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)

1. Dibutyryl cyclic AMP (Db cAMP, 75-500 microgram/kg), injected into the lateral ventricle of the brain of the cat increased blood pressure, heart rate and splanchnic discharge rate. 2. ATP, but not AMP, induced similar changes; GMP in small doses increased blood pressure. 3. A number of drugs are known to activate adenylate cyclase-induced hypertension, tachycardia and increase splanchnic discharge rate. This was shown for TRH, tetracosactide and a new beta2-adrenoceptor stimulant, NAB 365. 4. Injection into the lateral ventricle of theophylline or Ro 7/2956, both inhibitors of phosphodiesterase, similarly increased blood pressure. 5. Histamine administered by the same route induced similar reactions; it is not known if this action was exerted by activation of H1- or H2-receptors. 6. Somatostatin, known to reduce cAMP levels, induced a small but significant decrease in blood pressure. Melanocyte stimulating hormone release inhibiting factor (MIF) and TSH were ineffective. 7. These results provide evidence for the possibility of a role for cAMP in the central regulation of blood pressure at suprabulbar levels.
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PMID:Cyclic 3'5'-adenosine monophosphate and central circulatory control in cats and dogs. 2 Feb 56

1. Interaction of Ca2+ and cyclic nucleotides in stimulus-secretion coupling in rat pancreas in vitro was studied utilizing the divalent cation inophore A23187. phosphodiesterase inhibitors, cyclic nucleotides and cholera toxin. 2. Amylase secretion was increased by the ionophore in the presence of extracellular Ca2+ in a dose-dependent fashion. Activation of CCK-PZ receptors simultaneously with induction of amylase secretion by A23187 did not alter amylase secretion whereas theophylline or caffeine had effects additive to A23187. Dibutyryl cyclic AMP potentiated the effect of ionophore whereas dibutyryl cyclic GMP had no effect on basal or ionophore-induced amylase secretion. Cholera toxin by itself did not effect amylase secretion whereas it potentiated the effect of ionophore. 3. A23187 increased bidirectional fluxes of 45Ca and increased efflux of 45Ca in a fashion similar to CCK-PZ. Theophylline did not alter basal efflux of 45Ca. Dibutyryl cyclic AMP increased the basal efflux of 45Ca whereas, cholera toxin, dibutyryl cyclic GMP and sodium butyrate had no effect. 4. Theophylline increased basal cyclic AMP levels with a peak effect observed at 5 min. Combination of theophylline and ionophore did not lead to an increase in levels of cyclic AMP greater than that observed with theophylline alone. Cholera toxin increased cyclic AMP levels at 30 and 60 min of incubation. 5. Ionophore and CCK-PZ increased tissue cyclic GMP levels significantly greater than that obtained with theophylline alone. This effect was dependent on extracellular Ca2+. The effect of ionophore on tissue levels of cyclic GMP could be dissociated from its effect on 45Ca efflux and amylase secretion. 6. It is concluded from these studies that Ca2+ plays a predominant role in regulating amylase secretion with interactions occurring between Ca2+ and cyclic AMP and Ca2+ and cyclic GMP. It appears that by themselves cyclic AMP and cyclic GMP do not play a significant role in regulating enzyme secretion.
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PMID:Calcium and cyclic nucleotide interaction in secretion of amylase from rat pancreas in vitro. 9 37

A comparison was made of the action of three classes of substances with platelet aggregation inhibiting effect in normal and essential fatty acid deficient rats. In the latter group, the effect of indomethacin was considerably reduced, whereas the difference was smaller with aspirin. Dibutyryl cyclic AMP had the same inhibiting effect in both groups. Of the phosphodiesterase inhibitors tested, dipyridamole was inactive, whereas the inhibiting effects of caffeine and papaverine are slightly reduced in the deficient animals. The same differences between the two groups were seen in the magnitude of the release reaction after 14C-serotonin labelling. These data support the idea that the non-steroid anti-inflammatory drugs act by inhibiting the formation of an aggregation-inducing substance from arachidonic acid.
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PMID:The effect of non-steroid anti-inflammatory drugs, dibutyryl cyclic 3',5'-adenosine monophosphate and phosphodiesterase inhibitors on platelet aggregation and the platelet release reaction in normal and essential fatty acid deficient rats. 17

