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. The effects of phosphodiesterase (PDE) inhibition and forskolin pretreatment on the contractile responses of guinea-pig urinary bladder strips to electrical field stimulation, carbachol, ATP and KCl were studied. 2. Inhibition of cyclic AMP-specific PDE4 isozymes by rolipram significantly reduced the contractile response of bladder strips to field stimulation. Rolipram also suppressed the contractile response to low concentrations of carbachol, but potentiated the response to high concentrations. The contractile response to ATP was significantly reduced by rolipram treatment, but that to KCl was unaltered. 3. Inhibition of cyclic GMP-specific PDE5 isozymes by zaprinast had no effects on the contractile response of bladder strips to field stimulation, ATP or KCl. Zaprinast suppressed the contractile responses to 1 microM carbachol and potentiated the response to high concentrations. 4. Contractile responses to field stimulation and to carbachol after pretreatment with the adenylyl cyclase activator, forskolin, were qualitatively similar to those caused by rolipram treatment. beta-Adrenoceptor blockade with propranolol partially reversed the inhibitory effects of rolipram on the response to field stimulation. 5. Rolipram significantly reduced the contractile response of bladder strips from sensitized guinea-pigs to ovalbumin challenge, but zaprinast was ineffective. PDE inhibition had similar effects on the responsiveness of control and of sensitized guinea-pig bladder strips to field stimulation, carbachol, ATP and KCl. 6. The data suggest that the contractile response of guinea-pig bladder strips can be modified by increases in cyclic AMP levels.
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PMID:The role of cyclic nucleotides in guinea-pig bladder contractility. 928 1

We have previously reported that concanavalin A (ConA) stimulation of rat thymocytes induces an increase in the cellular phosphatidic acid mass as well as a change in its fatty acid composition. An increase in phosphodiesterase (PDE) activity, mostly due to cAMP-specific (PDE4) isoforms, has also been observed in thymocytes stimulated by ConA. Furthermore, phosphatidic acid was able to stimulate PDE4 activity in vitro. In the present study, cAMP levels have been shown to decrease upon ConA stimulation of thymocytes. Decreasing phosphatidic acid level using diacylglycerol kinase inhibitors induced a parallel decrease of the ConA-stimulated cAMP-specific PDE activity in these cells. Analyses of phosphatidic acid molecular species in cells stimulated for 5 min by ConA revealed a significant increase in 1-stearoyl-2-arachidonoyl-sn-glycerol-3-phosphate and a relative decrease in the other molecular species of phosphatidic acid, mainly species containing palmitate. On the other hand, phosphatidic acid extracted from ConA-stimulated cells activated more efficiently the recombinant PDE4A5 isoform in vitro, as compared to phosphatidic acid extracted from unstimulated cells. In addition, phosphatidic acid species containing unsaturated fatty acids were stimulatory, while those containing two saturated fatty acids had only a marginal effect on the enzyme activity. Taken together, these data suggest that the mitogenic stimulation of thymocytes is accompanied by the synthesis of peculiar phosphatidic acid molecular species able to activate a PDE4 isoform. This activation might be of physiological relevance since cAMP is a major negative effector of the mitogenic response.
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PMID:Selective stimulation of a cAMP-specific phosphodiesterase (PDE4A5) isoform by phosphatidic acid molecular species endogenously formed in rat thymocytes. 928 42

