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Biomedical subjects

G K Radda

Publications and source records attributed to G K Radda.

At least 91 records · Page 5Linked to original sources
PubMed1996

Skeletal muscle metabolism before and after gemfibrozil treatment in dialysed patients with chronic renal failure.

Patients with chronic renal failure appear at greater risk for skeletal muscle side effects from the fibric acid group of lipid lowering agents. In order to determine whether sub-clinical defects of skeletal muscle metabolism can be detected in dyslipidaemic dialysis-dependent patients receiving fibrates. we studied nine patients before and after three months of gemfibrozil therapy (300-600 mg daily). Aerobic and anaerobic metabolism of the right calf muscle was examined at rest and during exercise using 31P magnetic resonance spectroscopy. Near infra-red spectroscopy was used to assess skeletal muscle re-oxygenation following ischaemic exercise of the arm. Following gemfibrozil treatment plasma triglycerides fell significantly 3.0 +/- 0.5 mM (SEM) to 1.5 +/- 0.2 mM. Gemfibrozil did not affect the established metabolic defects that exist in the skeletal muscle of the dialysed patient. Skeletal muscle re-oxygenation was not significantly lower in renal failure and was not altered by gemfibrozil. Gemfibrozil (600 mg daily) significantly improved the lipid profile of chronic renal failure and was not associated with clinical or bioenergetic impairment of skeletal muscle metabolism.

Adult↗
PubMed1995

Assessment of mitochondrial function and control in normal and diseased states.

Mitochondrial function in muscle in vivo can be quantitatively evaluated using 31-phosphorus nuclear magnetic resonance. In resting muscle, the concentrations of ions (e.g. H+, Na+) and two of the major bioenergetic components (inorganic phosphate and creatine) are determined by regulated transcellular transport processes. During recovery after exercise the kinetics and control of mitochondrial ATP synthesis can be established. During exercise the relative contributions to ATP synthesis of phosphocreatine (using creatine kinase), anaerobic glycogenolysis and oxidative phosphorylation are dissected and have been shown to change with time. The consequences of mitochondrial lesions and dysfunctions on these processes have been summarised.

Adenosine Triphosphate↗
PubMed1995

Brain abnormalities in Duchenne muscular dystrophy: phosphorus-31 magnetic resonance spectroscopy and neuropsychological study.

Duchenne muscular dystrophy (DMD) is one of a range of muscular dystrophies caused by abnormalities of the short arm of the X chromosome (Xp21), which often cause mental retardation in addition to progressive muscular weakness. Normal dystrophin expression is lacking in both skeletal muscle and brain of affected subjects. Phosphorus-31 magnetic resonance spectroscopy has shown several abnormalities in skeletal muscle in DMD. We looked for similar abnormalities in brain in patients with DMD and related the findings to neuropsychological test results. We studied by magnetic resonance spectroscopy 19 boys (aged 76-167 months) diagnosed as having DMD and 19 control boys of similar age (87-135 months). Intelligence quotient (IQ) was assessed with the Wechsler Intelligence Scale for children. The DMD patients had significantly higher values than the controls in the brain ratios of inorganic phosphate to adenosine triphosphate (mean 0.53 [SD 0.21] vs 0.36 [0.09], p = 0.003), to phosphomonoesters (0.40 [0.07] vs 0.29 [0.07], p = 0.0001), and to phosphocreatine (0.44 [0.10] vs 0.37 [0.08], p = 0.02). There were significant differences between the DMD patients and the controls in full-scale IQ (76 [16] vs 101 [16], p = 0.0001), performance IQ (78 [17] vs 94 [14], p = 0.003), and verbal IQ (78 [17] vs 106 [17], p = 0.0001). These altered metabolite ratios parallel the findings in dystrophic muscle and suggest bioenergetic similarities in tissues that lack dystrophin.

Adenosine Triphosphate↗
PubMed1995

The creatine kinase equilibrium, free [ADP] and myosin ATPase in vascular smooth muscle cross-bridges.

