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)

1. Rat livers were dissociated into their constituent cells by perfusion through the portal vein with a medium containing collagenase, and hepatocytes separated from non-parenchymal cells. 2. It is shown that the procedure described by Wisher & Evans [(1975) Biochem. J. 146, 375-388] for preparation of plasma membranes from liver tissue when applied to isolated hepatocytes also yielded subfractions of similar morphology and marker-enzyme distribution. 3. Thus the distribution of alkaline phosphodiesterase, 5'-nucleotidase and the basal and glucagon-stimulated adenylate cyclase among two 'light' vesicular and one 'heavy' junction-containing plasma-membrane subfractions paralleled that reported for tissue-derived plasma-membrane subfractions. 4. Increased recoveries and specific activities of plasma-membrane marker enzymes were obtained when soya-bean trypsin inhibitor was included in the collagenase-containing perfusion media used to dissociate the liver. 5. Polyacrylamide-gel-electrophoretic analysis of the corresponding plasma-membrane subfractions prepared from liver tissue and isolated hepatocytes were generally similar. 6. The results indicate that the functional polarity of the hepatocyte's plasma membrane is retained after tissue dissociation. The damage occurring to plasma-membrane ectoenzymes by the collagenase-perfusion procedure is discussed.
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PMID:Preparation of plasma-membrane subfractions from isolated rat hepatocytes. 88 Feb 46

Electroretinographic (ERG), morphometric and biochemical studies on retinas from monkeys or rats reveal that moderate level developmental lead (Pb) exposure produces long-term selective rod deficits and degeneration. The present studies determined whether similar alterations occur following low level developmental Pb exposure. Long-Evans rats, exposed to Pb only via dam's milk from parturition to weaning, had mean blood Pb of 18.8 micrograms/dl at weaning and 6.6 micrograms/dl at 90 days of age. Morphometric and ultrastructural studies revealed no signs of rod loss or degeneration although the presence of glycogen in some rod mitochondria suggests the occurrence of a metabolic dysfunction. Retinal sensitivity and rhodopsin content per eye were decreased in a manner such that, they followed the established log-linear relationship. A- and b-wave voltage- and latency-log intensity functions, generated from single-flash ERGs in fully dark-adapted rats, revealed that low level Pb exposure caused a 25% and 15% decrease in mean amplitude, a 0.5 and a 0.5 log unit decrease in absolute sensitivity, and a 23% and 16% increase in mean latency, respectively. Scotopic (rod-mediated) and photopic (cone-mediated) flicker fusion frequency measures revealed selective rod deficits. Adult rats had a 15% inhibition of retinal cGMP-phosphodiesterase resulting in a 19% and 12% increase in cGMP in dark- and light-adapted states, respectively. The above data confirm and extend our previous studies conducted in rats with blood lead levels of 59 micrograms/dl during development. The rhodopsin and cyclic nucleotide metabolism data, as well as our recent data showing an inhibition of retinal Na+, K(+)-ATPase, are entirely consistent with the observed ERG changes. The fact that rat rods are similar to monkey and human rods suggests the relevance and applicability of these data to low level pediatric Pb poisoning. Thus, these data suggest that alterations in rod sensitivity and temporal processing may occur in children exposed to low levels of lead during perinatal development.
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PMID:Low level developmental lead exposure decreases the sensitivity, amplitude and temporal resolution of rods. 166 51

The action of excitatory amino acids (EAA) on inositol phosphates (IPs) synthesis was examined in forebrain synaptoneurosomes of Long Evans rats (6-9 days old). Glutamate (GLU) (EC50: 23 microM) and quisqualate (QA) (EC50: 0.12 microM) enhanced IPs turnover. N-methyl-D-aspartate (NMDA) and kainate (KA) were less potent. The EAA-elicited IPs response was not blocked by tetrodotoxin (2 microM) or by the absence of Ca2+. This suggests that the activation of EAA receptors stimulates directly the phosphodiesterase responsible for phosphoinositide breakdown. The three main agonists (QA, KA and NMDA) tested in pairs, induced additive responses on IPs accumulation. In synaptoneurosomes prepared from adult rat, the relative responses to QA and GLU were dramatically reduced, whereas those to KA and NMDA remained unchanged. We concluded that GLU stimulates IPs formation mainly via a QA-like receptor subtype (AA2). This stimulation is transient and could play a key role during synaptogenesis. GLU also enhanced IPs accumulation via other receptor subtypes (probably of the NMDA- or AA1-like class).
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PMID:Characterization of subtypes of excitatory amino acid receptors involved in the stimulation of inositol phosphate synthesis in rat brain synaptoneurosomes. 282 47

