (and muscle oxygen consumption).

An in vivo proton magnetic resonance spectroscopy study of schizophrenia patients.

The level of the 1H metabolites in the left dorsolateral prefrontal region of schizophrenia patients at different stages of illness were measured in vivo using a short echo time spectroscopy technique. During both the early onset and chronic stages, normal N-acetylaspartate levels were observed, which suggests that these patients had no significant neuronal cell damage and/or loss. The in vivo measurements of glutamate in the first-episode, drugnaive patients failed to provide convincing evidence for the involvement of the glutamatergic system in the dorsolateral prefrontal region. Significant differences in the glutamine levels were observed in the acutely medicated and chronic patients; however, the interpretation of these differences requires further study.

Nature of the N6 region of the adenosine receptor in guinea-pig ileum and rat vas deferens.

This study explored the nature of the purine domain N6 regions of the presynaptic adenosine receptors of guinea-pig ileum and of rat vas deferens. The experimental design tested a model of these receptors which is complementary to the structure of the N6 substituent of the classical A1 adenosine receptor agonist N6-1-phenyl-2R-propyladenosine, (R-PIA). Assays of activity employed ileal segments or the midportions of vasa deferentia under continuous electrical stimulation at 0.2 Hz. Structure activity correlations compared the EC-50s for twitch inhibition. As shown previously, R-PIA was 60-80 times more potent than its S diastereomer, the resultant of the positive contribution of propyl C-3 to activity as well as the negative influence of steric hindrance exerted by propyl C-3 of the S diastereomer. Other pairs of diastereomers having a chiral center adjacent to N6 showed that the stereoselectivity of the PIAs was generalizable. Biological activity appears to reside wholly in the N6 alkyl moiety; the phenyl or aryl groups of similar size actually diminished potency. The receptor subregions interacting with propyl C-1 and C-3 of R-PIA are each large enough to accommodate two - but not three - methylene residues, each methylene contributing additively to activity. Hydrophobicity is a prominent attribute of the propyl C-1 and C-3 subregions. The potencies of these analogs as inhibitors of presynaptic transmission in ileum or vas deferens are covariant with inhibition of [3H]N6-cyclohexyl-adenosine binding to rat cerebral cortical membranes. Singular exceptions to this generalization may represent organ- or species-dependent differences in receptor fine structure.

Spectroscopy of the isolated rabbit heart: effects of perfusion with oxygenated crystalloid cardioplegia at 4 degrees C and 20 degrees C.

Factors that limit survival of explanted cardiac allografts include intracellular acidosis and loss of high energy phosphates. This study was undertaken to determine if these processes could be retarded by specific interventions during organ storage and to determine the capabilities of phosphorus-31 (31P) nuclear magnetic resonance spectroscopy to monitor these intracellular changes noninvasively. Thirty-six excised rabbit hearts were studied in six groups according to the storage temperature and conditions of their perfusion: nonperfused, aerated perfusate or oxygenated perfusate, each at 4 degrees C and 20 degrees C. 31P spectra were continuously obtained starting 20 mins post explanation and continuing for at least 5 h. The resulting data were analyzed to determine metabolite concentration and intracellular pH. The phosphodiesters, inorganic phosphates and phosphomonoesters, as well as the phosphocreatine and adenosine triphosphate peaks, could be reproducibly resolved. Comparisons at 0.5, 1, 2, 3, 4, and 5 h indicated that high energy phosphates were the most quickly degraded, and intracellular acidosis progressed most rapidly in nonperfused hearts at 20 degrees C. Hearts perfused with oxygenated cardioplegic solution at 4 degrees C showed significantly prolonged preservation of high energy phosphates and delayed development of intracellular acidosis. It was concluded that continuous infusion of oxygenated cardioplegic solution improves preservation of high energy phosphates at low temperatures, and that 31P magnetic resonance spectroscopy can be used to monitor these important intracellular changes rapidly and nonivasively, permitting serial studies on the same heart. This technique substantially reduced the number of animals needed for the study (36 were used in this study rather than the 216 required by traditional techniques).

A model for in vivo serial investigation of hepatic metabolism using 31P nuclear magnetic resonance spectroscopy.

We have developed an animal model which allows serial, in vivo, evaluation of high energy phosphate metabolism in rat liver, using 31P nuclear magnetic resonance spectroscopy (MRS). In seven rats, the left lobe of the was surgically relocated into a subcutaneous position. The animals recovered quickly from the surgery and continued to thrive. Localization of the liver was obtained using simple surface coil technology. Typical MRS data acquisition times were less than 45 minutes. After the 28 days, the livers showed both normal histology and 31P metabolic measures.

