Delayed ischaemia after subarachnoid haemorrhage: a role for small vessel changes.
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Brain Ischemia↗
Biomedical subjects
B Rajagopalan
Publications and source records attributed to B Rajagopalan.
Abnormal ATP turnover in rat leg muscle during exercise and recovery following myocardial infarction.
OBJECTIVE: Clinical and animal studies show increased acidification of skeletal muscle during exercise in heart failure, implying increased anaerobic metabolism, and impaired recovery from exercise, implying defective oxidative function. This study aimed to define the quantitative relationship between these changes in exercise and recovery and relate skeletal muscle bioenergetics to cardiovascular function. METHODS: Wistar rats were studied four weeks after myocardial infarction or a sham operation. 31P magnetic resonance spectroscopy of the hind leg muscle was used to estimate rates of oxidative and non-oxidative ATP synthesis from changes in pH and phosphocreatine concentration during sciatic nerve stimulation and to estimate the maximum rate of mitochondrial ATP synthesis from the kinetics of phosphocreatine recovery after stimulation. RESULTS: Following myocardial infarction, cardiac function was abnormal, with evidence of left ventricular hypertrophy, failure, and diminished arterial pressure. There was impaired phosphocreatine recovery, suggesting an approximate halving of the maximum rate of mitochondrial ATP synthesis. CONCLUSIONS: The response to exercise of the infarct group was abnormal and was quantitatively consistent with the reduced maximum rate of mitochondrial ATP synthesis inferred from recovery, the oxidative deficit during exercise being made up by increased glycogenolysis, causing sufficient acidification to prevent an appropriate increase in [ADP].
Adenosine Triphosphate↗
Phosphorus-31 magnetic resonance spectra reveal prolonged intracellular acidosis in the brain following subarachnoid hemorrhage.
Subarachnoid hemorrhage may be complicated by cerebral ischemia which, though reversible initially, can progress to an irreversible neurological deficit. 31P magnetic resonance spectroscopy, which can determine intracellular pH and thus detect areas of ischemia noninvasively, was applied to 10 patients on 30 occasions, at various times after subarachnoid hemorrhage. In 5 of them, there were focal areas of the brain in which the intracellular pH was reduced to < 6.8 compared with the normal range of 7.05 +/- 0.05. Consciousness was impaired in 4 of these patients. Repeat studies in these 4 patients showed that intracellular pH remained abnormally low for several days but eventually returned toward normal. The return of intracellular pH to normal paralleled an improvement in clinical condition in each case. In the fifth patient with lowered regions of intracellular pH, there had been an impaired level of consciousness and a transient focal deficit prior to the single study. In the other 5 patients there were no areas of reduced pHi even though in 3 of them there was intraventricular or cisternal blood shown on brain computerized tomography. In 2 of these 3 patients there were no abnormal neurological signs at the time of the magnetic resonance study. The third patient had a dense and persistent hemiparesis. The remaining two patients had no abnormal neurological signs at any stage. We suggest that the areas of acidosis may reflect ischemia which is potentially reversible. Since the technique is noninvasive, sequential 31P magnetic resonance spectroscopy of the brain offers a method of detecting cerebral ischemia and, more importantly, of assessing methods of treatment.
Acidosis↗
Metabolic abnormalities in skeletal muscle after myocardial infarction in the rat.
1. The effect of experimental myocardial infarction on exercise and recovery of rat skeletal muscle was studied using 31P n.m.r. 4 weeks post-operatively. 2. Myocardial infarction (12 +/- 3% of left ventricular volume), insufficient to produce haemodynamic manifestations of heart failure, was without significant effect on exercise bioenergetics of skeletal muscle. 3. Citrate synthase activity was reduced by 17% in the infarcted animals and there was a marked slowing of the rate of phosphocreatine recovery after infarction (half-time 0.7 +/- 0.1 min to 1.6 +/- 0.2 min) in the absence of evidence of left ventricular failure or hypertrophy. 4. The study of recovery bioenergetics could provide a more sensitive measure of mitochondrial function than exercise, where no bioenergetic abnormality was detected. 5. Myocardial infarction can produce evidence of mitochondrial abnormality in skeletal muscle in the absence of haemodynamic compromise.
