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)

This review details the biochemical events that follow IgE dimerization by antigen and cross-linking of receptors and are linked with the early rise in cyclic AMP. That the monophasic rise in cyclic AMP at 15 s is essential to the degranulation process is evident by pharmacological manipulation of adenylate cyclase, using specific activators and inhibitors to achieve potentiation and inhibition of immunologic release, respectively. Although only a small percentage of membrane adenylate cyclase is transmembrane linked to IgE-Fc perturbation, its product, cyclic AMP, is elevated during activation and is responsible for the activation of two protein kinase isoenzymes at 30-60 s. This sequence appears to be essential for secretion to occur, as evidenced by dose-related inhibition of both beta-hexosaminidase release and protein kinase activation by adenylate cyclase inhibitors. Competitive activation of cyclic AMP-dependent protein kinase activity by a phosphodiesterase inhibitor leads to inhibition of mediator release by diverting an essential enzyme or recruiting an inhibitory sequence. The precise functional role of the mast cell cyclic AMP-dependent protein kinases has not yet been identified, but there is much evidence in other cell types that protein phosphorylation is an essential accompaniment to cellular regulation. Although other apparently essential biochemical steps are noted, such as uncovering a serine esterase, methylation of membrane phospholipid, and increased Ca2+ influx, only a portion of the activation-secretion response is presented here as a sequence, namely, the IgE-Fc receptor-initiated, transmembrane-coupled activation of adenylate cyclase and the subsequent cytoplasmic cyclic AMP-dependent activation of types I and II protein kinases.
...
PMID:Enzymatic regulation of mast cell activation and secretion by adenylate cyclase and cyclic AMP-dependent protein kinases. 617 64

The present investigation was designed to study the histamine release and pharmacologic characteristics of dispersed human lung mast cells, particularly in comparison with parenchymal tissue fragments. Dispersed human lung mast cells were prepared by enzymatic treatment (yield, 0.5 to 2 x 10(6) mast cells/g tissue). Purity was 1 to 8% (mean, 3.6% +/- 0.7%), and histamine content varied from 2 to 6 pg/cell (mean, 3.6 +/- 0.5 pg/cell). Release, studied using anti-IgE as the stimulus, was relatively rapid, being essentially complete within 15 min when high concentrations of anti-IgE (greater than or equal to 0.3 microgram/ml) were used and was not enhanced by phosphatidyl serine. The concentration of drug required to inhibit histamine release by 50% in dispersed cells for a series of pharmacologic agents, including the beta-adrenergic agent fenoterol, the prostaglandin E2, and the phosphodiesterase inhibitor isobutylmethylxanthine, were 0.1 to 1 microM, 50 microM, and 0.5 mM, respectively; similar results were obtained in simultaneous experiments performed using tissue fragments. Adenosine enhanced release (19 +/- 3.4%) at low concentrations (10 microM) and inhibited release (61 +/- 5.1%) at high concentrations (1mM). The H2 agonist, dimaprit (at 10(-5) to 10(-7) M) and prostaglandin D2 (at 10(-4) to 10(-6) M) had no effect on histamine release, whereas deuterium oxide potentiated histamine release. This study serves to quantitate the pharmacologic effects of several agents on anti-IgE-mediated histamine release from dispersed human lung mast cells and has further suggested that the dispersed cell system is similar to the standard chopped lung system in dose-response relationships, kinetics, and pharmacologic modulation. It also indicates that the enzymatic treatment of the cells does not affect the release characteristics or functional capacity of several different receptors, and that this preparation, therefore, appears suitable as an in vitro human model of mediator release that can be used for the evaluation of pharmacologic agents and for further mast cell purification.
...
PMID:Dispersed human lung mast cells. Pharmacologic aspects and comparison with human lung tissue fragments. 618 23

