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)

We have perfused isolated rat livers with hypocalcemic (4.4 mg 100 ml) Krebs-Ringer bicarbonate albumin buffer. After 15 min of perfusion, a substance appeared in the perfusate which decreased rat renal adenylate cyclase activation by parathyroid hormone (PTH). The material in the perfusate was purified greater than 50,000-fold by Bio-Gel P-10 chromatography. The purified antagonist decreased the activation of rat renal cortical adenylate cyclase by PTH, glucagon, and epinephrine 75 to 100%. Concentration response curves for each of the hormones indicated a noncompetitive interaction of the inhibitor with the hormone. The inhibition was not species-specific, as the activation of the parathyroid hormone-responsive adenylate cyclase in cat renal cortex was also abolished by the inhibitor from the perfused rat liver. The inhibitor is a peptide, Mr equal to similar to 1000, which is heat-stable, acid-stable, alkai-labile, and is destroyed by trypsin, leucine aminopeptidase, and elastase. It is not destroyed by phosphodiesterase, 5'-nucleotidase, alkaline phosphatase, neuraminidase, RNase, or phospholipase A. The inhibitor is not produced by isolated rat livers perfused with normocalcemic perfusion media. It is unclear whether the peptide is synthesized by the liver or whether it is a breakdown product of a larger peptide or protein in the liver. This is the first reported peptide inhibitor of adenylate cyclase.
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PMID:Isolation of a unique peptide inhibitor of hormone-responsive adenylate cyclase. 16 24

To investigate the mechanism of nonrenal capillary hyperfiltration, we studied the effect of atriopeptin (AP) III and AP I on permeability and intracellular cyclic nucleotide levels in cultured bovine pulmonary artery endothelial cell monolayers. Permeability to albumin was assessed by the albumin transfer rate across endothelial cell monolayers, following a 4-h incubation with atriopeptins. AP III (0.01, 0.1, and 1 microM) caused a concentration-dependent increase in the albumin transfer rate. AP III induced a threefold increase in intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels during the incubation period. A phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), enhanced the AP III-induced increase in permeability and cGMP accumulation by 16-fold at maximum. 8-Bromoguanosine 3',5'-cyclic monophosphate, a hydrolysis-resistant cGMP analogue, caused a slight but significant increase in permeability. In contrast, AP I, a weak agonist of the cGMP-coupled ANP receptor, did not elicit an increase in permeability at concentrations of 0.1 and 1 microM. Although AP I (1 microM) caused a significant increase in cGMP by 33 and 60% in the absence and presence of IBMX, the increase was markedly less compared with AP III. AP III did not cause a change in intracellular cAMP levels during the incubation period. These observations suggest that in our system AP III increases the permeability of endothelial cell monolayers in association with an elevated cGMP level. Thus an increase in permeability might be involved in the mechanism of ANP-induced capillary hyperfiltration.
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PMID:Atriopeptin-induced increases in endothelial cell permeability are associated with elevated cGMP levels. 132 30

Exposure of C62B rat glioma cells to fresh medium containing fetal bovine serum induced a sensitization of the subsequent ability of isoproterenol and forskolin to stimulate cyclic AMP accumulation, compared to cells exposed to fresh medium without serum. Isoproterenol stimulation was typically increased by 2- to 4-fold and forskolin stimulation by 3- to 5-fold. Sensitization occurred rapidly, was rapidly reversible and appeared to result from an increase in maximal stimulation. A commercial preparation of albumin, purified chromatographically so as to retain bound lipids and other factors, was able to mimic the effect of serum. In contrast to the effects of serum, exposure of cells to phorbol 12-myristate, 13-acetate induced little or no change in forskolin stimulation but a marked desensitization of isoproterenol stimulation that was due primarily to a decrease in potency. Neither the protein kinase C inhibitor staurosporine or overnight exposure to phorbol 12-myristate, 13-acetate to down-regulate protein kinase C prevented serum-induced sensitization. Pertussis toxin almost completely blocked serum-induced sensitization, suggesting involvement of a pertussis toxin-sensitive guanine nucleotide-binding protein in mediating the effects of serum. Sensitization was poorly retained in membrane adenylate cyclase assays. Studies with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, direct assays of cyclic AMP degradation by intact cells and assays of phosphodiesterase activity in cell lysates all indicated that degradation of cyclic AMP was decreased in serum-pretreated cells. Thus, both increased cyclic AMP synthesis and decreased cyclic AMP degradation may contribute to sensitization in these cells.
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PMID:Serum-induced sensitization of cyclic AMP accumulation in C62B rat glioma cells. 138 77