Long Evans rats were trained to discriminate 0.2 mg/kg IP (+/-)-rolipram from vehicle injection in a food-motivated two-lever operant task. Eight out of nine rats acquired the discrimination after an average of 91 sessions (min 65, max 137). The ED50 of (+/-)-rolipram was 0.06 mg/kg IP. Generalization tests with (-)- and (+)-rolipram showed that the (-)-isomer was 8 times more active than (+)-rolipram with an ED50 of 0.06 and 0.4 mg/kg IP respectively. The phosphodiesterase inhibitor RO 20-1724 partially (83%) generalized to (+/-)-rolipram in doses of 0.6 and 1.0 mg/kg IP. IBMX 5 mg/kg IP showed 63% generalization. Tests with imipramine and the (+)- and (-)-isomer of the noradrenaline uptake inhibitor oxaprotiline suggest that NA-uptake inhibiting drugs do not form an interoceptive cue which is (+/-)-rolipram-like. dbcAMP 12.5 mg/kg SC and 100 mg/kg SC dbcGMP did not generalize to the training drug. The nature of the discriminative stimulus produced by this dose of (+/-)-rolipram in rats remains to be elucidated.
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PMID:Rolipram forms a potent discriminative stimulus in drug discrimination experiments in rats. 301 92

We studied the effect of cilostazol, a cyclic nucleotide phosphodiesterase (PDE) III inhibitor, on a substance P (SP)-induced increase in lung resistance and in airway microvascular leakage in guinea pigs in vivo. Four minutes after intravenous (i.v.) administration of cilostazol (1.5 and 5 mg/kg) or vehicle, Evans blue dye (20 mg/kg) was given i.v. One minute later, 30 nmol/kg SP was administered i.v. The SP-induced increase in lung resistance was measured for 6 min. Following the measurement of lung resistance, microvascular leakage at the trachea, main bronchi and intrapulmonary airways was also examined. Cilostazol attenuated the SP-induced increase in lung resistance, with a significant inhibition at the concentration of 5 mg/kg. Five milligrams per kilogram cilostazol also significantly inhibited SP-induced Evans blue dye extravasation at the trachea and main bronchi. These results suggest that cilostazol might reduce airflow obstruction which is seen in diseases such as asthma through attenuation of bronchoconstriction and, possibly, airway edema resulting from airway microvascular leakage in man.
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PMID:Effects of cilostazol, a cyclic nucleotide phosphodiesterase III inhibitor, on substance P-induced airflow obstruction and airway microvascular leakage in guinea pigs. 751 49

Narrowing of the airway lumen as a result of plasma exudation could augment airflow obstruction after allergen-induced bronchoconstriction. Because leukotrienes are putative mediators of bronchial asthma, the effects of a lipoxygenase inhibitor, VZ564 (N-hydroxy-N-(6-methoxy-3,4-dihydro-2- naphthylmethyl) urea. CAS 147495-99-6), on increased pulmonary permeability and bronchoconstriction during anaphylactic reaction were studied in guinea pigs and compared to the effects of the phosphodiesterase inhibitor theophylline. An anaphylactic reaction was induced by ovalbumin challenge (0.2 mg/kg i.v.) in passively sensitized and antihistamine (mepyramine)-pretreated guinea pigs; bronchoconstriction was measured as increased intratracheal pressure; lung vascular permeability was evaluated as extravasation of Evans blue dye up to 10 min after antigenic challenge. Ovalbumin challenge induced an increase in intratracheal pressure by 31 +/- 3 mmHg; the pulmonary permeability index was higher in ovalbumin-challenged versus saline (sham)-challenged guinea pigs (1.49 +/- 0.17 vs 0.56 +/- 0.04, p < 0.05). VZ564 and theophylline dose-dependently reduced increased pulmonary permeability and bronchoconstriction. VZ564 (10 and 46.4 mg/kg p.o., given 1 h before ovalbumin challenge) inhibited increased lung permeability by 42% and 95% and reduced bronchoconstriction by 61% at the higher dose. Theophylline (1 and 10 mg/kg i.v., given 10 min before ovalbumin challenge) diminished increased pulmonary permeability by 88% and reduced bronchoconstriction by 63% at the higher dose. In conclusion, the novel lipoxygenase inhibitor VZ564 inhibits after oral application important symptoms of asthma, namely bronchoconstriction and alveolar exudation of plasma in anaphylactic guinea pigs. The acute effects of VZ564 in this experimental model are comparable with the effects of the well known antiasthmatic substance theophylline.
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PMID:Effect of the lipoxygenase inhibitor N-hydroxy-N-(6-methoxy-3,4-dihydro-2-naphthylmethyl)urea on bronchoconstriction and lung vascular permeability in anaphylactic guinea pigs. 771 Apr 38