Adenosine Diphosphate↗
Training partially reverses skeletal muscle metabolic abnormalities during exercise in heart failure.
Using 31P-magnetic resonance spectroscopy during and after exercise, we studied whether forearm metabolic responses to exercise were improved by 1 mo of training in 10 males with heart failure. In the control (untrained) arm, there were no changes in any of the measured variables. In the trained arm, maximal voluntary contraction increased 6% (P = 0.05). During incremental exercise, duration increased 19% (P < 0.05) and submaximal responses improved for pH (6.78 +/- 0.13 pretraining vs. 6.85 +/- 0.17 posttraining; P < 0.01) and PCr/(PCr+Pi) (where PCr is phosphocreatine; 0.48 +/- 0.09 pretraining vs. 0.52 +/- 0.07 posttraining; P < 0.01). The PCr resynthesis rate increased by 48% (P < 0.01), and estimated effective maximal rate of mitochondrial ATP synthesis increased by 37% (P < 0.05). Endurance exercise duration increased by 67% (P < 0.01), and submaximal levels of PCr/(PCr+Pi) (P < 0.05) and pH (P = 0.07) improved. The PCr resynthesis rate (P < 0.01) and the effective maximal rate of mitochondrial ATP synthesis (P < 0.05) also improved. These findings document that impaired oxidative capacity of skeletal muscle can be improved by local muscle training in heart failure, which is compatible with the hypothesis that a part of the abnormality present in heart failure may be due to inactivity.
Adenosine Triphosphate↗
Effects of cardiac transplantation on bioenergetic abnormalities of skeletal muscle in congestive heart failure.
BACKGROUND: Patients with advanced heart failure have bioenergetic abnormalities of skeletal muscle metabolism during exercise. Using 31P magnetic resonance spectroscopy, we sought to determine whether skeletal metabolic responses to exercise are normalized by orthotopic cardiac transplantation. METHODS AND RESULTS: Four groups were studied: healthy normal volunteers (n = 9), subjects awaiting heart transplantation (n = 10), subjects < 6 months (mean, 4 months) after transplant (n = 9), and subjects > 6 months (mean, 15 months) after transplant (n = 8). None of the posttransplant patients had biopsy evidence of rejection at the time of study. There were no significant differences in age, preoperative functional class, or symptom duration among the three patient groups. Metabolic responses were monitored in the dominant arm during incremental weight pull exercise and 10 minutes of recovery by 31P magnetic resonance spectroscopy, with measurement of pH and the phosphocreatine (PCr)/(PCr + inorganic phosphate [Pi]) ratio, an index of PCr concentration. In addition, based on recovery data, the rate of PCr resynthesis was calculated as a measure of oxidative metabolism that is independent of work level, recruitment, or muscle mass, and the effective maximal rate of mitochondrial ATP synthesis (Vmax) was determined. Analysis was by ANOVA. There were no differences between groups in pH or PCr/(PCr + Pi) at rest. Compared with the normal control group, the pretransplant group had a decreased exercise duration (11.3 +/- 2.5 versus 15.0 +/- 1.3 minutes, P = .02), a lower submaximal exercise PCr/(PCr + Pi) ratio (0.58 +/- 0.11 versus 0.76 +/- 0.08, P < .05), a reduced PCr resynthesis rate (13 +/- 6 versus 22 +/- 9 mmol/L per minute, P < .05), and a lower calculated Vmax (26 +/- 14 versus 53 +/- 26 mmol/L per minute, P < .05). In the group studied early after transplantation, all the changes noted in the pretransplant group persisted and were if anything somewhat worse. In the group studied late after transplantation, there was a significant improvement in the PCr resynthesis rate compared with the early-posttransplant group (27 +/- 6 late versus 15 +/- 6 mmol/L per minute early, P < .05) and statistically nonsignificant trends toward improvements in submaximal exercise pH (6.86 +/- 0.24 late versus 6.72 +/- 0.24 early) and submaximal PCr/(PCr + Pi) ratio (0.56 +/- 0.14 late versus 0.44 +/- 0.15 early) and Vmax (45 +/- 21 late versus 33 +/- 15 mmol/L per minute early). However, compared with normal subjects, exercise duration and submaximal PCr/(PCr + Pi) were still reduced in the late-posttransplant group. CONCLUSIONS: Despite successful heart transplantation, skeletal muscle abnormalities of advanced heart failure persist for indefinite periods, although partial improvement occurred at late times. The persistent abnormalities may contribute to the reduced exercise capacity that is present in most patients after transplantation.
