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)

In the frog retinal pigment epithelium (RPE), the cellular levels of cyclic AMP (cAMP) were measured in control conditions and after treatment with substances that are known to inhibit phosphodiesterase (PDE) activity (isobutyl-1-methylxanthine, SQ65442) or stimulate adenylate cyclase activity (forskolin). The cAMP levels were elevated by a factor of 5-7 compared with the controls in PDE-treated tissues and by a factor of 18 in forskolin-treated tissues. The exogenous application of cAMP (1 mM), PDE inhibitors (0.5 mM), or forskolin (0.1 mM) all produced similar changes in epithelial electrical parameters, such as transepithelial potential (TEP) and resistance (Rt), as well as changes in active ion transport. Adding 1 mM cAMP to the solution bathing the apical membrane transiently increased the short-circuit current (SCC) and the TEP (apical side positive) and decreased Rt. Microelectrode experiments showed that the elevation in TEP is due mainly to a depolarization of the basal membrane followed by, and perhaps also accompanied by, a smaller hyperpolarization of the apical membrane. The ratio of the apical to the basolateral membrane resistance increased in the presence of cAMP, and this increase, coupled with the decrease in Rt and the basolateral membrane depolarization, is consistent with a conductance increase at the basolateral membrane. Radioactive tracer experiments showed that cAMP increased the active secretion of Na (choroid to retina) and the active absorption of K (retina to choroid). Cyclic AMP also abolished the active absorption of Cl across the RPE. In sum, elevated cellular levels of cAMP affect active and passive transport mechanisms at the apical and basolateral membranes of the bullfrog RPE.
J Gen Physiol 1984 Jun
PMID:Cyclic AMP modulation of ion transport across frog retinal pigment epithelium. Measurements in the short-circuit state. 633 Feb 80

Interplasmidic and intraplasmidic recombination proficiencies were determined in E. coli bacterial strains carrying rec mutations. Our results defined the role of recF gene function, recB, recC, and sbcB gene products (exonuclease V and exonuclease I) in plasmidic recombination in wild-type E. coli cells and in cells in which the recE recombination pathway is activated. RecF gene function is required for interplasmidic recombination regardless of the recB recC genotype. Intraplasmidic recombination is recF dependent in cells having a functional exonuclease V, but not in recB recC mutants. Exonuclease V activity inhibits both interplasmidic and intraplasmidic recombination via the recE pathway.
Mol Gen Genet 1983
PMID:Plasmidic recombination in Escherichia coli K-12: the role of recF gene function. 634 18

Various adenosine derivatives, methylxanthines and other compounds were tested for their abilities to inhibit the rapid uptake of adenosine by rat cerebral cortical synaptosomes. Several pharmacologically potent derivatives of adenosine were weak inhibitors of uptake with IC20 values in excess of 10(-5) M. Derivatives in this category were adenosine-5'-N-ethylcarboxamide, adenosine-5'-cyclopropylcarboxamide, N6-cyclohexyladenosine, L-N6-phenylisopropyladenosine, 1-methylisoguanosine, 2-phenylaminoadenosine and 5-iodotubercidin. Several methylxanthines were very weak inhibitors of adenosine uptake. These included pentoxifylline, n-hexyltheophylline, n-butyltheobromine, and isoamyltheobromine. HL 725, a pyrimido-isoquinoline with potent phosphodiesterase inhibitory activity, inhibited adenosine uptake with an IC20 of 2.0 X 10(-6) M. PK 11195, a putative ligand for the peripheral benzodiazepine binding site did not alter uptake at a concentration of 10(-4) M.
Gen Pharmacol 1984
PMID:Further studies on the inhibition of adenosine uptake into rat brain synaptosomes by adenosine derivatives and methylxanthines. 673 39

