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)

A method is described that enabled us to study the adhesiveness of J-774 murine macrophages. Cell attachment was stimulated by activators of kinase C (i.e., phorbol esters) as well as kinase A (cyclic adenosine monophosphate; cAMP). This novel effect of cAMP was observed when its levels were increased via receptor triggering (prostaglandin E1, beta-adrenergic agonists), activation of Ns (cholera toxin), or inhibition of phosphodiesterase (Ro 20-1724) or when the kinase was directly activated by Br8-cAMP. The simultaneous treatment with kinase A and kinase C activators at the time of attachment resulted in a partially additive response. On the other hand, preincubation of the cells in suspension with one of the activators rendered them refractory to subsequent stimulation at the onset of the adhesion assay, whatever agent was used. Such a refractoriness was also observed in cells preincubated with oleoyl-acetyl-glycerol (OAG). On the other hand, when added at the time of attachment, this near-physiological activator of kinase C evoked a biphasic response: the early stimulation of cell attachment was followed by an accelerated rate of "detachment." In conclusion, kinase C and kinase A play a role in the sequence of events leading to cell adhesion. The cross desensitization observed is distal and takes place at or beyond the kinase step.
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PMID:Biphasic regulation of macrophage attachment by activators of cyclic adenosine monophosphate-dependent kinase and protein kinase C. 254 34

The effects of various biological detergents on the particulate cGMP-stimulated cAMP phosphodiesterase activity from rat heart were investigated. When added to particulate fractions, anionic and non-ionic detergents diversely increased both cAMP and cGMP phosphodiesterase activities and slightly decreased the stimulatory effect of cGMP on cAMP hydrolysis whereas cationic detergents were rather inhibitory and drastically lowered the stimulatory effect of cGMP. Among the most efficient detergents, only sodium cholate was able to solubilize phosphodiesterase activity and preserve the stimulatory effect of cGMP on cAMP hydrolysis. Furthermore, the addition of glycerol significantly improved the conservation of the allosteric properties of the enzyme. Kinetic properties of the cholate-solubilized phosphodiesterase were quite identical to those of the membrane-bound enzyme.
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PMID:Differential susceptibility to biological detergents of the particulate cGMP-stimulated phosphodiesterase from rat heart: preservation of the allosteric properties of the solubilized enzyme. 255 8

1-Oleoyl-2-acetyl-sn-glycerol (OAG), the membrane-permeable analogue of 1,2-diacylglycerol (DAG), which stimulates ascites tumor cell proliferation, was used to study its effect on phosphoinositide metabolism. Culturing of ascites cells labeled with [3H]inositol at low serum concentration in the presence of OAG suppressed the radioactivity level of the inositol phosphates, particularly IP3. Membrane-bound, Ca(2+)- and GTP gamma S-sensitive PI- and PIP2-specific phosphodiesterase (phospholipase C) showed much lower activities in OAG-stimulated cells, which could be enhanced by GTP gamma S in these but not in the unstimulated cells. A high susceptibility to Ca2+ of the PI- and PIP2-specific phospholipase C of non-stimulated cells was observed. The PIP-kinase activity was similarly reduced by about 85% in OAG-stimulated cells. These data indicate a negative feedback regulation of the phosphoinositide metabolism mediated by OAG. Reduction in synthesis and degradation of PIP2, which furnishes the two second messengers, DAG and IP3, provides a means of controlling the intracellular level of these molecules, which is important for a balanced proliferation rate.
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PMID:Effect of 1-oleoyl-2-acetyl-sn-glycerol on inositol lipid metabolism of ascites tumor cells in culture. 256 33

The mechanism of action of theophylline is still the subject of controversy. Possible mechanisms that have been suggested are inhibition of phosphodiesterase, release of catecholamines, effects on intracellular calcium, and adenosine antagonism. With regard to these aspects, it was the aim of this study to compare sympatho-adrenal responses after theophylline application during different anesthetic techniques. A total of 60 patients scheduled for orthopedic surgery were investigated: they were divided into three groups of 20 patients who received either halothane anesthesia with thiopentone induction, modified neurolept anesthesia with fentanyl and midazolam, or spinal anesthesia with bupivacaine and mepivacaine. Within these three groups, the patients were randomly allocated to a theophylline collective receiving an injection of theophylline, 4 mg/kg body weight and to the control group. Plasma levels of epinephrine and norepinephrine (by HPLC/ECD), glucose, lactate and free glycerol and MAP and HR were determined over a period of 120 min. In all groups, epinephrine levels increased immediately after injection of theophylline; group levels of epinephrine were higher in the theophylline-groups than in controls (P less than 0.0001). A remarkable increase was observed within 60 min. Peak epinephrine concentrations were comparable after single injections of 100 micrograms or infusions of 5 micrograms/min. The norepinephrine increase after theophylline injection was brief and less pronounced. MAP, HR, glucose, lactate and free glycerol were not influenced by theophylline. A comparison of the theophylline patients showed no statistical differences attributable to the different anesthetic techniques.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Sympatho-adrenergic reactions following theophylline administration with the use of various anesthesia technics]. 276 71

