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)

Luminal application of acid was recently shown to stimulate surface epithelial HCO3(-) transport in stomach and duodenum. Effects of some potential transmitters of this response were therefore studied in amphibian gastric fundic and proximal duodenal mucosa in vitro. Duodenal HCO3- transport, which could be titrated directly, was stimulated by dibutyryl cAMP (DBcAMP, 10(-6) M), the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-6) M), noradrenaline (10(-6) M), pancreatic glucagon (10(-8) M), and gastric inhibitory peptide (GIP, 10(-10) M). Stimulation by glucagon, but not by prostaglandin E2 (PGE2, 10(-6) M), required Cl- in the luminal solution and was prevented by furosemide (10(-3) M). This suggests that glucagon may affect HCO3(-)-Cl- exchange at the luminal membrane while transport stimulated by prostaglandins may be electrogenic. Stimulatory effects of glucagon and PGE2 were also additive. Gastric HCO3- transport, studied in tissues after inhibition of H+ secretion by histamine H2-antagonists, clearly differed from duodenum in that noradrenaline and GIP were inhibitory and DBcAMP was without effect. Stimulation of gastric HCO3- transport was observed with glucagon (10(-8) M), natural cholecystokinin (CCK, 10(-8) M), and CCK octapeptide (10(-7) M), CCK preparations had no effect in the duodenum. Although tested over a wide range of concentrations, no effect on either duodenal or gastric HCO3- transport was observed with histamine, pentagastrin, tetragastrin, urogastrone, ACTH, bombesin, motilin, secretin, serotonin, somatostatin, substance P, or vasoactive intestinal peptide.
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PMID:Gastric and duodenal HCO3- transport in vitro: effects of hormones and local transmitters. 697 77

The biological effects of pituitary adenylate cyclase-activating peptide (PACAP) 27 and 38 on peptide secretion and gene regulation were studied in the mouse corticotrope-derived cell line AtT20. Treatment of these cells with PACAP 27/38 led to a dose-dependent increase in cAMP content and ACTH accumulation in the medium with an apparent ED50 value close to 10(-9) M. The genomic effects of PACAP were first investigated by using a reporter gene containing a cAMP responsive element (CRE: TGACGTCA) PACAP 27/38 stimulate transcription from this construction and the effect is further increased when cells are cotreated with the phosphodiesterase inhibitor rolipram. Furthermore, we show by measuring nuclear heterologous proopiomelanocortin (POMC) RNA levels or by using a reporter gene containing the POMC promoter region, that PACAP stimulates POMC transcription. This transcriptional stimulation is mediated by the cAMP-dependent protein kinase (PKA) since genetic inactivation of PKA by a dominant inhibitory mutant of this enzyme completely abolished the effect of PACAP on POMC transcription. Finally, we show that the transcriptional stimulation of POMC by PACAP is repressed by the glucocorticoid receptor agonist dexamethasone. Taken together, these data suggest that PACAP is a hypophysiotropic hormone that exert similar if not identical functions as corticotropin-releasing hormone (CRH) on corticotrope cells.
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PMID:Pituitary adenyl cyclase-activating peptide: a hypophysiotropic factor that stimulates proopiomelanocortin gene transcription, and proopiomelanocortin-derived peptide secretion in corticotropic cells. 784 39

The activity of adipose tissue hormone-sensitive lipase in animals with hyperinsulinemia has been reported to be increased compared with that in control animals. We examined whether this results from a direct effect of insulin on the tissue and whether it is accompanied by alteration in the regulation of lipolysis. When rat epididymal fat pads are incubated in culture medium with bovine serum albumin for 2-4 h with 2 ng/ml or 50 microU/ml of insulin, hormone-sensitive lipase activity in the postmicrosomal supernatant fraction after acid precipitation and activation with ATP-Mg2+ increases significantly compared with preparations from tissues incubated with the vehicle. The specific activities of hormone-sensitive lipase in sonicates of adipocytes after primary culture with insulin at concentrations from 10 to 4000 ng/ml (250 microU to 100 mU/ml) increase in an insulin-dose-related manner. Lipolysis in response to 10(-7) M isoproterenol also increases in an insulin-dose-dependent manner. Enhancement of isoproterenol-mediated lipolysis is not attributable to a difference in the triglyceride content of the cells. Lipolysis caused by the beta-agonist could be completely blocked by the simultaneous presence of insulin in both control and insulin-treated cells reflecting normal responsiveness of both types of cells to the acute effect of insulin. Although an increase in lipolysis is seen with norepinephrine and growth hormone after insulin treatment, other lipolytic agents such as ACTH, thyrotropin, and glucagon evoke similar responses in insulin-treated and control cells. The simultaneous presence of growth hormone and insulin during the 16-h culture results in additive effects on the subsequent response of the cells to 10(-7) M isoproterenol compared with the responses of the cells cultured with each hormone alone. beta-Agonist-mediated cAMP accumulation in the presence of Ro-20.1724, a specific phosphodiesterase inhibitor, is significantly higher in cells cultured in the presence of insulin than in control cells. Forskolin (1-25 microM) increases the lipolytic responses of insulin-treated cells compared with control cells, but the maximal response of the insulin-treated cells to forskolin is lower than that to isoproterenol. We conclude that changes produced by chronic insulin treatment involve more than one site along the lipolytic cascade.
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PMID:Chronic exposure of rat fat cells to insulin enhances lipolysis and activation of partially purified hormone-sensitive lipase. 839 27