An in vivo animal model to study chronic adriamycin cardiotoxicity: a P-31 nuclear magnetic resonance spectroscopy investigation.

The mechanism responsible for adriamycin induced cardiotoxicity is unknown. We have developed an in vivo rabbit model for use with P-31 nuclear magnetic resonance spectroscopy which allows serial investigations of the drug's effects on myocardial metabolism. Eleven animals were studied over a 10 week period and changes in intracellular pH and phosphate metabolites were observed. The magnitude of changes in pH and inorganic phosphate were the best indicators of the severity of the cardiomyopathy. The results are consistent with an adriamycin induced degeneration of myofibrils rather than a severe metabolic impairment.

Post-polio fatigue: a 31P magnetic resonance spectroscopy investigation.

Changes in high energy phosphates (HEP) and intramuscular pH during exercise were measured in 17 patients with post-polio fatigue and in 28 healthy controls using 31P magnetic resonance spectroscopy (MRS). Subjects performed a dynamic hand grip exercise at low and high intensity. Mean changes in the HEP and pH showed no significant differences between the groups, although the post-polio group's response was highly variable. Six patients showed evidence of a lower lactate accumulation during the high intensity exercise when compared with controls. These data suggest that the whole body fatigue experienced by polio survivors is not related to any systemic metabolic abnormality.

A comparison of MR-based attenuation correction in PET versus SPECT.

Attenuation correction (AC) is a critical step in the reconstruction of quantitatively accurate positron emission tomography (PET) and single photon emission computed tomography (SPECT) images. Several groups have proposed magnetic resonance (MR)-based AC algorithms for application in hybrid PET/MR systems. However, none of these approaches have been tested on SPECT data. Since SPECT/MR systems are under active development, it is important to ascertain whether MR-based AC algorithms validated for PET can be applied to SPECT. To investigate this issue, two imaging experiments were performed: one with an anthropomorphic chest phantom and one with two groups of canines. Both groups of canines were imaged from neck to abdomen, one with PET/CT and MR (n = 4) and the other with SPECT/CT and MR (n = 4), while the phantom was imaged with all modalities. The quality of the nuclear medicine reconstructions using MR-based attenuation maps was compared between PET and SPECT on global and local scales. In addition, the sensitivity of these reconstructions to variations in the attenuation map was ascertained. On both scales, it was found that the SPECT reconstructions were of higher fidelity than the PET reconstructions. Further, they were less sensitive to changes to the MR-based attenuation map. Thus, MR-based AC algorithms that have been designed for PET/MR can be expected to demonstrate improved performance when used for SPECT/MR.

Effects of recovery time on phosphocreatine kinetics during repeated bouts of heavy-intensity exercise.

The purpose of this study was to examine the kinetics of phosphocreatine (PCr) breakdown in repeated bouts of heavy-intensity exercise separated by three different durations of resting recovery. Healthy young adult male subjects (n = 7) performed three protocols involving two identical bouts of heavy-intensity dynamic plantar flexion exercise separated by 3, 6, and 15 min of rest. Muscle high-energy phosphates and intracellular acid-base status were measured using phosphorus-31 magnetic resonance spectroscopy. In addition, the change in concentration of total haemoglobin (Delta[Hb(tot)]) and deoxy-haemoglobin (Delta[HHb]) were monitored using near-infrared spectroscopy. Prior exercise resulted in an elevated (P < 0.05) intracellular hydrogen ion ([H(+)](i)) after 3 min (182 +/- 72 (SD) nM; pH 6.73) and 6 min (112 +/- 19 nM; pH 6.95) but not after 15 min (93 +/- 8 nM; pH 7.03) compared to pre-exercise in Con (90 +/- 3 nM; pHi 7.05). The on-transient time constant (tau) of the PCr primary component was not different amongst the exercise bouts. However, in each of the subsequent bouts the amplitude of the PCr slow component, total PCr breakdown, and rise in [H(+)](i) were reduced (P < 0.05). At exercise onset, Delta[Hb(tot)] was increased (P < 0.05) and the Delta[HHb] kinetic response was slowed (P < 0.05) in the exercise after 3 min, consistent with improved muscle perfusion. In summary, neither the level of acidosis or muscle perfusion at the onset of exercise appeared to be directly related to the time course of the on-transient PCr primary component or the magnitude of the PCr slow component during subsequent bouts of exercise.