Ca2+/calmodulin-dependent phosphoprotein phosphatase (calcineurin, PP2B) of Saccharomyces cerevisiae is implicated in adaptation to high-salt conditions. Calcineurin mediates high salt-induced expression of the ENA1/PMR2 gene encoding the P-type ATPase, which is suggested to be involved in Na+ efflux. We identified the PDE1 gene encoding the low-affinity cAMP phosphodiesterase as a multicopy suppressor of the Li(+)- and Na(+)-sensitive calcineurin null mutant, suggesting that cAMP is a negative regulator of adaptation to high-salt stress. Genetic analysis indicated that calcineurin and cAMP act antagonistically in a common pathway for adaptation. The bcy1 disruption, which leads to constitutive cAMP-dependent protein kinase (PKA) activity inhibited high NaCl-induced expression of the ENA1/PMR2 gene, caused an elevation of the intracellular Na+ level and a growth defect in high-NaCl medium, all of which were analogous to the defects of a calcineurin mutant. A reduced cAMP level resulting from multiple copies of the PDE1 gene caused increased expression of the ENA1/PMR2 gene in response to high NaCl. We propose a model for the regulation of cation homeostasis, in which calcineurin antagonizes PKA to activate transcription of the ENA1/PMR2 gene in response to high-salt conditions.
Mol Gen Genet 1995 Nov 27
PMID:Adaptation to high-salt stress in Saccharomyces cerevisiae is regulated by Ca2+/calmodulin-dependent phosphoprotein phosphatase (calcineurin) and cAMP-dependent protein kinase. 750 Sep 49

In organ cultures of liver tissue from the axolotl, Ambystoma mexicanum, 1 nmol/l arginine vasotocin (AVT) increased tissue cyclic AMP (cAMP) concentration, activated glycogen phosphorylase, and caused glycogen breakdown and glucose release. Addition of 10 nmol/l insulin had no effect on any of these parameters. Addition of glucagon together with AVT caused a further increase in tissue cAMP but not in glucose release. Ten nanomoles per liter of insulin added to the cultures 5 min before 1 nmol/liter AVT inhibited all the above actions of AVT. This inhibitory action of insulin was not apparent in the presence of the cAMP phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), which indicates that insulin activates cAMP phosphodiesterase and so reduces the concentration of cAMP in the tissue. This cannot occur in the presence of IBMX. These findings confirm previous reports that AVT causes hepatic glycogenolysis in the axolotl via an increase in tissue cAMP level.
Gen Comp Endocrinol 1993 Feb
PMID:Insulin counters the glycogenolytic effect of arginine vasotocin in liver pieces from the axolotl, Ambystoma mexicanum, cultured in vitro. 768 Oct 19

1. In this investigation, the properties and possible mechanisms of the antiaggregatory effects of cryptolepine were evaluated. 2. Cryptolepine had no effect on platelet shape change but inhibited aggregation in a time-dependent manner. The inhibition of aggregation lacks agonist specificity, the IC50 values (x 10(-5) M) being 2.79 +/- 0.7 ADP 3.05 +/- 0.2 (U46619), 2.89 +/- 0.6 (A23187), 2.41 +/- 0.6 (thrombin), 4.05 +/- 0.9 (arachidonic acid) and 47.3 +/- 3.9 (PAF). 3. The antiaggregatory effects were fully reversible and surmountable at concentrations < or = 75 microM but unsurmountable at concentrations > or = 100 microM. 4. The coincubation of cryptolepine (25 and 50 microM) with cpt-cAMP (50 microM) resulted in increased inhibition of aggregation from 24.2 +/- 2.1% (25 microM) and 45.1 +/- 3.4% (50 microM) to 69.5 +/- 5.8% and 84.2 +/- 6.4%, respectively. 5. Cryptolepine (10 microM) synergized with stimulants of platelet adenylate cyclase, prostacyclin (0.5 and 1 nM) and forskolin (2.5 and 5 microM) to inhibit aggregation induced by adenosine diphosphate (ADP). The inhibition of aggregation by cryptolepine (10 microM; 18.2 +/- 1.5%) or prostacyclin (0.5 nM; 23.4 +/- 2.0%) increased to 62.6 +/- 3.8% (P < 0.01) on combined administration. 6. Following pretreatment with IBMX (50 microM), a phosphodiesterase (PDE) inhibitor, the inhibitory effect of cryptolepine (25 microM) increased from 21.5 +/- 2.1% to 42.3 +/- 3.7% (P < 0.01). In the presence of imidazole (2.5 mM), an activator of PDE, the inhibitory effects of cryptolepine reduced from 63.2 +/- 5.4% (50 microM) and 84.7 +/- 4.4% (75 microM) to 1.4 +/- 0.2% and 21.3 +/- 2.4%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Gen Pharmacol 1993 Mar
PMID:The mechanism(s) of the antiaggregatory effects of cryptolepine: the role of cyclic adenosine monophosphate and cellular Ca2+. 768 2

