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)

Tibenelast (LY186655), 5,6,-diethoxybenzo(b)thiophene-2-carboxylic acid, sodium salt, is an orally active anti-anaphylactic compound in guinea pigs, and has been shown to prevent bronchospasm in moderately severe asthmatic patients. Pharmacological studies with tibenelast demonstrated that it is a selective phosphodiesterase (PDE) inhibitor in that it is moderately active against the lung and stomach enzyme while being a very weak inhibitor of the heart enzyme. The compound was without cardiovascular effects at anti-anaphylactic doses. In contrast to theophylline, tibenelast did not have a direct inotropic effect in the cat papillary muscle system. The concentration that inhibited 50% of the enzymatic activity (IC50) for tibenelast was 20- to 30-fold lower for neutrophil PDE than for PDE of other tissues. It was 100 times more potent than aminophylline in inhibiting superoxide generation from platelet-activating factor (PAF)-primed polymorphonuclear leukocytes (PMNL) challenged with chemotactic factor, N-formyl-methionyl-leucyl-phenylalanine. However, tibenelast was less effective in the tumor necrosis factor-primed system, and did not inhibit superoxide generation during phagocytosis or when other soluble stimuli, such as phorbo-12-myristate-13-acetate or the calcium ionophore A23187, were used. Furthermore, tibenelast did not inhibit enzymes involved in arachidonic acid metabolism. These results suggest that tibenelast probably inhibits superoxide release from PMNL via a selective inhibition on PDE.
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PMID:Cardiovascular effect and stimulus-dependent inhibition of superoxide generation from human neutrophils by tibenelast, 5,6-diethoxybenzo(b)thiophene-2-carboxylic acid, sodium salt (LY186655). 217 1

The aim of this study was to investigate the effects of dietary calcium and sodium on blood pressure (BP) in normotensive rats (Wistar, WKY), spontaneously hypertensive rats (SHR) and Dahl rats and on calmodulin (CaM) activator, a newly-discovered hydrophobic compound that increases CaM activity in SHR and spontaneously hypertensive mice (SHM) tissues (J Clin Invest 82:276, 1988). The CaM activator was assessed by its capacity to stimulate a CaM-dependent phosphodiesterase (CaM-PDE). In Wistar rats, which were fed a high sodium diet (3.5%), BP significantly increased (P less than .01) from 106 +/- 4 to 128 +/- 8 mm Hg in parallel to an elevation of the CaM activator from 1.57 +/- 0.14 to 2.80 +/- 0.18 U. WKY, SHR, and Dahl salt-sensitive (DS/JR) and salt-resistant (DR/JR) rats were given low (0.15%) or high (2.5%) Ca diets, both with 1% sodium. In rats receiving high dietary Ca the progression of hypertension diminished and BP was lower in SHR (156 +/- 4 mm Hg) and young DS/JR rats (125 +/- 3 mm Hg) than in those receiving low dietary Ca (192 +/- 10 and 183 +/- 2 mm Hg). There was a concomitant decrease of CaM activator in these animals to levels indistinguishable from those of WKY or DR/JR rats. The activator was also found in the heart, kidneys and erythrocytes from SHM. In the presence of exogenously added CaM, lipidic extracts from the SHM heart showed augmented CaM-PDE activity relative to normotensive preparations. This difference was eliminated by trifluoperazine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increase of calmodulin activator in hypertension. Modulation by dietary sodium and calcium. 222 70

Cultured glomerular epithelial cells form a continuous monolayer of polyhedral-shaped cells. PGE2 (1 microgram/ml) in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (MIX) markedly raises intracellular and medium cyclic AMP (cAMP) levels at 20 min (intracellular: MIX alone, 112 +/- 6.6 pmol cAMP/mg protein, MIX plus PGE2, 2252 +/- 63 pmol cAMP/mg protein; medium: MIX, 20.6 +/- 2.1 pmol cAMP/mg protein; MIX plus PGE2, 117 +/- 3.8 pmol cAMP/mg protein). By 2 h, when cellular and medium cAMP levels were still elevated, the cells underwent a change in shape that was similar to dome formation (15 to 20% of the monolayer changing shape). Derivatives of cAMP [i.e. dibutyryl and 8-(4-chlorophenylthio)-cAMP], when added to the incubation medium also caused shape change in glomerular epithelial cells at 2 h; cAMP itself did not. The formation of domes has been used as a morphological indicator of the vectorial transport of salt and water in other cultured epithelial cells.
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PMID:Elevations of intracellular cAMP result in a change in cell shape that resembles dome formation in cultured rat glomerular epithelial cells. 242 42