[2-Cyano-3-(methylamino)phenylamino]oxoacetic acid, sodium salt (Wy-41,195) was found to be a potent oral inhibitor (viz., ED50, 0.3 mg/kg) of IgE-mediated release in the rat passive cutaneous anaphylaxis (PCA) model and was very effective by the aerosol and oral route in the rat passive lung anaphylaxis model. High doses (25-50 mg/kg p.o.) were effective when administered up to 180 min before antigen challenge in the rat PCA model. The compound had minimal phosphodiesterase activity and demonstrated no bronchodilator or antihistamine activity. In the dog, Wy-41,195 inhibited histamine-induced reflex bronchoconstriction but had little effect on Ascaris-induced bronchoconstriction. No significant ancillary pharmacology was observed for Wy-41,195 except for inhibition of gastric secretion in the rat. The compound is relatively nontoxic and possesses a very high therapeutic index (greater than 10 000). Activity in these animal systems indicates that Wy-41,195 may hold promise in the treatment of bronchial asthma and other allergic diseases in man.
...
PMID:The pharmacologic profile of wy-41,195, a new orally effective antiallergic agent. 618 61

Maximal leukocyte histamine release in response to concanavalin A was significantly higher in a group of 16 adult patients with moderate to severe atopic dermatitis when compared to 13 adult nonatopic, normal subjects. In a further four atopic dermatitis patients, histamine release was similar to that in the normal group suggesting the existence of "high-releaser" and "low-releaser" subsets within the atopic dermatitis group. Leukocyte cAMP phosphodiesterase activity was significantly higher in the high-releaser group than in the low-releaser and normal groups. High and low histamine release responses showed strong correlations with high and low phosphodiesterase activities. Pretreatment with the experimental cAMP phosphodiesterase inhibitor Ro-20-1724 in high releasers reduced the histamine release to normal levels. These findings suggest that increased histamine "releasability" in atopic dermatitis is related to abnormalities in cyclic nucleotide regulation. Basophil percentages within the leukocyte preparation and the histamine content per basophil were not significantly different between the atopics and normals. Histamine release did not correlate significantly with serum IgE levels.
...
PMID:Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. 618 71

The action of three compounds reported to elevate intracellular cyclic adenosine monophosphate (cAMP) namely 3-isobutyl-1-methylxanthine (IBMX) and prostaglandins D2 and E1 (PGD2 and PGE1), on histamine release was examined. Three test systems were used: (i) the perfused ovalbumin-sensitized guinea pig lung and (ii) isolated cells from ovalbumin-sensitized guinea pig lung, both of which are IgG-mediated models of anaphylaxis, and (iii) an IgE model of anaphylaxis, using isolated rat peritoneal mast cells from sensitized rats. Both PGD2 and PGE1 were without effect at concentrations likely to be found during anaphylaxis. In contrast, the phosphodiesterase inhibitor, IBMX, was highly active in all three test systems. The role of raised intracellular cAMP levels in the inhibition of histamine release is discussed.
...
PMID:Action of 3-isobutyl-1-methylxanthine and prostaglandins D2 and E1 on histamine release from rat and guinea pig mast cells. 619

RHC 2963 (7-methyl-pyrido (3',2':4,5)-thieno (3,2-d)-1,2,3 triazine-4(3H)-one and 20 related compounds have been investigated for their antiallergic activities in 3 in vitro models of anaphylaxis and for their effects on cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells (RMC). Nine compounds were potent (I50 less than or equal to 80 microM) inhibitors of antigen-induced release of histamine (AIR) from RMC, 2 compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 60 microM) and one compound inhibited AIR from guinea pig lung slices (I50 = 55 microM). RHC 2963 was 18 times more potent than disodium cromoglycate (DSCG) as inhibitor of AIR from RMC and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties and inability to inhibit non-immunologic release of histamine induced by compound 48/80. Neither RHC 2963 nor DSCG had any effect on anti-IgE-induced release of histamine from human basophils or IgG1-mediated release of histamine from guinea pig lung. Twelve of the compounds in this chemical series were more potent than theophylline as inhibitors of cyclic AMP and/or cyclic GMP phosphodiesterase (PDE) from RMC. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC revealed no statistically significant correlation between the inhibition of AIR and inhibition of cAMP- or cGMP-PDE. We conclude: (1) RHC 2963 and some of the related compounds are potent inhibitors of immunologic release of histamine from RMC with a mechanism of action similar to that of DSCG, and (2) inhibition of cAMP- or cGMP-PDE by these compounds is not the biochemical mechanism by which they inhibit AIR from RMC.
...
PMID:Antiallergic activity profile in vitro of RHC 2963 and related compounds. 619 98