Rabbit anterior mesenteric-portal vein was shown to exhibit a positive correlation between relaxation and cyclic AMP levels using different concentrations of isoproterenol for varying exposure times. No consistent relationship was found between cyclic AMP and relaxation using a series of phosphodiesterase inhibitors (papaverine, SC2964, or RA233). In sodium-free (Tris-substituted) Kreb's solution, the addition of isoproterenol still increased cyclic AMP levels, but there was no relaxation. Dibutyryl cyclic AMP was also ineffective in sodium-free solution. Under identical conditions, both relaxation and increases in cyclic AMP produced by papaverine and SC2964 were found to be independent of extracellular sodium. We conclude, therefore, that increased cyclic AMP may be involved in isoproterenol-induced relaxation possibly acting via increased Na+-Ca2+ exchange, but plays only a small role, if any, in smooth muscle relaxation produced by papaverine, RA233, or SC2964.
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PMID:Quantitative aspects of cyclic AMP and relaxation in the rabbit anterior mesenteric-portal vein. 17 62

Thyrotropin-releasing hormone (TRH) has 3 effects on clonal strains of rat pituitary cells in culture (GH-cells). Two long-term effects of TRH on GH-cells, which are measurable after 3 h or longer, have been previously reported; these are an increase in prolactin synthesis and a decrease in growth hormone production. We report here that TRH also stimulates the rapid release of stored intracellular prolactin. We have investigated the role of cyclic AMP as a possible mediator of the effects of TRH on GH-cells. Cyclic AMP concentrations are higher in cells treated with TRH compared with paired controls; a maximum difference of greater than 150% of control values is detected at 15 min if the incubation is performed in serum-free medium in the presence of 1 mM theophylline. The concentration of TRH required to give half-maximum increases in both prolactin release and cyclic AMP accumulation is 0.3 nM; half-maximal increases in prolactin synthesis occur at 3 nM TRH. Exogenous cyclic AMP (1 mM) causes only a slight increase in prolactin release; 8-bromo-cyclic AMP and 8-methylthio-cyclic AMP (1 mM) do not cause significant release. Phosphodiesterase inhibitors (0.3 mM theophylline, 0.03 mM isobutyl-methylxanthine) increase prolactin release but their effects on hormone synthesis are more complicated. Isobutylmethylxanthine, 8-bromo-cyclic AMP and 8-methylthio-cyclic AMP (0.4 MM) increase prolactin synthesis, but do not significantly affect growth hormone synthesis. Theophylline increases the synthesis of both hormones. Dibutyryl cyclic AMP (0.5 mM or more) increases prolactin release and both growth hormone and prolactin synthesis, but equivalent amounts of sodium butyrate have the same effects. We conclude that in GH-cells under carefully defined experimental conditions: 1) TRH causes an increase in intracellular cyclic AMP concentrations; 2) the increase in endogenous cyclic AMP and the effects of phosphodiesterase inhibitors are consistent with a model with cyclic AMP as a mediator of the effects of TRH on prolactin release; however, they do not prove this model, because the interpretation of these results depends on assumptions which may not all be valid; and 3) none of the analogs of cyclic AMP or the phosphodiesterase inhibitors tested mimic the decrease in growth hormone production caused by TRH.
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PMID:A possible role of cyclic AMP in mediating the effects of thyrotropin-releasing hormone on prolactin release and on prolactin and growth hormone synthesis in pituitary cells in culture. 17 74