The ability of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX) to inhibit histamine release from both peritoneal exudate cells (PEC) containing mast cells and lung fragments of rats was investigated in vitro. Low concentrations of TBX dose-dependently inhibited IgE-mediated histamine release from PEC of passively sensitized animals; its IC50 was 5.1 x 10(-9) g/ml. When TBX was added simultaneously with the antigen challenge, the highest inhibition was obtained. In contrast, extension of preincubation time with the agent resulted in a marked decrease in the inhibition of histamine release. The potent inhibition of histamine release by TBX was observed equally in glucose-free as well as complete Tyrode's solution, whereas TBX reduced its inhibitory action in Ca2+-free or D2O-supplemented medium. In addition, TBX inhibited compound 48/80- but not calcium ionophore A23187-induced histamine release from normal PEC. With regard to the intracellular cyclic AMP level in normal PEC, it was significantly enhanced by a high concentration of TBX (10(-3) g/ml). TBX also inhibited antigen-induced histamine release from lung fragments of actively immunized animals. Interestingly, TBX displayed non-competitive inhibition of cyclic AMP-dependent phosphodiesterase derived from lung homogenates; its K1 value was 8.70 x 10(-4) M.
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PMID:Immunopharmacological studies on TBX, a new antiallergic drug (2). Inhibitory effects on histamine release from peritoneal mast cells and lung fragments of rats. 246 73

The direct current electroretinogram and the standing potential of the eye were recorded from both eyes of unilaterally vitrectomized albino rabbits. The effect of intraocular irrigation with the nonselective phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) was compared with that of a balanced salt control solution. IBMX (0.5 mM) produced a reversible increase in the amplitudes of the a-wave (19%, p less than 0.02), b-wave (21%, p less than 0.001) and c-wave (12%, p less than 0.01) of the electroretinogram. A small elevation of the standing potential was found (0.4 +/- 0.2 mV), but this increase was not statistically significant (p greater than 0.05). The results indicate a primary and principal influence of IBMX on the photoreceptors.
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PMID:Influence of isobutylmethylxanthine on the direct current electroretinogram of albino rabbit eyes. 248 17

Polymer 3520, a non-polar styrene divinylbenzene polymer, provides a simple way to purify calmodulin (CAM) from soybeans. This polymer, which selectively adsorbs CAM by hydrophobic interaction within the polymer matrix, contains no exchangeable groups; thus, interaction with CAM requires no Ca++ ions, and elution is achieved with 50% ethanol. Purification by this form of reversed-phase liquid chromatography is a substantial improvement over the conventional method, which requires high salt in elution buffers. CAM in soybean meal is first extracted with 80% ethanol in the presence of EGTA at room temperature and then chromatographed directly on a polymer 3520 column to yield pure CAM. Addition of non-ionic detergent (Nonidet P-40) to the ethanolic extract helps to separate extraneous proteins, lipids, sugars, and isoflavones. Such isolated CAM migrates as a single band during polyacrylamide gel electrophoresis and reversed-phase HPLC, and it retains activity stimulatory to phosphodiesterase.
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PMID:Soybean metal-binding proteins: calmodulin purification by hydrophobic interaction with polymer 3520. 274 Feb 90

Phosphatases and phosphodiesterases that hydrolyse polyphosphoinositides are described in both membrane and cytosol fractions of human, pig, rat, rabbit, and sheep erythrocytes using exogenous substrates. With suitably optimized assay conditions, Ca2+-dependent phosphatidylinositol bisphosphate (PIP2) phosphodiesterase activity was found in the hemoglobin-free cytosol fraction, as well as the membrane. Membrane activity is completely dependent upon Triton X-100 and salt and inhibited by cetyltrimethylammonium bromide (CTAB), while the soluble activity requires CTAB and is inhibited by Triton. A low Ca2+-dependent PIP2 phosphatase activity, not present in other tissues, was also detected. The cation-independent phosphatidylinositol phosphate (PIP) phosphatase is localized in the membrane in most species, while the diesterase and the PIP2 phosphatases (both Mg2+ and Ca2+ dependent) are localized in the cytosol. Rat and rabbit erythrocytes are atypical in having a substantial proportion of their Mg2+-dependent PIP2 phosphatase activities in the membrane. All activities are lowest in sheep erythrocytes, except the PIP phosphatase, most of which is soluble in this species. Ca2+-dependent PIP2 phosphatase activity is not correlated with the activity or subcellular distribution of any of the other hydrolases and seems to be a separate enzyme. All the phosphoinositide hydrolase activities, particularly the diesterase, are orders of magnitude lower in erythrocytes than in other tissues. Both soluble and membrane diesterase activities are lost as erythrocytes age. Soluble polyphosphoinositide diesterase does not seem to be active with membrane-bound substrate, since pig and sheep erythrocytes that have negligible membrane activity do not respond to Ca2+ loading, yet have substantial diesterase activity in the cytosol. This supports the view that the diesterase is not physiologically functional in normal erythrocytes.
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PMID:Soluble and membrane-bound polyphosphoinositide phosphohydrolases in mammalian erythrocytes. 283 56