Energy Metabolism↗
Uraemic muscle metabolism at rest and during exercise.
The effect of chronic renal failure and the accompanying hyperphosphataemia on muscle metabolism at rest and during exercise was examined in a group of undialysed patients suffering from chronic renal failure. 31P magnetic resonance spectroscopy was used to measure intracellular high-energy phosphates in resting muscle as well as changes in the concentrations of these metabolites during exercise and recovery from exercise. In resting muscle, cell [Pi] rose with plasma [Pi], and free [ADP] changed such that the phosphorylation potential ([ATP]/([ADP] x [Pi])), which probably controls mitochondrial oxidation in resting muscle, was preserved despite a wide variation in cell [Pi]. The maximal oxidative capacity of the muscle was calculated from the kinetics of phosphocreatine recovery after exercise. There was no reduction in uraemic muscle oxidative capacity compared to control muscle. This contrasts with our finding of a reduction in the mitochondrial oxidative capacity in the muscle of patients established on dialysis, suggesting that a substance crucial for mitochondrial function or substrate supply to mitochondria is removed by dialysis.
Adenosine Diphosphate↗
Assessment of hepatic iron overload in thalassemic patients by magnetic resonance spectroscopy.
The transverse relaxation time of water protons is shortened by the presence of iron. This shortening depends on the amount and the environment of iron in the sample. We have developed a method for measuring short transverse relaxation time noninvasively by magnetic resonance spectroscopy. To evaluate magnetic resonance spectroscopy as a means of assessing hepatic iron content in patients with transfusional iron overload, we compared the results obtained with this method with those obtained by other means of assessing total body iron content. The correlation between the liver biopsy iron concentration and 1/transverse relaxation time was highly significant (r = 0.95, p < 0.004, n = 6) for iron loads up to 3% dry weight. The correlation between serum ferritin and 1/transverse relaxation time was also significant, but the correlation coefficient was much lower (r = 0.67, p < 0.002, n = 20). The correlation between 24-hr urinary iron excretion and 1/transverse relaxation time was not significant, nor was that between AST and 1/transverse relaxation time. We conclude that magnetic resonance spectroscopic determination of the transverse relaxation time of hepatic water is an accurate method of measuring liver iron content, especially when the iron content is below 3%. Because it is a noninvasive method that is associated with negligible side effects, it could provide clinicians with an excellent means of assessing the effectiveness of the various therapeutic strategies used in the management of patients with iron overload.
Adolescent↗
A phase I study of the left-shifting agent BW12C79 plus mitomycin C and the effect on the skeletal muscle metabolism using 31P magnetic resonance spectroscopy.
