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)

Cyclic nucleotide phosphodiesterase (PDE) activity from the 105,000 g supernatant of human, bovine and rat aorta smooth muscle cells was resolved by DEAE-trisacryl chromatography into three major forms showing similar properties in each species. In addition to the two PDE forms previously characterized in vascular tissues (a cAMP-PDE and a calmodulin-dependent PDE), a cGMP-PDE, insensitive to calmodulin, was isolated and characterized in the aorta of the three species. Each isolated PDE form was differently inhibited by various chemical compounds, and these compounds produced effects on cyclic nucleotide levels in isolated rat aorta which could be expected from their inhibitory effect on isolated PDE forms. At concentrations non-selectively inhibiting the three isolated PDE forms (including the calmodulin-dependent one), IBMX (3-isobutyl-1-methylxanthine) and trequinsin markedly and dose-dependently increased both cAMP and cGMP aorta levels (up to 7-fold, in presence of 500 microM IBMX). By contrast selective inhibitors of cGMP-PDE or cAMP-PDE could only induce a moderate elevation (by 1.5-3-fold) in cGMP or cAMP levels, respectively. In the case of M&B 22,948, a highly specific and potent inhibitor of cGMP-PDE, a concentration-dependent increase in tissue cGMP levels was produced by concentrations (in the microM range) active in inhibiting the isolated enzyme. In the case of selective cAMP-PDE inhibitors (rolipram and Ro 20-1724), however, a significant increase in aorta cAMP content was induced only in the presence of drug concentrations which were much higher (200 and 500 microM, respectively) than those inhibiting the isolated enzyme (IC50:5 and 18 microM, respectively). Inhibitors of both cGMP-PDE and cAMP-PDE (dipyridamole, cilostamide and its derivative AAL 05) produced the same moderate effects as did the combination of a selective cGMP-PDE inhibitor and a selective cAMP-PDE inhibitor on the levels of both cGMP and cAMP. These results show that the three forms of PDE isolated from aortic smooth muscle retain properties that they exhibit in the tissue and which are similar in the three species examined, including man. They suggest that each form participates in a specific manner to the regulation of cAMP and cGMP concentrations in aorta smooth muscle cells.
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PMID:Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta. 242 89

Molecular cloning, sequencing and Northern blot analysis have been performed on the gamma-subunit of cyclic-GMP phosphodiesterase (cGMP-PDE gamma) from the retina of mice affected with the rd mutation. The full length cDNA has a total of 926 bp which include 261 bp of coding region, 121 bp of 5'-untranslated and 544 bp of 3'-untranslated regions. The latter contains a poly A tail of 50 bp. The coding region has only one base changed from the normal mouse cGMP-PDE gamma cDNA, a C replaced by an A at position 105 (Tuteja and Farber, 1988), and 91% homology with the coding region of the bovine retinal enzyme (Ovchinnikov et al., 1986). The mRNA of cGMP-PDE gamma is 900 bp long in both normal and rd mouse retinas and codes for a protein containing 87 amino acids. The deduced amino acid sequence of cGMP-PDE gamma from rd retina has 100% homology with that of the enzyme from normal mouse retina and 97.7% homology with that of the bovine cGMP-PDE gamma suggesting that if this subunit of cGMP-PDE is properly transcribed and translated, it is not defective in the degenerative rd mouse retina.
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PMID:Cloning and sequencing of the gamma-subunit of retinal cyclic-GMP phosphodiesterase from rd mouse. 254 88

Distributions and activities of both cyclic adenosine 3',5'-monophosphate phosphodiesterase and cyclic guanosine 3',5'-monophosphate phosphodiesterase (cAMP-PDE and cGMP-PDE) in 43 human stomach cancer tissues were studied histochemically. The relationship between cyclic nucleotide phosphodiesterases and some patho-biologic behaviors of stomach cancer was preliminarily discussed, and so was the application of these two enzymes in clinical practice of gastric cancers. The Results showed that the two cyclic nucleotide phosphodiesterases were closely correlated with some patho-biologic behaviors of stomach cancer. The authors considered that the histochemical investigation of cyclic nucleotide phosphodiesterases in stomach cancer tissues can be useful in determining the malignant degree and estimating the prognosis of stomach cancer objectively.
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PMID:[Relationship between cyclic nucleotide phosphodiesterases (cPDE) and some patho-biologic behaviors of stomach cancer--I. Histochemical studies of CPDE in stomach cancer tissues]. 255 63

