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)

Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA). Biologically active prostanoids deriving from AA include stable prostaglandins (PGs), e.g. PGE(2), PGF(2alpha), PGD(2), PGJ(2) as well as labile prostanoids, i.e. PG endoperoxides (PGG(2), PGH(2)), thromboxane A(2) (TXA(2)) and prostacyclin (PGI(2)). A "Rabbit aorta Contracting Substance" (RCS) played important role in discovering of labile PGs. RCS was discovered in the Vane's Cascade as a labile product released along with PGs from the activated lung or spleen. RCS was identified as a mixture of PG endoperoxides and thromboxane A(2). Stable PGs regulate the cell cycle, smooth muscle tone and various secretory functions; they also modulate inflammatory and immune reactions. PG endoperoxides are intermediates in biosynthesis of all prostanoids. Thromboxane A(2) (TXA(2)) is the most labile prostanoid (with a half life of 30 s at 37 degrees C). It is generated mainly by blood platelets. TXA(2) is endowed with powerful vasoconstrictor, cytotoxic and thrombogenic properties. Again the Vane's Cascade was behind the discovery of prostacyclin (PGI(2)) with a half life of 4 min at 37 degrees C. It is produced by the vascular wall (predominantly by the endothelium) and it acts as a physiological antagonist of TXA(2). Moreover, prostacyclin per se is a powerful cytoprotective agent that exerts its action through activation of adenylate cyclase, followed by an intracellular accumulation of cyclic-AMP in various types of cells. In that respect PGI(2) collaborates with the system consisting of NO synthase (eNOS)/nitric oxide free radical (NO)/guanylate cyclase/cyclic-GMP. Both cyclic nucleotides (c-AMP and c-GMP) act in synergy as two energetic fists which defend the cellular machinery from being destroyed by endogenous or exogenous aggressors. Recently, a new partner has been recognized in this endogenous defensive squadron, i.e. a system consisting of heme oxygenase (HO-1)/carbon monoxide (CO)/biliverdin/biliverdin reductase/bilirubin. The expanding knowledge on the pharmacological steering of this enzymic triad (PGI(2)-S/eNOS/HO-1) is likely to contribute to the rational therapy of many systemic diseases such as atherosclerosis, diabetes mellitus, arterial hypertension or Alzheimer diseases. The discovery of prostacyclin broadened our pathophysiological horizon, and by itself opened new therapeutic possibilities. Prostacyclin sodium salt and its synthetic stable analogues (iloprost, beraprost, treprostinil, epoprostenol, cicaprost) are useful drugs for the treatment of the advanced critical limb ischemia, e.g. in the course of Buerger's disease, and also for the treatment of pulmonary artery hypertension (PAH). In this last case a synergism between prostacyclin analogues and sildenafil (a selective phosphodiesterase 5 inhibitor) or bosentan (an endothelin ET-1 receptor antagonist) points our to complex mechanisms controlling pulmonary circulation. At the Jagiellonian University we have demonstrated that several well recognised cardiovascular drugs, e.g. ACE inhibitors (ACE-I), statins, some of beta-adrenergic receptor antagonists, e.g. carvedilol or nebivolol, anti-platelet thienopyridines (ticlopidine, clopidogrel) and a metabolite of vitamin PP--N(1)-methyl-nicotinamide--all of them are endowed with the in vivo PGI(2)-releasing properties. In this way, the foundations for the Endothelial Pharmacology were laid.
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PMID:Prostacyclin among prostanoids. 1827 80

To date, there is an increasing interest in the nitric oxide (NO) pathway as a potential pharmacological target to treat male lower urinary tract symptomatology (LUTS). In the transition zone of the human prostate, a dense nitrinergic innervation has been shown of the fibromuscular stroma, glandular epithelium and blood vessels. The expression of key proteins of the NO pathway, such as the endothelial and neuronal nitric oxide synthase (eNOS, nNOS), cGMP-degrading phosphodiesterase type 5 (PDE5) and cGMP-binding protein kinase (cGK), has also been demonstrated. The hypothesis that an impaired NO/cGMP-signaling may contribute to the pathophysiology of benign prostatic hyperplasia (BPH) is supported by the results from randomized, placebo-controlled clinical studies, indicating that NO donor drugs and PDE5-inhibitors sildenafil, tadalafil and vardenafil may be useful to treat storage and voiding dysfunctions resulting from LUTS in men. Thus, given a potential role of the NO-pathway in the prostate and/or in other parts of lower urinary tract (e.g. bladder), the enhancement of the NO signaling by NO donor drugs, PDE5 inhibitors or activators of the soluble guanylyl cyclase (sGC) may represent a new therapeutic strategy for the treatment of LUTS. This review serves to focus on the role of NO and the NO-dependent signaling in the control of smooth muscle function in the human prostate. Results from clinical trials in men with LUTS/BPH are also discussed.
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PMID:The nitric oxide pathway in the human prostate: clinical implications in men with lower urinary tract symptoms. 1860 96