The authors studied structural and metabolic features of endothelium of greater vessels (aorta and vena cava posterior) of full-grown rabbits, making use of silver impregnation, transmission electronic microscopy and electronic-histochemical tests for non-compensated negative charges of glycocalyx, oxidoreductase, enzyms determining responsiveness of endotheliocytes in receptor-mediated influences (adenilcyclase and phosphodiesterase). Significant difference was established in respect of the average area of the endothelial stratum elements and total length of intercellular bounderies in the aorta zones with different permeability to Evans blue, as well as of the above measures for the studied arterial and venous portions of the vascular system; some of the regional features of glycocalix and endotheliocyte metabolism were disclosed.
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PMID:[The regional structural-metabolic characteristics of the vascular endothelium]. 881 41

We examined the effect of BBB022, a type IV phosphodiesterase inhibitor, on blood-brain barrier (BBB) integrity after transient middle cerebral artery occlusion (MCAo) in rats. Male Sprague-Dawley rats were anesthetized with halothane and subjected to 120 min of temporary MCAo by retrograde intraluminal insertion of a nylon suture coated with poly-L-lysine. The drug (BBB022 in saline, 1 mg kg-1 h-1, i.v.) or vehicle (0.9% saline, 1-2 ml kg-1 h-1) was administered by infusion after the onset of MCAo. Four animal groups were studied: Groups A and B were treated by infusion of vehicle or drug over 5 h, and groups C and D over 48 h. Damage to the BBB was judged by extravasation of Evans blue (EB) dye, which was administered i.v. at 3 h after the onset of MCAo in groups A and B; and at 46 h in groups C and D. Fluorometric quantitation of EB was performed 1 or 2 h later in six brain regions. In the 5-h infusion series (group B), BBB022 decreased dye extravasation in the ipsilateral cortex, striatum and hemisphere (hemisphere mean+/-S.E.M. : 41.2+/-5.4 vs. 82.4+/-9.2 microg/g, p=0.005) compared to the vehicle-treated group (A). The 48-h infusion of BBB022 (group D) also decreased dye extravasation in the ipsilateral cortex (7.4+/-2. 5 vs. 29.0+/-8.3 microg/g, p=0.05), striatum (17.2+/-2.2 vs. 50. 8+/-12.1 microg/g, p=0.03) and hemisphere (30.7+/-4.0 vs. 93.2+/-18 microg/g, p=0.01) compared to the vehicle-treated group (C). BBB022 also significantly improved the neurological score at 3 and 5 h after MCAo (in the 5-h infusion group) and at 60 min, 24 h and 48 h (in the 48-h infusion group) compared to the vehicle groups. These data indicate that BBB022 prevents ischemic damage to the BBB after focal cerebral ischemia in rats.
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PMID:Protection against blood-brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022: a quantitative study. 951 48

