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K Siddle

Publications and source records attributed to K Siddle.

144 records · Page 8Linked to original sources
PubMed1978

Effect of replacement of extracellular sodium ions and of D-600 on the activation by adrenalin of adenylate cyclase in intact pigeon erythrocytes.

The effect of replacement of extracellular Na+ by Li+, choline K+ or sucrose on cyclic AMP formation in pigeon erythrocytes has been investigated. Replacement of extracellular Na+ by Li+, choline or sucrose but not by K+ inhibited the stimulation by adrenalin of cyclic AMP formation, but had no detectable effect on cyclic AMP content in the absence of adrenalin. This inhibition was observed in the presence or absence of extracellular Ca2+. The relative inhibition caused by Na+ removal decreased with increasing adrenalin concentration. It was concluded that extracellular Na+ or K+ ions were required for maximal activation of adenylate cyclase by low concentrations of adrenalin, and that this effect of monovalent cations may have been due to an effect on the affinity of the receptor for adrenalin. The verapamil derivative D-600 also inhibited the stimulation by adrenalin of cyclic AMP formation. This effect occurred in the absence of extracellular Ca2+ and hence seemed to be unrelated to the inhibition by C-600 of the slow Ca2+ channel in electrically excitable tissues.

Adenosine Triphosphate↗
PubMed1978

Hormonal control of adipose-tissue lipolysis.

Adipose-tissue triacylglycerol is the major energy store in man. The physiological importance and biochemical mechanism of the hormonal control of lipolysis in white adipose tissue is reviewed. Rates of lipolysis and fatty acid release observed when adipose tissue is incubated in vitro are compared with rates of triacylglycerol turnover in man. It appears that enhanced rates of lipolysis in vivo, for example during fasting and exercise, may be a substantial fraction of the maximum obtainable by hormone stimulation in vitro. There is considerable species variation in the hormonal sensitivity of adipose tissue. Some hormones that stimulate lipolysis in vitro may not be significant lipolytic agents at physiological concentrations in vivo. In man and rat, the most important acutely acting lipolytic and anti-lipolytic hormones are catecholamines and insulin respectively. The sympathetic nervous system may play a role at least as important as circulating catecholamines in the mobilization of stored triacylglycerol. The effects of acute lipolytic hormones are modulated in the long term by corticosteroids and thyroid hormone. Stimulation of lipolysis is believed to be mediated by the increased intracellular cyclic AMP concentration that occurs after interaction of hormones with specific receptors in the plasma membrane. The properties of membrane receptors, adenylate cyclase, cyclic AMP phosphodiesterase, cyclic AMP-dependent protein kinase and triacylglycerol lipase, as studied in rat and human adipose tissue, are discussed. Several features of the action of lipolytic hormones in vitro are difficult to account for by the hypothesis that cyclic AMP is the only "second messenger" regulating lipase activity. These include anomalous effects of hormones at high concentrations and the possible existence of feedback inhibition limiting the accumulation of cyclic AMP and the stimulation of lipolysis. The mechanism of the anti-lipolytic action of insulin is at present unknown.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1977

The effect of 5-hydroxytryptamine and other indole derivatives on the formation of adenosine 3',5'-cyclic monophosphate in pigeon erythrocytes.

1. The effect of insulin, acetylcholine, histamine, 5-hydroxytryptamine and prostaglandins E1, E2 and F2alpha on basal and adrenalin-stimulated cyclic AMP content in intact pigeon erythrocytes was investigated. 2. None of these compounds influenced basal cyclic AMP contest, and only 5-hydroxytryptamine antagonized the effect of adrenalin. The increase in cyclic AMP with 0.55 micronM adrenalin was inhibited by approx. 60% in the presence of 10 muM 5-hydroxytryptamine. The interaction between adrenalin and 5-hydroxytryptamine was competitive. 3. 5-Hydroxytryptamine did not affect the rate of degradation of cyclic AMP in intact cells, but did inhibit adrenalin-stimulated cyclic AMP formation in permeable or resealed cell "ghosts". 4. The effect of 5-hydroxytryptamine to inhibit cyclic AMP accumulation was not dependent on the presence of Ca2+, in either intact cells or "ghosts". 5. Various indole derivatives and other compounds were tested for their ability to inhibit the effect of adrenalin on cyclic AMP accumulation. Only those derivatives with a free amino group and net positive charge in the side chain were effective. 6. It was concluded that 5-hydroxytryptamine inhibits adrenalin-stimulated adenylate cyclase activity in pigeon erythrocytes, possibly by competing with adrenalin for binding to the beta-adrenergic receptor.