Pentoxifylline, a methylxanthine with phosphodiesterase inhibitor activity, attenuates endotoxin-induced pulmonary vascular protein leak and decreases lung neutrophil accumulation in vivo. In vitro, pentoxifylline decreases neutrophil activation as measured by superoxide release and phagocytosis of latex beads. To test the hypothesis that the beneficial effect of pentoxifylline may be via a direct effect on the endothelial cells as well as via prevention of neutrophil activation, we incubated bovine pulmonary artery endothelial cell monolayers with endotoxin and pentoxifylline in the presence or absence of human neutrophils. Albumin clearance across the monolayers was used as an index of endothelial permeability. Endotoxin (1.0 micrograms/ml) increased albumin clearance in a dose- and time-dependent fashion (207.5 +/- 25%, P less than 0.05). Co-incubation with neutrophils enhanced this effect. Pentoxifylline significantly attenuated the endotoxin-induced increase in albumin clearance both with and without neutrophils, and lessened endotoxin-induced cell lysis (chromium release) and morphologic changes. Because increased endothelial cyclic adenosine monophosphate (cAMP) levels may decrease protein permeability and pentoxifylline increases cAMP in neutrophils, we measured cAMP levels in endothelial cells. Incubation with pentoxifylline failed to raise cAMP levels in endothelial cells, in contrast to incubation with aminophylline. In conclusion, pentoxifylline attenuates endotoxin-induced increase in albumin clearance across endothelial monolayers both in the presence and absence of neutrophils. These results suggest that part of the protective effect of pentoxifylline may be mediated via effects on endothelium. Furthermore, this pentoxifylline-mediated endothelial barrier effect appears to be independent of an effect on cAMP.
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PMID:Pentoxifylline lessens the endotoxin-induced increase in albumin clearance across pulmonary artery endothelial monolayers with and without neutrophils. 184 85

To see if phosphodiesterase inhibition might enhance the effect of beta-adrenergic stimulation on fetal lung liquid secretion, we studied the independent and combined effects of intrapulmonary terbutaline and aminophylline on net production of lung luminal liquid over time (Jv) in fetal lambs with chronically placed tracheal loop catheters. We calculated Jv during baseline and experimental periods (90-120 min each) by measuring serial concentrations of 125I-albumin, an impermeant tracer that was well mixed in the luminal liquid. In 21 experiments, tracheal instillation of terbutaline (10(-5) M) decreased Jv from 11 +/- 1 (mean +/- SEM) to -3 +/- 2 mL/h. In six other studies, aminophylline (10(-3) M) alone had no significant effect on Jv. In 12 experiments, we gave the two drugs sequentially: terbutaline decreased Jv from 11 +/- 2 to -3 +/- 2 mL/h and aminophylline further decreased Jv to -8 +/- 2 mL/h. Amiloride (10(-4) M), an inhibitor of epithelial Na+ transport, reversed the combined effect of terbutaline and aminophylline, increasing Jv to 8 +/- 1 mL/h. Thus, phosphodiesterase inhibition enhances the beta-adrenergic effect of terbutaline on Na(+)-dependent absorption of liquid from the lung lumen of fetal lambs.
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PMID:Intrapulmonary terbutaline and aminophylline decrease lung liquid in fetal lambs. 185 29

The pathogenesis of adult respiratory distress syndrome (ARDS) is not clear, and its therapy is still a problem. Pentoxifylline, a methylxanthine derivative, can inhibit phosphodiesterase activity and thus increase the intracellular cAMP. There are also some hypotheses that pentoxifylline can attenuate pulmonary edema. In order to evaluate the protective effect of pentoxifylline in acute lung injury, we set up an isolated lung perfusion model in rats and induced experimental acute lung injury similar to ARDS by intravenously infused phorbol myristate acetate (PMA) 7.5 micrograms/300 g body weight. Four groups of experimental rats were studied: group 1, normal control group, neither PMA nor pentoxifylline was used in 6 rats; group 2 (acute lung injury group), only PMA was infused in 8 rats; group 3 (protective group), pentoxifylline 100 mg/300 g body weight was given intravenously before PMA infusion in 6 rats; group 4, only pentoxifylline was given in 6 rats. Pulmonary arterial pressure (PAP) as well as lung weight changes were recorded before and 5, 10, 15, 20 and 25 minutes after drug injection. Bronchial lavage fluids were then measured for albumin concentration. We found that PAP was strikingly increased in group 2 (54.0 +/- 8.8 mmHg), but the increase was significantly reduced in group 3 (29.8 +/- 5.8 mmHg, p less than 0.001). Similarly, the lung weight gain was markedly increased in group 2 (4.69 +/- 1.28 g), but was significantly attenuated in group 3 (1.25 +/- 1.60 g, p less than 0.001). There was no apparent change in PAP and lung weight gain throughout the entire procedure in groups 1 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protective effect of pentoxifylline on phorbol myristate acetate-induced acute lung injury in rats. 198 33

1. Beta-adrenergic agonists were not effective inhibitors of lipogenesis in porcine adipose tissue slices in vitro; addition of theophylline permitted the inhibition. 2. Inhibition was increased to a greater extent by isoproterenol than epinephrine and was decreased by propranolol, therefore presumably via beta-adrenergic receptors. 3. Caffeine, isobutylmethylxanthine and theophylline all permitted inhibition of lipogenesis by beta-adrenergic agonists. 4. It is not clear whether the mechanism for this permissive action is via antagonism of the adenosine receptor, inhibition of cAMP phosphodiesterase or a combination of both. 5. Adenosine deaminase was weakly permissive, presumably through destruction of adenosine. Inhibition of lipogenesis was observed with glucose or acetate as lipogenic substrate and in the presence or absence of albumin.
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PMID:Inhibition of porcine adipose tissue lipogenesis by beta-adrenergic agonists. 248 29

