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)

This study was aimed at evaluating the effect of theophylline, a drug that increases the intracellular concentrations of cAMP by inhibiting phosphodiesterase activity, on somatostatin (SRIF)-mediated inhibition of insulin secretion in man. Acute insulin response (AIR) to i.v. glucose (mean change 3-10 min) was almost totally suppressed by SRIF (500 micrograms/h) and glucose utilization was reduced (p less than 0.0001). These SRIF-induced decreases failed to be eliminated by a concurrent infusion of theophylline (100 mg as a loading dose followed by a constant infusion of 5 mg/min). Theophylline alone resulted in a significant increase in both AIR (p less than 0.01) and glucose removal rates (p less than 0.05). Thus, our data disprove the involvement of the phosphodiesterase enzymes in the inhibitory action of SRIF on glucose-induced insulin secretion in man.
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PMID:Somatostatin and insulin secretion in man. II. The effect of theophylline. 4 65

Cyclic AMP has been implicated in the regulation of the immunologic release of histamine from lung and other tissues and cell types. The mechanism whereby intracellular levels of cAMP are altered during mediator release was investigated. Measurements of histamine, adenylate cyclase, and cAMP phosphodiesterase activities were made in actively and passively sensitized guinea pig lung after challenge with antigen. A transient decrease in basal adenylate cyclase activity occurred which returned to control levels after histamine release. There was no change in cAMP phosphodiesterase activity determined at substrate concentrations of 1 mM and 0.01 mM. The adenylate cyclase response did not occur under the following conditions: 1) incubation of nonsensitized lung with antigen, 2) incubation of sensitized lung with antigen in the absence of extracellular calcium, and 3) incubation of nonsensitized lung with compound 48/80. These observations indicate 1) the adenylate cyclase response and the immunologic release of histamine are intimately related, and 2) the reduction in intracellular levels of cAMP which have been reported to occur during immunologic histamine release are mediated via adenylate cyclase.
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PMID:Reduction in basal adenylate cyclase activity during the immunologic release of histamine from guinea pig lung. 6 29

Luteinizing hormone (LH) and follicle stimulating hormone (FSH) stimulated the accumulation of adenosine 3',5'-monophosphate (cAMP) within 30 minutes of addition to human testicular incubates. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine acted synergistically with FSH and to a lesser degree with LH to enhance cAMP accumulation. The findings indicate that cAMP accumulation may be involved in the mechanism of action of LH and FSH in the human testes, as has been proposed for rats. The prostaglandins (PG) PGE-1, PGE-2, PGA-1, and PGF-2-alpha stimulated cAMP levels at a concentration of 1/10,000 M in human testes. The E type prostaglandins were the most potent; they induced half-maximal stimulation of cAMP at 7/10,000,000 M.
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PMID:Stimulation of cyclic adenosine 3':5'-monophosphate accumulation in human testes in vitro by luteinizing hormone, follicle-stimulating hormone, and prostaglandins. 8 21

The role of cAMP as a mediator of gonadotropin stimulation of ovarian ornithine decarboxylase (ODC) activity was studied in granulosa cells isolated from small (1--2 mm) porcine ovarian follicles. These cells responded to both FSH and LH with significant increases in intracellular concentration of cAMP. At concentrations of gonadotropins which were saturating for the induction of ODC activity, FSH was a more potent stimulator of both cAMP production and ODC activity than LH. N,O'-Dibutyryl cAMP (1.0--10.0 mM) caused a dose-dependent stimulation of ODC activity which equaled the maximal effect of LH but was significantly less effective than the saturating dose of FSH. 8-Bromo-cAMP was more potent than N,O'-dibutyryl cAMP and as effective as FSH as an inducer of ODC activity. Addition of theophylline, a phosphodiesterase inhibitor, to the incubation medium resulted in a dose-dependent inhibition of ODC activity in both control and gonadotropin-stimulated cells. In contrast, 1-methyl,3-isobutyl xanthine, another phosphodiesterase inhibitor, potentiated effects of both submaximal and maximal effective doses of gonadotropins while producing no effect on basal ODC activity of these cells. The results of this study are consistent with the concept that cAMP can mediate gonadotropin stimulation of ODC in porcine granulosa cells. In addition, this study shows the importance of proper selection of cAMP analogs and phosphodiesterase inhibitors, and their concentration in studying such effects.
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PMID:Gonadotropin stimulation of porcine ovarian ornithine decarboxylase in vitro: the role of 3',5'-adenosine monophosphate. 8 47