Cyclic GMP-selective phosphodiesterase type 5 (PDE5) has been traditionally thought to play a little role in cardiac myocytes, yet recent studies using selective inhibitors such as sildenafil suggest it can potently modulate acute and chronic cardiac stress responses. To date, evidence for myocyte PDE5 expression and regulation has relied on small-molecule inhibitors and anti-sera, leaving open concerns regarding non-specific immune-reactivity, and off-target drug effects. To directly address both issues, we engineered a robust PDE5-gene silencing shRNA (inserted into miRNA-155 cassette) and DsRed-PDE5 fusion protein, both coupled to a CMV promoter and incorporated into adenoviral vectors. PDE5 mRNA and protein knock-down eliminated anti-sera positivity on immunoblots and fluorescent immuno-histochemistry in neonatal and adult cardiomyocytes, and suppressed PDE5 enzyme activity. Stimulation of myocyte hypertrophy by phenylephrine was blunted by PDE5 gene silencing in a protein kinase G dependent manner, and this effect was similar to that from sildenafil with no additive response by both combined. DsRed-PDE5 fusion protein expression showed normal z-band localization in adult myocytes but was diffused in eNOS(-/-) myocytes; echoing reported findings with anti-sera. PDE5 overexpression increased enzyme activity and amplified natriuretic peptide gene expression from phenylephrine stimulation. These data confirm PDE5 expression, activity, and targeted inhibition by sildenafil in cardiomyocytes, as well as the role of this PDE in cardiomyocyte hypertrophy modulation.
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PMID:Expression, activity, and pro-hypertrophic effects of PDE5A in cardiac myocytes. 1879 48

In addition to their canonical genomic action, sex hormones exhibit acute actions, which are designated as the non-genomic action. Non-genomic action takes only several seconds to minutes and takes place in a membrane-delimited signal pathway. We recently find in cardiac myocytes that testosterone, progesterone, and a high-concentration of 17beta-estradiol acutely shorten cardiac repolarization time by regulating L-type Ca(2+) current (I(Ca,L)) and slowly-activating delayed rectifier K(+) current (I(Ks)). The regulation of I(Ca,L) and I(Ks) occurs via the non-genomic pathway involving sequential activation of c-Src, PI3-kinase, Akt, and eNOS and resultant release of nitric oxide (NO), which occur in the caveolae/lipid raft domain. NO inhibits I(Ca,L), only when I(Ca,L) had been activated by sympathetic nervous system stimulation via antagonistic action between cAMP/protein kinase A and cGMP/protein kinase G/phosphodiesterase signals. NO likely to enhance I(Ks) in the basal condition via the protein s-nitrosylation mechanism. The non-genomic regulation by sex hormones is a novel regulatory mechanism of cardiac ion channels, and may be involved, in part, in the development of gender difference and dynamic fluctuation of QT(c) interval and arrhythmic risk during the menstrual cycle.
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PMID:Non-genomic regulation of cardiac ion channels by sex hormones. 1907 34

Sildenafil is the first commercially available selective inhibitor of phosphodiesterase-5 (PDE5) and is widely used for the treatment of erectile dysfunction. In recent years, investigations of the role of sildenafil in cardioprotection in animal models have received considerable interest. We evaluated whether sildenafil can attenuate cisplatin-induced nephrotoxicity in a rat experimental model. Male Sprague-Dawley rats were divided into five groups: control rats, sildenafil-control rats, cisplatin-injected rats (5 mg kg(-1) IP, single dose), sildenafil-treated cisplatin-injected rats (0.4 mg kg(-1), daily), and sildenafil+NG-nitro-l-arginine methyl ester hydrochloride (l-NAME)-treated rats. The molecular, functional, and structural parameters of the kidney were measured. At 96 h after cisplatin injection, serum levels of creatinine were lower in rats treated with both sildenafil+cisplatin compared with rats treated with cisplatin alone, and renal iNOS and eNOS expression was significantly higher in sildenafil+cisplatin-treated rats compared with rats treated with cisplatin alone (all P<0.05). Renal Bax gene and protein expression was significantly higher in cisplatin-treated rats compared with control rats, and sildenafil treatment significantly reduced the levels of Bax and increased the renal Bax/Bcl-2 ratio (P<0.05). Sildenafil treatment also reduced renal caspase-3 activation and TUNEL-positive apoptotic cells. These data suggest that sildenafil attenuates experimental cisplatin-induced nephrotoxicity by preventing apoptosis.
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PMID:Sildenafil attenuates renal injury in an experimental model of rat cisplatin-induced nephrotoxicity. 1915 27

