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)

Using different subtypes of cyclic nucleotide phosphodiesterase (PDE) isoenzymes isolated from canine left ventricle, we identified R 80122, a 1,2,3,5-tetrahydro2-oxoimidazo[2,1-b]quinazoline derivative that was a more selective and potent inhibitor of PDE type III than milrinone or enoximone. Such substances improve cardiac contraction and relaxation, elicit vasodilation, and increase cardiac output (CO). To determine the extent to which these compounds affect the contractile force of stunned myocardium, the effects of enoximone, milrinone, and R 80122 on cardiac function were compared in anesthetized dogs subjected to 15-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion, and treated beginning 30 min after reperfusion, with the compound being studied. During occlusion, all dogs exhibited passive systolic ventricular wall bulging in the ischemic area. Thirty minutes after reperfusion, systolic wall thickening was significantly decreased in the reperfused LAD segments and remained low (at 36% of baseline) in control animals. After enoximone administration, global left ventricular (LV) function was improved with i.v. doses greater than or equal to 0.64 mg/kg. Systolic wall thickening in the ischemic myocardium was restored less than or equal to 70% of baseline at 1.25 mg/kg i.v., but this dose also induced a marked decrease in arterial pressure and an increase in heart rate (HR). Milrinone and R 80122 significantly increased global LV function and systolic wall thickening in ischemic areas at doses greater than or equal to 0.16 mg/kg i.v. At the highest doses, HR increased slightly with both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative effects of R 80122, enoximone, and milrinone on left ventricular phosphodiesterase isoenzymes in vitro and on contractility of normal and stunned myocardium in vivo in dogs. 138 69

1. The present study compared the cyclic nucleotide phosphodiesterase (PDE) activities in cardiomyocytes and ventricular cardiac tissue from guinea-pigs. The aim of the study was to determine whether PDE activities in ventricular tissue accurately reflect the isoenzymes present in cardiomyocytes. 2. In homogenates of cardiomyocytes and multicellular ventricular tissue, four distinct soluble PDE activities could be separated by DEAE-sepharose chromatography. 3. In multicellular cardiac tissue as well as in cardiomyocyte preparations, adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE isoenzymes I-IV were comparable in terms of substrate affinities, and inhibition or stimulation by guanosine 3':5'-cyclic monophosphate (cyclic GMP). However, in cardiomyocytes the Vmax values of PDE I-IV were lower by a factor of about 2 to 7 and the basal activities were lower by a factor of about 3 to 5 as compared to multicellular cardiac tissue. 4. To investigate whether the PDE I-IV activities were similarly inhibited by PDE inhibitors in both preparations, we studied the effects of 3-isobutyl-1-methylxanthine (IBMX), UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4, 5-dihydro-2H-6-pyridazinyl)benzimidazole HCl) and rolipram. UD-CG 212 Cl was a selective PDE III inhibitor in cardiomyocytes (IC50 0.3 mumol l-1) and in ventricular tissue (IC50 value 0.1 mumol l-1). Rolipram selectively inhibited PDE IV in cardiomyocytes (IC50 1.4 mumol ml-1) and in ventricular tissue (IC50 1.1 mumol l-1) whereas IBMX was a nonselective PDE inhibitor in both preparations.5. It is concluded that the PDE isoenzymes I-IV from multicellular ventricular tissue can be used as a representative system for investigating PDE inhibiting properties of PDE inhibitors in the myocardium since comparable PDE isoenzymes I-IV exist in guinea-pig ventricular cardiomyocytes and multicellular ventricular tissue.
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PMID:Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea-pig hearts. 138 5

