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R A Challiss

Publications and source records attributed to R A Challiss.

At least 145 records · Page 8Linked to original sources
PubMed1987

Effects of dipyridamole on adenosine concentration, insulin sensitivity and glucose utilisation in soleus muscle of the rat.

Adenosine has been shown to modulate the sensitivity of skeletal muscle to insulin (Budohoski et al. 1984). In an attempt to further characterize the modulatory action of adenosine on insulin sensitivity in skeletal muscle we have investigated the effect of the nucleoside transport inhibitor dipyridamole in isolated incubated soleus muscle strips. At a concentration of 50 microM, dipyridamole increased the concentration of adenosine in the soleus muscle by 36% and in the incubation medium by 32%. At this concentration of dipyridamole, the basal rates (in the presence of 1 microunit of insulin/ml) of lactate formation, 2-deoxy [2,6-3H]glucose phosphorylation and glucose oxidation were decreased by 48%, 43% and 47% respectively, whilst the rate of glycogen synthesis was unaffected. Insulin-stimulated rates (in the presence of 10,000 microunits of insulin/ml) of lactate formation, 2-deoxy [2,6-3H] glucose phosphorylation, glycogen synthesis and glucose oxidation were decreased by 70%, 30%, 26% and 20% respectively in the presence of 50 microM dipyridamole. Although 50 microM dipyridamole was required to exert a significant effect on medium and soleus muscle adenosine concentrations, statistically significant effects on glycolytic rate were observed at concentrations as low as 2 microM dipyridamole. It is concluded that the results are not consistent with dipyridamole exerting an effect on skeletal muscle carbohydrate metabolism solely through elevation of the intracellular or interstitial adenosine concentration, but strongly suggest that dipyridamole inhibits glucose transport and/or phosphorylation in skeletal muscle.

Adenosine↗
PubMed1986

An investigation of arterial insufficiency in the rat hindlimb. Correlation of skeletal muscle bloodflow and glucose utilization in vivo.

Muscle bloodflow and the rate of glucose uptake and phosphorylation were measured in vivo in rats 7 days after unilateral femoral artery ligation and section. Bloodflow was determined by using radiolabelled microspheres. At rest, bloodflow to the gastrocnemius, plantaris and soleus muscles of the ligated limb was similar to their respective mean contralateral control values; however, bilateral sciatic nerve stimulation at 1 Hz caused a less pronounced hyperaemic response in the muscles of the ligated limb, being 59, 63 and 49% of their mean control values in the gastrocnemius, plantaris and soleus muscles respectively. The rate of glucose utilization was determined by using the 2-deoxy[3H]glucose method [Ferré, Leturque, Burnol, Penicaud & Girard (1985) Biochem. J. 228, 103-110]. At rest, the rate of glucose uptake and phosphorylation was statistically significantly increased in the gastrocnemius and soleus muscles of the ligated limb, being 126 and 140% of the mean control values respectively. Bilateral sciatic nerve stimulation at 1 Hz caused a 3-5-fold increase in the rate of glucose utilization by the ligated and contralateral control limbs; furthermore, the rate of glucose utilization was significantly increased in the muscles of the ligated limb, being 140, 129 and 207% of their mean control values respectively. For the range of bloodflow to normally perfused skeletal muscle at rest or during isometric contraction determined in the present study, a linear correlation between the rate of glucose utilization and bloodflow can be demonstrated. Applying similar methods of regression analysis to glucose utilization and bloodflow to muscles of the ligated limb reveals a similar linear correlation. However, the rate of glucose utilization at a given bloodflow is increased in muscles of the ligated limb, indicating an adaptation of skeletal muscle to hypoperfusion.

Animals↗
PubMed1986

An investigation of arterial insufficiency in rat hindlimb. A combined 31P-n.m.r. and bloodflow study.

