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)

Exposure of cultured bovine pulmonary endothelial cells to endotoxin (lipopolysaccharide, LPS) causes cytotoxicity and increased prostacyclin production. Since cyclic nucleotides have been proposed as modulators of inflammation, we wondered whether they were involved in LPS-induced endothelial damage. Bovine pulmonary endothelial cells were exposed for 24 h to LPS and the effects of 1-methyl-3-isobutylxanthine (MIX), a phosphodiesterase inhibitor, dibutyryl cyclic AMP (db-cAMP), forskolin (an adenylate cyclase activator), and sodium nitroprusside (an agent known to stimulate intracellular cyclic GMP generation) on LPS-induced injury were determined. Injury was assessed by measurement of lactate dehydrogenase (LDH) (activity) and prostacyclin (6-keto-PGF1 alpha) in the bathing medium. Incubation with MIX attenuated LPS-induced endothelial cytotoxicity and prostacyclin production in a dose-dependent manner (ANOVA, p less than 0.001). Dibutyryl cyclic AMP also inhibited LPS-stimulated LDH release from the endothelial cells but did not suppress increased prostacyclin production. The combinations of MIX and dibutyryl cyclic AMP produced protection similar to that of MIX alone. Neither nitroprusside nor forskolin affected LPS-induced endothelial injury. Measurements of intracellular cyclic nucleotide concentrations showed that MIX caused marked increases in both cyclic AMP and cyclic GMP within 30 min of incubation, while forskolin and nitroprusside failed to cause such early elevations. Thus, phosphodiesterase inhibition protects endothelial cells from the effects of LPS. Increased intracellular concentrations of cyclic AMP also protect endothelial cells from LPS-induced cytotoxicity but do not alter the prostanoid response. We conclude that increased intracellular concentrations of cyclic AMP protect against LPS-induced endothelial cytotoxicity if present early in the exposure. We further conclude that LPS-mediated endothelial cytotoxicity can be separated from increased prostacyclin production.
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PMID:Attenuation of endotoxin-induced cytotoxicity and prostacyclin production in cultured bovine pulmonary artery endothelial cells by phosphodiesterase inhibition. 246 43

In rat forebrain tissue of single rats beta-adrenoceptor density (Bmax) and affinity (Kd) were determined by saturation isotherms in receptor binding studies with the antagonist ligand (3H)-dihydroalprenolol at 8 different times of day in May. Rats were on a controlled 12L:12D photoperiod. In addition, the cAMP content, the formation of cAMP from ATP by the adenylate cyclase and the hydrolysis of the second messenger by the phosphodiesterase were determined at the same time points. No significant (ANOVA) daily variations were found in the total number of 3H-DHA binding sites (Bmax) nor in the affinity (Kd). In contrast, basal cAMP content as well as basal formation and hydrolysis of cAMP displayed significant rhythms. The peak value in cAMP was at the beginning of light. At that time the daily trough value in cAMP formation was found. Hydrolysis of cAMP by the phosphodiesterase displayed a 12-hr rhythm with trough values occurring at the early light and early dark period. The results demonstrate pronounced rhythmic changes in basal formation, content and hydrolysis of cAMP which are, however, not paralleled by changes in receptor number and/or affinity in the same tissue.
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PMID:On the daily variation in the beta-receptor-adenylate cyclase-cAMP-phosphodiesterase system in rat forebrain. 283 35