Erectile dysfunction frequently coexists with coronary artery disease and has been proposed as a potential marker for silent coronary artery disease in type 2 diabetes. In the present study, we comparatively assessed the structural and functional changes of both penile arteries (PAs) and coronary arteries (CAs) from a prediabetic animal model. PAs and CAs from 17- to 18-wk-old obese Zucker rats (OZRs) and from their control counterparts [lean Zucker rats (LZRs)] were mounted in microvascular myographs to evaluate vascular function, and stained arteries were subjected to morphometric analysis. Endothelial nitric oxide (NO) synthase (eNOS) protein expression was also assessed. The internal diameter was reduced and the wall-to-lumen ratio was increased in PAs from OZRs, but structure was preserved in CAs. ACh-elicited relaxations were severely impaired in PAs but not in CAs from OZRs, although eNOS expression was unaltered. Contractions to norepinephrine and 5-HT were significantly enhanced in both PAs and CAs, respectively, from OZRs. Blockade of NOS abolished endothelium-dependent relaxations in PAs and CAs and potentiated norepinephrine and 5-HT contractions in arteries from LZRs but not from OZRs. The vasodilator response to the phosphodiesterase 5 inhibitor sildenafil was reduced in both PAs and CAs from OZRs. Pretreatment with SOD reduced the enhanced vasoconstriction in both PAs and CAs from OZRs but did not restore ACh-induced relaxations in PAs. In conclusion, the present results demonstrate vascular inward remodeling in PAs and a differential impairment of endothelial relaxant responses in PAs and CAs from insulin-resistant OZRs. Enhanced superoxide production and reduced basal NO activity seem to underlie the augmented vasoconstriction in both PAs and CAs. The severity of the structural and functional abnormalities in PAs might anticipate the vascular dysfunction of the more preserved coronary vascular bed.
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PMID:Differential structural and functional changes in penile and coronary arteries from obese Zucker rats. 1954 83

In this study, we examine the effects of tissue inhibitor of metalloproteinases-2 (TIMP-2) on the phosphorylation status of specific phosphotyrosine residues on the vascular endothelial cell growth factor receptor-2 (VEGFR-2) cytoplasmic tail and examine the effects on associated downstream signaling pathways. To focus on metalloproteinase-independent mechanisms, we used the TIMP-2 analog known as Ala+TIMP-2 that is deficient in matrix metalloproteinase-inhibitory activity. Our experiments are designed to compare the effects of VEGF-A stimulation with or without Ala+TIMP-2 pretreatment, as well as basal responses in human microvascular endothelial cells. Our results show that Ala+TIMP-2 selectively alters the phosphorylation pattern of VEGFR-2 after VEGF-A stimulation and disrupts the downstream activation of PLC-gamma, Ca(+2) flux, Akt, and eNOS, as well as decreasing cGMP levels. Moreover, we observed an Ala+TIMP-2-induced reduction in cGMP levels typically elevated by exogenous NO donors implicating Ala+TIMP-2 in the direct activation of an isobutylmethylxanthine (IBMX)-sensitive cGMP phosphodiesterase activity. TIMP-2 suppression of endothelial mitogenesis and angiogenesis involves at least two mechanisms, one mediated by protein tyrosine phosphatase inhibition of VEGFR-2 activation as well as downstream signaling and a second mechanism involving direct activation of an IBMX-sensitive phosphodiesterase activity.
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PMID:TIMP-2 modulates VEGFR-2 phosphorylation and enhances phosphodiesterase activity in endothelial cells. 2008 57