A small animal model of arterial insufficiency is presented which involves unilateral femoral artery ligation and section. Invoked alterations in metabolism and perfusion of the affected muscle mass have been investigated 12 h, 4, 7 and 14 days post-ligation by 31P-n.m.r. and microsphere infusion, both at rest and during isometric muscle contraction at 1 Hz. At rest, the concentration of phosphocreatine was similar to the mean control value (36.0 +/- 1.0 mM) from 4 days post-ligation, but was significantly lower at 12 h (28.5 +/- 3.6 mM). Inorganic phosphate concentrations were significantly elevated for 7 days post-ligation. No significant differences were noted in intramuscular pH. Upon stimulation of the affected muscle mass, a time-dependent improvement in phosphocreatine utilization was observed such that 14 days post-ligation phosphocreatine utilization was not significantly different from mean control values. A similar amelioration was noted for the contraction-induced fall in intramuscular pH. At rest, no significant differences in bloodflow to the muscles of the ligated limb compared with the unaffected contralateral limb were observed. However, isometric contraction of the affected muscle mass resulted in a markedly reduced hyperaemic response 12 h post-ligation. Thereafter, a time-dependent improvement in tissue perfusion during stimulation was observed which paralleled the improvements in phosphocreatine utilization and intramuscular pH changes. The results presented are discussed with respect to the interrelationship between oxygen delivery, high energy phosphate utilization and force maintenance.

Animals↗
PubMed1986

An investigation of arterial insufficiency in rat hindlimb. An enzymic, mitochondrial and histological study.

A small animal model of arterial insufficiency has been used to investigate enzymic alterations in the gastrocnemius, plantaris and soleus muscles of the hypoperfused limb. At 7 days after induction of arterial insufficiency by unilateral femoral artery ligation, there were significant increases in the maximal activities of hexokinase, phosphorylase and 6-phosphofructokinase, whereas the activities of citrate synthase and 2-oxoglutarate dehydrogenase remained unchanged. Similar increases in hexokinase, phosphorylase and 6-phosphofructokinase were still apparent 8-10 weeks after unilateral artery ligation, although only hexokinase remained significantly higher than contralateral control values. No enhancement of oxidative enzyme activities was observed. The results are discussed in relation to the conflicting findings reported by other groups investigating enzymic adaptations in patients with arterial insufficiency.

Animals↗
PubMed1986

Effects of the beta-adrenoceptor agonist isoprenaline on insulin-sensitivity in soleus muscle of the rat.

The interactions between a beta-adrenoceptor agonist (isoprenaline) and insulin on rates of hexose transport, glucose phosphorylation, glycogen synthesis and glycogenolysis were investigated in the incubated stripped soleus-muscle preparation of the rat. In the presence of 1 microM-isoprenaline, insulin was less effective in stimulating glucose phosphorylation and glycogen synthesis. The stimulation of glycogenolysis by isoprenaline was only slightly decreased even at high (10000 microunits/ml) concentrations of insulin. Insulin-stimulated phosphorylation of 2-deoxyglucose was decreased by isoprenaline. It is suggested that this decrease in the rate of glucose phosphorylation is caused by the observed elevated concentration of glucose 6-phosphate, which inhibits hexokinase activity. This conclusion is supported by the fact that isoprenaline had no effect on the stimulation of 3-O-methylglucose transport by insulin.

3-O-Methylglucose↗
PubMed1985

Biochemical adaptation in the skeletal muscle of rats depleted of creatine with the substrate analogue beta-guanidinopropionic acid.

Rats were fed on a diet containing 1% beta-guanidinopropionic acid (GPA), a creatine substrate analogue, for 6-10 weeks to deplete their muscle of creatine. This manipulation was previously shown to give a 90% decrease in [phosphocreatine] in skeletal and cardiac muscle and a 50% decrease in [ATP] in skeletal muscle only. Maximal activities of creatine kinase and of representative enzymes of aerobic and anaerobic energy metabolism were measured in the superficial white, medial and deep red portions of the gastrocnemius muscle, in the soleus and plantaris muscle and in the heart. Fast-twitch muscles were smaller in GPA-fed animals than in controls, but the size of the soleus muscle was unchanged. The activities of aerobic enzymes increased by 30-40% in all fast-twitch muscle regions except the superficial gastrocnemius, but were unchanged in the soleus muscle. The activities of creatine kinase and phosphofructokinase decreased by 20-50% in all skeletal-muscle regions except the deep gastrocnemius, and the activity of glycogen phosphorylase generally paralleled these changes. There were no significant changes in the activities of any of the enzymes measured in the heart. The glycogen content of the gastrocnemius-plantaris complex was increased by 185% in GPA-fed rats. The proportion of Type I fibres in the soleus muscle increased from 81% in control rats to 100% in GPA-fed rats, consistent with a previous report of altered isometric twitch characteristics and a decrease in the maximum velocity of shortening in this muscle [Petrofsky & Fitch (1980) Pflugers Arch. 384, 123-129]. We conclude that fast-twitch muscles adapt by a combination of decreasing diffusion distances, increasing aerobic capacity and decreasing glycolytic potential. Slow-twitch muscles decrease glycolytic potential and become slower, thus decreasing energy demand. These results suggest that persistent changes in the [phosphocreatine] and [ATP] are alone sufficient to alter the expression of enzyme proteins and proteins of the contractile apparatus, and that fibre-type-specific thresholds exist for the transformation response.