In continuing studies on cyclic nucleotide involvement in the regulation of gonadotropin release, we have measured the cyclic nucleotide content and rate of LH and FSH release during stimulation by LHRH of dispersed overnight cultured cells from the pituitaries of adult female rats. The minimal effective concentration of LHRH was 0.1 nM and half maximal stimulation of gonadotropin release was observed in the presence of 1.0 nM LHRH. Significant release of both LH and FSH was detectable after only 10 min in the presence of 5 nM LHRH. The presence of fetal calf serum (FCS) in the overnight culture medium increased basal cGMP levels significantly, whereas horse serum (HS) had no effect, therefore all experiments were conducted on cells cultured in the presence of HS. Treatment of the cultured cells with the phosphodiesterase inhibitors theophylline (TH) or isobutyl-methyl-xanthine (MIX) revealed a preferential stimulatory effect of TH on basal cAMP levels and of MIX on cGMP levels. Throughout these experiments, LHRH had no effect on cAMP levels. In the presence of MIX, concentrations of the releasing hormone as low as 1 nM induced a significant rise in the level of cGMP whereas in its absence, cGMP levels appeared to be unchanged by LHRH. The increase was detectable after 10 min of incubation. MIX alone slightly increased LH and FSH release and significantly potentiated the response of the cells to increasing doses of LHRH up to, but not beyond, 10 nM. The data support the possibility that cGMP may be involved in the mechanism of action of LHRH.
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PMID:A possible role for cyclic GMP in mediating the effect of luteinizing hormone releasing hormone on gonadotropin release in dispersed pituitary cells of the female rat. 8 42

1. Extracellular recordings were made in vitro from single neurones of the myenteric plexus of the guinea-pig ileum. 2. Neuronal firing was inhibited by morphine and normorphine (10 nM to 1 micrometer). Cyclic adenosine 3',5'-monophosphate (cyclic AMP) (100 micrometer to 1 mM) also inhibited the firing of the majority of the neurones. Prostaglandin E2 usually caused a short-lasting excitation of myenteric neurones and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was usually without effect on firing rate. 3. The inhibition of neuronal firing by normorphine was unaffected by prior and/or concurrent administration of cyclic AMP, dibutyryl cyclic adenosine 3',5'-monophosphate, prostaglandin E2 or 3-isobutyl-1-methylxanthine. As these four treatments might be expected to elevate intracellular levels of cyclic AMP, the results lend no support to the notion that a reduction in intracellular cyclic AMP is essential to the inhibition of firing produced by morphine.
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PMID:Inhibition of neuronal firing by opiates: evidence against the involvement of cyclic nucleotides. 8 71

Isolated pancreatic islets of noninbred ob/ob mice were used to test the hypothesis that adenylate cyclase responds to changes of the transmembrane milieu or electric field in intact beta-cells. In the presence of a phosphodiesterase inhibitor, ouabainstimulated both the release of insulin and the islet content of cAMP. Ouabain had no noticeable effect on the islet content of cGMP. These results support the hypothesis at test. However, because ouabain also had some stimulatory effect on cAMP in islet homogenates, a direct action of ouabain on adenylate cyclase cannot be ruled out.
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PMID:Effects of ouabain on insulin release, adenosine 3',5'-monophosphate and guanine 3',5'-monophosphate in pancreatic islets. 8 35

Studies were carried out to simultaneously measure cAMP and cGMP accumulation and GH release from acutely dispersed purified somatotrophs obtained from rat adenohypophyses. cAMP accumulation was dramatically increased by both prostaglandin E2 (10(-6) M) and 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor, 0.5 mM) within 1 min of their addition, while there was a delay of 8--16 min before a significant increase in GH release was seen. SRIF (100, 10, or 1 ng/ml) completely blocked the stimulated release of GH. SRIF also consistently decreased the elevation of cAMP induced by the two secretagogues, but this decrease was small and not always significant. cGMP was unmeasurable (less than 0.02 fmol/1000 cells) in all of our experiments, while basal cAMP levels were about 1 fmol/1000 cells. We conclude that cAMP plays a role in the intracellular mechanisms governing GH release and that SRIF primarily acts subsequent to cAMP elevation, with a possible secondard or minor action on cAMP formation.
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PMID:Release of growth hormone from purified somatotrophs: role of adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate. 8 23