Peri-tumoral injection of recombinant human interleukin-1 beta in mice transplanted s.c. with Friend erythroleukemia cells (FLC) resulted in marked inhibition of tumor growth and increased survival. However, in vitro treatment of FLC (745 or 3Cl-8) with IL-1 beta barely inhibited cell multiplication. IL-1 beta, injected into established solid tumors, induced marked morphologic changes. Vascular congestion and focal extravasation of erythrocytes were observed as early as 6 hr after injection with IL-1 beta of FLC and L1210 tumors and HeJ16 fibrosarcomas. Focal areas of disaggregation of tumor cells and tumor necrosis were observed 6 and 24 hr after IL-1 injection. These morphologic changes were similar to those observed in FLC tumors or HeJ16 fibrosarcomas treated with TNF-alpha or beta. These cytokines determined morphological changes in tumor blood vessels of FLC tumors within 1 hr of injection. Freshly dissected FLC tumors and their tissue extracts were studied by Nuclear Magnetic Resonance (NMR) spectroscopy, shortly after peri-tumoral injection of IL-1 beta or TNF-beta. After 6 hr, both cytokines induced a 3-fold reduction in the levels of two catabolites, glycerophosphorylcholine and glycerophosphorylethanolamine, an accumulation of sn-glycerol 3-phosphate and a more than 10-fold increase in the choline/phosphorylcholine ratio. These results are similar to those reported for TNF-alpha, and can be interpreted on the basis of an activation of glycerophosphorylcholine phosphodiesterase (EC 3.1.4.2) and partial inhibition of choline kinase (EC 2.7.1.32). IL-1 beta and TNF-beta (like TNF-alpha) also induced alkaline shifts (0.10-0.25 units) in the average intratumoral pH value. We suggest that alterations of tumor blood vessels may be the primary events in solid tumors treated with IL-1 beta or TNF. Such alterations lead to early changes in tumor metabolism and subsequent tumor cell degeneration.
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PMID:Interleukin-1 beta induces tumor necrosis and early morphologic and metabolic changes in transplantable mouse tumors. Similarities with the anti-tumor effects of tumor necrosis factor alpha or beta. 278 94

In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 microM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found: 1. Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres. 2. During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles. 3. In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment. 4. Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts. Mild isoprenaline overload and hereditary cardiomyopathy both are forms of heart failure which are presumably not associated with a lack of activator Ca. It is concluded that cardiotonic agents increasing the cardiac myofibrillar sensitivity to Ca ions would be beneficial in both cases, representing a phenomenologically causative treatment in hearts failing due to isoprenaline pretreatment. A main advantage over "classical" cardiotonic agents like cardiac glycosides, beta adrenergic stimulants or phosphodiesterase inhibitors would be the absence of the risk of drug-induced Ca overload.
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PMID:Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533. 282 79

The effects of two phosphodiesterase inhibitors, e.g. theophylline and D-4-(3-butoxy-4 methoxybenzyl)-2-imidazolidinone (RO-20-1724) on the antilipolytic action of insulin in human adipocytes were investigated. At a concentration of 1 mmol/l (theophylline) and 0.1 mmol/l (RO-20-1724) both inhibitors increased cyclic AMP to a similar extent. However, their effects on insulin action were different. Whereas addition of theophylline abolished the ability of insulin to inhibit lipolysis, insulin was fully functional in depressing glycerol release in the presence of RO-20-1724. The results suggest that the insulin-sensitive phosphodiesterase of human adipocytes may be relatively resistant to RO-20-1724 as has been shown for the enzyme system of 3T3-L1 adipocytes.
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PMID:Effects of different phosphodiesterase inhibitors on the antilipolytic action of insulin in human adipocytes. 282 63