MgADP has a more pronounced effect on the relaxation behaviour in tonic vascular smooth muscle compared to phasic smooth muscle. An apparent dissociation constant of 1.3 microM has been reported for a high affinity binding site of vascular smooth muscle cross-bridges. For this high affinity to have an effect on the low energy costs of tension maintenance (latch) it would require that free [ADP] in the region of the contractile proteins (at least sometimes) be as low as 1.3 microM. We ask, in this report, whether [ADP] could be as low as 1.3 microM in vascular smooth muscle. If creatine kinase (CK) is at equilibrium, then micromolar [ADP] is incompatible with measured concentrations of phosphocreatine (PCr), free creatine (Cr) and ATP, which entail a mean equilibrium [ADP] of around 18 microM. But CK may not be quite at equilibrium: if there is net PCr synthesis at the mitochondrion, then maintenance of the steady-state requires that there be net PCr hydrolysis in the region of the contractile proteins up to or equal to the rate of myosin ATPase. We derive a simple relationship between net flux and displacement from equilibrium which we use to argue that an [ADP] of 1.3 microM at the contractile proteins would drive significant net PCr synthesis, incompatible with normal contractile function. Thus the CK system holds [ADP] at about 18 microM near the contractile proteins in vascular smooth muscle. We conclude that smooth muscle [ADP] cannot be far from equilibrium and that a role for ADP (at the low micromolar level) in controlling smooth muscle relaxation is unlikely.

Adenosine Diphosphate↗
PubMed1995

Skeletal muscle mitochondrial dysfunction in alternating hemiplegia of childhood.

Alternating hemiplegia of childhood is an uncommon disease characterized by repeated, transient attacks of hemiplegia. Its pathophysiology is uncertain, but attention recently has focused on possible mitochondrial abnormalities. Using 31P magnetic resonance spectroscopy, we studied gastrocnemius muscle in 5 patients with alternating hemiplegia, aged 8 to 30 (mean, 18) years, at rest and during incremental aerobic exercise and recovery. There were no significant differences in resting muscle between patients and a control group aged 7 to 42 (mean, 19) years. Exercise performance was grossly impaired in the patients, the mean duration being 30% of normal. The total change in pH during exercise was somewhat less than in control subjects, while the changes in phosphocreatine concentration and intracellular ADP were similar. Thus the average overall rate of fall of phosphocreatine concentration during exercise was three-fold greater than in control subjects. However, the initial rate of ATP turnover at the start of exercise (a measure of muscle mass and efficiency) was not abnormal. During recovery, both the initial rate of phosphocreatine resynthesis and the calculated mitochondrial capacity were reduced by about 35%. This mitochondrial defect probably explains most of the abnormalities seen during exercise.

Adolescent↗
PubMed1995

ATP production and mechanical work in exercising skeletal muscle: a theoretical analysis applied to 31P magnetic resonance spectroscopic studies of dialyzed uremic patients.

31P magnetic resonance spectroscopy (31P MRS) can yield much information about bioenergetics in skeletal muscle. During mixed aerobic/glycolytic exercise, changes in phosphocreatine (PCr) concentration and pH may be abnormal because of reduced muscle mass or reduced efficiency (which the authors combine here as "effective muscle mass") or because of reduced oxidative capacity. The authors show how these can be distinguished by calculating the nonoxidative and oxidative costs of mechanical work, and also of work per unit of effective muscle mass (measured using the initial rate of ATP turnover). These quantities are substantially time-independent during incremental exercise, and so can be used to compare exercise studies of differing duration. The authors illustrate this analysis by showing that in dialyzed patients with chronic renal failure, the substantial exercise abnormalities seen by 31P MRS are due mainly to a decrease in effective muscle mass, which outweighs the oxidative defect implied by the abnormal PCr recovery kinetics.

Adenosine Triphosphate↗
PubMed1995

The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: a 31P, 23Na and 87Rb NMR spectroscopic study.

An increase in intracellular Na+ during ischaemia has been associated with myocardial injury. In this study, we determined whether inhibition of Na+/K+ ATPase activity contributes to this increase and whether Na+/K+ ATPase activity can be maintained by provision of glucose to perfused rat hearts during low flow, 0.5 ml/min, ischemia. We used 31P NMR spectroscopy to determine changes in myocardial energetics and intracellular and extracellular volumes. 23Na NMR spectroscopy, with DyTTHA3- present as a shift reagent, was used to measure changes in intracellular Na+ and 87Rb NMR spectroscopy was used to estimate Na+/K+ ATPase activity from Rb+ influx rates, Rb+ being an NMR-sensitive congener of K+. In hearts provided with 11 mM glucose throughout ischemia, glycolysis continued and ATP was twofold higher than in hearts without glucose. In the glucose-hearts, Rb+ influx rate was threefold higher, intracellular Na+ was fivefold lower at the end of ischemia and functional recovery during reperfusion was twofold higher. We propose that continuation of glycolysis throughout low flow ischemia allowed maintenance of sufficient Na+/K+ ATPase activity to prevent the increase in intracellular Na+ that would otherwise have led to myocardial injury.