Increasing NO bioavailability improves hepatic endothelial dysfunction, which ameliorates intrahepatic resistance and portal hypertension. Acute administration of sildenafil increases hepatic production of NO with a reduction in hepatic sinusoid resistance in cirrhotic patients and enhances the vasorelaxation response to NO in cirrhotic rat livers. However, the mechanisms were still unclear. Therefore, our present study aims to evaluate the effects and mechanisms of administration of sildenafil for 1 week on the hepatic microcirculation of cirrhotic rats. Cirrhosis was induced by bile duct ligation with sham-operated rats serving as normal controls. Intrahepatic resistance was evaluated by in situ liver perfusion. Expression of phospho-eNOS (endothelial NO synthase), iNOS (inducible NO synthase), phospho-Akt, PDE-5 (phosphodiesterase-5) and sGC (soluble guanylate cyclase) were determined by Western blot analysis. Biosynthesis of BH4 (tetrahydrobiopterin) and GTPCH-I (GTP cyclohydrolase I) activity were examined by HPLC. Intravital microscopy was used to observe the direct change in hepatic microcirculation. In cirrhotic rat livers, sildenafil treatment increased hepatic sinusoid volumetric flow, NO bioavailability, BH4, GTPCH-I activity, and the protein expression of phospho-Akt, phospho-eNOS and sGC. These events were associated with reduced protein expression of PDE-5, portal perfusion pressure and portal vein pressure. In contrast, sham rats did not produce any significant change in these measurements. In conclusion, sildenafil treatment improves endothelial dysfunction by augmenting NO bioavailability in the hepatic microcirculation.
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PMID:Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability. 2013 96

Hypercholesterolemia is associated with decreased nitric oxide (NO) bioavailability and endothelial dysfunction, a phenomenon thought to have a major role in the altered cerebral blood flow evident in stroke. Therefore, strategies that increase endothelial NO production have potential utility. Vascular reactivity of the middle cerebral artery (MCA) from C57BL/6J wild-type (WT) mice, apolipoprotein-E knockout (ApoE(-/-)) mice, and mice treated with the phosphodiesterase inhibitor cilostazol (100 mg/kg) was analyzed using the tension myograph. Contractile responses to endothelin-1 were significantly enhanced in MCA from ApoE(-/-) mice compared with WT mice (P<0.01), an effect absent in cilostazol-treated ApoE(-/-) mice. Acetylcholine-induced relaxation (which is entirely NO-dependent) was significantly impaired in MCA of ApoE(-/-) mice compared with WT mice (P<0.05), again an effect prevented by cilostazol treatment. Endothelial NOS phosphorylation at Ser(1179) was decreased in the aorta of ApoE(-/-) mice compared with WT mice (P<0.05), an effect normalized by cilostazol. Taken together, our data suggest that the endothelial dysfunction observed in MCA associated with hypercholesterolemia is prevented by cilostazol, an effect likely due to the increase in eNOS phosphorylation and, therefore, activity.
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PMID:Alterations in nitric oxide and endothelin-1 bioactivity underlie cerebrovascular dysfunction in ApoE-deficient mice. 2023 80

The aim of the present study was to evaluate the effects of phosphodiesterase 5 inhibitors on renal tubular apoptosis and also on expressions of endothelial and inducible nitric oxide synthases (eNOS and iNOS) in the ipsilateral kidney after partial unilateral ureteral obstruction (PUUO) in a rat model. Forty Wistar albino rats were divided into five groups. In Groups 1-4, left experimental PUUO was created. Sildenafil, vardenafil, and tadalafil were administrated to the rats of Groups 2-4, respectively. The pills were orally given to the rats for 30 days. Group 5 was defined as sham. After 30 days, all rats were sacrificed, and nephrectomy was performed. The renal specimens were examined histopathologically. Left hydroureteronephrosis was observed in Groups 1-4. Mean apoptotic cell count and eNOS and iNOS levels were significantly increased in Group 1 when compared with the other groups. The rats in Groups 2-4 showed significantly decreased apoptotic cell count and eNOS and iNOS values in the renal tubular tissue in accordance with Group 1 (p<0.05). There were significant differences in apoptotic cell counts between sildenafil group and the other two study groups. The sildenafil group demonstrated lesser apoptotic cell count than the vardenafil (p=0.021) and tadalafil (p=0.009) groups. PUUO increases the renal tubular apoptosis and elevates NOS concentrations in renal tubular tissue after PUUO. Phosphodiesterase 5 inhibitors have a protective effect against the tubular apoptosis.
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PMID:Phosphodiesterase 5 inhibitors attenuate renal tubular apoptosis after partial unilateral ureteral obstruction: an experimental study. 2132 87


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