The time course of effects of caffeine on plasma glucose and non-esterified fatty acids (NEFA) were measured and related to various hormonal responses associated with substrate mobilization and utilization. Participation of the sympatho-adrenal system (SAS) in the metabolic and hormonal actions of caffeine was also investigated by the use of ganglionic blockade. Following 50 mg kg-1 i.p. injections of caffeine in rats, plasma glucose increased 25% and NEFA 40%, and these actions were parallelled by an elevation of plasma insulin, ACTH and corticosterone, without changes in glucagon. It is suggested that the insulin response is related to the plasma glucose increase and possibly also to an action of cAMP. When caffeine was injected in rats previously treated with the ganglionic blocker, hexamethonium, none of the responses mentioned above were modified. These results show that the glucose and NEFA responses are independent of glucagon secretion and are due not only to SAS activation but also to other mechanisms such as the increased ACTH and corticosterone secretion. It is also suggested that the mobilization of substrates by caffeine is mediated, through these various mechanisms, by the activation of cAMP and by phosphodiesterase inhibition.
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PMID:Metabolic and hormone-related responses to caffeine in rats. 874 42

1. Preliminary studies in our laboratories showed that the synthetic xanthine analogue denbufylline, a selective type 4 phosphodiesterase (PDE-4) inhibitor, is a potent activator of the hypothalamo-pituitary-adrenal (HPA) axis when given orally to adult male rats. This paper describes the results of experiments in which well established in vivo and in vitro models were used to (a) examine further the effects of denbufylline on HPA function and (b) identify the site and mode of action of the drug within the axis. 2. In vivo, administration of denbufylline (0.1-2.5 mg kg-1, i.p.) produced a significant increase in the serum corticosterone concentration; maximal responses were attained at a dose of 1.0 mg kg-1 (P < 0.01 vs. vehicle control, Scheffe's test). However, when denbufylline was administered by intracerebroventricular injection (0.05-1 micrograms kg-1) it failed to influence significantly the serum corticosterone concentration (P > 0.05 vs. vehicle control, Scheffe's test). The adrenocortical responses to peripheral injections of denbufylline (1 mg kg-1, i.p.) were reduced in rats in which the secretion of endogenous corticotrophin releasing factors (CRFs) from the hypothalamus was blocked pharmacologically (P < 0.01 vs. controls, Scheffe's test). However, denbufylline (0.1 mg kg-1, i.p.) potentiated the significant (P < 0.01) increases in serum corticosterone concentration provoked in "CRF blocked rats' by hypothalamic extract (5 hypothalamic extracts kg-1, i.v.) although it failed to influence (P > 0.05) the relatively moderate increases in corticosterone secretion evoked by CRH-41 (2 mg kg-1, i.v.). 3. In vitro, denbufylline (0.01-1 mM) evoked small but significant (P < 0.05) increases in the release of ACTH from rat anterior pituitary segments; furthermore, at these and lower concentrations (0.01 microM-1 mM), it potentiated the adrenocorticotrophic responses to sub-maximal concentrations of hypothalamic extract (P < 0.01) and forskolin (0.1 mM, P < 0.01) but not those to CRH-41 (10 nM) or 8-bromo-cyclic AMP (1-100 microM). In addition, denbufyline (0.1 mM) increased the anterior pituitary cyclic AMP content (P < 0.05) and potentiated the rises in tissue content of the cyclic nucleotide induced by hypothalamic extract (0.1 hypothalamic equivalents ml-1, P < 0.01) and forskolin (0.1 mM, P < 0.01) but not by CRH-41 (10 nM, P < 0.05). By contrast, denbufylline (1 microM-1 mM) failed to influence the release of AVP from rat isolated hypothalami and stimulated the secretion of CRH-41 (P < 0.01) release only at the highest concentration tested (1 mM). 4. The results suggest that the stimulatory actions of denbufylline on the hypothalamo-pituitary-adrenocortical axis are exerted predominantly at the level of the anterior pituitary gland and that they may be attributed, at least in part, to inhibition of type 4 phosphodiesterase enzymes.
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PMID:Stimulation of the hypothalamo-pituitary-adrenal axis in the rat by the type 4 phosphodiesterase (PDE-4) inhibitor, denbufylline. 889 65