Acetylcholine↗
PubMed1976

The effect of intracellular calcium ions on adrenaline-stimulated adenosine 3':5'-cyclic monophosphate concentrations in pigeon erythrocytes, studied by using the ionophore A23187.

1. The bivalent cation ionophore A23187 was used to increase the intracellular concentration of Ca2+ in pigeon erythrocytes to investigate whether the increase in cyclic AMP content caused by adrenaline might be influenced by a change in intracellular Ca2+ in intact cells. 2. Incubation of cells with adrenaline, in the concentration range 0.55--55 muM, resulted in an increase in the concentration of cyclic AMP over a period of 60 min. The effect of adrenaline was inhibited by more than 90% with ionophore A23187 (1.9 muM) in the presence of 1 mM-Ca2+. This inhibition could be decreased by decreasing either the concentration of the ionophore or the concentration of extracellular Ca2+, and was independent of the concentration of adrenaline. 3. The effect of ionophore A23187 depended on the time of incubation. Time-course studies showed that maximum inhibition by ionophore A23187 was only observed when the cells were incubated with the ionophore for at least 15 min before the addition of adrenaline. 4. The inhibition by ionophore A23187 depended on the concentration of extracellular Ca2+. In the absence of Mg2+, ionophore A23187 (1.9 muM) inhibited the effect of adrenaline by approx. 30% without added Ca2+, by approx. 66% with 10 muM-Ca2+ and by more than 90% with concentrations of added Ca2+ greater than 30 muM. However, even in the presence of EGTA [ethanedioxybis(ethylamine)tetra-acetate](0.1--10 mM), ionophore A23187 caused an inhibition of the cyclic AMP response of at least 30%, which may have been due to a decrease in cell Mg2+ concentration. 5. The addition of EGTA after incubation of cells with ionophore A23187 resulted in a partial reversal of the inhibition of the effect of adrenaline. 6. Inclusion of Mg2+ (2 mM) in the incubation medium antagonized the inhibitory action of ionophore A23187. This effect was most marked when the ionophore A23187 was added to medium containing Mg2+ before the addition of the cells. 7. The cellular content of Mg2+ was decreased by approx. 50% after 20 min incubation with ionophore A23187 (1.9 muM) in the presence of Ca2+ (1 mM) but no Mg2+. When Mg2+ (2 mM) was also present in the medium, ionophore A23187 caused an increase of approx. 80% in cell Mg2+ content. Ionophore A23187 had no significant effect on cell K+ content. 8. Ionophore A23187 caused a decrease in cell ATP content under some conditions. Since effects on cyclic AMP content could also be shown when ATP was not significanlty lowered, it appeared that a decrease in ATP in the cells could not explain the effect of ionophore A23187 on cyclic AMP. 9. Ionophore A23187 (1.9 muM), with 1 mM-Ca2+, did not enhance cyclic AMP degradation in intact cells, suggesting that the effect of ionophore A23187 on cyclic AMP content was mediated through an inhibition of adenylate cyclase rather than a stimulation of cyclic AMP phosphodiesterase. 10. It was concluded that in intact pigeon erythrocytes adenylate cyclase may be inhibited by intracellular concentrations of Ca2+ in the range 1-10 muM.

Adenosine Triphosphate↗
PubMed1976

The effect of insulin on adenosine 3':5'-monophosphate and guanosine 3':5'-monophosphate concentrations in human plasma.

1. The action of insulin on plasma cyclic nucleotide concentrations in normal human subjects has been studied after intravenous injection, alone and in combination with glucagon. 2. After injection of insulin alone there was an initial small, though not significant, decrease in plasma cyclic AMP at 15 min followed by an increase to more than twice the initial concentration at 30 min. The increase was absent when hypoglycaemia was lessened by infusion of glucose after insulin injection. 3. Injection of insulin caused no significant change in plasma cyclic GMP concentration, whether or not glucose was infused after the hormone. 4. Glucagon (3-300 nmol, 10-1000 mug), caused a dose-dependent increase in plasma cyclic AMP concentration. The rise in plasma cyclic AMP produced by 3 or 30 nmol of glucagon was not significantly modified by simultaneous injection of insulin (44 nmol; 6 units).

Adult↗
PubMed1975

Plasma adenosine 3':5'-cyclic monophosphate response to glucagon in thyroid disease.

1. The plasma adenosine 3':5'-cyclic monophosphate (cyclic AMP) response to intravenously administered glucagon has been studied in nine hyperthyroid, five hypothyroid and ten euthyroid patients. 2. Concentrations of the nucleotide rose to a peak at 15 min and declined to near basal values by 120 min, the response being greatest in hyperthyroid and least in hypothyroid subjects. The mean peak concentrations were 1028 nmol/1 in the hyperthyroid group, 252 nmol/1 in the hypothyroid group and 534 nmol/1 in the euthyroid group. 3. These results could not be accounted for by differences in serum insulin response. 4. It is suggested that the response of plasma cyclic AMP to glucagon may serve as an index of tissue thyroid status.

