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)

Since the discovery of cyclic nucleotide phosphodiesterase 30 years ago, there have been major advances in our knowledge of this group of isoenzymes. Five families, each composed of several isoforms and having differing tissue distributions, have been described. David Nicholson and colleagues compare the tissue distribution of phosphodiesterase isoenzymes and discuss the differential effects of inhibition of particular isoenzymes, with differing subcellular localization, on tissue function. They also review the potential use of isoenzyme selective phosphodiesterase inhibitors in a range of clinical disorders such as heart failure, asthma, depression and dementia.
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PMID:Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. 184 33

Xanthines are effective in the treatment of asthma, but the mechanism of action remains unclear. Pulmonary effects of seven xanthines, exhibiting a range of potencies as cyclic nucleotide phosphodiesterase (PDE) inhibitors and as adenosine antagonists, were investigated in anesthetized and ventilated guinea pigs. The bronchodilator effects of xanthines, determined from reversal of bronchoconstriction induced by aerosols of histamine and carbachol, correlated with their relative potencies as cyclic AMP-PDE inhibitors. The hypotensive effects of xanthines at bronchodilator doses were also consistent with PDE inhibition. Prophylactic effects of xanthines against bronchoconstriction induced by an aerosol of ovalbumin in sensitized guinea pigs, or by aerosols of leukotriene D4 and platelet-activating factor (PAF) in normal guinea pigs, occurred by a mechanism unrelated to bronchodilation and could not be readily attributed to PDE inhibition or adenosine A1/A2 receptor antagonism. There was a close association between inhibition of the responses to antigen and leukotriene D4, suggesting a common mechanism of action, but these effects gave a different profile from inhibition of the response to PAF. In addition, PAF-induced hypotension was unaffected in animals in which PAF-induced bronchoconstriction was inhibited, suggesting a mechanism other than PAF receptor antagonism. These results indicate that the bronchodilator, antiallergic and anti-inflammatory effects of xanthines occur through multiple molecular mechanisms of action, including at least one unknown mechanism. Furthermore, 8-phenyltheophylline produces these prophylactic effects at a dose that does not produce the cardiovascular or emetic side effects associated with xanthines, thereby exhibiting unique characteristics of potential therapeutic importance.
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PMID:Multiple mechanisms of xanthine actions on airway reactivity. 217 91

Atopic dermatitis, allergic rhinitis and asthma are a common group of diseases with a familial predisposition. At present there is no suitable predictive or diagnostic marker. Adults with atopic dermatitis or allergic respiratory disease have elevated mononuclear leukocyte cAMP-phosphodiesterase activity. This activity correlates closely with histamine release from basophils. We investigated newborn leukocyte phosphodiesterase activity and histamine release in umbilical cord blood. Phosphodiesterase activity was significantly elevated in cord blood leukocytes of 81 children with a positive history of atopy in first degree relatives, compared to 33 children with a negative history (p less than 0.025). In contrast to adults there was no correlation between phosphodiesterase activity and histamine release. Our studies suggest that elevated phosphodiesterase activity is a primary, genetically linked defect. Fetal basophils would appear to possess cytophilic IgE since they are capable of immunologically stimulated histamine release even without passive, in vitro IgE sensitization. In addition, there are functional differences between adult and cord blood basophils. Longitudinal studies may determine if elevated phosphodiesterase is predictive of atopic states.
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PMID:Cyclic AMP-phosphodiesterase activity and histamine release in cord blood leukocyte preparations. 240 31

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca++-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H1-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF2 alpha which could originate from mast cell-derived PGD2. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Relationship between mediator release from human lung mast cells in vitro and in vivo. 240 26

The atopic conditions, atopic dermatitis, asthma, and allergic rhinitis, may arise as a result of infiltrating bone marrow-derived cells into skin or respiratory mucosae. Release of inflammatory factors from these cells could account for cutaneous vascular instability and pruritus in atopic dermatitis. Erythema and itch have been induced by experimental stress interviews and by blind food challenges. In the latter, increased plasma histamine was detected and correlated with cutaneous reactions. Basophils from patients with atopic dermatitis have increased histamine release after exposure to immunologic or nonimmunologic lectin stimuli. This increased releasability may relate to inadequate cyclic AMP regulation of cell function. We have found that leukocytes of patients with atopic dermatitis have elevated phosphodiesterase activity and consequently reduced intracellular cyclic AMP. Exposure of the cells to a phosphodiesterase inhibitor caused considerable reduction in histamine release. Similarly, exposure of atopic B lymphocytes to a phosphodiesterase inhibitor greatly reduced the high spontaneous IgE synthesis in mononuclear leukocyte cultures. Elevated leukocyte phosphodiesterase activity may also serve as a marker for the atopic diathesis. We have found elevated enzyme activity in umbilical cord blood from newborns with atopic parents, suggesting that this defect may relate to a genetically determined defect. These studies have provided insight into basic abnormalities associated with atopic dermatitis and the atopic diathesis. Defects of regulatory mechanisms in immune and inflammatory cells may help explain the seemingly disparate disorders of physiologic, pharmacologic, and immunologic systems in atopy.
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PMID:Immunopharmacology of the atopic diseases. 240 83