Animals↗
PubMed1985

Effect of a novel thermogenic beta-adrenoceptor agonist (BRL 26830) on insulin resistance in soleus muscle from obese Zucker rats.

Young lean (Fa/?) and obese (fa/fa) rats were treated with the thermogenic beta-adrenoceptor agonist, BRL 26830, for 3 weeks. In lean rats this treatment had no effect on body weight but there was a marked increase in the insulin sensitivity of soleus muscle strips with respect to glycolytic rate. Treatment of obese rats with BRL 26830 produced a small but not significant decrease in body weight but the sensitivity of both glycolysis and glycogen synthesis to insulin was increased so that muscles of treated obese rats showed similar insulin sensitivity to untreated lean rats. It is suggested that such changes are unlikely to be merely a secondary consequence of an anti-obesity action.

Animals↗
PubMed1985

The effect of fructose 2,6-bisphosphate on muscle fructose-1,6-bisphosphatase activity.

Rat and rabbit muscle fructose 1,6-bisphosphatase (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11) are inhibited by fructose 2,6-bisphosphate. In contrast with the liver isozyme, the inhibition of muscle fructose-1,6-bisphosphatase by fructose 2,6-bisphosphate is not synergistic with that of AMP. Activation of fructose-1,6-bisphosphatase by fructose 2,6-bisphosphate has been observed at high concentrations of substrate. An attempt is made to correlate changes in concentrations of hexose monophosphate, fructose 1,6-bisphosphate and fructose 2,6-bisphosphate with changes in fluxes through 6-phosphofructokinase and fructose-1,6-bisphosphatase in isolated epitrochlearis muscle challenged with insulin and adrenaline.

Adenosine Monophosphate↗
PubMed1985

The effect of prostaglandins E1, E2 and F2 alpha and indomethacin on the sensitivity of glycolysis and glycogen synthesis to insulin in stripped soleus muscles of the rat.

Prostaglandins E1 and E2 increased the sensitivity of glycolysis to insulin in the isolated stripped soleus muscle of the rat, but prostaglandin F2 alpha had no effect. Indomethacin, which inhibits prostaglandin formation, markedly decreased the sensitivity of glycolysis to insulin. These findings suggest that prostaglandins of the E series increase the sensitivity of muscle glycolysis to insulin in vivo.

Animals↗
PubMed1984

Reversal of dietary-induced insulin resistance in muscle of the rat by adenosine deaminase and an adenosine-receptor antagonist.

Transfer of young rats from a maintenance diet to a breeding diet plus 10% sucrose in the drinking water for 4 weeks caused the development of insulin resistance. Inclusion of the enzyme adenosine deaminase or the adenosine-receptor antagonist 8-phenyltheophylline caused a marked increase in the sensitivity of the soleus-muscle strips isolated from the diet-induced insulin-resistant rats: the concentration of insulin giving 50% of maximum response of glycolysis shifted from 500 to less than 20 microunits/ml.

Adenosine Deaminase↗
PubMed1984

Measurement of the rate of substrate cycling between fructose 6-phosphate and fructose 1,6-bisphosphate in skeletal muscle by using a single-isotope technique.

The effects of several agents on the rates of the fructose 6-phosphate/fructose 1,6-bisphosphate substrate cycle were measured in incubated epitrochlearis muscles of the rat by monitoring the transfer of radiolabel from [6-14C]glucose to the 1-position of glucose residues in glycogen. The cycling rates observed were almost identical with those previously obtained by using the well-established dual-isotope technique. In particular, it was found that the beta-adrenoceptor agonist isoprenaline increased the cycling rate about 12-fold.

Animals↗
PubMed1984

Increased insulin sensitivity in soleus muscle from cold-exposed rats: reversal by an adenosine-receptor agonist.