1. The role of adenosine 3':5'-phosphate (cyclic AMP) and guanosine 3':5'-phosphate (cyclic GMP) as second messengers for the enzyme secretory response evoked by the autonomic neurotransmitters, noradrenaline and acetylcholine, is examined in this in vitro study on the guinea-pig submandibular gland. 2. Noradrenaline increased enzyme (kallikrein) secretion. The initial stimulation of enzyme release appeared to be dose-dependent. The time course of cumulative kallikrein secretion revealed a complex pattern. Isoprenaline and phenylephrine were almost as potent as noradrenaline in releasing kallikrein. Both propranolol and phentolamine were required to fully inhibit the noradrenaline-stimulated enzyme secretion. 3. The cumulative secretion of kallikrein evoked by acetylcholine was dose-dependent. The onset of secretion showed a significantly greater time-lag than that observed with noradrenaline. Atropine effectively blocked the release of kallikrein by acetylcholine. 4. Dibutyryl cyclic AMP stimulated enzyme secretion. Dibutyryl cyclic GMP caused an initial increase which was not maintained. 5. The cyclic nucleotide phosphodiesterase inhibitors, theophylline and papaverine, increased basal kallikrein secretion. The action of the cyclic phosphodiesterase inhibitors on the secretory response to noradrenaline, acetylcholine, dibutyryl cyclic AMP and dibutyryl cyclic GMP was complex. In general, the increase in enzyme release produced by the secretagogues was additively enhanced by both inhibitors. 6. Omission of calcium inhibited both acetylcholine and dibutyryl cyclic GMP stimulated kallikrein release, but to a lesser degree than that of noradrenaline and dibutyryl cyclic AMP. High concentrations of extracellular calcium (10 mM) appeared to enhance the action of acetylcholine. 7. Noradrenaline produced a rise in the intracellular level of cyclic AMP. The increase preceded the stimulated secretion of kallikrein. Of the various adrenergic agonists, noradrenaline and isoprenaline were the most potent, whereas phenylephrine was significantly less effective in raising basal cyclic AMP values. Acetylcholine was without effect, even in the presence of a cyclic phosphodiesterase inhibitor. 8. Acetylcholine and noradrenaline raised intracellular levels of cyclic GMP only when the tissue incubations were performed in the presence of a cyclic phosphodiesterase inhibitor. The increase in cyclic GMP produced by acetylcholine preceded enzyme secretion. 9. Morphological data substantiated the finding that the in vitro release of kallikrein evoked by the secretagogues was associated with the depletion of secretory granules and vacuolations in acinar cells of the gland slices. 10. The molecular mechanisms which control enzyme secretion in the exocrine submandibular gland are discussed. Models are presented for the role of transmitter-specific cyclic nucleotides and calcium in stimulus-secretion coupling.
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PMID:Stimulus-secretion coupling: role of cyclic AMP, cyclic GMP and calcium in mediating enzyme (kallikrein) secretion in the submandibular gland. 18 62

Utilization of 14C-prelabeled endogenous triglycerides was studied in isolated perfused working rat hearts. Lipolysis was estimated by the disappearance of 14C-labeled and total triglycerides. Metabolic 14CO2 production was continuously monitored to evaluate triglyceride fatty acid oxidation. Triglyceride utilization was enhanced by an increase in ventricular pressure development as evidenced by a faster rate of triglyceride mobilization and oxidation. Added catecholamines stimulated lipolysis in hearts perfused with glucose-containing buffer but were without effect in the presence of exogenous fatty acids; the latter were shown to be potent and, possibly, direct inhibitors of myocardial lipolysis. Mediation of catecholamine-induced lipolysis by cyclic AMP has not been settled. Dibutyryl cyclic AMP produced only a slight lipolytic effect, although theophylline, a known phosphodiesterase inhibitor, was a potent lipolytic agent. Theophylline may have exerted its lipolytic effect through an alternative mechanism. Hypoxia per se was a strong inhibitor of heart triglyceride utilization. Furthermore, added epinephrine was without effect on triglyceride lipolysis in hypoxic hearts. Thus, cardiac muscle triglyceride utilization is influenced by such factors as mechanical function, exogenous substrates, hormones, and oxygen availability. The mechanisms involved in these areas of regulation need to be resolved.
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PMID:Regulation of triglyceride metabolism in the isotopically prelabeled perfused heart. 19 38

