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)

The key event in penile erection is relaxation of the cavernous smooth muscle. As phosphodiesterases (PDEs) are key enzymes of the signaling pathway, knowledge about cavernous PDEs is of major importance in understanding the effects and side-effect profile of new and selective pharmacological agents for erectile dysfunction. Experimental studies revealed that gene transcripts of 14 different PDE isoenzymes are present in human cavernous tissue. Of these, PDE3 and 5 have the most prominent functional role. The effects and side effects of clinically available PDE5 inhibitors can be explained both by the distribution pattern of these two isoenzymes in various tissues, by direct inhibition of PDE5 and indirect inhibition of PDE3 in various tissues, and by the putative selectivity for a cavernous-specific PDE splice variant.
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PMID:Phosphodiesterase inhibitors for the treatment of erectile dysfunction. 1243 Oct 25

1. Chronic hypoxic treatment of rats (to induce pulmonary hypertension, PHT) for 14 days increased cGMP-inhibited cAMP specific phosphodiesterase (PDE3) and cGMP binding cGMP specific phosphodiesterase (PDE5) activities in pulmonary arteries. The objective of this study was to establish the molecular basis for these changes in both animal and cell models of PHT. In this regard, RT-PCR and quantitative Western blotting analysis was applied to rat pulmonary artery homogenates and human pulmonary "artery" smooth muscle cell (HPASMC) lysates. 2. PDE3A/B gene transcript levels were increased in the main, first, intrapulmonary and resistance pulmonary arteries by chronic hypoxia. mRNA transcript and protein levels of PDE5A2 in the main and first branch pulmonary arteries were also increased by chronic hypoxia, with no effect on PDE5A1/A2 in the intra-pulmonary and resistance vessels. 3. The expression of PDE3A was increased in HPASMCs maintained under chronic hypoxic conditions for 14 days. This may be mediated via a protein kinase A-dependent mechanism, as treatment of cells with Br-cAMP (100 microM) mimicked chronic hypoxia in increasing PDE3A expression, while the PKA inhibitor, H8 peptide (50 microM) abolished the hypoxic-dependent increase in PDE3A transcript. 4. We also found that the treatment of HPASMCs with the inhibitor of kappaB degradation Tosyl-Leucyl-Chloro-Ketone (TLCK, 50 microM) reduced PDE5 transcript levels, suggesting a role for this transcription factor in the regulation of PDE5 gene expression. 5. Our results show that increased expression of PDE3 and PDE5 might explain some changes in vascular reactivity of pulmonary vessels from rats with PHT. We also report that NF-kappaB might regulate basal PDE5 expression.
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PMID:Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. 1246 27

We have previously reported that cyclic guanosine-3',5'-monophosphate (cGMP) protects spinal motor neurons against acute reactive oxygen species (ROS)-induced toxicity but not against chronic ROS-induced or glutamate (Glu)-induced toxicity. In this study, we investigated the effects of phosphodiesterase (PDE) inhibitors on the survival of cultured spinal motor neurons. Selective PDE5 inhibitors (dipyridamole, T-1032, and zaprinast) as well as a nonselective PDE inhibitor (aminophylline) protected motor and nonmotor neurons against both acute ROS-induced and chronic Glu-induced neurotoxicity, whereas selective inhibitors of PDE1-4 offered no protection. 8-Bromo-cGMP (8br-cGMP), a cGMP analogue, protected both motor and nonmotor neurons against acute ROS-induced toxicity but protected only nonmotor neurons against chronic Glu-induced toxicity. This neuroprotection was blocked by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Immunohistochemical staining confirmed that PDE5 and PKG are located in almost all rat lumbar spinal neurons. Furthermore, semiquantitative analysis of the immunostaining intensity revealed that PDE5 was more abundant in motor neurons than in nonmotor neurons. Our results suggest that this difference in the amount of PDE5 may be responsible for the vulnerability of motor neurons to chronic excitotoxicity. In addition, the results of this study raise the possibility that PDE5 inhibitors might be used as a treatment for amyotrophic lateral sclerosis.
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PMID:Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons. 1254 4

cGMP-specific, cGMP-binding phosphodiesterase (PDE5) regulates such physiological processes as smooth muscle relaxation and neuronal survival. PDE5 contains two N-terminal domains (GAF A and GAF B), but the functional roles of these domains have not been determined. Here we show that recombinant PDE5 is activated directly upon cGMP binding to the GAF A domain, and this effect does not require PDE5 phosphorylation. PDE5 exhibited time- and concentration-dependent reversible activation in response to cGMP, with the highest activation (9- to 11-fold) observed at low substrate concentrations (0.1 micro M cGMP). A monoclonal antibody directed against GAF A blocked cGMP binding, prevented PDE5 activation and decreased basal activity, revealing that PDE5 in its non-activated state has low intrinsic catalytic activity. Activated PDE5 showed higher sensitivity towards sildenafil than non-activated PDE5. The stimulatory effect of cGMP binding on the catalytic activity of PDE5 suggests that this mechanism of enzyme activation may be common among other GAF domain-containing proteins. The data also suggest that development of agonists and antagonists of PDE5 activity based on binding to this site might be possible.
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PMID:PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. 1255 48

