Biomedical subjects

G K Radda

Publications and source records attributed to G K Radda.

At least 199 records · Page 11Linked to original sources

PubMed1991

Spatially localized magnetic resonance spectroscopy of the brains of normal and asphyxiated newborns.

Phase-modulated rotating frame imaging is a modification of magnetic resonance spectroscopy, which uses a linear radiofrequency field gradient to obtain spatially localized biochemical information. Phase-modulated rotating frame imaging was used to study regional cerebral energy metabolism in the brains of 9 normal newborns and 25 newborns after birth asphyxia. Relative concentrations of phosphorus-containing metabolites and intracellular pH were determined for brain tissue at three specified depths below the brain surface for all neonates. Wide variations in metabolite ratios were seen among normal neonates, and considerable metabolic heterogeneity was demonstrated in individual neonates by depth-resolved spectroscopy. Asphyxiated neonates with severe hypoxic-ischemic encephalopathy and a poor neurodevelopmental outcome showed the expected rise in inorganic orthophosphate and fall in phosphocreatine concentrations in both global and spatially localized spectra. Phase-modulated rotating frame imaging showed that metabolic derangement was less in superficial than in deeper brain tissue. The inorganic orthophosphate-adenosine triphosphate ratio from 1 to 2 cm below the brain surface was more accurate than any global metabolite ratio for the identification of neonates with a poor short-term outcome. These data are consistent with the known vulnerability of subcortical brain tissue to hypoxic-ischemic injury in the full-term neonate.

Adenosine Triphosphate↗

PubMed1990

Hyperthyroidism results in increased glycolytic capacity in the rat heart. A 31P-NMR study.

We have investigated the metabolic adaptations that occur in the thyroxine-treated rat heart. Rats were made hyperthyroid by daily intra-peritoneal injections of thyroxine (35 micrograms/100 g body weight) over seven days. 31P-NMR investigations of isolated glucose-perfused isometric hearts showed that thyroxine treatment caused an increase in Pi (from 4.9 mumols.(g dry wt.)-1 in control hearts to 11.7 mumols.(g dry wt.)-1 in hyperthyroid hearts), a decrease in phosphocreatine (from 36.5 mumols.(g dry wt.)-1 to 21.8 mumols.(g dry wt.)-1) with no change in ATP or ADP concentrations under the same conditions of cardiac work. The unidirectional exchange flux Pi----ATP was measured by saturation transfer NMR in hyperthyroid rat hearts. This exchange (which has been shown to contain a significant glycolytic component) increased by 2.2-fold in thyroxine-treated hearts in comparison to control hearts (to 3.6 mumols.(g dry wt.)-1.s-1, from 1.6 mumols.(g dry wt.)-1.s-1). In parallel experiments, NMR analysis of extracts from hyperthyroid rat hearts showed significantly elevated levels of glucose 6-phosphate, and fructose 6-phosphate. Measurements of enzyme activities isolated from hyperthyroid and control tissue showed a 40% increase in phosphofructokinase activity. These data together with the increased concentration of Pi show that both glycolytic and glycogenolytic fluxes are increased in the hyperthyroid rat heart. This metabolic adaptation may be necessary to cope with the increased number and activity of Na+/K(+)-ATPase pumps that occur in response to thyroxine treatment.

Adenosine Diphosphate↗

PubMed1990

Spin-spin relaxation of the phosphodiester resonance in the 31P NMR spectrum of human brain. The determination of the concentrations of phosphodiester components.

The phosphodiester peak in 31P nuclear magnetic resonance spectra of human brain in vivo is often the most prominent feature of the spectrum. We have demonstrated that this resonance exhibits bi-exponential spin-spin relaxation, giving relaxation times of 2 and 10 ms. We interpret this in terms of the two components which make up the peak, bilayer lipids and the small cytosolic phosphates glycerophosphoethanolamine and glycerophosphocholine. Using the relaxation times and the relative peak heights of the two components we have also been able to quantitate the concentration of the bilayer lipids as 20-40 times that of ATP.

Brain Chemistry↗

PubMed1990

Spatially resolved changes in diabetic rat skeletal muscle metabolism in vivo studied by 31P-n.m.r. spectroscopy.

