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

---

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

The effects of several cyclic nucleotide analogs and of phosphodiesterase inhibitors on the release of norepinephrine (NE) and dopamine-beta-hydroxylase activity (DBH) by electrical stimulation were studied in the isolated, perfused cat spleen. N-6-butyryl-3',5'-adenosine monophosphate (mbcAMP), 8-methylthio-3',5'-adenosine monophosphate, 8-bromo-3',5'-guanosine monophosphate (8-Br-cGMP) and two potent phosphodiesterase inhibitors: 1-methyl-3-isobutylxanthine and 4-(3-butoxy-4-methoxy-benzyl)-2-imidazolidinone (Ro 20-1724) enhanced the overflow of NE and total H and reduced pressure responses elicited by nerve stimulation. A concomitant outflow of DBH activity was observed in the presence of mbcAMP, 8-Br-cGMP or Ro 20-1724. Synergistic effects on the nerve stimulation-mediated overflow of NE and DBH were obtained with low concentratons of Ro 20-1724 and mbcAMP (5 muM). Adenosine 5'-monophosphate produced a very slight increase in nerve stimulated release of NE and DBH activity in concentrations which inhibited pressor responses considerably. cAMP produced slight inhibition of pressure responses but failed to influence the release of either NE or DBH activity during nerve stimulation. In contrast to the enhanced overflow of NE and DBH activity induced by nerve stimulation, with the exception of Ro 20-1724, the spontaneous release of these substances was not modified by any of the cyclic nucleotide analogs or phosphodiesterase inhibitors examined. This effect of Ro 20-1724 can probably be explained by the ability of this compound to inhibit the activity of monoamine oxidase and therefore reduce the formation of deaminated metabolites. The present results suggest that cyclic nucleotides are not directly responsible for the release of the adrenergic neurotransmitter, but may facilitate the normal process of release by nerve stimulation. Phentolamine, a blocker of the alpha adrenergic receptors, produced a marked increase in the nerve stimulation-mediated overflow of NE, total H and DBH activity and inhibited pressure responses. This effect was several times greater than that produced by either cyclic nucleotide analogs or phosphodiesterase inhibitors. In addition, the effect of phentolamine was not modified by prior treatment with 1-methyl-3-isobutylxanthine or Ro 20-1724, suggesting that the effect of phentolamine is not related to its ability to inhibit phosphodiesterase and is probably not mediated via an increase in cAMP.
...
PMID:Release of norepinephrine and dopamine-beta-hydroxylase by nerve stimulation. IV. An evaluation of a role for cyclic adenosine monophosphate. 16 57

8-(p-Chlorophenylthio)-cGMP (8-pCPT-cGMP) and 8-bromo-cGMP were compared with respect to their chemical and biological properties in order to evaluate their potential as selective activators of cGMP-dependent protein kinase (cGMP-PK; EC 2.7.1.37) in intact human platelets. 8-pCPT-cGMP, 8-Br-cGMP and cGMP were shown to be potent and selective activators of purified bovine lung cGMP-PK and of cGMP-PK present in human platelet membranes when compared with the activation of cAMP-dependent protein kinase (cAMP-PK; EC 2.7.1.37). 8-pCPT-cGMP was not hydrolysed by the purified cGMP-stimulated phosphodiesterase (cGS-PDE), cGMP-inhibited phosphodiesterase (cGI-PDE) and Ca(2+)-calmodulin-dependent phosphodiesterase (CaM-PDE), whereas cGMP and, to a lesser extent, 8-Br-cGMP were hydrolysed by all three types of 3',5' cyclic nucleotide phosphodiesterases (EC 3.1.4.17) examined. Also, 8-pCPT-cGMP was not hydrolysed by a human platelet homogenate which contains a high level of the cGMP-specific cGMP-binding phosphodiesterase (cGB-PDE). Additionally, 8-pCPT-cGMP did not activate the cGS-PDE or inhibit the cGI-PDE, whereas half-maximal inhibition of cGI-PDE occurred at 8 microM 8-Br-cGMP. The apparent lipophilicity of 8-pCPT-cGMP was higher than that of 8-Br-cGMP. Extracellular application of 8-pCPT-cGMP to intact human platelets reproduced the pattern of protein phosphorylation induced by sodium nitroprusside (SNP), a cGMP-elevating inhibitor of platelet activation. Quantitatively, 8-pCPT-cGMP was more effective than 8-Br-cGMP in inducing phosphorylation of the 46/50 kDa vasodilator-stimulated phosphoprotein, a major substrate of cGMP-PK in intact platelets. As observed with SNP, pretreatment of human platelets with 8-pCPT-cGMP prevented the aggregation induced by thrombin. The results suggest that 8-pCPT-cGMP is a very potent and selective activator of cGMP-PK in cell extracts and in intact human platelets and, in this respect, is superior to 8-Br-cGMP and other cGMP analogs used for intact cell studies. The data also suggest that inhibition of platelet activation in intact human platelets by nitrovasodilators is mediated by cGMP-PK.
...
PMID:Analysis of the functional role of cGMP-dependent protein kinase in intact human platelets using a specific activator 8-para-chlorophenylthio-cGMP. 132 24