1 The aims of the present study were to characterize the cyclic nucleotide phosphodiesterase (PDE) isoenzyme activities present in human bronchi and to examine the ability of selective isoenzyme inhibitors to relax histamine and methacholine precontracted preparations of human bronchi. 2 Three separations of pooled human bronchial tissue samples were performed. Ion-exchange chromatography showed that the soluble fraction of human bronchial preparations contains PDE I, II, III, IV and V isoenzyme activities. Multiple forms of PDE I and PDE IV were observed and PDE IV was the main cyclic AMP hydrolytic activity. 3 3-Isobutyl-l-methylxanthine (IBMX) non-selectively inhibited all separated isoenzyme activities. Zaprinast selectively inhibited PDE V, but also effectively inhibited one of the two PDE I isoforms identified. The PDE IV selective inhibitors rolipram and RO-201724, inhibited the PDE IV activities as did the dual PDE III/IV inhibitor, Org 30029. Org 9935, a PDE III selective inhibitor, potently attenuated part of the PDE IV activity peak in one of three separations performed, indicating that some PDE III activity may co-elute with PDE IV under the experimental conditions employed. 4 PDE IV-selective (rolipram), PDE III-selective (Org 9935) and dual PDE III/IV (Org 30029) inhibitors were effective relaxants of human bronchial smooth muscle. The PDE V/PDE I inhibitor, zaprinast was relatively ineffective. 5 The present study demonstrates in human bronchi, as in animal airways smooth muscle, that inhibitors of PDE III, PDEIV and dual PDE III/IV have potentially useful bronchodilator activity and are worthy of further consideration as anti-asthma drugs.
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PMID:Human bronchial cyclic nucleotide phosphodiesterase isoenzymes: biochemical and pharmacological analysis using selective inhibitors. 139 76

The smooth muscle relaxant, AH 21-132, was tested for its inhibitory effect on the cyclic nucleotide phosphodiesterase (PDE) activities fractionated from guinea-pig cardiac ventricle and bovine trachealis muscle. Both tissues yielded significant PDE-I and PDE-II activities. The cardiac ventricle also contained a significant amount of PDE-III whilst the trachealis contained PDE-IV. AH 21-132 inhibited PDE-III and PDE-IV selectively (Ki values 0.30-0.55 microM) compared with PDE-I and PDE-II (Ki values 20-140 microM).
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PMID:The isoenzyme selectivity of AH 21-132 as an inhibitor of cyclic nucleotide phosphodiesterase activity. 164 99

Analysis of cyclic nucleotide phosphodiesterase (PDE) activity in cellular fractions from cultured rat pheochromocytoma (PC12) cells has shown that the predominant hydrolytic activity in both cytosolic and particulate compartments is characteristic of a PDE II, the cGMP-activatable family of PDE isozymes. Cytosolic PDE activity was purified to a high degree utilizing DE-52 anion exchange and cGMP-Sepharose affinity chromatographies. The physicochemical properties of PC12 PDE II were similar to those of PDE II isolated from particulate or soluble fractions of other tissues, including subunit molecular weight of approximately 102,000, activation of cAMP hydrolysis by cGMP, and positive cooperative kinetic behavior for cAMP and cGMP hydrolysis. The potential role of PDE II in regulating cAMP metabolism in intact PC12 cells was studied using an [3H]adenine prelabeling technique. Stimulation of PC12 cell adenosine receptors resulted in a 5-8-fold increase in cAMP accumulation. Removal of the adenosine stimulus by the addition of exogenous adenosine deaminase resulted in a rapid decay of cAMP to prestimulated basal levels within 2 min. Treatment of PC12 cells with atrial natriuretic factor or sodium nitroprusside caused 1) increased intracellular cGMP levels, 2) attenuation of adenosine-stimulated cAMP accumulation, and 3) increased rates of cAMP decay after removal of the adenosine stimulus. Treatment of PC12 cells with HL-725 (a potent inhibitor of isolated PDE II activity in vitro) caused 1) increased basal cAMP accumulation, 2) potentiation of adenosine-stimulated cAMP accumulation, and 3) retardation of the rate of cAMP decay after removal of the adenosine stimulus. HL-725 blocked both the attenuation of cAMP accumulation and the accelerated rate of cAMP decay observed with the cGMP-elevating agents. These results suggest that, in PC12 cells, drugs or hormones that inhibit PDE II or increase intracellular cGMP levels to activate PDE II can modulate cAMP metabolism by altering the catalytic status of the enzyme.
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PMID:Phosphodiesterase II, the cGMP-activatable cyclic nucleotide phosphodiesterase, regulates cyclic AMP metabolism in PC12 cells. 164 46