1. The involvement of cyclic AMP-dependent protein kinase (PKA) and cyclic GMP-dependent protein kinase (PKC) in the effects of cyclic AMP-elevating agents on vascular smooth muscle relaxation, cyclic nucleotide dependent-protein kinase activities and ATP-induced calcium signalling ([Ca2+]i was studied in rat aorta. Cyclic AMP-elevating agents used were a beta-adrenoceptor agonist (isoprenaline), a phosphodiesterase 3 (PDE3) inhibitor (SK&F 94120) and a PDE4 inhibitor (rolipram). 2. In rat intact aorta, the relaxant effect induced by isoprenaline (0.01-0.03 microM) was decreased by a specific inhibitor of PKA, H-89, whereas a specific inhibitor of PKG, Rp-8-Br-cyclic GMPs, was without effect. NO significant difference in PKA and PKG activity ratios was detected in aortic rings when isoprenaline 10 microM was used. At the same concentration, isoprenaline did not modify ATP-induced changes in [Ca2+]i in smooth muscle cells. Neither H-89 nor Rp-8-Br-cyclic GMPs modified this response. These findings suggest that PKA is only involved in the relaxant effect induced by low concentrations of isoprenaline (0.01-0.3 microM), whereas for higher concentrations, other mechanisms independent of PKA and PKG were involved. 3. The relaxant effects induced by SK&F 94120 and rolipram were inhibited by Rp-8-Br-cyclic GMPS with no significant effect of H-89. Neither SK&F 94120, nor rolipram at 30 microM significantly modified the activity ratios of PKA and PKG. Rolipram inhibited the ATP-induced transient increase in [Ca2+]i. This decrease was abolished by Rp-8-Br-cyclic GMPS whereas H-89 had no significant effect. These results suggests that PKG is involved in the vascular effects induced by the inhibitors of PDE3 and PDE4. Moreover, since it was previously shown that PDE3 and PDE4 inhibitors only increased cyclic AMP levels with no change in cyclic GMP level, these data also suggest a cross-activation of PKG by cyclic AMP in rat aorta. 4. The combinations of 5 microM SK&F 94120 with rolipram markedly potentiated the relaxant effect of rolipram. This relaxation was decreased by H-89 and not significantly modified by Rp-8-Br-cyclic GMPS. Moreover, the association of the two PDE inhibitors significantly increased the activity ratio of PKA without changing the PKG ratio. The present findings show that PKA rather than PKG is involved in this type of vasorelaxation. The differences in the participation of PKA vs PKG observed when inhibitors of PDE3 and PDE4 were used alone or together could be due to differences in the degree of accumulation of cyclic AMP, resulting in the activation of PKA or PKG which are differently localized in the cell. 5. These findings support for both PKA and PKG in cyclic AMP-mediated relaxation in raT aorta. Their involvement depends on the cellular pathway used to increase the cyclic AMP level.
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PMID:Involvement of cyclic nucleotide-dependent protein kinases in cyclic AMP-mediated vasorelaxation. 929 42

1. Rat cultured aortic vascular smooth muscle cells (VSMC) express both cyclic GMP-inhibited cyclic AMP phosphodiesterase (PDE3) and Ro 20-1724-inhibited cyclic AMP phosphodiesterase (PDE4) activities. By utilizing either cilostamide, a PDE3-selective inhibitor, or Ro 20-1724, a PDE4-selective inhibitor, PDE3 and PDE4 activities were shown to account for 15% and 55% of total VSMC cyclic AMP phosphodiesterase (PDE) activity. 2. Treatment of VSMC with either forskolin or 8-bromo-cyclic AMP caused significant concentration- and time-dependent increases in total cellular cyclic AMP PDE activity. Using cilostamide or Ro 20-1724, we demonstrated that both PDE3 and PDE4 activities were increased following forskolin or 8-bromo-cyclic AMP treatment, with a relatively larger effect observed on PDE3 activity. The increase in cyclic AMP PDE activity induced by forskolin or 8-bromo-cyclic AMP was inhibited by actinomycin D or cycloheximide, demonstrating that new mRNA synthesis and protein synthesis were required. An analogue of forskolin which does not activate adenylyl cyclase (1,9-dideoxyforskolin) or an analogue of cyclic GMP (8-bromo-cyclic GMP) did not affect total cyclic AMP PDE activity. 3. Incubation of VSMC with 8-bromo-cyclic AMP for 16 h caused a marked rightward shift in the concentration-response curves for both isoprenaline- and forskolin-mediated activation of adenylyl cyclase. A role for up-regulated cyclic AMP PDE activity in this reduced potency is supported by our observation that cyclic AMP PDE inhibitors (IBMX, cilostamide or Ro 20-1724) partially normalized the effects of isoprenaline or forskolin in treated cells to those in untreated cells. 4. We conclude that VSMC cyclic AMP PDE activity is increased following long-term elevation of cyclic AMP and that increases in PDE3 and PDE4 activities account for more than 70% of this effect. Furthermore, we conclude that increases in cyclic AMP PDE activity contribute to the reduced potency of isoprenaline or forskolin in treated VSMC. These results have implications for long-term use of cyclic AMP PDE inhibitors as therapeutic agents.
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PMID:Cyclic AMP-mediated regulation of vascular smooth muscle cell cyclic AMP phosphodiesterase activity. 931 30

A selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) 4, rolipram, markedly enhanced the forskolin-induced increase of intracellular dopamine and dihydroxyphenylacetate (DOPAC, a metabolite of dopamine) levels in primary cultured rat mesencephalic neurons and the forskolin-induced increase of dopamine and DOPAC in extracellular medium. Selective inhibitors of PDE2, PDE3, PDE5 and PDE6 did not have such a promoting effect, and the PDE1 inhibitor vinpocetine and W-7 caused dopamine depletion in the neurons. These findings suggested that PDE4 plays a major role in regulating the intracellular cAMP level to control the dopamine biosynthesis in mesencephalic neurons, whereas PDE1 regulates dopamine release instead.
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PMID:Rolipram, a selective inhibitor of phosphodiesterase type 4, pronouncedly enhanced the forskolin-induced promotion of dopamine biosynthesis in primary cultured rat mesencephalic neurons. 933 90

