Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin-sensitive cAMP phosphodiesterase (PDE) in the microsomal fraction (Fraction P-2) from basal (-insulin) rat adipocytes was stimulated upon incubation with 2 mM ATP plus the soluble fraction from insulin-treated adipocytes (Fraction S-2+). Fraction S-2+ was prepared in the presence of p-nitrophenylphosphate, sodium vanadate, and EGTA. The ATP-dependent stimulation of PDE was routinely 60-70%. The unknown factor in Fraction S-2 was water-soluble, heat-labile, excluded by Sephadex G-50, mostly retained by Sephadex G-100, and not inhibited with 1 microgram/ml heparin, 3 mM CaCl2, or 30 mM NaF. The soluble factor may be a mediator of insulin action on PDE, possibly a protein kinase.
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PMID:Stimulation of the insulin-sensitive cAMP phosphodiesterase by an ATP-dependent soluble factor from insulin-treated rat adipocytes. 215 11

The ability of positive inotropic drugs to inhibit phosphodiesterase was assessed by observance of the potentiation of inotropic responses to the low intrinsic efficacy beta-adrenoceptor partial agonist prenalterol. Previous studies have shown that an increase in tissue stimulus response capability, as is produced for beta-adrenoceptors by blockade of phosphodiesterase, produces an increase in the maximal response to beta-adrenoceptor partial agonists. Using this principle, we tested cardiotonic drugs on normal and prenalterol-pretreated guinea pig left atria and compared the resulting inotropic responses statistically. Prenalterol pretreatment did not potentiate inotropic responses to methoxamine and CaCl2 and blocked (in accordance with beta-adrenoceptor occupation by a low-efficacy partial agonist) responses to norepinephrine (NE), tyramine, and to a certain extent ouabain. This latter finding was attributed to a low-level catecholamine-release by ouabain in this tissue. The inotropic responses to the phosphodiesterase inhibitors isobutylmethylxanthine (IBMX), theophylline, and enprophylline were greatly potentiated. Similarly, the responses to the cardiotonic drugs (known also to be inhibitors of phosphodiesterase) milrinone, amrinone, and fenoximone were potentiated. Positive inotropy to the cardiotonic drug sulmazole was not significantly potentiated by this procedure, indicating that in this tissue sulmazole may produce inotropic responses by other mechanisms as well. In general, this simple assay may be useful to detect blockade of cardiac phosphodiesterase concomitant with positive inotropy. Although a causal relationship between the PDE inhibition and positive inotropy may not be made from these data, knowledge of PDE blockade may still be useful in the assessment of inotropic mechanism and propensity for toxic side effects.
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PMID:A method to assess concomitant cardiac phosphodiesterase inhibition and positive inotropy. 245 Feb 36

Microelectrodes were used to investigate the possible involvement of cAMP and Ca2+ ions in the parathyroid hormone's, bPTH(1-34), effect on the membrane potential of rat osteoblasts in primary culture. Parathyroid hormone (10(-7) M) depolarized cell membrane by 25.0 +/- 6.1 mV (mean +/- standard deviation, SD; n = 17). Blocking Ca2+ influx with the Ca channel blocker cobalt revealed two phases in the hormone effect: a rapid and slight membrane hyperpolarization followed by sustained depolarization. In addition, cobalt significantly (p less than 0.01) decreased the magnitude of the PTH depolarizing action. The addition of dibutyryl-cAMP (10(-3) M) to the perfusion solution also resulted in a biphasic effect. At a lower concentration (10(-4) M), dibutyryl-cAMP produced only membrane hyperpolarization, suggesting a cAMP dose dependence of the opposite membrane potential changes. Forskolin (10(-5) M) and the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) (10(-4) M) mimicked the depolarizing effect of PTH. IBMX at a low concentration (5 x 10(-6) M) potentiated the depolarizing effect of PTH. Increases in [Ca2+]i using Ca2+ ionophore A23187 and intracellular injection of CaCl2 or inositol trisphosphate decreased the PTH depolarizing action, whereas intracellular injection of EGTA enhanced this effect. These results indicate that PTH evokes a biphasic change in rat osteoblast membrane potential that seems to be mediated by an increase in cAMP and modulated by intracellular calcium.
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PMID:Early effects of parathyroid hormone on membrane potential of rat osteoblasts in culture: role of cAMP and Ca2+. 246 41