The present study describes the effect of norepinephrine on lipolysis and adenylate cyclase activity in adipocytes from Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The adipocytes were incubated in the presence of norepinephrine (10(-7) to 10(-4) mol/L) and the lipolytic activity was measured according to the accumulation of glycerol after one hour incubation. The results showed that norepinephrine induced a lower lipolytic activity in adipocytes from SH rats. cAMP-phosphodiesterase activities in adipocyte homogenates from WKY and SH rats were the same for both preparations. The effect of norepinephrine (10(-7) to 10(-4) mol/L) on adenylate cyclase activity in fat cell membranes from SH rats was decreased compared with WKY fat cell membranes. Adenylate cyclase activities in the presence of 10 mmol/L NaF were the same in both preparations. beta-receptor characteristics were examined, and the data demonstrate a statistically significant decrease in beta-receptor density in fat cell membranes from SH rats. The dissociation constants (Kd) were the same for WKY and SH preparations. This article suggests that adipocyte responsiveness to norepinephrine is decreased in SH rats. The decreased response to norepinephrine may be explained by a lower beta-receptor density in fat cell membranes from SH rats.
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PMID:Adipocyte responsiveness to norepinephrine in spontaneously hypertensive rats. 283 79

The species pattern of phosphatidic acid was compared with that of CDP-diacylglycerol and diacylglycerol synthesized de novo by glycerol 3-phosphate acylation in a CoA ester-generating system in liver microsomes. The similarity of the species patterns of phosphatidic acid and CDP-diacylglycerol indicated that the CTP-phosphatidyl cytidylyltransferase showed no selectivity for individual species of its phosphatidic acid substrate. Since the species pattern of diacylglycerol deviated from that of phosphatidic acid, a slight acyl selectivity of the phosphatidic acid phosphohydrolase or a slight inhomogeneity of its substrate pool might be assumed. For the determination of the molecular species of CDP-diacylglycerol, a new method was developed. By incubation of CDP-diacylglycerol with oligonucleate 5'-nucleotidohydrolase (phosphodiesterase), phosphatidic acid was produced. The CDP-diacylglycerol-derived phosphatidic acid was methylated with diazomethane and then separated by reverse-phase HPLC in 15 molecular species.
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PMID:Comparison of the HPLC-separated species patterns of phosphatidic acid, CDP-diacylglycerol and diacylglycerol synthesized de novo in rat liver microsomes (a new method). 284 Sep 68

Activation of glycolysis by insulin in cultured adult rat hepatocytes is accompanied by an activation of phosphofructokinase 2 (PFK 2). PFK 2 activation might be caused by insulin-dependent changes of (a) metabolite levels, (b) basal and (c) Br8cAMP-stimulated cAMP-dependent protein kinase activity; this problem was investigated. 1. Cells cultured with 0.1 nM insulin for 48 h exhibited a low glycolytic rate and low fructose 2,6-bisphosphate [Fru(2,6)P2] levels. Addition of insulin increased Fru(2,6)P2 and Fru(1,6)P2 levels sequentially which points to PFK 2 as first target enzyme of insulin action. 2. Concentrations of Glc6P, Fru6P, phosphoenolpyruvate, glycerol 3-phosphate and citrate, which modulate PFK 2/fructose 2,6-bisphosphatase 2 activity, were not altered by insulin. 3. Activation of PFK 2 by insulin occurred without changes in the levels of total and protein-bound cAMP. Bound cAMP amounted to about 14% of total cAMP. 4. Insulin neither decreased the basal dissociation state of the cAMP-dependent protein kinase nor lowered the sensitivity of the kinase towards cAMP in cell extracts. 5. Addition of the phosphodiesterase-resistant Br8cAMP to the cultures increased cAMP levels 3-4-fold, elevated the protein kinase activity ratio from 0.14 to 0.6 and decreased the Fru(2,6)P2 level and the rate of glycolysis. When Br8cAMP and insulin were given together, insulin was capable of counteracting Br8cAMP in that it activated glycolysis and PFK 2 and elevated the Fru(2,6)P2 level; however, it did not decrease the elevated protein kinase activity ratio. It is concluded that insulin presumably does not activate PFK 2 through changes in cAMP and effector levels or through inhibition of cAMP-dependent protein kinase dissociation. The data support the hypothesis that insulin may act via activation of PFK 2 phosphatase.
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PMID:Activation of phosphofructokinase 2 by insulin in cultured hepatocytes without accompanying changes of effector levels or cAMP-stimulated protein kinase activity ratios. 284 74


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