Phase-modulated rotating-frame imaging (p.m.r.f.i.), a localization technique for 31P-n.m.r. spectroscopy, has been applied to obtain information on the heterogeneity of phosphorus-containing metabolites and pH in the skeletal muscle of control and streptozotocin-diabetic rats. Using this method, the metabolic changes in four spatially resolved longitudinal slices (where slice I is superficial and slice IV is deep muscle) through the ankle flexor muscles have been investigated at rest and during steady-state isometric twitch-contraction at 2 Hz. At rest, intracellular pH was lower, and phosphocreatine (PCr)/ATP was higher, throughout the muscle mass in diabetic compared with control animals. The change in PCr/ATP in diabetic muscle correlated with a decrease in the chemically determined ATP concentration. During the muscle stimulation period, the decrease in pH observed in diabetic muscle at rest was maintained, but not exacerbated, by the contractile stimulus. Stimulation of muscle contraction caused more marked changes in PCr/(PCr + Pi), PCr/ATP and Pi/ATP in the diabetic group. These changes were most evident in slice III, which contains the greatest proportion of fast glycolytic-oxidative (type IIa) fibres, in which statistically significant differences were observed for all metabolite ratios. The results presented suggest that some degree of heterogeneity occurs in diabetic skeletal muscle in vivo with respect to the extent of metabolic dysfunction caused by the diabetic insult and that regions of the muscle containing high proportions of type IIa fibres appear to be most severely affected.

Adenosine Triphosphate↗

PubMed1990

Metabolic consequences of positive inotropy in rat and guinea-pig hearts.

The metabolic and physiological responses of hearts from male rats and guinea-pigs to isoprenaline and SK&F 94120 (a phosphodiesterase III inhibitor), have been studied. Doses which gave similar chronotropic stimulation gave different inotropic responses. In both species, isoprenaline generated a greater increase in developed tension than SK&F 94120. With both drugs the inotropic response in the rat was less than than in the guinea-pig. 31P-NMR investigation of high-energy phosphate levels showed reduction in PCr concentration and an accompanying acidosis in the isoprenaline-perfused rat heart only. In both species, lactate production was stimulated by SK&F 94120 but not by isoprenaline. These results are discussed with reference to G-protein activation of ion channels and differences in Ca2+ handling by the two species.

Acidosis↗

PubMed1990

Role of phosphocreatine in energy transport in skeletal muscle of bullfrog studied by 31P-NMR.

To evaluate the energy-shuttle hypothesis of the phosphocreatine/creatine kinase system, diffusion rates for ATP, phosphocreatine and flux through the creatine kinase reaction were determined by 31P-NMR in resting bullfrog biceps muscle. The diffusion coefficient of phosphocreatine measured by 31P-pulsed gradient NMR was 1.4-times larger than ATP in the muscle, indicating the advantage of phosphocreatine molecules for the intracellular energy transport. The flux of the creatine kinase reaction measured by 31P-saturation transfer NMR was 3.6 mmol/kg wet wt. per s in the resting muscle. The flux is equal to the turnover rate of ATP, ADP, phosphocreatine and creatine molecules, therefore, the life-times of these substrates and the average distance traversed after the life-times by the diffusing molecules were calculated using the diffusion coefficients obtained by 31P-NMR. The mean square length of one-dimensional diffusion was 22 microns in ATP molecules and the minimum diffusion length was 1.8 microns in ADP molecules. The latter was calculated using free ADP concentration, 30 mumol/kg wet wt., obtained from the equilibrium constant of the creatine kinase reaction and the diffusion coefficient assumed to be the same of ATP in muscle. Similar diffusion lengths of ADP were calculated using the reported values for the flux of the creatine kinase reaction in heart and smooth-muscle. The diffusion lengths of all substrates involved in the creatine kinase reaction were larger than the radii of myofibrils. Therefore, in the muscles with an alternating arrangement of mitochondria and myofibrils, such as heart and certain skeletal muscles, ATP and ADP molecules can move freely between myofibrils and mitochondria without the aid of the creatine kinase reaction; thus, we conclude that the energy-shuttle hypothesis is not obligatory for energy transport between the mitochondria and the myofibrils.

Adenosine Triphosphate↗

PubMed1990

Multiple quantum filtered 23Na NMR spectroscopy in the perfused heart.

It has been proposed that multiple quantum filtered (MQF) 23Na NMR spectroscopy may distinguish between sodium in the intra- and extracellular spaces, in vivo, and without the requirement for toxic shift reagents. We have investigated the origin of such signals in perfused rat hearts, using shift reagents to discriminate between NMR signals from the two compartments. We find that the observed MQF signal arises predominantly from the extracellular space in the normal heart, and from the intracellular space in the ischaemic heart. However, the quenching effect of the shift reagent may hide some of the extracellular MQF signal, especially during ischaemia. Estimates of intracellular and extracellular relaxation times are obtained and possible mechanisms of the interaction discussed.