The effects of various benzodiazepines on chronotropic responses were assayed in spontaneously beating rat isolated atria. The increases in atrial rate obtained from concentration-response curves to noradrenaline were reduced dose dependently by both the peripheral agonist, Ro 5-4864 5 and 10 microM, and the mixed agonist, diazepam 5, 10 and 50 microM, but not by the central benzodiazepine agonist, clonazepam 10 and 30 microM. The inhibitory effects of the benzodiazepines on the atrial responses to noradrenaline were not counteracted by either the peripheral benzodiazepine antagonist, PK 11195 10 microM, or the central benzodiazepine antagonist, Ro 15-1788 10 and 100 microM. Both 10 microM Ro 5-4864 and 10 microM diazepam also reduced the increases in atrial rate produced by either the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, or the adenylate cyclase activator, forskolin. On the contrary, diazepam and Ro 5-4864 did not modify the chronotropic responses of the atria either to direct exposure to CaCl2 or to the calcium agonist, BAY K 8644. The increases in the intracellular levels of cAMP induced by noradrenaline were not modified by Ro 5-4864 and were even increased by 50% in the presence of diazepam. It is concluded that benzodiazepines probably reduce the chronotropic responses to noradrenaline in rat isolated atria through the interaction with the cAMP-linked chain of events that follows the activation of beta-adrenoceptors.
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PMID:Diminution by benzodiazepines of the chronotropic responses to noradrenaline in rat isolated atria. 247 48

Mannosylphosphodolichol phosphodiesterase, which catalyzes the release of mannose from mannosylphosphodolichol, was solubilized from chicken liver microsomes by treatment with the non-ionic detergent, Emulgen 909. The enzyme was partially purified using ammonium sulfate precipitation, DEAE-cellulose chromatography, and gel filtration on Sepharose 6B. The enzyme showed absolute requirement for sulfhydryl reducing agents. The enzyme activity was stimulated by the addition of CaCl2 and Emulgen 909 and exhibited a pH optimum around 5.3. The Km value for mannosylphosphodolichol was found to be 0.43 microM. The activity was competitively inhibited by dolichyl phosphate and dolichol and the Ki value for dolichyl phosphate was estimated to be 12.5 microM. The purified preparation had no activity toward N-acetylglucosaminyldiphosphodolichol, glucosylphosphodolichol, mannose 1-phosphate, or artificial substrates for mannosidases, glucosidases, acid phosphatase, and acid phosphodiesterase. A heat-stable factor which stabilizes the mannosylphosphodolichol phosphodiesterase was separated from the enzyme by DEAE-cellulose chromatography. It was precipitated by trichloroacetic acid and not extracted into lipid solvents. The separation resulted in the complete loss of the enzyme activity and the restoration of the activity was not observed when the factor was added back to the enzyme solution.
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PMID:Characterization and partial purification of a novel mannosylphosphodolichol phosphodiesterase from chicken liver microsomes. 282 59

The pharmacological properties of 3-methylflavone-8-carboxylic acid (MFCA), the main metabolite of flavoxate, have been studied in vitro and in vivo. MFCA did not display antispasmodic activity on isolated organs contractions induced by histamine, acetylcholine or CaCl2, nor did it exhibit significant affinity for the rat brain alpha- and beta-adrenergic, serotoninic, muscarinic, D2, opiate and Ca2+ receptors. However, it showed a remarkable phosphodiesterase (PDE) inhibiting activity. Moreover in vivo studies indicate an interesting activity of MFCA which inhibited the rat urinary bladder voiding contractions, increased bladder volume capacity and decreased micturition pressure in the rat cystometric recordings. The activity of MFCA in the two in vivo experimental models, probably related to cAMP-PDE inhibitory properties, suggests that flavoxate's therapeutical potential might be partially sustained by its main metabolite.
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PMID:Pharmacological activities of the main metabolite of flavoxate 3-methylflavone-8-carboxylic acid. 283 33