The effect of three types of phosphodiesterase (PDE) inhibitors on in vivo antilipolysis was investigated in healthy subjects using a 2-h euglycemic, hyperinsulinemic (40 mU.m-2.min) clamp together with microdialysis of abdominal subcutaneous adipose tissue. During hyperinsulinemia (approximately 330 pmol/l), the circulating glycerol concentration was reduced to approximately 50% of the basal level of 53.2 +/- 3.6 mumol/l, indicating an antilipolytic effect. The decrease in adipose tissue dialysate glycerol, which mirrors the change in interstitial glycerol concentration, was about 40% during hyperinsulinemia when Ringer's solution alone was perfused. Local perfusion with a selective PDE IV inhibitor, rolipram (10(-4) mol/l), did not influence the insulin-induced decrease in dialysate glycerol (F = 0.8 vs. perfusion with Ringer's solution by two-factor analysis of variance [ANOVA]), although rolipram increased the dialysate glycerol level by 144 +/- 7% of the baseline value. However, local perfusion with a selective PDE III inhibitor, amrinone (10(-3) mol/l), or a nonselective PDE inhibitor, theophylline (10(-2) mol/l), abolished the ability of insulin to lower dialysate glycerol (F = 16.5, P < 0.01 and F = 8.5, P < 0.01, respectively, as compared with perfusion with Ringer's solution). The findings could not be explained by changes in the local blood flow (as measured by a microdialysis--ethanol escape technique), which was not affected by hyperinsulinemia in the presence or the absence of PDE inhibitors in the dialysis solvent. We conclude that PDEs play an important role in mediating the antilipolytic effect of insulin in vivo and that PDE III is the dominant isoenzyme modulating this effect.
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PMID:Role of phosphodiesterase III in the antilipolytic effect of insulin in vivo. 755 53

This study was designed to determine the effects of a membrane permeant phosphodiesterase-resistant analog of cGMP on lung liquid production and pulmonary blood flow at the time of birth. Experiments were performed on seven fetal sheep prepared for chronic measurements of lung liquid production (Jv), pulmonary blood flow (Qp) and pressure, as well as systemic pressure. Injection of either 8-bromo-cGMP or saline were made via a catheter inserted in the left pulmonary artery. Experiments consisted of 1 h of control, 1 h of infusion, and 2 h of recovery. Data were analyzed by ANOVA and Newman-Keuls test. After infusion of 8-bromo-cGMP, Jv was decreased by 70 and 44% from control in h 3 and 4, respectively. Qp was elevated by 100 mL/min in h 2 and 3 and continued to be elevated by 50 mL/min in h 4. Saline infused animals showed no significant changes in Qp and Jv. This study demonstrates that 8-bromo-cGMP decreases lung liquid production and increases pulmonary blood flow in near term fetal sheep. Although blood flow increased in h 2, lung liquid production did not decrease at this time, suggesting a time dissociation between changes in pulmonary blood flow and lung liquid production. Thus, it is possible that a common transduction pathway involving cGMP may be responsible for lung liquid reduction and elevation of pulmonary blood flow at birth. However, Qp and Jv may not be causally related.
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PMID:The effects of cGMP on fetal sheep pulmonary blood flow and lung liquid production. 950 69

The present investigation aimed to clarify the role of phosphodiesterase (PDE) type 3 for in vivo lipolysis in human adipose tissue during simultaneous insulin and catecholamine stimulation. Therefore, ten healthy subjects were investigated during insulin-induced hypoglycemia. Microdialysis probes were implanted in the subcutaneous adipose tissue and perfused by solvents with or without addition of the specific PDE 3 antagonist amrinone. Furthermore, changes in the local blood flow surrounding the dialysis probes were assessed by the ethanol escape technique. During the 60 min period before the start of the insulin infusion, adipose tissue glycerol levels (lipolysis index) increased significantly when amrinone was added to the perfusate (p = 0.0006, one-factor ANOVA). The antilipolytic response to the early phase of insulin infusion decreased (delta glycerol 9.0+/-3.5 vs. 29.9+/-6.0 micromol/l, p = 0.04) and the lipolytic response after hypoglycemia increased (AUC 122.4+/-18.0 vs. 13.4+/-16.3 micromol x l(-1) x h, p = 0.0001) comparing the experiments with or without amrinone, respectively. When amrinone was excluded from the perfusate, there was an increase in the nutritive blood flow during hypoglycemia, whereas there were no significant changes in the local blood flow surrounding the probe when amrinone was added to the perfusate. In conclusion, during insulin-induced hypoglycemia, PDE 3 activation clearly counteracts the lipolytic effect of catecholamines. When PDE 3 is specifically blocked, lipolysis increases greatly. Thus, PDE 3 is important for the in vivo regulation of the antilipolytic and lipolytic responses to hormones in human adipose tissue.
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PMID:Importance of phosphodiesterase 3 for the lipolytic response in adipose tissue during insulin-induced hypoglycemia in normal man. 991 86