Animals↗
PubMed1995

Is lactate-induced myocardial ischaemic injury mediated by decreased pH or increased intracellular lactate?

The detrimental effect of exogenous lactate during ischaemia on post-ischaemic contractile function may be mediated either by a lactate-induced intracellular H+ load or by an increase in intracellular lactate. To distinguish between these two mechanisms, isolated rat hearts were perfused with lactate or pyruvate during low flow ischaemia, the rationale being that both would decrease H+ efflux via lactate/H+ cotransport and lead to decreased pH, but only exogenous lactate would decrease lactate efflux and lead to increased intracellular lactate. 31P NMR spectra were acquired sequentially while hearts were subjected to 32 min low flow (0.5 ml/min) ischaemia and 32 min reperfusion. During ischaemia, hearts were perfused with Krebs-Henseleit buffer containing 11 mM glucose (controls) or 11 mM glucose plus either 10 mM lactate or 10 mM pyruvate. Reperfusion of all hearts was with buffer containing only glucose. Intracellular volume, estimated to be 0.52 ml/heart using 31P NMR spectroscopy with phosphonate space markers, did not change under any of the ischaemic conditions during the protocol. Control and pyruvate hearts recovered approximately 85% of pre-ischaemic contractile function, but there was no recovery of function in lactate hearts. This lack of recovery correlated with a 57% loss of ATP during ischaemia, which was significantly greater (P < 0.001) than the 41% loss of ATP in control and pyruvate-perfused hearts. End-ischaemic intracellular pH was 6.60 in both lactate-perfused and control hearts, but significantly lower (P < 0.05) at pH 6.43 in pyruvate-perfused hearts. Both exogenous pyruvate and lactate should have decreased H+ efflux, however the higher pH in the lactate-perfused hearts could be explained by a 60% inhibition of glycolysis, determined by measurement of myocardial lactate production. Thus, the intracellular pH during ischaemia does not necessarily predict the extent of myocardial injury. We propose that lactate-induced damage is a consequence of increased intracellular lactate leading to inhibition of glycolysis, presumably via an increased NADH/NAD ratio. This study highlights the important role of glycolysis in the ischaemic rat heart.

Animals↗
PubMed1995

A relationship between impaired fetal growth and reduced muscle glycolysis revealed by 31P magnetic resonance spectroscopy.

Thinness at birth is associated with insulin resistance and an increased prevalence of non-insulin-dependent diabetes mellitus in adult life. As muscle is an important site of insulin resistance, and because thin babies have reduced muscle mass, thinness at birth may affect muscle structure and function and impair carbohydrate metabolism. We have therefore used 31P magnetic resonance spectroscopy to investigate the bioenergetics of gastrocnemius and flexor digitorum superficialis muscles in 16 normoglycaemic women who had a low ( < or = 23 kg/m3) and 9 women who had a high (> 23 kg/m3) ponderal index at birth. In the flexor digitorum superficialis study anaerobic metabolism was stressed with a constant heavy workload. Low ponderal index subjects fatigued more rapidly (3.3 vs 5.8 min); as phosphocreatine decreased, the accompanying drop in muscle pH was less than in the high ponderal index group. In the first minute of exercise phosphocreatine fell and adenosine diphosphate rose more rapidly (p=0.04 and 0.03, respectively). Gastrocnemius showed a similar trend late in exercise (this exercise was more oxidative, becoming more anaerobic with increasing workload). These changes were not explained by differences in body composition, muscle mass or blood flow. The findings are consistent with a decreased lactic acid and glycolytic adenosine triphosphate production in the low ponderal index group and suggest the possibility that the mechanisms which control substrate utilisation and metabolism in adult life be programmed during prenatal life.

Adenosine Diphosphate↗
PubMed1995

Effects of glucosamine on insulin-stimulated glucose metabolism in rat soleus muscle.

