Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucagon increases the rate of glycogenolysis in in vitro cultures of hepatic tissue from the axolotl Ambystoma mexicanum. The hormone causes an increase in the concentration of cyclic AMP in the tissue which is followed by activation of glycogen phosphorylase and subsequent breakdown of glycogen and release of glucose from the tissue. Insulin counteracts the glycogenolytic effect of glucagon by inhibiting the increase in tissue cyclic AMP concentration brought about by glucagon. This inhibitory effect of insulin is not seen in the presence of the phosphodiesterase inhibitor IBMX and so it appears that the initial action of insulin is a stimulation of cyclic AMP phosphodiesterase activity which lowers the tissue concentration of cyclic AMP and so counters the actions of hormones that act by raising the tissue concentration of cyclic AMP. This model for the mode of action of insulin is supported by the finding that insulin also interferes with the glycogenolytic actions of adrenaline, a second hormone which acts by raising tissue cyclic AMP concentrations.
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PMID:Glucagon and insulin regulate in vitro hepatic glycogenolysis in the axolotl Ambystoma mexicanum via changes in tissue cyclic AMP concentration. 241 34

Several insulinotropic hormones have been shown to increase the level of cyclic AMP in isolated islets. This study was performed to investigate whether gastric inhibitory polypeptide (glucose-dependent insulin-releasing polypeptide) has a similar effect, in particular at concentrations close to the physiological level in blood. Collagenase isolated rat islets were maintained for 24 h in tissue culture (medium 199) and then incubated for 30 min for measurement of insulin release and cyclic AMP content. Glucose-induced (16.7 mmol/l) insulin release was enhanced by gastric inhibitory polypeptide 1-100 ng/ml (0.196-19.6 nmol/l) in a dose-related fashion. The cyclic AMP content was enhanced only by 100 ng/ml. However, when 0.1 mmol/l of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was present, even 1 ng/ml of gastric inhibitory polypeptide increased both cyclic AMP content and insulin release. Such a concentration of the hormone can be measured in human blood after a meal. In contrast, in freshly isolated islets no effect of the hormone on glucose-induced insulin release or cyclic AMP content could be detected for concentrations ranging from 1 to 100 ng/ml. These findings demonstrate that the hormone sensitivity of isolated islets is markedly enhanced by short-term maintenance in tissue culture. The results suggest that an increase in cyclic AMP is seen in response to gastric inhibitory polypeptide and may be causally related to the insulinotropic effect of the hormone.
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PMID:Stimulation of insulin release in isolated rat islets by GIP in physiological concentrations and its relation to islet cyclic AMP content. 241 5

The widely used phosphodiesterase inhibitor MIX (1-methyl 3-isobutyl xanthine) blocked insulin antagonism of cAMP-stimulated glycogenolysis in rat hepatocytes but other phosphodiesterase inhibitors including Ro 20-1724 had no effect. Dose-response curves for MIX potentiation of cAMP-stimulated glycogenolysis and for MIX inhibition of the effects of insulin on cAMP-stimulated glycogenolysis suggested that at higher concentrations (250 microM) MIX may act at a site other than phosphodiesterase inhibition. MIX, at 250 microM, attenuated the insulin antagonism of glucose release stimulated by 8-bromo-cAMP, an extremely poor substrate for phosphodiesterase; other phosphodiesterase inhibitors did not. The possibility that MIX acts as an adenosine antagonist interfering with a postulated role for adenosine in insulin action was examined using N6-phenylisopropyladenosine (PIA), an Ra adenosine receptor agonist which increases hepatic cAMP levels. MIX inhibited insulin antagonism of PIA-stimulated glycogenolysis under conditions where it did not act as an adenosine antagonist (MIX and Ro 20-1724 both increased the response to PIA equally). The effect of concanavalin A on cAMP-stimulated glycogenolysis was antagonized by MIX, suggesting a post-receptor site of action for MIX. MIX paradoxically increased lactate production in the presence of 8-bromo-cAMP, reminiscent of the reported actions of calcium mobilizing hormones on lactate formation in fed hepatocytes. Cytosolic free Ca2+, as measured in Quin 2-loaded cells, was increased by MIX. In cells depleted of calcium, MIX no longer blocked insulin antagonism of 8-bromo-cAMP-stimulated glucose release, suggesting that MIX may function through an insulin-insensitive release of calcium. MIX greatly potentiated the stimulation of glycogenolysis by phenylephrine but did not alter the response to vasopressin. The relationship of this effect of MIX to the mechanism of insulin action and the ability of insulin to antagonize only alpha-adrenergic responses and not those of vasopressin is discussed.
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PMID:Methylisobutylxanthine blocks insulin antagonism of cAMP-stimulated glycogenolysis at a site distinct from phosphodiesterase. Evidence favoring an insulin-insensitive calcium release mechanism. 241 37