1. The potassium currents evoked by glutamate agonists on isolated and identified neurones of molluscan pedal ganglia were investigated using the voltage clamp technique. 2. Glutamate responses were not modified by increasing intracellular cyclic nucleotide concentrations (treatment with 8-Br-cAMP, 8-Br-cGMP, forskolin and/or the phosphodiesterase inhibitor isobutylmethylxantine, IBMX), whereas inward-going currents induced by the nucleotides were observed. It follows that glutamate currents are independent of intracellular cyclic nucleotide control. 3. Protein kinase C activation with phorbol esters or oleoylacetylglycerol induced a slowly developing outward current and reduced glutamate response amplitude. Staurosporine itself did not affect the glutamate responses but completely prevented the effects of phorbol esters and oleoylacetylglycerol. This indicated that protein kinase C was not involved in the transduction mechanism for the potassium component of the glutamate response. 4. The possible involvement of inositol-1,4,5-trisphosphate seems to be improbable because the glutamate responses were independent of intracellular calcium concentration. Intracellular injection of calcium buffer BAPTA, failed to affect any of the glutamate currents, although it effectively blocked the after-hyperpolarization following directly evoked action potentials. 5. Nordihydroguaiaretic acid (NDGA) and indomethacin, inhibitors of the lipoxygenase and cyclo-oxygenase pathways of arachidonic acid metabolism, correspondingly, did not change the glutamate responses of these neurones. 6. The failure to demonstrate the involvement of any known secondary messenger systems in glutamate response transduction favours two assumptions: (1) the receptor-G protein complex controls the potassium channel directly; or (2) some still unknown transduction system is used.
...
PMID:Transduction mechanism for glutamate-induced potassium current in neurones of the mollusc Planorbarius corneus. 136 43

Odors activate at least two distinct transduction pathways in lobster olfactory receptor cells that, respectively, excite and inhibit the cell. Data presented suggest that odors selectively activate the inhibitory conductance through the second messenger cAMP. Not all cells support both odor-evoked excitatory and inhibitory conductances; in the current investigation, about 50% of the cells tested were inhibited by odors. In the majority of cells that, as a group, support an inhibitory response to odor stimulation, activation of adenylate cyclase with forskolin or inhibition of phosphodiesterase activity with 3-isobutyl-1-methylxanthine (IBMX) elicits an outward current with a time course similar to that of odor-evoked outward currents. The membrane-permeant cyclic nucleotide analogs 8-Br-cAMP and 8-Br-cGMP have a similar effect. Forskolin and IBMX enhance the magnitude of odor-evoked outward currents when the drug and the odor are copresented to the cell. In contrast, these same drugs have little or no effect on cells that, as a group, fail to support an inhibitory response to odor stimulation. This study provides the first direct evidence implicating cAMP in olfactory transduction in an invertebrate and contrasts with similar studies in vertebrates that have implicated cAMP as a second messenger mediating excitation.
...
PMID:Cyclic nucleotides mediate an odor-evoked potassium conductance in lobster olfactory receptor cells. 138 77