The aim of this study was to investigate the effects of selective phosphodiesterase inhibitors and their combination with salbutamol on antigen-induced microvascular leakage in the trachea. In actively sensitized anaesthetized guinea-pigs, the non-selective phosphodiesterase inhibitor theophylline (100 mg/kg p.o.) and the selective phosphodiesterase type 4 inhibitor Ro 20-1724 (30 mg/kg p.o.) inhibited antigen-induced microvascular leakage (-73.8% and -44.1%, respectively) as demonstrated by a reduced extravasation of plasma proteins measured by the use of Evans blue dye. No significant reduction in microvascular leakage was seen with (a) the selective phosphodiesterase type 4 inhibitor rolipram (10 mg/kg p.o.), (b) the selective phosphodiesterase type 3 inhibitors milrinone (30 mg/kg p.o.) and SK and F 94-836 (30 mg/kg p.o.) or (c) the selective phosphodiesterase type 1/5 inhibitor zaprinast (30 mg/kg p.o.). Neither Ro 20-1724 nor rolipram and theophylline inhibited microvascular leakage induced by either substance P or histamine. Pretreatment with aerosolized salbutamol (10 microg/ml) potentiated the inhibitory effects of theophylline (-49.8% at 30 mg/kg p.o.) and Ro 20-1724 (-52.6% at 10 mg/kg p.o.) versus antigen-induced microvascular leakage. Furthermore, a significant inhibitory effect of rolipram (10 mg/kg, p.o.) was obtained following pretreatment with this concentration of aerosolized salbutamol. Even at higher concentrations (0.3-2 mg/ml) salbutamol did not augment the corresponding inhibitory effects of rolipram and Ro 20-1724 versus microvascular leakage induced by either histamine or substance P. Theophylline had no effect versus substance P-induced microvascular leakage, but did inhibit it significantly (P < 0.05) after pretreatment with aerosolized salbutamol (0.3 mg/ml). The potentiation by salbutamol of the inhibitory effects of both non-selective and selective phosphodiesterase type 4 inhibitors versus antigen-induced microvascular leakage probably results from a synergistic reduction in the release of anaphylactic mediators.
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PMID:Effects of phosphodiesterase inhibitors and salbutamol on microvascular leakage in guinea-pig trachea. 957 Apr 49

ATP causes relaxation of the K(+)-contracted rat vas deferens. Possible sites of action were investigated. ATP and adenosine relaxed the vas deferens precontracted with 80 mM K(+); EC(50) values and maximal relaxations averaged, respectively, 760 microM and 56% for ATP and 74 microM and 30% for adenosine. The adenosine P1 receptor antagonist 8-(para-sulfophenyl)theophylline (8-SPT) reduced relaxations caused by adenosine and low concentrations of ATP, as did the Rp-diastereomer of adenosine 3',5'-cyclic phosphorothioate (Rp-cAMPS), an inhibitor of protein kinase A. The phosphodiesterase inhibitor 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724) augmented responses to adenosine and low concentrations of ATP. alpha,beta-Methylene ADP, an inhibitor of 5'-nucleotidase, reduced relaxations caused by ATP to a similar extent as did 8-SPT. In the presence of an almost saturating concentration of adenosine, ATP caused further relaxation. Conversely, in the presence of ATP, adenosine had little effect. Like ATP, UTP and other nucleoside triphosphates relaxed the vas deferens. The P2 receptor antagonists reactive blue 2, acid blue 25 and 4,4'-diisothiocyanotostilbene-2,2'-disulphonate (DIDS) attenuated the relaxation caused by ATP; suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulphonate (PPADS), Evans blue, trypan blue, reactive red 2 and brilliant blue G had no effect. Three non-selective inhibitors of protein kinases, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), staurosporine and (8R*,9S*,11S*)-(-)-9-hydroxy-9-carboxy-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one (K-252b), markedly reduced the relaxation caused by ATP. The results indicate that adenosine, derived from enzymatic dephosphorylation, contributes to the relaxant effect of ATP, presumably by activation of a smooth muscle adenosine receptor linked to the accumulation of cAMP and activation of protein kinase A. Yet, the main part of the response to ATP is mediated by a site distinct from the adenosine receptor. The pharmacological properties of this site differ from known P2 receptor subtypes. Possibly, the nucleotide-evoked relaxation is due to a phosphoryl transfer catalyzed by an ecto-protein kinase.
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PMID:Nucleotide-evoked relaxation of rat vas deferens: possible mechanisms. 1183 57


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