The aim of this investigation was to substantiate the hypothesis that the vasorelaxant effects of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27) are mediated by accumulation of intracellular cyclic nucleotides as a consequence of inhibition of cyclic nucleotide phosphodiesterase activity. Both activities of adenosine 3',5'-monophosphate-phosphodiesterase (cAMP-PDE) in the presence of ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) and guanosine 3',5'-monophosphate-phosphodiesterase (cGMP-PDE) in the presence of calcium-calmodulin from rabbit thoracic aorta were inhibited in a concentration-dependent manner by ZSY-27 (10(-5) - 10(-3) M). The IC50 values for ZSY-27 on cAMP- and cGMP-PDE activity were 2.1 x 10(-4) and 8.8 x 10(-4) M, respectively. Furthermore, ZSY-27 antagonized competitively cAMP-PDE (Ki = 1.9 x 10(-4) M). On the other hand, ZSY-27 exhibited a mixed-type inhibitory pattern, with reduction of both maximum velocity and affinity for the substrate of the cGMP-PDE, with a Ki value of 1.0 x 10(-3) M. Spontaneous myogenic tone of rabbit thoracic aorta was significantly attenuated from 1 min after addition of ZSY-27 (3 x 10(-4) M). Contents of cAMP and cGMP were significantly increased from 1 and 3 min after addition of ZSY-27, respectively. Temporally, relaxant effects of ZSY-27 were associated with increases of cAMP content, but not with that of cGMP content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship between cyclic nucleotide levels and 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a new positive inotropic agent with a vasodilatory action, -induced relaxation of rabbit thoracic aorta. 256 Nov 55

Kinetically distinct classes of cyclic AMP (cAMP) and cyclic GMP (cGMP) phosphodiesterase activities (PDEs) were detected in homogenates of cultured pigment epithelium (PE) from both normal and Royal College of Surgeons (RCS) rats. PDE activities with apparent low Michaelis constants (Low Km cAMP- and cGMP-PDEs) were associated with the supernatant, while PDE activities with apparent high Michaelis constants (high Km cAMP- and cGMP-PDEs) were slightly higher in the pellet than in the supernatant after ultracentrifugation (100,000 g). Activity of the low Km PDEs was significantly reduced while that of high Km PDEs was not affected by known inhibitors of PDE. In both normal and RCS rat PE low Km PDEs required calcium and magnesium ions for optimal activity while the high Km PDEs required neither. In homogenates of cultured RCS rat pigment epithelium (PE), the kinetic parameters for cAMP- and cGMP-PDEs were comparable to normal, with the exception of the Km value of the low Km cGMP-PDE. This Km value was two-fold higher in the RCS compared with the normal (indicative of a reduced affinity for cGMP). It remains to be determined if the reduced affinity for cGMP in the RCS PE is related to the genetic defect which is expressed as a deficiency in the phagocytosis of outer segments by these cells.
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PMID:Cyclic nucleotide phosphodiesterases in cultured normal and RCS rat pigment epithelium: kinetics of cyclic AMP and cyclic GMP hydrolysis. 282 Jul 72

Three isoforms of cyclic nucleotide phosphodiesterase (PDE) have been recently isolated from aortic tissue and two of them specifically hydrolyzed adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3':5'-cyclic monophosphate (cGMP), respectively (Lugnier et al., Biochem. Pharmac. 35, 1743, 1986). The role of these forms in controlling cyclic nucleotide levels and smooth muscle tone was investigated by the use of PDE inhibitors. The effects of selective inhibitors of the two forms specifically hydrolyzing cAMP or cGMP (cAMP-PDE and cGMP-PDE, respectively) were compared to those of non-selective inhibitors of the three aortic PDE forms, including the calmodulin-sensitive one (CaM-PDE). Relaxation responses and accumulation of tissue cAMP and cGMP induced by these drugs were studied in precontracted rat isolated aorta, and compared to the effects of isoprenaline and forskolin (stimulants of adenylate cyclase) or sodium nitroprusside (SNP) and sodium azide (stimulants of guanylate cyclase). The eight PDE inhibitors tested all relaxed aorta with potencies that correlated with their potencies as inhibitors of cAMP-PDE, but not of cGMP-PDE. At a concentration producing half-maximal relaxation, all PDE inhibitors induced a moderate but significant accumulation of cAMP, which was comparable to the accumulation of cAMP elicited by half-maximally relaxing concentrations of adenylate cyclase stimulating agents. At this concentration, some PDE inhibitors (M&B 22,948, dipyridamole and to a lesser extent, trequinsin) also induced a significant increase in cGMP levels, of the same order of magnitude as that caused by agents stimulating guanylate cyclase. However, the cGMP-increasing effect of these inhibitors was dissociated from their relaxing effect. In particular, the relaxing concentrations of M&B 22,948 (a selective inhibitor of cGMP-PDE) were clearly higher than the cGMP-increasing concentrations of the compound. At a concentration at which they elicited 10% relaxation by themselves, the selective cAMP-PDE inhibitor, rolipram, as well as the mixed inhibitor of cAMP- and cGMP-PDE, AAL 05 (a cilostamide analogue) enhanced both the cAMP-increasing and the relaxing effect of isoprenaline. Under the same conditions, no clear enhancement of the relaxation induced by SNP was observed. Only M&B 22,948 showed a slight potentiating effect on SNP-induced relaxation, but this effect was limited to low concentrations of SNP (less than 10 nM).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of cyclic AMP- and cyclic GMP-phosphodiesterases in the control of cyclic nucleotide levels and smooth muscle tone in rat isolated aorta. A study with selective inhibitors. 282 8