Porcine vasoactive intestinal peptide stimulated adenosine 3':5'-monophosphate (cyclic AMP) production in rat intestinal epithelial cells. The stimulation was dependent on time and temperature and was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Under optimal conditions (at 15 degrees C, with 0.2 mM 3-isobutyl-1-methylaxanthine, at a cell concentration up to 18 microgram DNA/ml), the cyclic AMP production produced by vasoactive intestinal peptide was constant for 10 min and stopped after 15 min incubation, at either low (1 nM) or high (30 nM) concentration of the peptide. This plateau effect was demonstrated not to be due to an inactivation of vasoactive intestinal peptide in the medium nor to an alteration of receptors for the peptide. Cyclic AMP production was sensitive to a concentration as low as 0.1 nM vasoactive intestinal peptide. Maximal stimulation of cyclic AMP levels by vasoactive intestinal peptide was observed with 30 nM vasoactive intestinal peptide and represented an 11-fold increased above basal. The dorse-response curve was monophasic with a Km of 2.3 x 10(-9) M. No cooperative effects were detected by Hill analysis. The positive non-linear relationship observed between stimulation of cyclic AMP production and occupancy of binding site was not time-dependent as indicated by experiments performed after 15, 45 and 120 min incubation. Maximal and half-maximal responses were obtained at about 70% and 7% occupation of binding sites, respectively. Chicken vasoactive intestinal peptide and porcine secretin were agonists of porcine vasoactive intestinal peptide with a 6-times and a 120-times lower potency, respectively. Among secretin analogs that were found to have low affinity for vasoactive intestinal peptide binding sites, [4-alanine, 5-valine]secretin, that resembles vasoactive intestinal peptide at the first seven amino acids at the N-terminal end, was a partial agonist of vasoactive peptide at the first seven amino acids at the N-terminal end, was a partial agonist of vasoactive intestinal peptide and others failed to stimulate cyclic AMP production. Glucagon (10microM), gastric inhibitory peptide (0.1 microM), substance, P, neurotensin, octapeptide of cholecystokinin, bovine pancreatic polypeptide, human gastrin I with leucine at residue 15, Leu-enkephalinand somatostatin (1 microM) did not alter cyclicAMP levels. Non-peptide mediators such as dopamine, serotonin, acetylcholine and histamine, tested at 10 microM, were also ineffective. Prostaglandins E2, E1 and isoproterenol, tested at 10 microM, induced an increase of cyclic AMP levels above basal but were 9.5, 13.7 and 17.5 times less efficient than vasoactive intestinal peptide, respectively. Thus vasoactive intestinal peptide is a unique stimulus of cyclic AMP production in rat intestinal epithelial cells.
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PMID:Interaction of vasoactive intestinal peptide with isolated intestinal epithelial cells from rat. 2. Characterization and structural requirements of the stimulatory effect of vasoactive intestinal peptide on production of adenosine 3':5'-monophosphate. 8 68

Incubation of bovine coronary artery (BCA) rings with isobutylmethylxanthine (IBMX) resulted in a time-dependent increase of cAMP content. This effect was blocked, when the rings were preincubated with indomethacine or 15-hydroperoxy-arachidonic acid for 5 min, indicating that the IBMX-induced increase in cAMP content may depend on endogenous PGI2 formation. PGE2 did not increase the cAMP content in BCA rings. Dipyridamole did not effect cAMP content, when used as a substitute for IBMX. It is suggested that PGI2 stimulates cAMP formation in arterial walls, but that this effect only becomes visible in the presence of a phosphodiesterase inhibitor.
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PMID:PGI2 enhanced cAMP content in bovine coronary arteries in the presence of isobutylmethylxanthine. 9 76


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