Neurohormone C (NC) is a glycopeptide isolated from bovine hypothalamus, which inhibits Ca-calmodulin (CaM)-dependent cAMP and cGMP phosphodiesterase (PDE) and is a regulator of Ca in the cell. Distribution of [45Ca]CaCl2 in the mitochondria and reticulum (SR) of heart and brain mitochondria and changes of Ca-binding proteins in these organelles under NC influence have been studied in the myocardium before and after isoproterenol-induced necrosis. Intraperitoneal administration of 80-100 mU of PDE inhibitory activity of NC to rats did not cause any noticeable changes in the protein content of intracellular organelles, but altered the affinity of certain proteins to 45Ca2+. This property of NC was especially noticeable after isoproterenol necrosis. Necrotic injury of the myocardium induced Ca2+ storage in the mitochondria and SR of brain, and decreased the Ca2+ concentration in myocardial mitochondria. NC injection to the animals with necrosis was followed by Ca2+ release from all the studied organelles.
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PMID:Neurohormonal regulation of calcium in the cell. 340 76

Stimulatory effects of Ca2+-CaM and PKI on partially purified hypothalamic HD (10 fold purification) have been shown under conditions involving inhibition of the enzyme by cAMP-induced phosphorylation and under control conditions. A 1:1 (v/v) mixture of 0.1 mM CaCl2 and 10 units of CaM from human red blood cells reversed the inhibition of HD induced by cAMP-dependent protein phosphorylation activity to the control level. Verapamil (0.01 mM) could partially block the former effect without affecting the control level of enzyme activity. 0.01 mM TPA did not further increase the effect of Ca2+-CaM on HD, in the presence of 0.01 mM ATP, indicating that this stimulation does not require the action of Ca2+-dependent protein kinase. The control level of HD is not influenced by 0.1 mM CaCl2 or 0.02 mM EGTA but is raised by CaM in the presence of CaCl2 (0.1 mM). A highly purified protein kinase (cAMP-dependent) inhibitor (PKI) from bovine heart and a crude inhibitor from rat cerebellum could also reverse the inhibitory effect of cAMP-dependent protein kinase under phosphorylating conditions and enhanced HD activity above control levels. PKI and Ca2+-CaM, added together, produced single, not additive effects. We conclude that cAMP-induced phosphorylation is probable the main regulatory mechanism of histamine formation and this could be influenced by both Ca2+-CaM and PKI. Inhibition of cAMP-dependent protein kinase as well as stimulation of phosphoprotein phosphatase and Ca2+-CaM-dependent phosphodiesterase might be involved in the above actions.
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PMID:Stimulation of hypothalamic histidine decarboxylase by calcium-calmodulin and protein kinase (cAMP-dependent) inhibitor. 360 3

The present study was undertaken to elucidate the effect of calcium ion on the granulation tissue formation during wound healing. Male guinea pigs of Pilbright strain were chosen as the experimental animal. An appropriate open wound was aseptically made on the dorsum of the guinea pigs, which was then equipped with a sterile Teflon-cylinder. The amounts of granulation tissues developed within the cylinder were determined during 10 day period of the observation. In addition, various concentrations of CaCl2 were applied on the wound surface for up to 3 days after the wounding. Calmodulin contents in the granulation tissue were also determined using calmodulin-deficient phosphodiesterase prepared from bovine heart. Purified pig skin epidermal calmodulin was used as the standard. The results obtained were as follows: The amount of the granulation tissue increased in a stepwise manner during 3, 5, 7, and 10 days after the wounding. Calmodulin content in the granulation tissue was maximal on the day 3 after the wounding, waned on the day 5, and remained low on the days 7 and 10. A significant augmentation of the granulation tissue production as well as of calmodulin content was observed when CaCl2 was applied on the wound surface during 3 days after the wounding. These results suggest that calcium ion might have a significant role on granulation tissue development, possibly through the Ca++-calmodulin system, during early stages of wound healing process.
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PMID:[Effects of the calcium ion on the wound healing process]. 361 30

The adrenal medulla contains an enzyme which catalyzes the hydrolysis of 2',3'-cAMP to 2'-AMP. For the parameters which have been examined, the adrenal medulla 2',3'-cAMP phosphodiesterase appears to be similar to brain 2',3'-cyclic nucleotide 3'-phosphodiesterase (also commonly referred to as CNPase). The apparent Km of the adrenal medulla CNPase for 2',3'-cAMP is 0.88 mM. The enzyme activity is unaltered by either EDTA, MgCl2 or CaCl2 in the presence or absence of calmodulin. The apparent molecular weight is 102,500 daltons. The function of the enzyme in either the brain or the adrenal medulla is, at the present time, unknown.
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PMID:Identification of 2',3'-cyclic nucleotide 3'-phosphodiesterase in bovine adrenal medulla. 370 18


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