The effects of denbufylline, a xanthine derivative with selective inhibitory activity on the phosphodiesterase (PDE) 4 isoenzyme, on bone loss in Walker 256/S-bearing rats and on mineralized nodule formation and osteoclastlike cell formation in bone marrow culture systems were examined. Serial oral administrations of denbufylline inhibited the decrease in the bone mineral density of femurs from Walker 256/S-bearing rats, without influence on the healthy rats. Denbufylline restored the bone mass and the number of osteoclasts and osteoblasts per trabecular surface in the femur metaphysis. Among PDE inhibitors, only PDE4-selective inhibitors increased the number of mineralized nodules and decreased the number of osteoclastlike cells in the in vitro bone marrow culture systems, and dibutyryl cyclic AMP mimicked these effects in the in vitro systems. These results suggest that the PDE4 isoenzyme may play an important role in bone turnover through cyclic AMP and that its inhibitors are candidates for therapeutic drugs for the bone loss diseases.
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PMID:Reduction of bone loss by denbufylline, an inhibitor of phosphodiesterase 4. 933 78

Four closely related cyclic-nucleotide specific phosphodiesterase (PDE4) genes have been identified in both humans and rats: PDE4A, 4B, 4C and 4D. We have now cloned cDNAs for multiple splice variants of human PDE4C. Two splice variants, PDE4C-791 and PDE4C-426, were isolated from a fetal lung library. The longest open reading frame (ORF) of 791 amino acids (aa) is encoded by PDE4C-791, which is similar to a recently described cDNA [Engels, P., Sullivan, M., Muller, T. and Lubbert, H. FEBS Lett. 358 (1995) 305-10], except that an alternative 5'-end sequence upstream of the first methionine extends the PDE4C-791 ORF by 79 aa. The PDE4C-426 variant contains 3 insertions that are located 5' to the catalytic domain and encode several in-frame stop codons. The predicted 426 aa protein initiates at a methionine 365 aa within PDE4C-791. A baculovirus clone starting at this methionine expressed an enzymatically active protein. Two additional splice variants, PDE4C-delta54 and PDE4C-delta109, were found in testis mRNA. PDE4C-delta54 contained a novel 5'-end region and a deletion of 162 nt; the predicted protein deletes 54 aa from the amino-terminal region. The PDE4C-delta54 protein produced in baculovirus-infected cells was enzymatically active and sensitive to PDE4-specific inhibitors. The PDE4C-delta109 protein is similar to PDE4C-delta54 but has an additional 55 aa deleted in the catalytic domain; it lacked enzymatic activity. Analysis of uncloned total mRNA from 4 tissue sources by polymerase chain reaction (PCR) confirmed the presence of mRNAs with the two deletions and three insertions that we observed in cDNA clones. The PDE4C-delta54 variant was found only in testis and the 5'-extended region of PDE4C-791 was seen only in lung and the melanoma cell line G361. Hence, tissue-specific expression of various PDE4C isoforms should be considered in understanding how these gene products modulate cellular responses to cAMP.
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PMID:Multiple splice variants of phosphodiesterase PDE4C cloned from human lung and testis. 934 24

CP-80,633, a selective phosphodiesterase (PDE) 4 inhibitor, potently reverses histamine bronchoconstriction in anesthetized guinea pigs (ED50 10 micrograms/kg) but only weakly relaxes histamine-constricted guinea pig trachea (EC50 137 microM). Using CP-80,633 as a prototype PDE4 inhibitor, we evaluated the hypothesis that bronchodilation induced by PDE4 inhibitors is not mediated by direct relaxation of airway smooth muscle. In anesthetized guinea pigs, a bronchodilatory dose of CP-80,633 did not increase plasma catecholamines, nor did propranolol pretreatment significantly alter the ability of CP-80,633 to reverse histamine bronchoconstriction. In an isolated organ system, the activity of bronchorelaxants may be attenuated by the lack of endogenous activators of adenylyl cyclase or by decreased levels of intracellular cyclic nucleotides. Pretreatment with the beta-adrenoceptor agonist, salbutamol, or the PDE3 inhibitor imazodan did not potentiate the bronchorelaxant ability of CP-80,633. Milrinone pretreatment increased the potency of CP-80,633 to relax carbachol-constricted tracheal rings, but only at concentrations where nonspecific effects have been reported. By comparing the bronchorelaxant abilities of PDE inhibitors in tracheal rings with or without epithelium, we determined that the epithelium did not serve as a barrier to drug penetration. In conclusion, CP-80,633 is a potent bronchodilator in vivo, whose activity is neither mediated by direct airway smooth muscle relaxation nor dependent upon endogenous catecholamines.
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PMID:Differential in vivo and in vitro bronchorelaxant activities of CP-80,633, a selective phosphodiesterase 4 inhibitor. 936 15