Animals↗

PubMed1990

Persistent metabolic sequelae of severe head injury in humans in vivo.

Six patients who had suffered severe non-penetrating high velocity head injuries were investigated with phosphorus (31P) magnetic resonance spectroscopy (MRS) to determine, non-invasively, long-term alteration in intracellular biochemistry. The normal subjects were found to have a constant intracellular pH (pHi, 7.03 +/- 0.03) with depth into the brain. The adenosine triphosphate (ATP, 3.46 +/- 0.66 mmol/L of brain tissue), inorganic phosphate (Pi, 1.15 +/- 0.41 mmol/L) and phosphomonester (PME, 2.76 +/- 1.0 mmol/L) tissue concentrations did not alter significantly with depth into normal brain. The phosphocreatine (PCr, 2 cm = 5.21 +/- 1.25, 5 cm = 4.85 +/- 1.49 mmol/L) was slightly reduced, whilst phosphodiesters (PDE, 2 cm = 9.53 +/- 2.6, 5 cm = 14.41 +/- 4.2 mmol/L) rose significantly between tissue comprising mainly of gray (2 cm) and white matter (5 cm). In comparison the contra-lateral hemisphere to the side of worst spasticity showed significant changes a considerable time after injury (6-18 months). The intracellular metabolite tissue concentrations were all reduced by 30% (ATP 2.53 +/- 1.0 mmol/L, PCr 3.44 +/- 0.8 mmol/L) with PDE reduced most significantly at depth (5 cm = 8.4 +/- 3.4 mmol/L), compatible with the cerebral atrophy seen in these patients. In white matter the pHi also decreased with depth (2 cm = 7.03 +/- 0.03, 5 cm = 6.89 +/- 0.05). The reduction in pHi so long after injury is difficult to explain in these steady-state conditions. A structural abnormality, such as a disorder in the blood brain barrier or accumulation of large acidic lysosomes, could cause these pHi changes. There may also be a failure in blood flow regulation, with near critical fluctuations in blood flow both with time and space.

Accidents, Traffic↗

PubMed1990

Effects of repeated low calcium perfusion on the rat heart: a gradual induction of calcium related damage.

The calcium paradox occurs immediately upon perfusion with calcium-containing medium after a period of calcium-free perfusion. The sequence of events occur so rapidly that it is difficult to distinguish causal factors from resultant. The present study describes a model in which calcium induced damage is produced more gradually. Isolated perfused rat hearts were subjected to brief periods of hypocalcium perfusion (less than 50 microM) alternated with normal calcium perfusion (1.25 mM) over 60 min. Changes in high energy phosphate content were monitored using 31P-NMR. With repeated sequential 2-min periods of alternate hypo- and normocalcium perfusion, there was a gradual reduction in ATP and phosphocreatine with a concomitant loss of function and decline in coronary flow. There was no change in inorganic phosphate content and a small degree of acidosis. Increasing the hypocalcium concentration from 5 to 40 microM resulted in a more gradual depletion in energy stores. Trifluoroperazine (a calmodulin inhibitor) had no effect on the energetic changes. Electron microscopic studies reveal that this model of damage induced by repeated low and normal calcium perfusion has some features in common with the calcium paradox. The extent of damage induced is greater when lower calcium concentrations (5 microM) are used.

Adenosine Triphosphate↗

PubMed1990

Muscle ischaemia in peripheral vascular disease studied by 31P-magnetic resonance spectroscopy.

We have used 31phosphorus magnetic resonance spectroscopy (31P-MRS) to study foot muscle metabolism in patients with peripheral vascular disease. Sixteen patients with calf claudication, 32 patients with rest pain and 13 control subjects had spectra collected from the foot muscle, Extensor digitorum brevis, ankle pressures measured and, in most cases, transcutaneous O2 and CO2 recordings made over the foot. The intracellular pH and the ratio of inorganic phosphate to phosphocreatine (Pi/PCr) obtained from the MR spectra were significantly higher (p less than 0.005 and p less than 0.02, respectively) in the muscle of patients with rest pain and were particularly high in those with gangrene or ulceration. Ankle pressures and transcutaneous O2 and CO2 measurements failed to distinguish those patients with advanced peripheral ischaemia. These results suggest that MRS measurements of metabolic changes in foot muscle are useful in the detection and quantitation of significant distal ischaemia.

Aged↗

PubMed1990