The action mechanism of the bronchodilator activity of BB-1502 was studied in comparison with aminophylline. Orally administered BB-1502 did not inhibit passive cutaneous anaphylaxis in rats, an immediate allergic reaction of Type I, but strongly protected the same antigen-mediated anaphylactic asthma by the intraduodenal route, the activity being approximately 13 times more potent than that of aminophylline. BB-1502 also inhibited IgG-mediated anaphylactic asthma in guinea pigs by the oral route. Both IgE- and IgG-mediated histamine releases from rat lung were similarly inhibited by BB-1502, the potency being 2--3 times that of aminophylline. Disodium cromoglycate showed specific inhibition of the IgE-mediated reaction. BB-1502 and aminophylline showed nonspecific inhibition of the spasms of guinea pig ileum elicited by histamine, acetylcholine and BaCl2. Both compounds inhibited cyclic AMP and cyclic GMP phosphodiesterases (PDEs) derived from guinea pig organs. BB-1502 specifically inhibited the cyclic AMP PDE of lung and brain origins, while aminophylline showed no such specificity. The results of the present study suggested that the bronchodilator and anti-asthmatic actions of BB-1502 might, at least in part, be due to the regulation of cyclic nucleotide PDEs.
...
PMID:[Experimental study on the action mechanism of a new bronchodilator agent, BB-1502]. 620 Apr 10

Extracts from purified human basophils revealed activity of cAMP-phosphodiesterase with a km-value of 0.59 microM. The enzyme was not activated by Ca-ions. Enprofylline and theophylline inhibited the enzyme in a competitive manner. Enprofylline was more potent than theophylline. These drugs did also inhibit the anti-IgE-induced histamine release from the basophils. These results favour the hypothesis that inhibition of histamine release of enprofylline is caused by an inhibition of phosphodiesterase. Although accumulating data have indicated that theophylline, at therapeutic concentrations, is a weak inhibitor of cAMP-phosphodiesterase activity, there is reason to believe that enprofylline, at therapeutic concentrations, may act at least partly as a phosphodiesterase inhibitor.
...
PMID:Effects of enprofylline and theophylline on purified human basophils. 620 6

The uptake of 14C-ring labelled histamine and histidine was studied in human and guinea-pig leucocytes, and in rat peritoneal mast cells. Histamine uptake by sensitized human leucocytes was partly released by antigen or anti-IgE challenge, suggesting that histamine is taken up by the same cells that synthesize and secrete that amine, i.e. basophils. Histamine antagonists, particularly of the H2-subclass, had an inhibitory effect, but histamine agonists had a relatively small and inconsistent effect. Adrenoceptor stimulants and phosphodiesterase inhibitors produced small effects, but dibutyryl cAMP at a concentration of 4-10 mM consistently increased histamine uptake by more than 100% during a 30 min incubation. By contrast, ATP exerted an inhibitory effect, starting at a concentration of 0.2 mM and reaching a maximum (90% inhibition) at 10 mM. Histidine uptake was inhibited by ATP and slightly stimulated by cAMP. Propranolol caused stimulation of histamine uptake and inhibition of histidine uptake at micromolar concentrations. These results suggest that the uptake of histamine is not due to simple diffusion. Although it does not contribute significantly to total cell histamine content or to the removal mechanism of extracellular histamine, it may contribute to the auto-regulatory processes modulating histamine release, synthesis and metabolism. It may also have a significant effect on the extracellular level of histamine, under the influence of drugs or in pathological states.
...
PMID:Effect of purine nucleotides and other compounds on the uptake of histamine and histidine. 628 73

Rat peritoneal mast cells were desensitized up to 100% with 1-4 additions of suboptimal concentrations of anti-rat IgE over 60-90 min. Desensitized cells rechallenged with anti-IgE showed a 2- to 10-fold increase in cAMP during the initial 1-5 min. Membrane preparations from desensitized cells showed up to a 100-fold rise in cyclase activity following incubation with anti-IgE, compared to a 5- to 10-fold rise in control cells. Control and desensitized cell membranes rechallenged with anti-IgE showed nearly identical levels of phosphodiesterase activation. We conclude that following desensitization, repetitive low levels of anti-IgE binding induce atypically high and sustained activation of adenylate cyclase which may reflect primary or secondary regulatory events in the development of desensitization.
...
PMID:Adenylate cyclase, cyclic AMP and IgE-mediated desensitization in rat mast cells. 629 15


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---