A sustained high voltage-activated (HVA), nifedipine- and cadmium-sensitive calcium current and a sustained calcium action potential (AP) were recorded from horizontal cells isolated from catfish retina. pH indicator dyes showed that superfusion with NH4Cl alkalinized these cells and that washout of NH4Cl or superfusion with Na-acetate acidified them. HVA current was slightly enhanced during superfusion of NH4Cl but was suppressed upon NH4Cl washout or application of Na-acetate. When 25 mM HEPES was added to the patch pipette to increase intracellular pH buffering, the effects of NH4Cl and Na-acetate on HVA current were reduced. These results indicated that intracellular acidification reduces HVA calcium current and alkalinization increases it. Sustained APs, recorded with high resistance, small diameter microelectrodes, were blocked by cobalt and cadmium and their magnitude varied with extracellular calcium concentration. These results provide confirmatory evidence that the HVA current is a major component of the AP and indicate that the AP can be used as a measure of how the HVA current can be modified in intact, undialyzed cells. The duration of APs was increased by superfusion with NH4Cl and reduced by washout of NH4Cl or superfusion with Na-acetate. The Na-acetate and NH4Cl washout-dependent shortening of the APs was observed in the presence of intracellular BAPTA, a calcium chelator, IBMX, a phosphodiesterase inhibitor, and in Na-free or TEA-enriched saline. These findings provide supportive evidence that intracellular acidification may directly suppress the HVA calcium current in intact cells. Intracellular pH changes would thereby be expected to modulate not only the resting membrane potential of these cells in darkness, but calcium-dependent release of neurotransmitter from these cells as well. Furthermore, this acidification-dependent suppression of calcium current could serve a protective role by reducing calcium entry during retinal ischemia, which is usually thought to be accompanied by intracellular acidosis.
J Gen Physiol 1993 May
PMID:Modulation of a sustained calcium current by intracellular pH in horizontal cells of fish retina. 768 44

1. The signal transduction process mediated by cyclic AMP that leads to the characteristic positive inotropic effect (PIE) in association with a positive lusitropic effect (acceleration of rate of twitch relaxation) has been well established. Relationships between accumulation of cyclic AMP, changes in intracellular Ca2+ transients and the PIE differ, however, depending on the mechanism of particular drugs that affect different steps in the metabolism of cyclic AMP. Selective partial agonists of beta 1-adrenoceptors and inhibitors of phosphodiesterase (PDE) III cause the accumulation of less cyclic AMP for a given PIE than does isoproterenol. In addition, in aequorin-microinjected canine ventricular muscle, selective inhibitors of PDE III, OPC 18790 and Org 9731, produced smaller decreases in the responsiveness of myofilaments to Ca2+ ions than isoproterenol, while a partial agonist of beta 1-adrenoceptors, denopamine, elicits a decrease in Ca2+ responsiveness of the same extent as does isoproterenol. 2. Activation of myocardial alpha 1-adrenoceptors, as well as stimulation of receptors for endothelin and angiotensin II, which accelerates hydrolysis of phosphoinositide (PI) to result in production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) are associated with very similar inotropic regulation: (1) the dependence on the species of animals of induction of the PIE; (2) an excellent correlation between the extent of acceleration of hydrolysis of PI and the PIE; (3) isometric contraction curves associated with a negative lusitropic effect; (4) the PIE associated with increases in myofibrillar responsiveness to Ca2+ ions; and (5) the selective inhibition of the PIE by an activator of protein kinase C (PKC), phorbol 12,13-dibutyrate (PDBu), with little effect on the PIE of isoproterenol and Bay k 8644. 3. A novel class of cardiotonic agents, namely, Ca2+ sensitizers such as EMD 53998 and Org 30029, act on the Ca(2+)-binding site of troponin C, increasing the affinity of these sites for Ca2+ ions, or at the actin-myosin interface to facilitate the cycling of cross-bridges. These agents produce a PIE with little change or decrease in Ca2+ transients and may bring about a significant breakthrough in the development of drugs for reversal of myocardial failure in the treatment of congestive heart failure.
Gen Pharmacol 1995 Jan
PMID:The effects of various drugs on the myocardial inotropic response. 771 48