To understand changes in cyclic nucleotide metabolism in muscle disease states, the expression of phosphodiesterase (PDE) isozymes in normal mouse leg muscle was examined. Four subcellular fractions were generated by differential centrifugation at 10,000 x g and 100,000 x g. cAMP PDE activity was found predominately in the soluble fractions, while cGMP PDE activity was more evenly distributed amongst soluble and particulate fractions. Pharmacological inhibitors demonstrate that PDE4 represents the major cAMP hydrolyzing activity and PDE2 represents the major cGMP hydrolyzing activity in mouse leg muscle. PDE1 is expressed at low levels, while PDE3 and PDE5 are intermediate. Between 20 and 40% of total PDE activity remained in the presence of inhibitors for PDE1-PDE5, indicating that other PDE families contribute to the total PDE pool. Reverse-transcription PCR with family-specific primers showed expression of mRNA for PDE7-PDE9, supporting this conclusion. Total PDE activity was found to be elevated in tissue extracts from a mouse model of Duchenne's muscular dystrophy.
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PMID:Cyclic nucleotide phosphodiesterase isozymes expressed in mouse skeletal muscle. 1256 38

Erectile dysfunction (ED) and cardiovascular disease share many of the same risk factors and have some common elements of pathophysiology. Clinically, they often coexist. Another link between the two conditions is that sildenafil, the first oral therapeutic agent effective in treating ED, has been shown to potentiate the hypotensive effects of nitrates, a potentially serious side effect. Nitrates are commonly used in the treatment of coronary artery disease. As such, sildenafil (and, likely, other new phosphodiesterase type 5 [PDE5] inhibitors) is contraindicated in men who use nitrate medications. This article will examine the risk of an acute coronary event during sexual activity, and review an algorithm for evaluating the cardiac risk of a patient with ED. The interaction between PDE5 inhibitors and cardiac medications will be discussed, along with guidelines for using sildenafil in men with cardiac disease.
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PMID:Cardiovascular safety of PDE5 inhibitors. 1262 47

(1) Cyclic GMP (cGMP) has been shown to be an important modulator of cardiac contractile function. A major component of cGMP regulation of contractility is cGMP-mediated inhibition of the cardiac calcium current (I(Ca)). An under-appreciated aspect of cyclic nucleotide signalling is hydrolysis of the cyclic nucleotide (i.e., breakdown by phosphodiesterases (PDEs)). The role of cGMP hydrolysis in regulating I(Ca) has not been studied. Thus the purpose of this study was to investigate if inhibition of cGMP hydrolysis can modulate I(Ca) in isolated guinea-pig ventricular myocytes. (2) Zaprinast, a selective inhibitor of cGMP-specific PDE (PDE5), caused a significant increase in cGMP levels in myocytes, but was without affect on basal or beta-adrenergic stimulated cAMP levels (consistent with its actions as a specific inhibitor of PDE5). (3) Zaprinast inhibited I(Ca) that was pre-stimulated with cAMP elevating agents (isoproterenol, a beta-adrenergic agonist; or forskolin, a direct activator of adenylate cyclase). The effect of zaprinast was greatly reduced by KT5823, an inhibitor of cGMP-dependent protein kinase (PKG). (4) Zaprinast also significantly inhibited basal I(Ca) when perforated-patch or whole-cell recording with physiological pipette calcium concentration (10(-7) M) was used. However, this effect was not observed when using standard calcium-free whole-cell recording conditions. (5) These results indicate that inhibition of cGMP hydrolysis can decrease both basal and cAMP-stimulated I(Ca). Thus, cGMP hydrolysis may likely be an important step for physiological modulation of I(Ca). This regulation may also be important in disease states in which cGMP production is increased and PDE5 expression is altered, such as heart failure.
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PMID:Inhibition of cyclic GMP hydrolysis with zaprinast reduces basal and cyclic AMP-elevated L-type calcium current in guinea-pig ventricular myocytes. 1264 1

Cyclic GMP (cGMP) has been implicated in the modulation of long-term potentiation (LTP) and depression (LTD) in the hippocampus. Transcripts for subunits of several types of cGMP specific phosphodiesterase are found in the mammalian brain but their relative role in hippocampal function is unclear. The retinal degeneration (rd) mutation in the gene encoding the PDE6B subunit causes a loss of function in PDE6 enzyme and in adult mice homozygous to the mutation it causes blindness. We have used this natural mutation, and the cGMP phosphodiesterase inhibitor zaprinast, in wild-type and rd/rd mouse littermates to investigate whether PDE5 and/or PDE6 regulates excitatory synaptic transmission in the hippocampus. Mice were genotyped using two independent PCR methods. Glutamate-mediated synaptic transmission in the CA1 region or dentate gyrus was unaffected in hippocampal brain slices from mice carrying the rd mutation. Similarly the facilitation of synaptic events by paired-pulse stimuli, and LTP induced by a theta-burst (10 bursts of four events at 100 Hz with a 200-ms inter-burst interval) were normal in rd/rd mice. Inhibition of cGMP-specific PDE activity by zaprinast (10 microM, an inhibitor of PDE5 and PDE6) induced a slowly developing and sustained depression of field synaptic potentials that was quantitatively similar in both wild-type and rd/rd mice. Thus in the CA1 region synaptic plasticity is likely to be regulated by the PDE5 rather than the PDE6 isoform.
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PMID:Hippocampal synaptic plasticity in mice carrying the rd mutation in the gene encoding cGMP phosphodiesterase type 6 (PDE6). 1265 Sep 75

The SAR of a series of beta-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function.
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PMID:Design, synthesis and biological activity of beta-carboline-based type-5 phosphodiesterase inhibitors. 1266 4

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochemical mechanisms responsible for the increased survival by an analysis of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochemistry was used to determine cyclic GMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatography and the pharmacological sensitivity to exisulind, and additional known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.
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PMID:Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival. 1274 10


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