5'-Rapid amplification of cDNA ends, done on poly(A)+ RNA from human U87 cells, was used to identify 420 bp of novel 5' sequence of a PDE4B cAMP-specific phosphodiesterase (PDE). This identified an open reading frame encoding a putative 721-residue 'long-form' PDE4B splice variant, which we term HSPDE4B3. HSPDE4B3 differs from the two known PDE4B forms by virtue of its unique 79-residue N-terminal region, compared with the unique N-terminal regions of 94 and 39 residues found in HSPDE4B1 and HSPDE4B2 respectively. In transfected COS7 cells the two long forms, HSPDE4B1 and HSPDE4B3, had molecular masses of approx. 104 and approx. 103 kDa respectively. Expressed in COS-7 cells, the three HSPDE4B isoforms were found in the high-speed supernatant (cytosol) fraction as well as both the high-speed pellet (P2) and low-speed pellet (P1) fractions. All isoforms showed similar Km values for cAMP hydrolysis (1.5-2.6 microM). The maximal activities of the soluble cytosolic activity of the two long forms were very similar, whereas that of the short form, HSPDE4B2, was approx. 4-fold higher. Particulate-associated HSPDE4B1 and HSPDE4B2 were less active (approx. 40%) than their cytosol forms, whereas particulate HSPDE4B3 was similar in activity to its cytosolic form. Particulate and cytosolic forms of HSPDE4B1 and HSPDE4B3 were similarly inhibited by rolipram {4-[3-(cyclopentoxyl)-4-methoxyphenyl]-2-pyrrolidone}, the selective inhibitor of PDE4 (IC50 0.05-0.1 microM), whereas particulate-associated HSPDE4B2 was profoundly (approx. 10-fold) more sensitive (IC50 0.02 microM) to rolipram inhibition than its cytosolic form (IC50 0.2 microM). The various particulate-associated HSPDE4B isoforms showed very different susceptibilities to solubilization with the detergent Triton X-100 and high NaCl concentration. A novel cDNA, called pRPDE74, was obtained by screening a rat olfactory lobe cDNA library. This contained an open reading frame encoding a 721-residue protein that showed approx. 96% amino acid identity with HSPDE4B3 and is proposed to reflect the rat homologue of this human enzyme and is thus called RNPDE4B3. Alternative splicing of mRNA generated from both the human and rat PDE4B genes produces long and short splice variants that have unique N-terminal splice regions. It is suggested that these alternatively spliced regions determine changes in the maximal catalytic activity of the isoforms, their susceptibility to inhibition by rolipram and mode of interaction with particulate fractions.
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PMID:Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase, HSPDE4B3. 937 14

In previous studies we observed that inhibition of cyclic 3',5'-nucleotide phosphodiesterase (PDE) isozymes, namely isozyme PDE3, suppresses proliferation of rat renal glomerular mesangial cells in vitro and in vivo. To determine whether activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway coupled to specific PDE isozymes modulates accelerated proliferation of renal epithelial cells, we investigated the effect of selective PDE isozyme inhibition on renal epithelial cell proliferation induced in rats by injection of folic acid (FA). In extracts from suspensions of renal cortical tubules, cAMP was metabolized predominantly by isozyme PDE4; activity of PDE3 was about three times lower. The increase in proliferative activity of renal cortical tissue from FA-injected rats, evaluated by immunostaining with Mib-1 antibody, was limited to tubular epithelial cells. Administration of the PDE3 inhibitors cilostazol or cilostamide together with the PDE4 inhibitor rolipram blocked mitogenic synthesis of DNA, as determined by (3H)-thymidine incorporation into renal cortical DNA, in FA-treated rats. FA injection caused an increase of more than 10-fold in proliferating cell nuclear antigen (PCNA) in renal cortical tissue; administration of the potent PDE3 inhibitor lixazinone or, to a lesser degree, cilostazol suppressed these high PCNA levels, whereas rolipram alone had no effect. The results indicate that FA-stimulated in vivo proliferation of renal tubular epithelial cells is down-regulated by activation of a cAMP-PKA signaling pathway linked to PDE3 isozymes. These observations are consistent with the notion that negative crosstalk between cAMP signaling and mitogen-stimulated signaling pathways regulates mitogenesis of renal cells of different terminal differentiation, including tubular epithelial cells.
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PMID:Inhibitors of cyclic nucleotide phosphodiesterase isozymes block renal tubular cell proliferation induced by folic acid. 939 Jun 32


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