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)

Murine peritoneal macrophages primed in vivo by trehalose dimycolate (TDM) express cytostatic activity against tumor cells after treatment in vitro with 10 ng/ml lipopolysaccharide (LPS) during a 4-hr period (activation step). There is a strict correlation (P < 0.0001) between acquisition of antitumoral activity and induction of NO synthase quantified by its end products citrulline and NO2-. LPS also stimulates the release of cyclooxygenase products which exert a retroinhibitory action on NO synthase and cytostatic activities, as judged by an increase of both parameters by indomethacin (1 microM) and a decrease by externally added PGE2 (1 microM). LPS increases cellular and extracellular cAMP levels through an indomethacin-sensitive pathway, pointing to cAMP as a second messenger in the retroinhibitory action of LPS-induced prostaglandins. In fact, the addition of 8-bromo-cAMP or of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine during the activation step decreases NO synthase activity; however, at the same time these drugs increase the apparent efficiency of NO as an antitumor agent.
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PMID:LPS-induced activation of primed murine peritoneal macrophages is modulated by prostaglandins and cyclic nucleotides. 768 61

Prostacyclin analogues have been reported to inhibit the expression of tissue factor procoagulant activity in human monocytes, primarily by elevating intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP). The present studies have investigated whether prostacyclins can also inhibit tissue factor expression in endothelial cells. Iloprost, carbacyclin, and ciprostene had no effect on human umbilical vein endothelial tissue factor activity induced by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), or interleukin-1 beta (IL-1 beta). Iloprost failed to elevate intracellular levels of cAMP, even when combined with a phosphodiesterase inhibitor. In contrast, forskolin increased endothelial cAMP and inhibited tissue factor expression. Conditioned medium from LPS-challenged monocytic THP-1 cells, which contained both TNF-alpha and IL-1 beta, induced endothelial cell procoagulant activity to levels 20-fold higher than those achieved in response to LPS alone. Iloprost abolished LPS-induced TNF-alpha secretion by THP-1 cells and inhibited IL-1 beta secretion by 45%. In keeping with this, iloprost reduced levels of TNF-alpha and IL-1 beta mRNA in LPS-challenged cells. Treatment of THP-1 cells with iloprost strongly inhibited the ability of conditioned medium to induce endothelial tissue factor expression, an effect that was mimicked by treating the medium with blocking antibodies to the cytokines. We conclude that although prostacyclin analogues do not directly suppress endothelial tissue factor expression due to their failure to elevate cAMP, they may do so indirectly by inhibiting the amplification produced by monocyte-derived cytokines.
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PMID:Effects of prostacyclin analogues on human endothelial cell tissue factor expression. 768 94

We observed that lipopolysaccharide (LPS, 1 micrograms/ml) can suppress [3H]thymidine incorporation into acid-insoluble fraction in a mouse macrophage cell line J774 (over 70% at 6 h) without affecting the uptake of [3H]thymidine or DNA polymerase activity. Paralleling this suppression, a decrease in the thymidine kinase (TK) activity, but not of thymidine monophosphate (TMP) kinase and thymidine diphosphate (TDP) kinase, was observed. LPS dose-dependently increased intracellular cAMP levels to about 3.5-times basal at 6 h, proportionally to the decrease of the TK activity. Elevation of intracellular cAMP by several reagents also decreased TK activity. Apparently LPS treatment elevates cAMP concentration by decreasing the low Km cAMP phosphodiesterase activity (58% at 6 h). The time course of cAMP-dependent protein kinase (PK-A) activity during the first 6 h after LPS treatment correlated with that of cAMP concentration. Treatment with a PK-A inhibitor restored about 63% of LPS-induced reduction of TK activity at 6 h. At longer times, however, there was a discrepancy between the change of cAMP concentration or PK-A activity and the reduction of TK activity. Therefore, protein kinase activation caused by the accumulation of intracellular cAMP probably triggers some mechanism responsible for the reduction of the TK activity.
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PMID:The role of cyclic AMP in the lipopolysaccharide-induced suppression of thymidine kinase activity in macrophage. 769 50