Intracellular accumulation of glucosamine metabolites (which can be achieved by pre-incubation of cells with glucosamine) during hyperglycaemia may decrease the rate of insulin-mediated glucose transport in cells. Soleus muscle preparations were pre-incubated in the presence or absence of glucosamine in media that contained glutamine (Dulbecco's modified Eagle medium, DMEM; Medium 199, M199) or devoid of glutamine (Krebs-Henseleit's buffer, KHB). Subsequently, muscles were transferred to fresh media, in the absence of glucosamine, but with various concentrations of insulin and the rates of 2-deoxyglucose transport or intracellular glucose metabolism were measured. Glucosamine pre-exposure decreased both insulin-stimulated (1000 microU/ml) glucose transport and phosphorylation. The percentage decreases for 3H-2-deoxyglucose transport after pre-incubation with 40 mM glucosamine compared with untreated muscles were: DMEM, 48%; KHB, 50%; M199, 29%. The percentage decreases for 3H-2-deoxyglucose-6-phosphate accumulation were: DMEM, 53%; KHB 60%; M199, 37%. In DMEM and KHB, glucosamine pre-treatment of soleus muscle preparations markedly decreased the rate of lactate release and stimulated the rate of 14C-glucose incorporation into glycogen. Thus, a distinct shift of glucosyl units from glycolysis to glycogenesis occurred with low and high insulin concentrations. For the latter (1000 microU of insulin/ml) the ratio of moles of glucose converted to lactate divided by moles of glucose incorporated into glycogen in muscles pre-incubated in the absence or presence of glucosamine (40 mM) was, respectively: DMEM, 4.34 + 0.52 vs 1.55 + 0.06, P < 0.001; KHB, 2.80 + 0.44 vs 0.76 + 0.03, P < 0.005). Glycogen synthesis was not stimulated in muscles pre-exposed to glucosamine in M199. In muscles pre-incubated to glucosamine and incubated in DMEM or KHB, there was a marked shift of glucose transported into the cell from glycolysis to glycogenesis. Thus, glucosamine or its metabolites had distinct effects on intracellular glucose handling.

Animals↗
PubMed1995

Altered Na(+)- H(+)- exchange activity in the spontaneously hypertensive perfused rat heart.

Intracellular pH (pHi) and developed pressure during hypercapnic acidosis were studied in the spontaneously hypertensive rat (SHR) heart and Wistar-Kyoto controls. Developed pressure was determined using a modified Langendorff isovolumic perfusion technique and 31P magnetic resonance spectroscopy was used to determine pHi. In response to acidosis, both developed pressure and pHi first decreased and then partially recovered. In the SHR group, pHi during the early periods of acidosis was significantly higher than in the control group while there was no significant difference in the steady-state pHi. The addition of 5-(N,N)-hexamethylene-amiloride (HMA), a specific inhibitor of Na(+)-H+ exchange, abolished these difference. Furthermore, HMA was found to inhibit recovery in pHi and developed pressure during acidosis in both groups. These results demonstrate that Na(+)-H(+)-exchange in the rat heart plays a major role in pHi regulation and contributes to functional recovery during acidosis. In addition, Na(+)-H(+)-exchange activity, as previously found in other tissues in hypertension, is increased in the SHR heart.

Acidosis↗
PubMed1995

Bryostatin 1, a novel antineoplastic agent and protein kinase C activator, induces human myalgia and muscle metabolic defects: a 31P magnetic resonance spectroscopic study.

Bryostatin 1, a novel antineoplastic agent and protein kinase C (PKC) activator, has been found to induce myalgia (muscle pain) 48 h after administration in clinical trials. This is the dose-limiting toxicity and has restricted the duration of therapy in phase I trials. To investigate the mechanisms and try to increase toleration of the drug, we studied calf muscle metabolism of 14 patients at rest and during exercise and subsequent recovery using 31P magnetic resonance spectroscopy (MRS) before and 4 h, 48-72 h and 1-2 weeks following bryostatin therapy. In resting muscle there was a significant (P < 0.001) increase in the phosphodiester/adenosine 5'-triphosphate (PDE/ATP) ratio 48 h post bryostatin and in patients with myalgia compared with pre-bryostatin control studies. Following exercise, patients with myalgia showed significantly slower phosphocreatine (PCr) and ADP recovery half-time (P < or = 0.05) suggesting impaired mitochondrial (oxidative) energy production, possibly due to a direct effect on the mitochondria or secondary to reduced blood flow. The apparent proton efflux rate following exercise was significantly reduced 4 h after bryostatin (P < or = 0.05), suggesting reduced blood flow. The rate of post-exercise reoxygenation was studied in four patients by near-infrared spectroscopy 4 h post bryostatin. In three of these the rate was reduced, consistent with reduced muscle blood flow. Bryostatin 1 appeared to cause a long-lasting impairment of oxidative metabolism and proton washout from muscle, consistent with a vasoconstrictive action. Thus these studies provide evidence for two mechanisms of the dose-limiting toxicity for bryostatin. Prospective studies on the use of vasodilators to improve the tolerance of the drug should be carried out.

Adenosine Triphosphate↗