BW12C79 stabilizes the oxyhemoglobin molecule resulting in a reversible left-shift of the oxygen saturation curve. The activity of a number of bioreductive anticancer drugs, such as mitomycin C, may be enhanced under hypoxic conditions. Twenty-four patients with various malignancies received BW12C79 and mitomycin C. BW12C79 was administered i.v. with a loading dose (20-50 mg/kg) over 1 h followed by a maintenance infusion of 4 mg/kg/h for 5 h. Percentage modification of the oxyhemoglobin (degree of left-shift) was dose related with maximum modification of 56% and was maintained for the duration of maintenance infusion of BW12C79. Hemoglobin electrophoresis showed a fast moving band consistent with the BW12C79-oxyhemoglobin complex. Side effects at the top dose level comprised headache, nausea/vomiting, vein irritation, and myocardial ischemia. One other patient suffered from an acute encephalopathy of unknown etiology a few days following BW12C79. 31P magnetic resonance spectroscopy of exercising calf muscles showed increased breakdown of high energy phosphate stores and a greater reduction in pH. Recovery of the high energy phosphate stores after exercise was slow. These results were consistent with reduced oxygen supply due to either a left shift of the oxygen saturation curve and/or reduced muscle blood flow. BW12C79 did not interfere with the pharmacokinetics of mitomycin C. In conclusion, this phase I study demonstrates the feasibility of achieving a significant left shift in the oxygen saturation curve in cancer patients which is maintained for at least 5 h with acceptable toxicity. The maximum tolerated dose of BW12C79 was 50 mg/kg loading infusion followed by a maintenance infusion of 4 mg/kg/h. Magnetic resonance spectroscopy results were consistent with reduced supply of oxygen to exercising skeletal muscle. BW12C79 may be of potential benefit as an adjunct to bioreductive drugs in the treatment of solid tumors.
Adult↗
Oral phosphate supplements reverse skeletal muscle abnormalities in a case of chronic fatigue with idiopathic renal hypophosphatemia.
A 57-yr-old man presented with a long history of undiagnosed fatigue but no evidence of bone disease. He was noted to have hypophosphatemia due to an idiopathic phosphaturia. Marked abnormalities of exercising skeletal muscle detected by phosphorus magnetic resonance spectroscopy and by plasma metabolite measurements were consistent with mitochondrial dysfunction. Oral phosphate supplements restored plasma phosphate concentration and muscle biochemistry to normal and produced considerable improvement in symptoms and exercise tolerance, although the phosphate concentration in muscle was only marginally low and increased little by treatment. We conclude that hypophosphatemia should be excluded in unexplained fatigue.
Adenosine Diphosphate↗
Quantitative analysis of defects of mitochondrial oxidation during recovery from exercise.
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Adenosine Diphosphate↗
Effect of tri-iodothyronine administration on skeletal muscle intracellular pH in the rat.
1. Male Wistar rats were injected with tri-iodothyronine intraperitoneally for either 3 or 5 days. 2. Using 31P nuclear magnetic resonance spectroscopy, skeletal muscle intracellular bioenergetics of the leg were studied at rest and during sciatic nerve stimulation. 3. Tri-iodothyronine caused intracellular alkalinization of the cell, implying that administration of tri-iodothyronine induces an alteration in the set point for the sodium/proton antiport, the chief controller of intracellular pH. 4. During stimulation, there was less acidification of the skeletal muscle cell in the tri-iodothyronine-injected rats, implying either increased intrinsic buffering capacity of the muscle or increased proton efflux possibly due to increased activity of the sodium/proton antiport. 5. Effective proton efflux from the skeletal muscle cell may be sensitive to circulating levels of tri-iodothyronine.
Animals↗
Abnormalities in skeletal muscle metabolism in cyanotic patients with congenital heart disease: a 31P nuclear magnetic resonance spectroscopy study.
1. Exercise tolerance is impaired in congenital heart disease. To examine the possible contribution of abnormalities in skeletal muscle bioenergetics, we used 31P nuclear magnetic resonance spectroscopy to investigate muscle metabolism in 10 subjects with congenital heart disease with cyanosis (median age 17.3 years) and in eight healthy age-matched control subjects. Spectra were collected from the gastrocnemius muscle at rest and during exercise and recovery. 2. In resting muscle there were significant elevations in cytosolic pH and in the cytosolic concentration of inorganic phosphate in the patients, and a strong positive correlation between cytosolic pH and blood haemoglobin concentration in all subjects. 3. During plantar flexion exercise the patients showed increased phosphocreatine depletion and cytosolic acidification over a shorter duration of exercise. The rise in calculated cytosolic ADP concentration was similar in both groups. 4. After cessation of exercise, the recovery half-times of phosphocreatine, ADP and phosphate were two to three times longer in the patients, and the initial rate of phosphocreatine resynthesis (a measure of the rate of mitochondrial ATP synthesis) was half the control value, consistent with a reduction in the effective maximum rate of oxidative ATP synthesis (expressed per volume of muscle). Also, recovery was faster in the young control subjects than in our earlier studies of older healthy control subjects. 5. The high phosphate concentration in resting muscle and the abnormalities found in exercise and recovery are consistent with a decrease in oxidative ATP synthesis due to reduced oxygen delivery by the blood in chronic hypoxaemia. The correlation between cytosolic pH and haemoglobin concentration remains to be explained.