Field electrical stimulation (ES), K+ (50 mM) or ionophore X-537A (0.01 mM) induced tritium release from cat cerebral arteries preincubated with [3H]noradrenaline (NA). Adenosine and AMP (0.5 mM) did not modify tritium release caused by ionophore X-537A, but these agents and ATP (0.5 mM) significantly reduced that elicited by ES and K+; this reduction was antagonized by 1-methyl-3-isobutylxanthine (MIX; 0.05 mM). Inosine (0.5 mM) and the agonist of purinergic A2-receptors, 5'N-ethyl-carboxamide adenosine (NECA; 0.5 mM) had no effect, but the agonist of purinergic A2-receptors L-N6-phenylisopropyl adenosine (L-PIA; 0.1 mM) diminished tritium efflux caused by ES and K+. The adenosine inhibition of ES-induced radioactivity release was not affected by indomethacin (0.05 mM). MIX (0.05 mM) increased tritium release evoked by ES and K+. Agents that increase intracellular cyclic (c)AMP levels, such as dibutyryl cAMP (0.5 mM), the phosphodiesterase inhibitor Ro 20-1724 (0.1 mM), and the activators of adenylate cyclase, forskolin (0.005 mM) and NaF (2 mM) reduced tritium secretion elicited by ES and K+. However, the intracellular increase of cyclic GMP (cGMP) caused by 8-Br-cGMP did not affect this secretion. Dipyridamole (0.05 mM) and the adenosine deaminase inhibitor erythro-9-2-hydroxy-3 nonyl adenosine (EHNA; 0.1 mM) also produced inhibition of tritium secretion elicited by ES and K+. Dipyridamole reduced both the uptake of [3H]NA and [3H]adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Role of presynaptic purinoceptors and cyclic AMP on the noradrenaline release in cat cerebral arteries. 198 Feb 88

Cyclic GMP depresses Ba2+ current through high-voltage-activated Ca2+ channels (ICa) in acutely isolated hippocampal neurons. The effect is produced by intra-, but not extracellular, cGMP or by 5' GMP. The membrane-permeant derivative, 8-Br-cGMP, produces a reversible suppression. The effect of 8-Br-cGMP is similar to phorbol ester-induced ICa depression, except that ICa depression due to 8-Br-cGMP is not blocked by protein kinase inhibitors H-8 or H-7, whereas phorbol ester effects are. The data suggest that cGMP depresses ICa by a cGMP-kinase- and protein kinase C (PKC)-independent mechanism. Cyclic AMP, which enhances ICa, and the cyclic nucleotide phosphodiesterase inhibitor, IBMX, both antagonize ICa depression induced by 8-Br-cGMP, but not that due to phorbol esters. Cyclic IMP, a more potent activator of phosphodiesterase than of cGMP-dependent protein kinase, is also a powerful depressant of ICa. We conclude that cGMP-induced depression of ICa is mediated by activation of cyclic nucleotide phosphodiesterase with consequent reduction of intracellular cAMP.
...
PMID:Cyclic GMP depresses hippocampal Ca2+ current through a mechanism independent of cGMP-dependent protein kinase. 285 1

Atrial natriuretic factor (ANF) is a collective term used to describe a group of peptides isolated from mammalian atria which have vasorelaxant activity as well as diuretic and natriuretic activity. Recently, ANF peptides have been shown to bind to specific receptors on vascular smooth muscle cells (VSMC) and to cause an elevation in cGMP levels. We have previously demonstrated that VSMC possess a prominent, cyclic-nucleotide-sensitive Na/K/Cl cotransport system. In the present study, the effects of the ANF peptide rat atriopeptin III (rAP III) were measured on Na/K/Cl cotransport of VSMC by using primary cultures derived from rat thoracic aorta. It was found that rAP III caused a marked elevation of Na/K/Cl cotransport. Maximal stimulation occurred at 100 nM, and the dose of rAP III required for half-maximal potassium influx (K1/2) was 9 nM. We also investigated the effect of rAP III on cGMP levels in VSMC. It was found that rAP III increased cGMP in a dose-dependent manner, with a K1/2 value of 10 nM. Finally, we measured the effect of the permeable cGMP analog 8-bromo-cGMP on Na/K/Cl cotransport. It was found that 8-bromo-cGMP stimulated cotransport to the same extent as did a saturating dose of rAP III (K1/2 = 0.2 microM). Saturating doses of rAP III and 8-Br-cGMP in combination did not stimulate cotransport in an additive manner, suggesting that rAP III probably does not elevate cGMP via inhibition of phosphodiesterase. These findings suggest that activation of Na/K/Cl cotransport via elevations in cGMP may be associated with ANF-mediated vasorelaxation and/or ANF-mediated diuresis and natriuresis.
...
PMID:Atrial natriuretic factor stimulates Na/K/Cl cotransport in vascular smooth muscle cells. 294 44