Adult↗
PubMed1974

The relationship between the concentration of adenosine 3':5'-cyclic monophosphate and the anti-lipolytic action of insulin in isolated rat fat-cells.

The relationship between cyclic AMP content and lipolysis, as measured by glycerol formation, was studied in isolated rat fat-cells. Inhibition of lipolysis by insulin in the presence of a low concentration of adrenaline was accompanied by little or no lowering of cyclic AMP content, measured after 15min incubation. The time-course of cyclic AMP content after addition of adrenaline showed that the effect of insulin in lowering cyclic AMP content measured after 2-5min was gradually lost over the next hour, mainly because of the fall in cyclic AMP content after an early peak in the presence of adrenaline alone. There was a 44% loss of immunoreactive insulin, from an initial concentration of 0.3nm, during a 1h incubation with fat-cells. Insulin did not affect partitioning of cyclic AMP between cells and incubation medium. When the correlation between cyclic AMP content and rate of lipolysis was investigated for a wide range of adrenaline concentrations, it was found that the lowering of cyclic AMP content by insulin was much less than that required to account for the amount of inhibition of lipolysis. It is concluded that inhibition of adrenaline-stimulated lipolysis by insulin involves factors in addition to a decrease in intracellular cyclic AMP concentration.

Adipose Tissue↗
PubMed1974

The action of local anaesthetics on lipolysis and on adenosine 3':5'-cyclic monophosphate content in isolated rat fat-cells.

1. Local anaesthetics inhibited hormone-stimulated lipolysis in isolated rat fat-cells. The most potent anaesthetic was dibucaine, which inhibited adrenaline-stimulated lipolysis by 50% at a concentration of 0.16mm. 2. The amount of inhibition produced by a given concentration of anaesthetic was very similar with adrenaline, theophylline and dibutyryl cyclic AMP, at submaximal and maximal concentrations. 3. The inhibitory effect of dibucaine on lipolysis was apparent within 5 min and was constant over 1h. 4. Dibucaine inhibited basal, adrenaline-stimulated and insulin-stimulated glucose uptake at concentrations 6-10-fold higher than those inhibiting lipolysis. 5. The effects of dibucaine on lipolysis and glucose uptake were reversed after removal of anaesthetic and washing of cells. 6. Dibucaine further elevated the concentration of cyclic AMP in the presence of adrenaline or adrenaline plus theophylline. 7. Dibucaine had no effect on ATP content at concentrations causing 80% inhibition of lipolysis, but lowered ATP content at higher concentrations. 8. The relative potency of different local anaesthetics as inhibitors of hormone-stimulated lipolysis paralleled their potency as inhibitors of ion movements in other systems. 9. The possibility is discussed that Ca(2+) ions are involved in the regulation of lipolysis, and that local anaesthetics inhibit lipolysis by interfering with Ca(2+) translocation.

Adipose Tissue↗
PubMed1973

The effects of glucagon and insulin on adenosine 3':5'-cyclic monophosphate concentrations in an organ culture of mature rat liver.

1. A modified radioimmunoassay for cyclic AMP was developed from the method of Steiner et al. (1969). Cyclic [(3)H]AMP was used as the radioactive tracer. Free and antibody-bound nucleotides were separated by adsorption of protein to Millipore filters. The assay was used to measure amounts of cyclic AMP down to 0.1pmol in 50mul. 2. The effect of glucagon on cyclic AMP content in pieces of mature rat liver maintained for 6 days in organ culture was studied. 3. Cyclic AMP content in the tissue reached a maximum in 5-15min and then decreased. This may have been partly due to an inhibitor of glucagon action formed in the tissue. Small amounts of cyclic AMP were released into the incubation medium. 4. The maximal increase in cyclic AMP content produced by glucagon decreased over 6 days in culture. However, liver pieces cultured for 2 and 6 days were more sensitive to low concentrations of glucagon than were fresh liver pieces. Glucagon concentrations for half-maximal effects were approx. 1mum and 0.05mum for fresh liver and 2-day cultured liver respectively. 5. Insulin (3.5mum) lowered the cyclic AMP content by 30% in the presence of a submaximal glucagon concentration in liver cultured for 2 days. No effect of insulin was demonstrated on fresh liver pieces. 6. Insulin and glucagon were rapidly destroyed by fresh liver pieces.

Adenosine Triphosphate↗