Adolescent↗
No evidence of mitochondrial abnormality in skeletal muscle of patients with iron-deficient anaemia.
OBJECTIVES: Patients with iron deficiency anaemia complain of decreased exercise capacity. We asked whether this is due to defective oxidative ATP synthesis in skeletal muscle as a consequence of reduced blood oxygen content and/or intrinsic mitochondrial abnormalities. DESIGN: We used 31P magnetic resonance spectroscopy to examine skeletal muscle bioenergetics in iron-deficient patients and in age- and sex-matched controls. SETTING: The patients were recruited from the primary care population. SUBJECTS: We studied seven symptomatic female iron-deficient patients (aged 32-70 years) with haemoglobin (Hb) concentration, [Hb], 8.0 g dl-1. Six had menorrhagia, the cause in the seventh patient remained undiagnosed. Results were compared with those of 8 healthy female controls (aged 25-48 years) with mean [Hb] 13.7 g dl-1. RESULTS: The right calf muscle was by studied 31P magnetic resonance spectroscopy in a 1.9 T super-conducting magnet. We measured the intracellular concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), adenosine triphosphate (ATP) and the intracellular pH at rest, during plantar flexion exercise and during recovery from exercise. Exercise duration was reduced in the patients, yet end-exercise PCr/(PCr+Pi) was higher and adenosine diphosphate (ADP) lower than in controls. After exercise, initial PCr recovery was slowed but this was probably because of the lower cytosolic ADP concentration. CONCLUSIONS: Mitochondrial ATP synthesis was not limited by oxygen supply or an intrinsic mitochondrial defect. Therefore, the reduced exercise capacity seen in iron deficiency could be due to central causes and not to skeletal muscle metabolic abnormalities.
Adenosine Triphosphate↗
The effect of iron deficiency on skeletal muscle metabolism of the rat.
Using 31P magnetic resonance spectroscopy we compared skeletal muscle bioenergetics in Wistar rats made chronically anaemic by being fed a diet deficient in iron for 6 weeks with chronically iron deficient animals given a normal diet as well as 5 mg iron dextran at 2 or 7 days before experimentation. Spectra of the gastrocnemius muscle were taken at rest and during stimulation of the sciatic nerve at 2 Hz for 10 min. Relative concentrations of intracellular phosphate (Pi), phosphocreatine (PCr) and ATP were determined. Iron deficiency increased PCr breakdown and production of acid in stimulated skeletal muscle. Recovery of PCr and Pi concentrations after exercise was slow. These metabolic changes are consistent with either a reduction in supply of oxygen to the muscle cell or altered oxidative phosphorylation by the mitochondria. The latter may be mediated by defective function of iron-containing proteins crucial in oxidative phosphorylation and this is suggested both by the observation that treatment with iron, sufficient to correct the anaemia, does not completely reverse the metabolic changes and that there is a different time course for such metabolic improvements and the observed increase in haemoglobin concentration.
Adenosine Diphosphate↗
Skeletal muscle metabolism during exercise and recovery in patients with respiratory failure.