1. Previous studies in our laboratory have shown that the synthetic xanthine analogue denbufylline, a selective type 4 phosphodiesterase (PDE-4) inhibitor, is a potent activator of the hypothalamo-pituitary-adrenal (HPA) axis when given orally or intraperitoneally (i.p.) to adult male rats. This paper describes the results of experiments in which well established in vivo and in vitro methods were used to compare the effects of denbufylline on HPA function with those of two other selective PDE-4 inhibitors, rolipram and BRL 61063 (1,3-dicyclopropylmethyl-8-amino-xanthine). For comparison, parallel measurements of the immunoreactive- (ir-) luteinising hormone (LH) were made where appropriate. 2. When injected intraperitoneally, rolipram (40 and 200 micrograms kg-1, P < 0.005), denbufylline (0.07-0.6 microgram kg-1, P < 0.05) and BRL 61063 (30 micrograms kg-1, P < 0.005) each produced marked rises in the serum ir-corticosterone concentrations. However, lower doses of rolipram (1.6 and 8 micrograms kg-1) and BRL 61063 (0.25-6 micrograms kg-1) were without effect (P > 0.05). By contrast, intracerebroventricular (i.c.v.) injection of rolipram (8 ng-1 micrograms kg-1) or denbufylline (50 ng-1 microgram kg-1) failed to influence the serum ir-corticosterone concentration. BRL 61063 (8-120 ng kg-1, i.c.v.) was also ineffective in this regard although at a higher dose (1 microgram kg-1, i.c.v.) it produced a small but significant (P < 0.05) increase in ir-corticosterone release. Denbufylline also increased the serum ir-LH concentration when given peripherally (0.2-0.6 microgram kg-1, i.p., P < 0.05) or centrally (100 ng kg-1, i.c.v., P < 0.05) but rolipram (1.6-200 micrograms kg-1, i.p. or 8 ng-1 microgram kg-1, i.c.v.) and BRL 61063 (0.25-30 micrograms kg-1, i.p. or 1 ng-1 microgram kg-1, i.c.v.) did not (P > 0.05). 3. In vitro rolipram (10 microM, P < 0.01), denbufylline (1 mM, P < 0.001) and BRL 61063 (1 and 10 microM, P < 0.05) stimulated the release of corticotrophin releasing hormone (ir-CRH-41) but lower concentrations of the drugs were without effect as also was BRL 61063 at 100 microM (P > 0.05); the rank order of potency was thus BRL 61063 > rolipram > denbufylline. The adenylyl cyclase activator forskolin (100 microM, P < 0.01) also stimulated the release of ir-CRH-41, producing effects which were additive with those of rolipram and denbufylline but not with those of BRL 61063. The secretory responses to forskolin (100 microM) were accompanied by a highly significant increase in the cyclic AMP content of the hypothalamic tissue (P < 0.005). Rolipram (10 microM) also significantly (P < 0.05) elevated the hypothalamic cyclic AMP but denbufylline (10 mM) and BRL 61063 (10 microM) did not. However, all three PDE-inhibitors potentiated the rise in cyclic AMP induced by forskolin (P < 0.05). None of the drugs tested, alone or in combination, modified the release of arginine vasopressin (ir-AVP) from the hypothalamus. 4. Rolipram (100 microM), denbufylline (100 microM) and BRL 61063 (100 microM) stimulated the release of corticotrophin (ir-ACTH) from pituitary tissue in vitro (P < 0.05) but in lower concentrations they were without significant effect. In addition, rolipram (10 microM, P < 0.05), denbufylline (0.1 microM, P < 0.05) and BRL 61063 (10 microM, P < 0.05) potentiated the significant (P < 0.05) rises in ir-ACTH secretion induced by forskolin (100 microM). Forskolin (100 microM) also produced a highly significant increase (P < 0.01) in the tissue cyclic AMP content which was further potentiated by rolipram (10 microM), denbufylline (10 microM) and BRL 61063 (10 microM) which, alone did not affect the cyclic AMP content of the tissue. 5. Since both denbufylline and BRL 61063 possess significant adenosine A1 receptor blocking activity, further studies examined the potential influence of these receptors on the secretion in vitro of CRH-41, AVP and ACTH. The release of ir-CRH-41 was increased significantly by adenosine deaminase (ADA, 5microml-1, P<0.05) and the A1-receptor antagonist, 1,3-dicyclopropyl-8-cyclopentylxanthine (DPCPX, 0.1-10nM, P<0.05). The responses to ADA were abolished by the A1 receptor agonist N6-cyclo-hexyladenosine (CHA, 100nM, P<0.05) which alone had no significant effect on ir-CRH-41 release. ADA (0.1-10microml-1) and DPCPX (1nM) had weak stimulant and inhibitory effects, respectively, on the release of ir-ACTH from the pituitary gland while CHA (0.1-10nM) was without effect. Ligand binding studies with [3H]-DPCPX as a probe demonstrated the presence of specific high affinity A1 binding sites in the hypothalamus (Kd=0.7nM; Bmax=367+/-32fmolmg-1 protein) and in the hippocampus (Kd=1nM; Bmax=1165 +/-145fmolmg-1 protein). In both tissues binding of the ligand was displaced by CHA (IC50=1nM (hypothalamus) and 2nM (hippocampus)), BRL 61063 (IC50=80nM (hypothalamus) and 100nM (hippocampus)) and denbufylline (IC50=5microM (hypothalamus) and 9microM(hippocampus)) but not by rolipram. 6.The results suggest that rolipram, denblufylline and BRL 61063 stimulate the HPA axis in the rat, acting at the levels of both the hypothalamus and the pituitary gland. Their actions may be explained, at least in part, by inhibition of PDE-4 but additional actions including blockade of hypothalamic adenosine A1 receptors by denbufylline and BRL 61063 cannot be excluded.
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PMID:Stimulation of the hypothalamo-pituitary-adrenal axis in the rat by three selective type-4 phosphodiesterase inhibitors: in vitro and in vivo studies. 917 87