1. Peripheral-type benzodiazepine ligands (Ro 5-4864, AHN-086, PK 11195 and PK 14105) inhibit, in a concentration-dependent and non-competitive manner, noradrenaline-induced contractions in isolated rat aortic rings (IC50 values: 24 +/- 1.8, 49 +/- 2.5, 15 +/- 1.2, 49 +/- 3.2 microM, respectively). 2. This effect is probably not mediated by peripheral-type benzodiazepine receptors and is not related to the presence of endothelium. 3. All compounds inhibited phosphodiesterase activity in vitro. 4. From the results obtained with nucleotide analogs, calcium antagonists and specific inhibitors of PDE isoenzymes, it can be concluded that the actions of AHN-086 and PK 11195 are related to effects on PDE I, III and IV.
Gen Pharmacol 1994 Dec
PMID:The role of cyclic nucleotides in the action of peripheral-type benzodiazepine receptor ligands in rat aorta. 772 Oct 28

1. The antiischemic properties of the flavonoids acetylvitexin-rhamnoside (AVR) and luteolin-7-glucoside-(LUT), combining phosphodiesterase (PDE)-inhibitory and antioxidant properties, were studied in comparison to amrinone (AMR) or superoxide dismutase (SOD). The effects of the new dihydropyridine-type calcium-agonist Bay T 5006 were studied in comparison to Bay K 8644. 2. In isolated Langendorff-rabbit hearts perfused at constant pressure, acute regional ischemia (MI) was induced by coronary artery occlusion (CAO) and quantitated from epicardial NADH-fluorescence photography. Drugs were applied either before or after CAO (pre-treatment or treatment) to permit distinguishing the influence of functional and direct cytoprotective actions in the poorly collateralized rabbit hearts. 3. SOD did not affect left ventricular pressure (LVP) or coronary flow (CF) and reduced MI only if applied before CAO. LVP and CF were enhanced by LUT or AMR but not by AVR. MI was reduced to a similar extent in hearts treated with either drug. Cardioprotection by LUT was not improved by starting drug application before CAO. 4. Bay K 8644 reduced LVP and particularly CF, whereas Bay T 5006 did not affect functional parameters. MI was enlarged by Bay K 8644 and remained unaffected by treatment or pretreatment with Bay T 5006. 5. AMR, LUT and AVR possess antiischemic properties related to an improvement of myocardial perfusion. Although oxygen free radicals contribute to ischemic tissue injury, as shown by the cardioprotective effectiveness of SOD, antioxidant properties of the flavonoids LUT and AVR do not seem to be relevant for the antiischemic effects. Our findings also give no evidence for antioxidant properties of dihydropyridines relevant for cardioprotection.
Gen Pharmacol 1995 May
PMID:Effects of different inotropes with antioxidant properties on acute regional myocardial ischemia in isolated rabbit hearts. 778 35


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