The morphological change of several neuroblastoma cell lines induced by griseolic acid, a novel and potent inhibitor of cyclic nucleotide phosphodiesterase (PDE), was examined. In the cell lines tested, Neuro-2a (a murine neuroblastoma cell line) showed dose-dependent (1 microM-1 mM) neurite extension. Griseolic acid markedly increased the intracellular cyclic AMP level of Neuro-2a cells, suppressed DNA synthesis (82% at 1 mM), and induced multipolar (multiple-neurite-bearing)-type neuritogenesis. A similar type of neurite outgrowth was induced by 8-bromo-cyclic AMP, which also elevated the intracellular cyclic AMP concentration. In contrast, when Neuro-2a cells were treated with retinoic acid, neurite formation was of the monopolar (single-neurite-bearing) type. Papaverine and theophylline, which have been frequently used as PDE inhibitors, failed to induce these morphological changes up to 1 mM, probably owing to the lesser potency of these compounds as compared with griseolic acid on the inhibition of PDE. Retinoic acid, theophylline, and papaverine were ineffective at elevating the intracellular cyclic AMP level. These results suggest that multipolar-type cell shape change in Neuro-2a cells is correlated with the accumulation of intracellular cyclic AMP and that griseolic acid is a useful compound to induce neuroblastoma cells into terminal differentiation.
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PMID:Multiple neurite formation in neuroblastoma cell lines by griseolic acid, a potent inhibitor of cyclic nucleotide phosphodiesterases. 164 54

Experiments have been performed to characterize guinea-pig peritoneal eosinophil cyclic nucleotide phosphodiesterase (PDE) activity and establish whether it is involved in regulating superoxide (.O2-) generation. Eosinophils were found to contain a predominantly membrane-bound cAMP PDE(s) (92.5 +/- 2.4% of total activity) which was resistant to solubilization with Triton X-100 (1%). This particulate PDE exhibited complex kinetics (Km = 1.3 and 31.4 microM) and was unaffected by cGMP (IC50 greater than 100 microM) or CaCl2 (2 mM) + calmodulin (10 units/mL). Little cGMP PDE activity was detected in either the soluble or particulate fractions. Inhibitors of the Ro-20-1724-inhibited (Type IV) cAMP PDE, namely Ro-20-1724 (IC50 = 0.92 +/- 0.43 microM), rolipram (IC50 = 0.20 +/- 0.04 microM) and denbufylline (IC50 = 0.20 +/- 0.01 microM), potently inhibited the particulate cAMP PDE, as did the non-selective inhibitors trequinsin (IC50 = 0.11 +/- 0.02 microM) and AH-21-132 (IC50 = 2.57 +/- 0.02 microM). Eosinophil cAMP PDE was resistant to SK&F 94120 (IC50 greater than 1000 microM), the cGMP-inhibited (Type III) cAMP PDE inhibitor, and the cGMP PDE (Type I) inhibitor, zaprinast, was only weakly active (IC50 = 35.33 +/- 10.74 microM). .O2- release from resting cells was potently inhibited by rolipram (IC50 = 0.05 +/- 0.03 microM) and denbufylline (IC50 = 0.06 +/- 0.04 microM) but surprisingly, in view of its potent cAMP PDE inhibitory activity, was only weakly decreased by trequinsin (IC50 = 8.0 +/- 2.7 microM). AH-21-132 (IC50 greater than 10 microM), SK&F 94120 (IC50 greater than 10 microM) and zaprinast (IC50 greater than 10 microM) were without effect. Rolipram and denbufylline alone exerted little effect on cAMP in intact cells but, in the presence of 10 microM isoprenaline, potently increased intracellular accumulation (EC50 = 0.45 +/- 0.16 and 0.28 +/- 0.08 microM, respectively). Trequinsin and AH-21-132 only weakly enhanced isoprenaline-stimulated cAMP accumulation. Although it induced a marked rise in cAMP only in the presence of isoprenaline, rolipram (50 microM) alone was able to increase the activity ratio of cAMP-dependent protein kinase from 0.24 to 0.84. The results suggest that Ro-20-1724-inhibited cAMP PDE plays a role in regulating eosinophil .O2- generation. The poor correlation between the PDE inhibitory actions of certain compounds and their effectiveness in elevating cAMP and inhibiting .O2- suggests the existence of a barrier impeding access to the enzyme.
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PMID:Characterization of guinea-pig eosinophil phosphodiesterase activity. Assessment of its involvement in regulating superoxide generation. 165 Oct 83