The cDNA nucleotide and corresponding amino acid sequences of the gamma-subunit of cyclic-GMP phosphodiesterase (cGMP-PDE gamma) from mouse retina have been determined. The cDNA translated region was found to be 91.5% homologous to the cDNA coding region for the enzyme from bovine retina [(1986) FEBS Lett. 204, 288-292]. On Northern blots of normal mouse retinal RNAs this cDNA hybridized the cGMP-PDE gamma mRNA which is 900 bp long. The mouse gamma-subunit contains 87 amino acid residues which share 97.7% homology with the bovine polypeptide [(1986) FEBS Lett. 204, 288-292]. Only two amino acids have been changed, Ala 8 to Gly and Met 17 to Ile.
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PMID:Gamma-subunit of mouse retinal cyclic-GMP phosphodiesterase: cDNA and corresponding amino acid sequence. 283 67

The activity of adenosine cyclic 3':5'-monophosphate phosphodiesterase in granulocytes of patients with CML essentially depends on the granulocyte donor's WBC count. The ratio of cAMP-PDE/cGMP-PDE activities in CML granulocytes strongly correlates with CML host WBC count. The regression analysis of cyclic nucleotide phosphodiesterase activities and counts of individual constituents of the white blood cell population present in the blood of CML patients showed the primary relationship between the natural logarithm of total WBC count and the cAMP-PDE/cGMP-PDE activity. The results suggest that the properties of CML granulocytes depend on the accumulation of these cells in the CML host.
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PMID:Correlation of granulocyte intracellular activities of cyclic nucleotide phosphodiesterases with leukocyte count in patients with chronic myelogenous leukaemia. 302 17

Cyclic nucleotide phosphodiesterase (PDE) activities were studied in peripheral blood monocyte-depleted lymphocytes and enriched T-lymphocyte suspensions from thirteen patients with previously untreated Hodgkin's disease (HD) and fourteen age and sex matched healthy volunteers. Monocyte-depleted lymphocytes from HD patients showed PDE-activities which were two times higher than in their normal counterpart cells. The mean cAMP-PDE activity present in enriched HD T-lymphocyte suspensions was four times higher than in control T-lymphocytes, and the mean cGMP-PDE associated with HD T-lymphocytes was three times higher than in the controls. The hydrolytic activities present in both monocyte-depleted and T-lymphocyte enriched cells suspensions remained unchanged in absence or in the presence of calmodulin and calcium. Since depressed cAMP and cGMP resting levels have been observed in HD lymphocytes and lymphocyte subpopulations, our results suggest that the elevated PDE activities are, at least in part, responsible for the alterations in lymphocyte cyclic nucleotide levels.
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PMID:Cyclic AMP and cyclic GMP phosphodiesterase activities in Hodgkin's disease lymphocytes. 304 Jun 9

RHC 2963 (7-methyl-pyrido (3',2':4,5)-thieno (3,2-d)-1,2,3 triazine-4(3H)-one and 20 related compounds have been investigated for their antiallergic activities in 3 in vitro models of anaphylaxis and for their effects on cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells (RMC). Nine compounds were potent (I50 less than or equal to 80 microM) inhibitors of antigen-induced release of histamine (AIR) from RMC, 2 compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 60 microM) and one compound inhibited AIR from guinea pig lung slices (I50 = 55 microM). RHC 2963 was 18 times more potent than disodium cromoglycate (DSCG) as inhibitor of AIR from RMC and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties and inability to inhibit non-immunologic release of histamine induced by compound 48/80. Neither RHC 2963 nor DSCG had any effect on anti-IgE-induced release of histamine from human basophils or IgG1-mediated release of histamine from guinea pig lung. Twelve of the compounds in this chemical series were more potent than theophylline as inhibitors of cyclic AMP and/or cyclic GMP phosphodiesterase (PDE) from RMC. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC revealed no statistically significant correlation between the inhibition of AIR and inhibition of cAMP- or cGMP-PDE. We conclude: (1) RHC 2963 and some of the related compounds are potent inhibitors of immunologic release of histamine from RMC with a mechanism of action similar to that of DSCG, and (2) inhibition of cAMP- or cGMP-PDE by these compounds is not the biochemical mechanism by which they inhibit AIR from RMC.
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PMID:Antiallergic activity profile in vitro of RHC 2963 and related compounds. 619 98


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