Vasopressin has been shown previously to lower the glucagon-induced increase of cyclic AMP levels in isolated rat hepatocytes by way of an enhanced phosphodiesterase (EC 3.1.4.17) activity. Five phosphodiesterase inhibitors were tested for their ability to prevent vasopressin from lowering cyclic AMP levels in intact hepatocytes and for their inhibitory effect in vitro on soluble and particulate phosphodiesterase activities partially purified from hepatocytes. Three soluble activities have been separated by DEAE-cellulose chromatography: a phosphodiesterase hydrolyzing both cyclic AMP and cyclic GMP, a form stimulated by cyclic GMP and a cyclic AMP-specific activity. The absence of any statistically significant correlation between the in vivo (in intact cells) and the in vitro (on isolated phosphodiesterases) potencies of the inhibitors does not support a role for the cytosolic phosphodiesterases in mediating the vasopressin-induced decrease in cyclic AMP levels. No statistically significant correlation was observed between the inhibition of the vasopressin effect on cyclic AMP accumulation and the inhibition of phosphodiesterase activity either associated with the native plasma membranes or solubilized from these membranes with 0.4 M NaCl. In contrast, a statistically significant correlation was observed between the degree of inhibition of the vasopressin effect in the intact cells and the degree of inhibition of the intrinsic phosphodiesterase still associated with the plasma membranes after high-salt treatment. These data indicate that a phosphodiesterase activity integral to the plasma membrane is very likely involved in the negative control of cyclic AMP levels by vasopressin.
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PMID:Involvement of a plasma membrane phosphodiesterase in the negative control of cyclic AMP levels by vasopressin in rat hepatocytes. 284 89

Nitrate tolerance is defined as an attenuation or even loss of hemodynamic and anti-ischemic effects during continuous nitrate medication. The blunted response may be due to the development of pseudotolerance and true pharmacologic tolerance. Pseudotolerance is the result of volume and salt retention, as well as the stimulation of counter-regulatory mechanisms which may alter the baseline hemodynamics of a patient during nitrate therapy. Far less important are changes in nitrate pharmacokinetics. True pharmacological tolerance may also be of practical importance. Diminished uptake of nitrates into the vascular smooth muscle cell, a decrease in intracellular SH groups, inhibition of the guanylate-cyclase, and stimulation of a specific phosphodiesterase may result in a decrease of cyclic GMP formation and hence to a decrease in nitrate induced vasodilatation. Tolerance development may be prevented by intermittent nitrate administration providing intervals with low plasma and tissue nitrate levels. In consequence, nitrates should be used predominantly for treatment of ischemic episodes, but 24-hour anti-ischemic action for the prevention of ischemia can be better achieved by treatment with a beta-blocker and/or a calcium antagonist. Nitrates should be added in times of maximum susceptibility to ischemia, while allowing nitrate levels to fall at other times.
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PMID:[Nitrate tolerance]. 290 73

After incubation with 3H-noradrenaline, strips of human pulmonary arteries from patients undergoing surgery for lung tumour were superfused with physiological salt solution containing cocaine and corticosterone. Forskolin, AH 21-132 (a cAMP phosphodiesterase inhibitor), 8-Br-cAMP and isoprenaline did not affect the basal tritium efflux from the strips, but produced a concentration-dependent facilitation of the tritium overflow evoked by transmural electrical stimulation (2 Hz). The facilitatory effect of isoprenaline was potentiated by forskolin which produced a shift to the left of the concentration-response curve of isoprenaline. It is concluded that cAMP plays a role in the modulation of noradrenaline release in the human pulmonary artery and that presynaptic beta-adrenoceptors appear to be coupled to an adenylate cyclase in the sympathetic nerve terminals.
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PMID:Involvement of cAMP in modulation of noradrenaline release in the human pulmonary artery. 299 30


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