Previous research with pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor, suggests that this drug may be capable of suppressing the activation of Kupffer cells and thereby help decrease liver injury after transplantation. To investigate this possibility, the current study sought to determine whether the release of O2- and tumor necrosis factor (TNF) from Kupffer cells in donor livers can be suppressed if the organs are exposed to PTX before preservation. In an in vitro experiment, rat livers were flushed with PTX (25 mg/kg body weight) in University of Washington (UW) solution or UW solution alone (control) and then and stored in UW solution for either 4 or 24 hours. Kupffer cells then were purified and their degree of activation determined by measuring O2- release and the production of TNF after lipopolysaccharide stimulation. In an in vivo experiment, a group of rats underwent orthotopic liver transplantation with grafts prepared in the same manner as in the in vitro study. TNF and aspartate transaminase (AST) were measured in blood samples taken 3 hours and 24 hours after transplantation. Compared with controls, the Kupffer cells from grafts pretreated with PTX produced significantly less O2- and TNF, and the recipients of PTX-pretreated grafts had lower levels of TNF and AST 3 hours after transplantation. The current data indicate that O2- and TNF production in liver grafts is suppressed by PTX pretreatment. Through its suppressive effect on Kupffer cells, PTX may help minimize preservation-reperfusion injury and improve graft survival.
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PMID:Effects of pentoxifylline pretreatment on Kupffer cells in rat liver transplantation. 770 82

The synthesis of 1,3-disubstituted pyrrolidines 2 and their activities as type IV phosphodiesterase (PDE) inhibitors are described. Various groups were appended to the nitrogen of the pyrrolidine nucleus to enable structure-activity relationships to be assessed. Groups which render the pyrrolidine nitrogen of 2 nonbasic yielded potent PDE-IV inhibitors. Analogs of amides, carbamates, and ureas of 2 were synthesized to determine the effects that substitution on these functional groups had on PDE-IV inhibitor potency. The structural requirements for PDE-IV inhibitor potency differed among the three classes. A representative amide, carbamate, and urea (2c,d,h) were shown to be > 50-fold selective for inhibiting PDE-IV versus representative PDEs from families I-III and V. Furthermore, these same three inhibitors demonstrated potent functional activity (IC50 < 1 microM) by inhibiting tumor necrosis factor-alpha (TNF-alpha) release from lipopolysaccharide (LPS)-activated purified human peripheral blood monocytes and mouse peritoneal macrophages. These compounds were also tested orally in LPS-injected mice and demonstrated dose-dependent inhibition of serum TNF-alpha levels.
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PMID:Phosphodiesterase type IV inhibition. Structure-activity relationships of 1,3-disubstituted pyrrolidines. 773 9

Tumor necrosis factor-alpha (TNF) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock. Elevated circulating levels of TNF have also been reported in patients with severe chronic heart failure. We studied the effect of amrinone, a class III cyclic nucleotide phosphodiesterase inhibitor used in the treatment of acute heart failure, on the synthesis of TNF in vitro. Peripheral blood mononuclear cells from healthy volunteers or cells of a permanent monoblast cell line were stimulated for 20 h with bacterial lipopolysaccharide and different doses of amrinone. TNF production is suppressed in a dose-dependent manner to a minimum of 9% of controls with 1000 microM of amrinone, reaching half-maximal inhibition at 80 microM amrinone. This effect appears to be mediated via cAMP, which accumulated nearly twofold in the presence of amrinone. Suppression of TNF synthesis by therapeutically administered phosphodiesterase inhibitors such as amrinone may contribute to their beneficial effect in the treatment of heart failure.
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PMID:Amrinone suppresses the synthesis of tumor necrosis factor-alpha in human mononuclear cells. 774 41

Effects of amrinone (AMR), a phosphodiesterase inhibitor, alone and in combination with dobutamine (DOB), on hemodynamics and O2 delivery were studied during porcine endotoxemia. Pentobarbital-anesthetized pigs were randomly administered either Escherichia coli lipopolysaccharide (endotoxin) or equivolumetric .9% NaCl (control) as a continuous infusion for 4 h. From 2 to 4 h (T = 120-240 min) of endotoxin infusion, pigs were randomly administered one of the following treatments; AMR infusion (40 micrograms/kg/min) (AMRlow); DOB (10 micrograms/kg/min) (DOB); AMR infusion (40 micrograms/kg/min) + DOB (AMRlow+DOB); AMR bolus (.75 mg/kg) followed by AMR infusion (40 micrograms/kg/min) (AMRhigh); or AMR bolus (.75 mg/kg) followed by infusion (40 micrograms/kg/min) + DOB (AMRhigh+DOB). Myocardial samples were obtained at the end of the experiment and flash-frozen for beta-adrenergic receptor analysis. Endotoxin significantly (p < .05) decreased cardiac index, right ventricular ejection fraction, stroke volume index, maximum rate of rise of left ventricular pressure (dP/dtmax), mean arterial pressure, and O2 delivery, and increased pulmonary vascular resistance and mean pulmonary arterial pressure (p < .05). AMRlow+DOB significantly (p < .05) increased cardiac index, dP/dtmax, right ventricular ejection fraction, stroke volume index, O2 delivery and consumption, and decreased mean pulmonary arterial pressure, pulmonary vascular resistance, mean arterial pressure, and systemic vascular resistance. beta-Adrenergic receptor density (Bmax) and binding equilibrium dissociation constant (KD) for [3H]dihydroalprenolol were not affected by endotoxin or any treatment (p < .05). Endotoxin-induced hemodynamic deterioration and decreased O2 delivery was attenuated by AMRlow+DOB. Potential applications of this combination may exist in treatment of septic patients with inadequate myocardial performance and reduction in O2 delivery complicated by pulmonary hypertension.
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PMID:Amrinone combined with dobutamine improves hemodynamics and oxygen delivery without down-regulation of cardiac beta-adrenergic receptor density in porcine endotoxemia. 777 3