Thyrotropin (TSH) stimulation of ornithine decarboxylase (ODC) activity and polyamine levels was studied in vitro in rat thyroids. The elevation in ODC activity was related to the concentration of TSH in the incubation medium with peak activity at a concentration of 25mU/ml. ODC activity with 50 mU/ml of TSH was 3 to 5-fold higher than control activity at 5 h of incubation; this stimulation was enhanced by the addition of 0.5 mM 3-isobutyl-l-methyl xanthine (MIX), a phosphodiesterase inhibitor. Dibutyryl cyclic AMP (DbcAMP) also stimulated ODC activity with a dose response up to 2.0 mm. The increase in ODC activity with TSH and MIX was prevented by incubation with actinomycin D (10 microgram/ml) or puromycin (0.2 mM). Putrescine concentrations in rat thyroids rose to three times basal levels after 6 h of incubation with TSH and MIX; no significant elevation in spermidine or spermine was observed after up to 7 h incubation. The increase in tissue putrescine preceded a rise in [3H]uridine incorporation into acid-soluble material that occurred at 7 h. The results suggest that stimulation of thyroid ODC activity by TSH is mediated by a cyclic AMP; the data further are consistent with a role for polyamines in the control of RNA synthesis in the thyroid.
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PMID:In vitro stimulation of thyroid ornithine decarboxylase activity and polyamines by thyrotropin. 19 94

Mouse neuroblastoma cells grown in the presence of 1 mM N6,O2'-dibutyryl-cyclic AMP showed a 3-fold increase in cyclic AMP-binding proteins. The role of dibutyryl cyclic AMP in the introduction of cyclic AMP-binding proteins in these cells has been studied. Induced cyclic AMP-binding proteins were observed in the cytoplasm 15 h after dibutyryl cyclic AMP treatment. The increase in cyclic AMP-binding proteins required RNA and protein synthesis. It is suggested that the 15-h lag occurs at the post-transcriptional and/or translational level. Cyclic AMP-binding proteins are found in both soluble and particulate cell fractions. Dibutyryl cyclic AMP increased binding proteins in both fractions. The control and dibutyryl cyclic AMP-induced binding proteins showed similar affinity for cyclic AMP. The data indicate that dibutyryl cyclic AMP caused the following sequential events: a 12-fold increase in cyclic AMP levels; a 40% increase in phosphodiesterase activity; and a 300% (3-fold) increase in cyclic AMP-binding proteins. It is suggested that the differentiation of mouse neuroblastoma cells involves increased levels of cyclic AMP and cyclic AMP-binding proteins.
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PMID:Induction of cyclic AMP-binding proteins by dibutyryl cyclic AMP in mouse neuroblastoma cells. 20 71

Cerebral cortical slices from rats were incubated in physiologic saline, and the uptake, release, and K+-stimulated release of norepinephrine were measured. Dibutyryl cyclic AMP, the phosphodiesterase inhibitors aminophylline and papaverine, and adenosine (which stimulates adenyl cyclase) all caused a variable increase in uptake of norepinephrine at concentrations ranging from 10(-7) to 10(-4) M. Prostaglandins E1 and E2 appeared to have no effect on uptake, but this may be because the alcohol required to dissolve them had an inhibitory effect on uptake. None of these compounds appeared to affect basal or K+-stimulated release of norepinephrine. These agents therefore seem to have an effect opposite to that of the tricyclic antidepressants (which inhibit uptake of norepinephrine). Since norepinephrine's postsynaptic effects are usually inhibitory in the cortex, the stimulatory effect of the drugs tested on the presynaptic uptake of norepinephrine may explain the stimulant and epileptogenic effects of these drugs.
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PMID:Uptake and release of norepinephrine by slices of rat cerebral cortex: effect of agents that increase cyclic AMP levels. 21 64


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