Inoculation of golden Syrian hamsters with Venezuelan encephalitis (VE) virus results in a sustained diminution in glucose-stimulated insulin release that is correctable by cyclic (c) AMP analogs and phosphodiesterase inhibitors. This suggested the importance of directly measuring cAMP content in VE-infected and control islets in response to insulin secretagogues. The basal cAMP content of VE-infected islets (0.14 +/- 0.02 pmol/micrograms islet DNA) was approximately half that of control islets (0.27 +/- 0.02 pmol/micrograms islet DNA) (P less than 0.05). In the presence of 10 microM glucagon (and 3 mM glucose), the rate of cAMP generation in VE-infected islets was only half that of control islets. With 10 mM alpha-ketoisocaproic acid, the rates of cAMP generation were indistinguishable between control and experimental groups. In response to 20 mM glucose and 3-isobutyl-1-methylxanthine (IBMX) (a phosphodiesterase inhibitor), cAMP generation in VE-infected islets was 81% (NS) of the control rate. When a more specific phosphodiesterase inhibitor, RO 20-1724, was used with 20 mM glucose, cAMP generation in the infected islets was only 44% (P less than 0.001) of the control value. Insulin secretion over the perifusion period paralleled the cAMP levels. In the presence of 10 mM alpha-ketoisocaproic acid, there was no difference in insulin secretion between VE-infected and control islets, while there was a statistically significant (P less than 0.05) difference with 10 microM glucagon or 20 mM glucose (in 1 mM RO 20-1724). These data point to a defect in the cAMP generation system of VE-infected islets, although additional factors involved in insulin secretion may also be impaired by the virus.
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PMID:Virus-induced alterations in cyclic adenosine monophosphate generation in hamster islets of Langerhans. 241 63

The phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine (IBMX) was able to elevate rat small intestinal cyclic AMP levels to 300% of basal values. Active jejunal D-glucose transport was enhanced parallel to the rise of intracellular cyclic AMP levels to 140% of control values at 100 mumol/l IBMX. Transport parameters, as determined in a three compartment model in vitro using a dual label method, indicate increased 'uphill' glucose transport at the site of the brush border membrane, higher intracellular accumulation of the sugar, with unchanged passive permeabilities. Phlorizin-inhibited D-glucose transport and L-glucose transfer in the rat were not affected by the persisting cyclic AMP elevation produced by IBMX. Stimulating effects could also be demonstrated with D-galactose as a substrate. IBMX 100 mumol/l also increased active D-glucose as well as 3-O-methylglucose transport in mouse jejunum. Stimulatory effects on intestinal hexose transport and mucosal cyclic AMP levels were also found with the adenylate-cyclase activator forskolin. In the present study, forskolin effects on jejunal mucosal cyclic AMP levels were enhanced in the presence of 100 mumol/l IBMX, resulting in a 20-fold increase compared to controls at 20 mumol/l forskolin. The concentration response for the effect of forskolin in the presence of 100 mumol/l IBMX on D-glucose transport did not produce a significant increase compared to transport stimulation with IBMX alone. At higher concentrations of forskolin however, glucose transport decreased to levels well below the IBMX controls. The elevation of cellular cyclic AMP levels had no effects on passive permeability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Response of rat small intestinal active aldohexose transport to elevation of mucosal cyclic AMP by forskolin and 3-isobutyl-1-methylxanthine in vitro. 241 72

The use of a new density gradient medium, Dextran M 70, is described for isolation of islets of Langerhans from collagenase digested pancreases of neonatal Wistar rats. Centrifugation in continuous as well as in discontinuous gradients of a less expensive dextran with a mol. wt. of 70,000 was performed and the results were compared with those obtained with Ficoll gradients. About 100 islets free from exocrine acinar parenchyma were obtained from each neonatal rat pancreas. There were no differences in glucose-stimulated insulin release and in potentiation of glucose-stimulated insulin release by the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX) between the islets isolated by centrifugation in Dextran M 70 or Ficoll 400 and those directly harvested from the pancreatic digest without density media. These data demonstrate that high numbers of pancreatic islets can be rapidly isolated in dextran gradients without any impairment of their functional integrity. Dextran M 70 gradients can be readily formed as continuous or 4-step discontinuous gradients without special osmotic compensators and its maximum density of 1.097 g/ml at a concentration of 23% (w/w) seems to be sufficient for the purification of other cell types too.
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PMID:The use of a new dextran gradient medium for rapid isolation of functionally intact neonatal rat pancreatic islets. 242 May 3

Previous studies of embryonic rat skeletal muscle cultures suggested that there was a correlation between intracellular adenosine 3',5'-cyclic monophosphate (cAMP) concentration and activities of enzymes of oxidative energy metabolism. We investigated the ability of agents that elevate intracellular cAMP by three different mechanisms (activation of adenylate cyclase, inhibition of phosphodiesterase, and analogues) to alter not only the activities of 11 glycolytic and mitochondrial enzymes but also the rate of flux through aerobic glucose oxidation in intact myotubes derived from regenerating rat muscle satellite cells. The enzyme activities were not consistently altered when cAMP was elevated, with the exception of the electron transport enzyme, NADH cytochrome c reductase, whose activity was elevated by exposure of the myotubes to cholera toxin (110% of control), 3-isobutyl-1-methylxanthine (112%), caffeine (119%), and 8-bromoadenosine 3',5'-cyclic monophosphate (120%). The rate of flux of aerobic glucose oxidation was elevated by all agents (116-157% of control) except cholera toxin. This study allowed us to compare the metabolic characteristics of myotube cultures derived from satellite cells with those from embryonic muscle, from a previous study. Despite differences between these two models, together, the data present strong evidence that an increase in intracellular cAMP can cause an increase in oxidative capacity.
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PMID:Increased aerobic glucose oxidation by cAMP in cultured regenerated skeletal myotubes. 242 46

