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)

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.
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PMID:Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. 618 71

Histamine inhibited the contractile response of the mouse vas deferens to various frequencies of stimulation, and the inhibition was inversely related to the frequency of stimulation. This effect of histamine was mimicked by cyclic AMP, db-cyclic AMP and various phosphodiesterase inhibitors (IBMX, aminophylline and theophylline). Histamine-produced inhibition, but not that produced by the other compounds, was blocked by cimetidine. The low concentrations (10-100 microM) of various phosphodiesterase inhibitors caused inhibition but failed to potentiate the inhibitory response to histamine. The basal cyclic AMP levels of the tissues were unaffected at these concentrations of aminophylline. At higher concentrations (1 and 5 mM), however, aminophylline significantly elevated the basal cyclic AMP levels of the tissues and markedly inhibited the contractile response to various frequencies of stimulation but still failed to enhance or potentiate the inhibitory response to histamine. In fact, the inhibitory response to histamine at these concentrations of aminophylline was reduced. Based on these and earlier [3] findings, it is concluded that, although histamine increases the accumulation of cyclic AMP in the mouse vas deferens and although its inhibitory effect on the preparation can be mimicked by both the cyclic nucleotides and phosphodiesterase inhibitors, the involvement of cyclic AMP in the mediation of its inhibitory response is still unresolved.
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PMID:Effect of cyclic AMP, db-cyclic AMP and phosphodiesterase inhibitors on histamine inhibition of the contractile response of the mouse vas deferens. 619 54

The effects of secretin and vasointestinal peptide (VIP) on the production of cyclic AMP have been studied in gastric glands isolated by means of EDTA from rat fundic and antral mucosa. (1) In gastric fundus, secretin and VIP caused a time- and temperature-dependent stimulation of cyclic AMP production that was maximal when the test agents were incubated for 60 min at 20 degrees C in the presence of 0.5 mM 3-isobutyl-1-methylxanthine as a phosphodiesterase inhibitor. The dose-response curve was monophasic for both peptides, the production of cyclic AMP being sensitive to 10(-10) M secretin and to 5 . 10(-8) M VIP. Half-maximal stimulation was obtained with 2.9 10(-9) M secretin or 2 . 10(-7) M VIP and the maximal stimulation represented a 21-fold and a 19-fold increase above control for secretin and VIP, respectively. Histamine also stimulated cyclic AMP production, with a Km of about 5 . 10(-4) M. No additive effect on cyclic AMP production was oberved when secretin and VIP were simultaneously added at maximally active concentrations, while an additive effect was observed when secretin and histamine were added together. (2) In gastric antrum, the characteristics of the secretin- and VIP-stimulated cyclic AMP production were similar to those observed in gastric fundus. Histamine nevertheless failed to stimulate the formation of cyclic AMP in antral mucosa. (3) These data demonstrate the existence of a cyclic AMP system highly sensitive to secretin in gastric glands isolated from the rat fundus and antrum and suggest that VIP operates through this system. (4) It is proposed that the pepsinogen- and/or mucous-secreting cells are implicated in the regulation of cyclic AMP production by secretin in gastric glands of the rat.
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PMID:Evidence for a cyclic AMP system highly sensitive to secretin in gastric glands isolated from the rat fundus and antrum. 624 85

In vitro and in vivo studies showed that methylation of homologous DNA in nuclear homogenates of rat bone marrow is controlled by cyclic nucleotides and some hormones. The cyclic nucleotides and their dibutyryl analogs inhibited homologous methylation of DNA in the presence and absence of phosphodiesterase inhibitors. In the presence of Ca2+ the inhibiting effect of the nucleotides was more pronounced. Prostaglandins inhibited DNA methylation in a weaker degree while insulin and erythropoietin had a stronger effect in comparison with the nucleotides. Histamine stimulated DNA methylation, whereas acute hypoxic hypoxia caused a reduction in the rate of DNA methylation.
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PMID:[Effect of cyclic nucleotides and hormones of homologous methylation in nuclear homogenates of rat bone marrow]. 626 Feb 37