Phosphodiesterase (PDE) 4, mixed PDE3/4, and non-selective PDE inhibitors have been shown to inhibit the proliferation of human peripheral blood mononuclear cells (HPBM). The aim of the present study was to examine whether endogenous prostaglandins, in particular prostaglandin E2 (PGE2), are involved in mediating the antiproliferative actions of PDE inhibitors, by comparing their effects with drugs which elevate or mimic adenosine 3',5'-cyclic monophosphate (cAMP) through mechanisms other than PDE inhibition. Indomethacin significantly reduced the antiproliferative effects of the PDE4 inhibitors rolipram and CDP840 and the mixed PDE3/4 inhibitor zardaverine, increasing the IC50 values from 2.51 microM to >10 microM, 0.81 microM to 2.82 microM, and 1.58 microM to 4.82 microM, respectively (P < 0.05), but did not alter the effects of theophylline. Forskolin, PGE2, and dibutyryl cAMP also inhibited HPBM proliferation, and in the presence of indomethacin the effects of forskolin and dibutyryl cAMP were reduced (although this was not significant), whereas PGE2 was not affected. Rolipram, CDP840, zardaverine, and dibutyryl cAMP all produced a concentration-related increase in PGE2 production (P < 0.05, ANOVA), but theophylline significantly increased PGE2 production only at the highest concentration examined, 1000 microM. The ability of indomethacin to reduce the antiproliferative effects of rolipram, CDP840, and zardaverine, together with the fact that these drugs can stimulate PGE2 production, suggests that their antiproliferative actions may be mediated in part by stimulation of endogenous PGE2 production. In contrast, it appears that endogenous PGE2 is not critical for the antiproliferative actions of theophylline, forskolin, and dibutyryl cAMP in HPBM. These results establish the importance of co-ordinated regulation of the cAMP phosphodiesterase and cyclooxygenase-PGE2 systems for the regulation of lymphocyte function in man, and have clinical implications for therapeutic approaches to diseases associated with lymphocyte dysregulation.
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PMID:Possible Contribution of Prostaglandin E2 to the antiproliferative effect of phosphodiesterase 4 inhibitors in human mononuclear cells. 1051 92

Nitric oxide (NO) donors are believed to exert their vasodilatory action through the activation of soluble guanylate cyclase (sGC), the heme site of which can be specifically inhibited by 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). We examined the vascular relaxation of the rat aorta mediated by eight different NO donors in the presence of ODQ (0.1, 1, or 10 microM), and demonstrated that these NO donors displayed different sensitivities toward ODQ inhibition (ANOVA, P <.05). Among the NO donors studied, S-nitrosothiols such as S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione exhibited partial resistance toward ODQ inhibition at 0.1 microM ODQ, whereas nitroglycerin (NTG) showed nearly complete inhibition at this concentration of ODQ. Three NO donors representing increasing sensitivity toward ODQ inhibition, SNAP < sodium nitroprusside (SNP) < NTG, were chosen for additional mechanistic studies. ODQ (1 microM) inhibition of vascular relaxation by SNAP and SNP, but not that by NTG, was partially reversed by a sulfhydryl donor, N-acetylpenicillamine (100 microM), and by a phosphodiesterase inhibitor, zaprinast (10 microM), specific for cGMP. Our results strongly indicate that the vascular relaxation mechanism(s) of NO donors is not identical for each. In the rat aorta, NTG appeared to exhibit its vasodilatory effect exclusively through activation of the heme site of sGC. On the other hand, in the intact vascular tissue, SNAP and SNP could bring about vasodilation through a secondary pathway. These results are consistent with the view that SNAP and SNP, but not NTG, can induce vascular relaxation additionally through the activation of the sulfhydryl site of sGC.
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PMID:Differential sensitivity among nitric oxide donors toward ODQ-mediated inhibition of vascular relaxation. 1064 Mar 13

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.
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PMID:Effect of sildenafil on coronary active and reactive hyperemia. 1104 68