The role of guanosine 3',5'-cyclic monophosphate (cGMP) in the net K+ efflux following parasympathomimetic and sympathomimetic stimulation in dispersed rat submandibular cells was evaluated. In unstimulated cells, approx. 70 per cent of the total cGMP content was present in the incubation medium; the addition of 1-methyl-3-isobutylxanthine (MIX), a phosphodiesterase inhibitor, to the medium elevated both intracellular and extracellular levels of cGMP. Cholinergic receptor stimulation resulted in a rapid increase of the cGMP content in the cells and in the medium. Extracellular Ca2+ was necessary for an increased cGMP response and MIX potentiated the cGMP response. Adrenergic-receptor activation produced a slight increase in cGMP after 5 min of stimulation but only when MIX was present in the medium. cGMP analogues (8-Br-cGMP and Bt2cGMP) had no effect on the rate of maximal net K+ efflux, on submaximal net K+ efflux, or on K+ re-uptake following parasympathomimetic or sympathomimetic stimulation. The dose-response relationship for a cholinergic agonist, carbamylcholine, or an adrenergic agonist, norepinephrine, was unaffected by the presence of either 8-Br-cGMP or Bt2cGMP in the medium. MIX, at a concentration sufficient to increase intracellular and extracellular cGMP levels, had no effect on net K+ efflux. These data do not support a role for cGMP in modulating rat submandibular potassium release.
...
PMID:Evidence against a role for guanosine 3',5'-cyclic monophosphate in rat submandibular salivary gland potassium release. 619 59

In primary cultures of chick 11-day embryonic tissue a number of phosphodiesterase inhibitors were found to elevate acetylcholine receptor levels. Of these agents, Ro20-1724 was the most effective, elevating surface receptor content by 2-fold after 48 h of treatment. 8-Br-cAMP and cholera toxin, a natural activator of adenylate cyclase, mimicked the effect of Ro20-1724, while 8-Br-cGMP and dibutyryl cGMP had no effect. Cholera toxin, 8-Br-cAMP, and Ro20-1724 all increased the insertion rate of new receptor into the surface membrane without altering degradation. The enhanced insertion appears related to an actual increase in synthesis since total acetylcholine receptor was elevated by exposure to cholera toxin. In contrast, no change in creatine phosphokinase activity, myosin heavy chain content, or [35S] methionine incorporation into total cellular protein was observed during cholera toxin treatment. These results suggest that cAMP plays a role in the regulation of acetylcholine receptor.
...
PMID:Regulation of acetylcholine receptor by cyclic AMP. 624 32

Reestablishment of vascular homeostasis following ex vivo preservation is a critical determinant of successful organ transplantation. Because the nitric oxide (NO) pathway modulates pulmonary vascular tone and leukocyte/endothelial interactions, we hypothesized that reactive oxygen intermediates would lead to decreased NO (and hence cGMP) levels following pulmonary reperfusion, leading to increased pulmonary vascular resistance and leukostasis. Using an orthotopic rat model of lung transplantation, a porphyrinic microsensor was used to make direct in vivo measurements of pulmonary NO. NO levels measured at the surface of the transplanted lung plummeted immediately upon reperfusion, with levels moderately increased by topical application of superoxide dismutase. Because cGMP levels declined in preserved lungs after reperfusion, this led us to buttress the NO pathway by adding a membrane-permeant cGMP analog to the preservation solution. Compared with grafts stored in its absence, grafts stored with supplemental 8-Br-cGMP and evaluated 30 min after reperfusion demonstrated lower pulmonary vascular resistances with increased graft blood flow, improved arterial oxygenation, decreased neutrophil infiltration, and improved recipient survival. These beneficial effects were dose dependent, mimicked by the type V phosphodiesterase inhibitor 2-o-propoxyphenyl-8-azapurin-6-one, and inhibited by a cGMP-dependent protein kinase antagonist, the R isomer of 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate. Augmenting the NO pathway at the level of cGMP improves graft function and recipient survival following lung transplantation.
...
PMID:The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation. 752 50


1 2 3 4 5 6 7 8 Next >>

---