BACKGROUND: Patients with respiratory failure have early fatiguability which may be due to limitation of oxygen supply for oxidative (mitochondrial) ATP synthesis. Skeletal muscle in exercise and recovery was studied to examine the effect of chronic hypoxia on mitochondrial activity in vivo. METHODS: The skeletal muscle of five patients with respiratory failure (PaO2 < 9 kPa) was studied by phosphorus-31 magnetic resonance spectroscopy and compared with 10 age and sex matched controls. Patients lay in a 1.9 Tesla superconducting magnet with the gastrocnemius muscle overlying a six cm surface coil. Spectra were acquired at rest, during plantar flexion exercise, and during recovery from exercise. Relative concentrations of inorganic phosphate (Pi), phosphocreatine (PCr) and ATP were measured from peak areas, and pH and free ADP concentration were calculated. For the start of exercise, the rates of PCr depletion and estimated lactic acid production were calculated. For the post exercise recovery period, the initial rate of PCr recovery (a quantitative measure of mitochondrial ATP synthesis), the apparent Vmax for mitochondrial ATP synthesis (calculated from initial PCr resynthesis and the end exercise ADP concentration which drives this process), and the recovery half times of PCr, Pi, and ADP (also measures of mitochondrial function) were determined. RESULTS: Considerably greater and faster PCr depletion and intracellular acidosis were found during exercise. This is consistent with limitation of oxygen supply to the muscle and might explain the early fatiguability of these patients. There was no abnormality in recovery from exercise, however, suggesting that mitochondria function normally after exercise. CONCLUSIONS: These results are consistent with one or more of the following: (a) decreased level of activity of these patients; (b) changes in the fibre type of the muscle; (c) decreased oxygen supply to the muscle during exercise but not during recovery. They are not consistent with an intrinsic defect of mitochondrial ATP synthesis in skeletal muscle in respiratory failure.
Adenosine Triphosphate↗
Effect of chronic uraemia on skeletal muscle metabolism in man.
Fatigue and lethargy, common symptoms in uraemia, have been attributed to many factors. To assess possible bioenergetic contributions to this, we examined the forearm muscle of five patients in end-stage renal failure using 31P-magnetic resonance spectroscopy. There was a small increase in the ratio of intracellular inorganic phosphate to ATP in resting muscle, suggesting an increased cytosolic phosphate concentration. During exercise, increased phosphocreatine breakdown was accompanied by rapid intracellular acidification and an increase in calculated lactic acid accumulation in the muscle of the uraemic subjects, suggesting glycolysis dominating over oxidative phosphorylation as a source of ATP. After exercise, the half-time of phosphocreatine (PCr) recovery was longer in the uraemic subjects, suggesting diminished mitochondrial function. The initial rate of PCr resynthesis was not significantly decreased, but when account was taken of the high cytosolic ADP concentration (which drives mitochondrial oxidative ATP synthesis) the calculated maximum oxidative capacity was significantly reduced in the uraemic subjects. Thus there was evidence of mitochondrial dysfunction in uraemia due either to limitation of oxygen supply, reduced mitochondrial content, or an intrinsic mitochondrial defect. This resulted in increased phosphocreatine depletion and increased glycolytic ATP production during exercise and there was partial compensation of the mitochondrial abnormality by increased ADP concentration. In three of these patients studied after elevation of haemoglobin with erythropoeitin (from 8 to 12 g/dl), initial phosphocreatine breakdown and lactic acid accumulation during exercise were normalized, while exercise duration and calculated maximum oxidative capacity remained significantly abnormal. This suggests that anaemia contributes to these metabolic abnormalities but does not fully explain them.
Adenosine Triphosphate↗
Endoplasmic reticulum: the major contributor to the PDE peak in hepatic 31P-NMR spectra at low magnetic field strengths.
31P-NMR spectra of liver in vivo, subcellular fractions and model systems were acquired in order to characterise further the hepatic phosphodiester peak seen at low magnetic field strengths previously shown to be predominantly due to phospholipid bilayers. The data obtained in this study in vitro suggested that the phospholipid membranes of the endoplasmic reticulum provide the dominant contribution to this phosphodiester peak. Support for this hypothesis was provided by experiments on rats. Phenobarbitone, which is known to induce proliferation of the endoplasmic reticulum produced a considerable increase in intensity of the phosphodiester peak in liver spectra in vivo.
Animals↗