Elevated tumor necrosis factor (TNF) levels have been reported in various models of acute and chronic inflammation and used by many investigators to determine the stage of disease and effectiveness of treatment. Because of the documented involvement of TNF in the mechanism of septic shock, experiments were done to determine whether serum TNF levels paralleled the pathology in endotoxic shock and other models of inflammation. When mice received an intraperitoneal injection of lipopolysaccharide, serum TNF levels increased dramatically, peaking 90 minutes after injection. In a dose-response experiment with lipopolysaccharide alone, we found no correlation between serum levels of TNF and survival rate of mice. All three lipopolysaccharide concentrations resulted in comparable elevations of serum TNF, yet only in the high-dose group did the animals die. In a second model of endotoxic shock, TNF-alpha levels in serum were again compared with the survival rate of mice receiving lipopolysaccharide plus galactosamine. As in the first model, we found no relationship between the level of TNF in mouse serum and mouse survival rate. The two lowest concentrations of lipopolysaccharide/galactosamine induced identically low levels of serum TNF, yet in one group all of the animals survived and in the other all died. Discrepancies between serum TNF level and mortality rate were also seen in drug treatment experiments. GI 147404X, a standard phosphodiesterase type IV inhibitor, inhibited lipopolysaccharide/galactosamine-induced elevation of serum TNF by 90% at doses of 1 and 10 mg/kg. However, the high dose resulted in 66% protection while the low dose afforded no protection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evaluation of the significance of elevated levels of systemic and localized tumor necrosis factor in different animal models of inflammation. 779 95

We investigated cooperative effects of phosphodiesterase (PDE) inhibitors and prostanoids on cyclic adenosine monophosphate (cAMP) accumulation and tumor necrosis factor (TNF)-alpha synthesis in human peripheral blood mononuclear cells (PBMC). PDE inhibitors alone induced only a small increase in cAMP levels in lipopolysaccharide (LPS)-stimulated PBMC. Cicaprost (a stable analogue of prostacyclin) and pentoxifylline added simultaneously to LPS-stimulated PBMC (2.0 x 10(6)/ml) induced a rapid increase of cAMP to a level of 100 nM that peaked within 10 min and remained at a plateau for up to 4 h. Thus combined prostanoids and PDE inhibitors enhanced cAMP accumulation. TNF-alpha suppression in the presence of pentoxifylline and prostanoids exceeded that of either drug alone. The potency of different PDE inhibitors (theophylline, pentoxifylline, penthydroxifylline, albifylline, torbafylline, A 80 2715, amrinone and rolipram) to increase cAMP levels in combination with cicaprost was evaluated after 1 h of incubation. The dose-dependent increase of cAMP for all PDE inhibitors tested in this combined stimulation provided a useful tool for evaluating the potency of PDE inhibitors on cAMP accumulation. The effective concentration of PDE inhibitors, which raised cAMP levels to 300% of control, (EC300), correlated with the IC50 for TNF-alpha suppression (r = 0.930, p = 0.007, with theophylline excluded from the analysis). Interestingly, by contrast, the specific type IV PDE inhibitor rolipram caused only a moderate rise of accumulated cAMP in the same cells. Our data support cAMP as an essential mediator for TNF-alpha suppression by PDE inhibitors. Furthermore, an enhanced inhibiting effect on TNF-alpha production may prove therapeutically advantageous. It may occur in inflammatory and infectious diseases in vivo, since high levels of endogenous prostaglandins are liberated in these conditions.
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PMID:Enhanced tumor necrosis factor suppression and cyclic adenosine monophosphate accumulation by combination of phosphodiesterase inhibitors and prostanoids. 784 25

Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selective for different classes of phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production by human monocytes. The selective cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effective in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF alpha production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNF alpha mRNA expression, and at the protein level was also active when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNF alpha production in vivo in a rat endotoxemia model. Collectively, these data suggest that the prototypic inhibitor of PDE IV isozyme, rolipram, can effectively and selectively inhibit LPS-induced TNF alpha production through elevation of intracellular cAMP.
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PMID:Characterization of cAMP-dependent inhibition of LPS-induced TNF alpha production by rolipram, a specific phosphodiesterase IV (PDE IV) inhibitor. 784 52


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