With an SV40-transformed hamster beta-cell line (HIT cells) as a model system, we tested the hypothesis that a rise in cAMP levels potentiates insulin release by an effect on the cytosolic free-Ca2+ concentration ([Ca2+]i). Intracellular cAMP levels were measured by radioimmunoassay, and [Ca2+]i was monitored with the fluorescent Ca2+ indicator quin 2. Insulin secretion was followed in static incubations or perifusion of the cells. In perifusion, both high glucose and depolarization of the beta-cell with 40 mM K+ trigger a monophasic pattern of insulin release without altering the HIT cell cAMP content. Addition of either the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) or the adenylate cyclase activator forskolin dramatically increased the cellular cAMP content, potentiated the burst phase of insulin release, and coupled the immediate phase of insulin secretion to a sustained secretory response. However, increases in cellular cAMP content were not associated with a change in [Ca2+]i. Thus, the potentiation of insulin secretion by a rise in cAMP in the HIT cell is not mediated by a release of stored Ca2+. Either a glucose-generated signal or a rise in [Ca2+]i triggered by high K+ can synergize with a rise in cAMP to couple the burst or immediate release of insulin evoked by either secretagogue to the sustained release of insulin.
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PMID:Increase in cAMP levels in beta-cell line potentiates insulin secretion without altering cytosolic free-calcium concentration. 243 78

Dantrolene sodium, used clinically as a muscle relaxant because of its ability to block Ca2+ efflux from sarcoplasmic reticulum, was used to study the role of intracellular stored Ca2+ in the stimulation of insulin release from rat pancreatic islets. Under basal conditions (2.8 mM glucose), dantrolene (25 microM) decreased 45Ca2+ efflux by 40% without affecting the rate of insulin release. When the islets were exposed to a submaximal stimulatory concentration of glucose (8.3 mM), dantrolene potentiated insulin release. When a supermaximal concentration of glucose (33.3 mM) was used, dantrolene neither increased nor decreased the maximal rate of insulin release. In all cases studied, 45Ca2+ efflux was depressed by dantrolene. 3-Isobutyl-1-methyl-xanthine (IBMX) a phosphodiesterase inhibitor, stimulated insulin release and caused a transient increase in 45Ca2+ efflux from preloaded islets in accord with the idea that it mobilizes Ca2+ from an intracellular store. Dantrolene inhibited IBMX-induced 45Ca2+ efflux and potentiated IBMX-stimulated insulin release. That dantrolene acts to trap calcium in stores is supported by wash-out experiments in which, under basal conditions, removal of the drug after a preincubation period increased both insulin release and 45Ca2+ efflux. The apparent contradiction that a calcium store blocker potentiates insulin release is reconciled by the hypothesis that dantrolene, by filling intracellular Ca2+ stores, causes them to regulate cytosolic Ca2+ at a higher set point.
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PMID:Paradoxical potentiation of stimulated insulin release by dantrolene in rat pancreatic islets. 243 18

Pulsatile administration of glucagon to perifused rat hepatocytes stimulates hepatocyte glucose production (HGP) more effectively than continuous administration. Having established that this effect was due to delayed relaxation of glucagon-stimulated HGP (t1/2 for decay = 3.54 +/- 0.60 min) we wished to examine the mechanism of response termination. Delayed dissociation of glucagon from its receptor was excluded by the brisk washout of [125I]glucagon from perifusion columns (t1/2 = 1.00 +/- 0.13) and the rapid decay in glucagon-stimulated cAMP released into the perifusion medium (t1/2 = 1.14 +/- 0.12). The relaxation of the HGP response to a pulse of administered cAMP was comparable to the decay in glucagon-stimulated HGP (t1/2 = 3.28 +/- 0.22). Furthermore, the phosphodiesterase inhibitor isobutyl-methylxanthine did not alter the decay of the HGP response to glucagon despite increasing the amplitude of the response (t1/2 = 3.04 +/- 0.36). These data place the rate-limiting step for HGP relaxation distal to cAMP generation and degradation. The decay of the beta-hydroxybutyrate response to a glucagon pulse was not different from the cAMP response (t1/2 = 1.14 +/- 0.23), whereas the decay of gluconeogenesis from lactate was not significantly different from HGP relaxation (t1/2 = 1.94 +/- 0.08). We conclude that rate-limiting events for HGP relaxation occur distal to the second messenger cascade; however, ketogenesis is more closely coupled to the kinetics of cAMP. These results may help to explain the absence of excessive ketosis during fasting in normal humans, who secrete glucagon episodically at 10- to 14-min intervals.
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PMID:A kinetic analysis of hepatocyte responses to a glucagon pulse: mechanism and metabolic consequences of differences in response decay times. 243 20


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