Adenosine is an endogenous antiaggregating substance that influences the platelet responses through specific A-type receptors that activate adenylate cyclase increasing the levels of 3',5'-cyclic adenosine monophosphate (cAMP). In this study, we investigated whether adenosine can also influence the levels of 3',5'-cyclic guanosine monophosphate (cGMP) and decrease the aggregating response of human platelets to adenosine-5-diphosphate (ADP) through this nucleotide. In platelet samples from healthy volunteers, we evaluated the effect of adenosine on ADP-induced aggregation and cyclic nucleotide synthesis. Some experiments were repeated in the presence of dipyridamole (inhibitor of adenosine uptake and phosphodiesterase activity), N(G)-monomethyl-L-arginine (L-NMMA, nitric synthase inhibitor), ionomycin (calcium ionophore), and ambroxol (2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine, inhibitor of nitric oxide (NO)-dependent activation of guanylate cyclase). Adenosine decreased the response to ADP in a concentration-dependent way (analysis of variance, ANOVA: P<.0001): cAMP levels increased from 30.0 +/- 2.0 (control) to 46.0 +/- 3.0 pmol/10(9) platelets (in the presence of 15 mumol/l adenosine) and cGMP levels increased from 5.6 +/- 1.0 (control) to 10.9 +/- 2.0 pmol/10(9) platelets (in the presence of 15 mumol/l adenosine). Also, nucleotide levels measured at the end of aggregation were higher in platelet samples exposed to adenosine than in controls. Dipyridamole at 40 mumol/l slightly increased adenosine's effects on both nucleotides. L-NMMA blunted the effect of adenosine on cGMP both in unstimulated samples and in aggregated platelets without any effect on cAMP synthesis. Platelet exposure to L-NMMA and ambroxol partially prevented adenosine's effect on ADP-induced aggregation. In conclusion, adenosine, which enhances intraplatelet cAMP levels, was determined to also cause an increase in cGMP concentrations through a mechanism that involves NO synthesis. This effect plays a direct role in the adenosine-induced antiaggregation.
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PMID:Adenosine increases human platelet levels of cGMP through nitric oxide: possible role in its antiaggregating effect. 1186 10

Sildenafil inhibits cGMP breakdown by phosphodiesterase 5. In vitro, increased cGMP levels inhibit cAMP breakdown by phosphodiesterase 3. It is uncertain, however, whether sildenafil increases biological effects of interventions increasing cAMP levels in vivo. The objective of the present study in 40 healthy male volunteers was to determine the existence and extent of interactions with sildenafil and vasodilators acting via cGMP or cAMP or independently from these mediators on the arterial tone of the human forearm. Forearm blood flow (FBF) responses (plethysmography) to brachial artery infusions of 3 doses each of nitroglycerin, which increases cGMP levels; of isoprenaline and milrinone, which increase cAMP levels; and of verapamil as a control were assessed at baseline and 80 minutes after 50 mg oral sildenafil in 10 volunteers each. Sildenafil increased FBF (2.5+/-0.1 to 3.5+/-0.2 mL/min per 100 mL, P<0.001; n=40). At equipotent vasodilator dosages, sildenafil increased FBF from 7.5+/-1.0 to 9.8+/-1.2 mL/min per 100 mL for nitroglycerin, from 8.3+/-1.0 to 10.4+/-1.4 mL/min per 100 mL for isoprenaline, and from 8.1+/-1.0 to 10.3+/-1.2 mL/min per 100 mL for milrinone and slightly decreased FBF from 7.7+/-1.3 to 7.1+/-1.2 mL/min per 100 mL for verapamil. ANOVA for repeated measures revealed a significant interaction between sildenafil and the type of vasodilator on FBF (P<0.01). The responses of FBF to nitroglycerin, milrinone, and isoprenaline after sildenafil were similarly increased compared with the response to verapamil (P<0.01). Sildenafil markedly enhanced the arterial vasodilator response to nitroglycerin, milrinone, and isoprenaline. The response to milrinone and isoprenaline is compatible with an interaction between cGMP and phosphodiesterase 3 or an enhancement of the NO component of cAMP-mediated vasodilation, and raises the possibility of enhanced biological effects of interventions leading to increases of cAMP in the presence of sildenafil.
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PMID:Interaction of sildenafil with cAMP-mediated vasodilation in vivo. 1262 68


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