Atopic dermatitis (AD) is a familial inflammatory skin disorder, which is characterized by extreme pruritus, the typical morphology and distribution, the chronic or chronically relapsing course, and the personal or family case history of atopy (asthma, allergic rhinitis, atopic dermatitis); moreover, we find a variety of additional features, which are either less specific or relatively rare. Although this disease has been well-known since the beginning of the century, we have not clearly understood its pathogenesis so far. This article reviews the reported deviations of the immune system and the alterations of the mediators of inflammation as well as the abnormalities of cyclic nucleotide regulation. These findings are correlated to the clinical symptoms. The following topics have been dealt with in detail: association with HLA-antigens, elevation of serum IgE and generation of IgE immune complexes, numerical and functional deficiencies of T-suppressor cells, involvement of granulocytes, alterations of mediators of inflammation, and particularly, observations on the cAMP-phosphodiesterase. These extremely complex findings, which are based on the interaction between disregulation of the autonomous nervous system and alterations of the immune system, may provide a better understanding of the pathogenesis of atopic dermatitis.
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PMID:[Pathogenesis of atopic dermatitis]. 243 53

Terfenadine dose-dependently inhibited rat homologous PCA (2.5-10 mg/kg, p.o.) and experimentally-induced asthma in guinea pigs (0.5-5 mg/kg, p.o.). Similarly, metabolites I and II dose-dependently inhibited experimentally-induced asthma but their respective potencies were approximately 1/2 and 1/15th that of terfenadine. These results suggest that the metabolites contribute to the antiallergic effects of terfenadine. In ex vivo, terfenadine (5-20 mg/kg, p.o.) also inhibited the release of both antigen-induced histamine and SRS-A from sensitized guinea pig lung samples and that of histamine from rat peritoneal mast cells. Terfenadine dose-dependently increased the cAMP content in rat mast cells and in the lungs; in the latter, the augmented cAMP is associated with an increase in adenylate cyclase activity, but not with the inhibition of phosphodiesterase activity. The above evidence indicates that the inhibitory effects of terfenadine on mediator release from mast cells are in some way related to its antiallergic effects, and that an elevated cAMP content may be effective to enhance mediator release inhibition.
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PMID:Antiallergic effects of terfenadine on immediate type hypersensitivity reactions. 244 87

Eosinophils may play a critical role in asthma and bronchial hyperresponsiveness, yet the effect of theophylline on their function is not certain. We have examined the effects of theophylline on opsonized zymosan-induced superoxide anion (O2-) release from guinea pig eosinophils harvested from the peritoneal cavity and from human eosinophils obtained by differential centrifugation of blood from patients with peripheral eosinophilia. Theophylline at high concentration (10(-3) M) inhibited O2- release by 27.6 +/- 9.4% (mean +/- SEM, p less than 0.05), whereas at clinically relevant concentrations (10(-6) and 10(-5) M), it significantly potentiated this by 26.8 +/- 9.9% (p less than 0.05) and 36.9 +/- 6.3% (p less than 0.01), respectively. 8-phenyltheophylline (10(-7) to 10(-3) M), which like theophylline inhibits adenosine receptors but does not inhibit phosphodiesterase activity, produced potentiation at all concentrations. Preincubation of eosinophils with adenosine deaminase (0.1 U/ml) enhanced O2- release by 72.4 +/- 15.2% (p less than 0.01), whereas addition of adenosine (3 x 10(-8) to 10(-6) M) reversed the potentiation induced by theophylline (10(-5) M) in a concentration-dependent manner. Inhibition was greater with the A2-selective analog N-ethylcarboxamide adenosine than the A1-selective analog phenylisopropyladenosine, suggesting that A2-receptors are involved. In human eosinophils we have demonstrated a similar effect of theophylline and adenosine on O2- release. Our results indicate that therapeutic concentrations of theophylline may potentiate eosinophil activation in vivo by competing with circulating adenosine for eosinophil A2-receptors. This would be consistent with the lack of effect of theophylline on bronchial hyperresponsiveness, which may be related to eosinophilic inflammation.
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PMID:Effect of theophylline and adenosine on eosinophil function. 254 25

Two forms of cAMP phosphodiesterase were isolated from lymphocytes by using centrifugation in sucrose density gradient. The activities of both forms do not differ in healthy persons and in patients with bronchial asthma during asphyxia-free period. During the attack the activity of the high molecular form of the enzyme increases. Euphylline exerts the inhibitory effect on the activity and consequently on the general activity of the enzyme.
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PMID:[Characteristics of the action of euphylline and the activity of forms of cAMP phosphodiesterase in lymphocytes of patients with bronchial asthma]. 255 34

Desensitization of beta-adrenergic receptors means loss of receptor activity due to overstimulation by beta-mimetic drugs. Desensitization has been demonstrated in experimental studies using cell cultures, isolated organs and in vivo models. It generally evolves in two steps: uncoupling between the receptor and adenylate cyclase is followed by a decrease of the number (or down-regulation) of receptors. Desensitization can be either specific or non specific. In the first case, the phenomenon is related to the occupation of the receptor by an agonist and the occupied receptor only is altered (homologous desensitization). In the second case, the phenomenon is related to production in excess of cyclic AMP and other adenylate cyclase-coupled receptors are altered (heterologous desensitization). Studies performed on cellular models have shown that beta-receptor desensitization can be related to phosphorylation of the receptor by a cyclic AMP-dependent protein-kinase and that down-regulation corresponds to the incorporation of the beta-receptors in cytoplasmic vesicles. Desensitization has also been related to the activation of membrane phospholipid metabolism and the production of prostaglandins. Studies of bronchial beta-adrenergic receptors, mostly performed on isolated organs, have shown that beta-mimetic and, in some cases, phosphodiesterase inhibitor drugs can induce desensitization of beta-receptors. The possibility of beta-adrenergic receptor activity and desensitization independent of adenylate cyclase and cyclic AMP has also been evoked. In clinical practice, the reality of beta-adrenergic desensitization is still controversial. The existence of a variable proportion of "spare" receptors could explain the variability of patient responses to the long-term treatment of asthma by beta-mimetic drugs.
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PMID:[Mechanisms of desensitization of beta-adrenergic receptors]. 286 91


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