The neuroendocrine system plays a key role in the regulation of the secretion of the thymic peptide, thymulin, but it remains to be determined whether thymulin exerts reciprocal regulatory actions on the functional activity of the hypothalamo-pituitary axis. In the present study, we have used a well established in vitro preparation to examine the influence of thymulin on cyclic nucleotide formation and hormone secretion by the rat anterior pituitary gland. Thymulin-Zn2+ (0.5-50 pM) stimulated the release of immunoreactive corticotrophin (ir-ACTH), producing effects which were maximal at 10 pM (p < 0.01). At the two highest concentrations tested (10 and 50 pM), it also produced small but significant increases in immunoreactive luteinising hormone (ir-LH) release (p < 0.05), but the secretion of immunoreactive growth hormone (ir-GH) was unaffected by the peptide (p > 0.05) while that of immunoreactive prolactin (ir-PRL) was reduced (p < 0.01). The ACTH responses to thymulin were accompanied by increased cyclic nucleotide formation. Thus, thymulin (0.5-50 pM) raised the cyclic 3',5'-adenosine monophosphate (cyclic AMP) content of the pituitary tissue (p < 0.01). At high concentrations (10-50 pM), it also increased cyclic 3',5'-guanosine monophosphate (cyclic GMP; p < 0.01) accumulation, although lower concentrations of the peptide were ineffective in this regard. The increases in ir-ACTH release provoked by thymulin-Zn2+ (0.5-5.0 pM) were potentiated markedly by rolipram (1 microM; p < 0.01), a selective inhibitor of the cyclic-AMP-specific phosphodiesterase enzyme. By contrast, zaprinast (10 microM), a selective inhibitor of cyclic-GMP-specific phosphodiesterase, attenuated the corticotrophic responses to higher concentrations of the peptide (10 and 50 pM; p < 0.05). Neither rolipram (1 microM) nor zaprinast (10 microM) influenced the release of ir-LH, ir-PRL or ir-GH in the presence or absence of thymulin-Zn2+ (0.5-50 pM; p > 0.05). The results suggest that thymulin modulates the secretion of ACTH and possibly LH by the anterior pituitary gland and that its actions are associated with increased cyclic nucleotide formation; in addition, it appears to exert an inhibitory influence on ir-PRL release.
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PMID:Thymulin stimulates corticotrophin release and cyclic nucleotide formation in the rat anterior pituitary gland. 948 96