Rat hepatocytes were incubated in monolayer culture in modified Leibovitz L-15 medium containing either 10% (v/v) newborn-calf serum or 0.2% (w/v) fatty-acid-poor bovine serum albumin. The addition of 100 nM-dexamethasone increased the activities of both phosphatidate phosphohydrolase and tyrosine aminotransferase by about 3.5-fold after 8h, and these activities continued to rise until at least 24h. Incubating the hepatocytes in the albumin-containing medium with 10 microM- or 100 microM-8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate increased the activities of the phosphohydrolase and aminotransferase by 2.6- and 3.4-fold respectively after 8h. These increases were blocked by actinomycin D. The increases in the activities that were produced by the cyclic AMP analogue and dexamethasone were independent and approximately additive. Insulin when added alone did not alter the phosphohydrolase activity, but it increased the aminotransferase activity by 34%. The dexamethasone-induced increase in the phosphohydrolase activity was completely blocked by 7-144 microM-insulin, whereas that of the aminotransferase was only partly suppressed. Insulin had no significant Effects on the increases in the activities of phosphatidate phosphohydrolase and tyrosine aminotransferase that were produced by the cyclic AMP analogue, but this may be because the analogue is fairly resistant to degradation by the phosphodiesterase. The activity of glycerol kinase was not significantly changed by incubating the hepatocytes with insulin, dexamethasone and the cyclic AMP analogue alone or in combinations. It is proposed that high concentrations of cyclic AMP and glucocorticoids increase the total activity of phosphatidate phosphohydrolase in the liver and provide it with an increased capacity for synthesizing triacylglycerols and very-low-density lipoproteins, which is expressed when the availability of fatty acids is high. There appears to be a co-ordinated hormonal control of triacyglycerol synthesis and gluconeogenesis in diabetes and in metabolic stress to enable the liver to supply other organs with energy.
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PMID:Effects of cyclic AMP, glucocorticoids and insulin on the activities of phosphatidate phosphohydrolase, tyrosine aminotransferase and glycerol kinase in isolated rat hepatocytes in relation to the control of triacylglycerol synthesis and gluconeogenesis. 285

Bovine serum albumin inhibits the light activation of bovine rod disc membrane (RDM) cyclic GMP phosphodiesterase. The KI for inhibition is 32 microM at pH 8 and 37 degrees C. Trypsin-activated phosphodiesterase was not inhibited under these conditions, suggesting that albumin does not alter substrate access to the enzyme. Light titration curves of phosphodiesterase activity were vertically displaced downwards by albumin. The lack of displacement along the bleach axis indicated no loss in relative light sensitivity, but rather loss of a constant fraction of the normal activity for each bleach level. Thus, activated rhodopsin appeared to be functional in the presence of albumin. However, the metarhodopsin II yield with less than 10% bleached was reduced in the presence of albumin. This effect was quantitatively explained by albumin elution of GTP-binding protein from the RDM. Similarly, the reduction in light-induced phosphodiesterase activity quantitatively matched GTP-binding protein elution by albumin. beta-Lactoglobulin, which, like albumin, is known to bind hydrophobic molecules, also inhibits phosphodiesterase activation. In contrast, ovalbumin, which has little hydrophobic binding affinity, had little or no inhibitory effect on phosphodiesterase light activation. We conclude that albumin and other molecules capable of hydrophobic interactions inhibit light activation of RDM-phosphodiesterase by selectively eluting GTP-binding protein from the membrane into the surrounding medium where it is unable to efficiently gain access to activated rhodopsin.
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PMID:Albumin inhibits light activation of cGMP phosphodiesterase on rod disc membranes. 609 63

Nucleotide pyrophosphatase and phosphodiesterase I activities were determined in sera from 126 patients with different types of liver disease and in two additional groups of patients with intra- and extrahepatic cholestasis, respectively. Both activities probably represent the same enzyme, and were positively correlated with alkaline phosphatase, lipoprotein X, and several other tests reflecting cholestasis. Also, we found by discriminant analysis that tests for cholestasis frequently replaced the results of both enzymes. In some groups of liver disease, nucleotide pyrophosphatase and phosphodiesterase I were correlated with the concentrations of prealbumin and albumin. The sensitivity of phosphodiesterase I (and nucleotide phosphatase) is rather low when compared with alkaline phosphatase, and we do not recommend it for use in the clinical routine. Nevertheless, it appears to be of potential value for studies on classification of liver diseases, adding information to a panel of 20 commonly used "liver tests" by appearing in some of the best four test-sets for distinguishing between groups of liver disease by discriminant analysis.
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PMID:Usefulness of serum nucleotide pyrophosphatase and phosphodiesterase I activities in classifying liver disease. 611 26


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