A great deal of knowledge has been gained concerning the activation of adenylate and guanylate cyclase in epidermal cells. Adenylate cyclase is activated by 4 different independent receptors-responding respectively to catecholamine (beta), to prostaglandins (E), to histamine (H2), and to adenosine and it phosphorylated derivatives. Upon activation, each of these receptors becomes unresponsive to further stimulation by its specific stimulator. Guanylate cyclase, on the other hand, is activated by histamine (H1) and epidermal growth factor (EGF). Unlike EGF, the histamine activation is extremely rapid (less than 5 minutes). Epidermal cells are permeable (leak) to cyclic GMP but not cyclic AMP. When the skin is traumatized or injured in any way (even by intradermal injection) there is a sudden catastrophic change in the intracellular levels of the cyclic nucleotides (and of ATP). Cyclic AMP rapidly rises to perhaps 5-10 times its normal resting level while cyclic GMP falls to 10-20% of its level in vivo. The rise in cyclic AMP is due to activation of adenylate cyclase while the fall in cyclic GMP is due in major part to activation of cyclic GMP phosphodiesterase (and perhaps the fall in ATP is due to activation of ATPase). The changes in ATP and cyclic AMP can be reversed by incubating the tissue in a buffered salt solution containing glucose, but this does not normalize the cyclic GMP content. The fall in cyclic GMP can be prevented by a phosphodiesterase inhibitor (IBMX ). This series of events has been called the "ischemia effect." However, it implies that a lack of oxygen is at fault, and that has not been shown to be the case. Its underlying cause and possible physiologic significance are not known. Do these changes in cyclic nucleotides have effects on epidermal proliferation? And does EGF? Agents which increase cyclic AMP do inhibit the epidermal outgrowth and mitotic activity of explant cultures of pig skin. Cyclic GMP does increase outgrowth at a particular concentration. Histamine, which elevates both cyclic nucleotides, has a biphasic action depending on its concentration. These findings imply that these nucleotides do act as one of the controls of epidermal proliferation. The action of cyclic GMP is not accompanied by detectably increased phosphorylation of epidermal proteins. On the other hand, EGF action which also enhances epidermal outgrowth is characterized by an increased protein phosphorylation that precedes any increase in cellular cyclic GMP. We conclude that the action of EGF is independent of the cyclic nucleotide system.
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PMID:Cyclic GMP system in the epidermis. 626 50

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.
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PMID:Effect of purine nucleotides and other compounds on the uptake of histamine and histidine. 628 73

We have previously demonstrated heterologous desensitization of human mononuclear leukocytes (MNL) by incubation of low (e.g., 10(-6)M) concentrations of histamine, isoproterenol and prostaglandin E1. Subsequent exposure of the cells to stimulating (e.g., 10(-3) to 10(-5)M) concentrations of any one of the three agonists shows reduced cAMP responses. Possible mechanisms for the subnormal responsiveness include rapid degradation of cAMP. In this report we demonstrated time-dependent elevation of cAMP-phosphodiesterase (PDE) activity following agonist desensitization. The increased enzyme activity was accompanied by a mirror-image decrease in cAMP responsiveness. The effect was rapid and prolonged, with recovery time proportional to desensitization time. Cycloheximide failed to inhibit the increase of cAMP-PDE activity caused by short-term histamine exposure, but partially diminished the elevation as the result of chronic histamine desensitization. We observed three different kinetic forms of cAMP-PDE in MNL, designated as I, II and III, each with distinctive Km and Vmax. Histamine desensitization increased the activity of form II and drastically reduced that of form I. Also we observed a possible conversion of lymphocyte cAMP-PDE from form I to the form II more characteristic of monocytes. Agonist-induced increases in cAMP-PDE activity and changes in enzyme kinetic characteristics represent a potentially important mechanism of functional desensitization. This may have significant effects on biological regulation of cyclic nucleotides.
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PMID:Functional desensitization due to stimulation of cyclic AMP-phosphodiesterase in human mononuclear leukocytes. 630 Feb 7