Ovalbumin (OvA) inhalation by sensitized guinea-pigs caused a pronounced rise in interleukin (IL)-5 in bronchoalveolar lavage (BAL) fluid at both 3 and 24 h after antigen exposure. The increased levels at 24 h were attenuated by the phosphodiesterase inhibitors Ro 20-1724 and aminophylline and by dexamethasone, all of which also attenuated the concurrent lung eosinophilia. The rise in IL-5 at 3 h was additionally attenuated by the PDE3 inhibitor, siguazodan, which failed to attenuate the eosinophilia at 24 h. These results suggest a pivotal action of these compounds on the later rise in IL-5. Ro 20-1724, aminophylline, siguazodan and dexamethasone attenuated a rise in IL-8 levels in BAL fluid at 3 h and the subsequent neutrophilia at 24 h. There was no increase in plasma ACTH at 3 and 24 h after OvA challenge but cortisol levels were elevated at 3 h. This was inhibited by Ro 20-1724, siguazodan and dexamethasone. Thus, elevation of plasma cortisol does not explain the anti-inflammatory actions of these compounds. Aminophylline, however, did raise plasma cortisol at both 3 and 24 h after antigen challenge which may be an important further mechanism of action for this compound.
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PMID:The potential roles of cytokines, IL-5 and IL-8, and plasma cortisol in the anti-inflammatory actions of phosphodiesterase inhibitors in sensitized guinea-pig airways. 977 91

Activation of protein kinase C (PKC) stimulates adrenocorticotropin (ACTH) release synergistically in the presence of corticotropin releasing factor (CRF). We examined the effect of a cyclic nucleotide-specific phosphodiesterase inhibitor, 1-isoamyl-3-isobutylxanthine (IIX), on arginine vasopressin (AVP)-induced ACTH release and intracellular cAMP accumulation in normal rat anterior pituitary cells. IIX alone elevated intracellular cAMP accumulation. IIX potentiated AVP-induced ACTH release synergistically without further increase in cAMP accumulation, suggesting that synergistic ACTH release has an alternative mechanism other than the synergistic elevation of intracellular cAMP accumulation which has been reported. Phorbol 12-myristate-13-acetate (PMA) also induced synergistic ACTH release when incubated with IIX. IIX had no additional effect on ACTH response when incubated with maximal dose of CRF, forskolin or 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP). Moreover, the combination of PMA and 8-Br-cAMP produced synergistic ACTH response. In conclusion, the synergistic ACTH release from rat pituitary corticotrophs occurs at least in the presence of directly activating events of PKC and PKA as well as PKC-induced inhibition of phosphodiesterase activity.
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PMID:Mechanism involved in synergistic adrenocorticotropin response to activating protein kinase-A and -C in rat anterior pituitary cells. 1021 Feb 88

The present study investigated the role and identity of cyclic nucleotide phosphodiesterases (PDEs) in the regulation of basal and ACTH-stimulated levels of intracellular cAMP in human and rat adrenal glomerulosa cells. Comparative dose-response curves indicated that maximal hormone-stimulated cAMP accumulation was 11- and 24-fold higher in human and rat cells, compared with cAMP production obtained in corresponding membranes, respectively. Similarly to 3-isobutyl-1-methyl-xanthine, 25 microM erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA, a specific PDE2 inhibitor), caused a large increase in ACTH-stimulated cAMP accumulation; by contrast, it did not change cAMP production in membranes. Moreover, in membrane fractions, addition of 10 microM cGMP inhibited ACTH-induced cAMP production, an effect completely reversed by addition of 25 microM EHNA. These results indicate that PDE2 activity is involved in the regulation of cAMP accumulation induced by ACTH, and suggest that ACTH inhibits this activity. Indeed, time-course studies indicated that ACTH induced a rapid decrease in cGMP production, resulting in PDE2 inhibition, which in turn, contributed [with adenylyl cyclase (AC) activation] to an accumulation in cAMP for 15 min. Thereafter, cAMP content decreased, because of cAMP-stimulated PDE2, as confirmed by measurement of PDE activity that was activated by ACTH, but only after a 10-min incubation. Hence, we demonstrate that the ACTH-induced increase in intracellular cAMP is the result of a balance between activation of AC and direct modulation of PDE2 activity, an effect mediated by cGMP content. Although similar results were observed in both models, PDE2 involvement is more important in rat than in human adrenal glomerulosa cells, whereas AC is more stimulated in human than in rat glomerulosa cells.
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PMID:Comparative involvement of cyclic nucleotide phosphodiesterases and adenylyl cyclase on adrenocorticotropin-induced increase of cyclic adenosine monophosphate in rat and human glomerulosa cells. 1043 16


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