1. The cyclic nucleotide phosphodiesterase (PDE) of guinea-pig eosinophils was partially characterized and the effects of selective inhibitors of PDE isoenzymes upon opsonized zymosan (OZ)-stimulated respiratory burst were studied. 2. PDE activity in eosinophil lysates appeared to be membrane-associated, displayed substrate specificity for adenosine 3':5' cyclic monophosphate (cyclic AMP) versus guanosine 3':5' cyclic monophosphate (cyclic GMP) and was insensitive to cyclic GMP or Ca2+ and calmodulin. 3. The non-selective PDE inhibitor, 3-isobutyl-1-methylxanthine caused a concentration-dependent inhibition of both OZ-stimulated hydrogen peroxide (H2O2) generation and cyclic AMP hydrolysis. The type IV-selective PDE inhibitors, rolipram and denbufylline, also inhibited H2O2 generation and cyclic AMP hydrolysis in a concentration-dependent manner whilst SK&F 94120 and Org 9935 (type III-selective) and zaprinast (type Ia or V-selective) were ineffective. 4. Dibutyryl cyclic AMP, a cell-permeable, non-hydrolysable analogue of cyclic AMP, caused a concentration-dependent inhibition of H2O2 generation stimulated by OZ. Dibutyryl cyclic GMP was ineffective. 5. It is concluded that eosinophil respiratory burst activity induced by OZ can be regulated by intracellular cyclic AMP and that the levels of cyclic AMP are controlled exclusively by a rolipram- and denbufylline-sensitive PDE isoenzyme that resembles a type IV species.
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PMID:Inhibition of eosinophil cyclic nucleotide PDE activity and opsonised zymosan-stimulated respiratory burst by 'type IV'-selective PDE inhibitors. 165 70

Four cyclic nucleotide phosphodiesterase activities (PDEs) could be resolved from rat mesenteric artery by DEAE-Sephacel chromatography: a calmodulin-activated fraction, a cyclic GMP-inhibited fraction, a cyclic AMP-specific rolipram-sensitive fraction and a cyclic GMP-specific fraction containing PDE I, III, IV and V. Cardiotonic drugs (CI 930 and LY 195115) selectively inhibited PDE III; rolipram and zaprinast selectively inhibited PDE IV and PDE V, respectively. These results show that the rat mesenteric artery contains the same PDEs as previously found in the aorta, and suggest that these PDEs may be implicated in the regulation of arterial contraction.
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PMID:Characterisation of cyclic nucleotide phosphodiesterases from rat mesenteric artery. 165 22

The calmodulin-dependent cyclic nucleotide phosphodiesterase represents an important junction between the Ca2+ and the cyclic AMP/cyclic GMP second messenger systems. In brain it is a major cyclic nucleotide-degrading activity and is selectively expressed in the soma and dendrites of regional output neurons [Kincaid et al. (1987) Proc. natn. Acad. Sci. U.S.A. 84, 1118-1122]. In this study the subcellular localization of this enzyme in cerebral cortex, hippocampus and inferior colliculus of rat brain was analysed by electron microscopic immunocytochemical methods using affinity-purified antibodies. The immunoreactivity was found exclusively within neurons whereas glial cells were unstained; preabsorption of antibody with phosphodiesterase eliminated this reactivity, demonstrating the specificity of immunostaining. In the neuronal cell bodies, deposits of immunoreaction product occurred as sparse patches in the cytoplasm and were often associated with organelles such as mitochondria, Golgi-complex and endoplasmic reticulum; nuclei, however, were free from immunoreaction product. In the neuronal processes immunoreactivity was found within dendrites and dendritic spines, whereas the myelinated axons and axon terminals were immunonegative. The postsynaptic densities of asymmetric synapses were associated with especially high concentrations of immunoreaction product. However, the immunopositive synaptic profiles appeared to be quite selective, comprising only a small percentage of the total number of synapses in the neuropil. Our results indicate that the calmodulin-dependent cyclic nucleotide phosphodiesterase is concentrated at postsynaptic sites in specific classes of neurons. This finding supports other morphological evidence indicating a primary role for cyclic nucleotide action in postsynaptic and not presynaptic structures. Furthermore, since this enzyme is regulated by Ca2+, this interface between second messenger systems seems to play a significant role in the postsynaptic integration of Ca(2+)-mediated neuronal inputs.
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PMID:Electron microscopic immunocytochemical evidence that the calmodulin-dependent cyclic nucleotide phosphodiesterase is localized predominantly at postsynaptic sites in the rat brain. 165 82


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