Histamine (HA) potently stimulated cyclic AMP accumulation in intact pineal glands taken from light-exposed chicks. The action of HA was stronger in the presence of forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). The effect of HA was mimicked by HA H1- and H2-receptor-selective agonists in the following order of potency: HA > 4-methylhistamine (H2) > 2-methylhistamine (H1) > 2-thiazolylethylamine (H1) >> dimaprit (H2). The HA H3-receptor-selective agonist (R)alpha-methylhistamine was poorly active. The effect of HA was antagonized by selective H2-receptor blockers (tiotidine > oxmetidine > cimetidine = ranitidine) and was not significantly affected by the selective H1- and H3-receptor blockers mepyramine and thioperamide. A detailed analysis of an antagonistic action of ranitidine (versus HA) revealed a noncompetitive mode of action of the H2 blocker. The stimulatory action of the H1 agonist 2-thiazolylethylamine (both under basal conditions and in the presence of forskolin or IBMX) was not significantly influenced by three H1-receptor-selective blockers (mepyramine, triprolidine, and diphenhydramine), but it was totally counteracted by ranitidine. Using accepted selective agonists and antagonists of the HA H1, H2, and H3 receptor we were unable to identify clearly the receptor subtype mediating the HA action on the cyclic AMP-generating system of the chick pineal. It is suggested that the receptor under consideration may represent either an H2-like (in terms of mammalian criteria) or avian-specific HA receptor. The data suggest that HA may be considered a modulator of the pineal activity in chicks.
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PMID:Stimulatory effect of histamine on cyclic AMP formation in chick pineal gland. 752 89

Adriamycin (ADR) induces nonimmunological and noncytotoxic histamine release from peritoneal and pleural rat mast cells. This secretion is unaffected by the pretreatment with pertussis toxin, cholera toxin and benzalkonium chloride. Histamine release induced by compound 48/80, was markedly inhibited by pertussis toxin, cholera toxin, benzalkonium chloride and neuraminidase. The ADR dose-response curve is significantly shifted to the right when cells were preincubated with the unspecific phosphodiesterase inhibitor IBMX. The activation of protein kinase C (PKC) with the phorbol esther TPA increases the response to ADR, while PKC inhibition with trifluoperazine decreases histamine release. The pretreatment of mast cells with okadaic acid did not modify the response to ADR. These results suggest that ADR elicits histamine release with a mechanism notably different from compound 48/80.
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PMID:Study of the activation mechanism of adriamycin on rat mast cells. 753 76

We studied the effects of modulators of the adenylyl cyclase pathway on the accumulation of cAMP in endothelial cells isolated from bovine aortas, pig pulmonary arteries, human umbilical veins, and human subcutaneous adipose microvessels. In addition to quantitative differences in the basal levels, cAMP stimulation in different endothelial cell types varied in sensitivity and magnitude in response to both the direct adenylyl cyclase activator forskolin and the beta-adrenergic receptor agonist isoproterenol. Furthermore, the ubiquitous phosphodiesterase inhibitor IBMX differentially enhanced both the basal and the stimulated cAMP levels in the various cell types. Histamine caused an elevation of cAMP only in bovine aortic endothelial cells and in human umbilical vein endothelial cells. Treatment of the cells with cholera and pertussis toxins, which uniquely affect G-protein subunits, resulted in divergent elevation of cAMP in the various cells. Thus, in each cell type, a distinct profile of regulation of the cAMP levels was found. Our results suggest that the adenylyl cyclase signaling system in various types of endothelial cells can be differentially regulated at the levels of receptors, G-proteins, adenylyl cyclase, and phosphodiesterase.
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PMID:Regulation of the adenylyl cyclase signaling system in various types of cultured endothelial cells. 754 52


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