The effect of 0.5, 2, 7 and 14 days cold exposure at 4 degrees C on insulin sensitivity was investigated in the stripped soleus muscle preparation incubated in vitro. Cold-exposure for 2 or 7 days increased the sensitivity of glycolysis, but did not affect the sensitivity of glycogen synthesis to insulin. Cold-exposure for 0.5 or 14 days had no effect on the sensitivity of either process to insulin. The increased sensitivity to insulin after exposure of animals to the cold for 2 days was completely reversed by addition of the adenosine receptor agonist, 2-chloroadenosine, to the incubation medium. This suggests that cold exposure may increase insulin sensitivity in the muscle, either by a decrease in the concentration of adenosine in the muscle, or by a decrease in the number or affinity of the adenosine receptors.

2-Chloroadenosine↗
PubMed1984

The rate of substrate cycling between fructose 6-phosphate and fructose 1,6-bisphosphate in skeletal muscle.

Substrate cycling of fructose 6-phosphate through reactions catalysed by 6-phosphofructokinase and fructose-1,6-bisphosphatase was measured in skeletal muscles of the rat in vitro. The rate of this cycle was calculated from the steady-state values of the 3H/14C ratio in hexose monophosphates and fructose 1,6-bisphosphate after the metabolism of either [5-3H,6-14C]glucose or [3-3H,2-14C] glucose. Two techniques for the separation of hexose phosphates were studied; t.l.c. chromatography on poly(ethyleneimine)-cellulose sheets or ion-exchange chromatography coupled with enzymic conversion. These two methods gave almost identical results, suggesting that either technique could be used for determination of rates of fructose 6-phosphate/fructose 1,6-bisphosphate cycling. It was found that more than 50% of the 3H was retained in the fructose 1,6-bisphosphate; it is therefore probable that previous measurement of cycling rates, which have assumed complete loss of 3H, have underestimated the rate of this cycle. The effects of insulin, adrenaline and adrenergic agonists and antagonists on rates of fructose 6-phosphate/fructose 1,6-bisphosphate cycling were investigated. In the presence of insulin, adrenaline (1 microM) increased the cycling rate by about 10-fold in epitrochlearis muscle in vitro; the maximum rate under these conditions was about 2.5 mumol/h per g of tissue. The concentration of adrenaline that increased the cycling rate by 50% was about 50 nM. This effect of adrenaline appears to be mediated by the beta-adrenergic receptor, since the rate was increased by beta-adrenergic agonists and blocked by beta-adrenergic antagonists. From the knowledge of the precise rate of this cycle, the possible physiological importance of cycling is discussed.

Animals↗
PubMed1984

A problem in the radiochemical assay of glucose-6-phosphatase in muscle.

A radiochemical assay for glucose-6-phosphatase, which depends on the absorption of radiolabelled substrate on to a nascent precipitate of BaSO4 and Zn(OH)2, can give rise to erroneously high activities. Adsorption on to a Fe(OH)3 precipitate does not expose the incubation medium to extreme alkaline conditions and provides a satisfactory and simple assay. This method demonstrates a very low activity of the enzyme in mammalian muscle, in contrast with previous findings.

Animals↗
PubMed1984

Effects of analogues of adenosine and methyl xanthines on insulin sensitivity in soleus muscle of the rat.

The concentration of insulin that produces half-maximal stimulation of glycolysis by stripped soleus muscle preparations is markedly increased by the adenosine analogues, 2-chloroadenosine and N6-phenylisopropyladenosine, but is markedly decreased by the methyl xanthine analogue, 8-phenyltheophylline. 2-Chloroadenosine increases the concentration of insulin required to stimulate glycolysis half maximally, from about 100 to 2000 mu units/ml. 8-Phenyltheophylline decreases this concentration of insulin from about 100 to 10 mu units/ml, an effect which is similar to that produced either by addition of adenosine deaminase to the medium or to exercise-training of the donor animals for 4 weeks.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Effect of adenosine deaminase and an adenosine analogue on insulin sensitivity in soleus muscle of the rat.

The concentration of insulin that produces half-maximal stimulation of glycolysis in stripped soleus muscle preparations is decreased from approximately 100-10 muunits/ml by the presence of adenosine deaminase in the incubation medium. This suggests that adenosine decreases insulin sensitivity. The effect of the deaminase is abolished by addition of the adenosine analogue, N6-phenylisopropyladenosine which is not metabolised by the deaminase. The effect of the deaminase in isolated soleus muscle is similar to that of a period of physical training of the rat.

Adenosine↗