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)

Natriuretic peptides (NP) activate particulate guanylate cyclase (pGC) and nitric oxide (NO) activates soluble guanylate cyclase (sGC). Both guanylate cyclases catalyse the formation of the same second messenger, cyclic guanosine 3',5'-monophosphate (cGMP), which activates the cGMP-dependent protein kinases (PKG). PKG then starts a signalling cascade that mediates many cardiovascular and renal effects, such as smooth muscle relaxation and diuresis. Many cell types possess both sGC and pGC. Because both GC-cGMP systems play complementary roles, an interaction between the two pathways might represent an important physiological control mechanism. In this report we demonstrate an interaction between the two pathways. C-type natriuretic peptide (CNP) decreased the beta-subunit of sGC (sGC-beta) steady-state protein levels and enzymatic activity in cultured human mesangial cells (HMC) in a time- and dose-dependent manner. This down-regulation was not dependent on changes in sGC-beta mRNA levels. Treatment of the cells with the stable cGMP analogue 8-Br-cGMP or the phosphodiesterase type-5 inhibitor Zaprinast produced the same down-regulatory effect. Inhibition of PKG or proteasome activity prevented the CNP-induced reduction of sGC-beta protein levels and activity. Taken together, these results demonstrate that pGC activation induces a post-transductional down-regulation of sGC by a mechanism involving PKG and the proteasome pathway.
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PMID:C-type natriuretic peptide decreases soluble guanylate cyclase levels by activating the proteasome pathway. 1465 33

Glutamate is the main excitatory neurotransmitter in mammals. However, excessive activation of glutamate receptors is neurotoxic, leading to neuronal degeneration and death. In many systems, including primary cultures of cerebellar neurons, glutamate neurotoxicity is mainly mediated by excessive activation of NMDA receptors, leading to increased intracellular calcium which binds to calmodulin and activates neuronal nitric oxide synthase (NOS), increasing nitric oxide (NO) which in turn activates guanylate cyclase and increases cGMP. Inhibition of NOS prevents glutamate neurotoxicity, indicating that NO mediates glutamate-induced neuronal death in this system. NO generating agents such as SNAP also induce neuronal death. Compounds that can act as "scavengers" of NO such as Croman 6 (CR-6) prevent glutamate neurotoxicity. The role of cGMP in the mediation of glutamate neurotoxicity remains controversial. Some reports indicate that cGMP mediates glutamate neurotoxicity while others indicate that cGMP is neuroprotective. We have studied the role of cGMP in the mediation of glutamate and NO neurotoxicity in cerebellar neurons. Inhibition of soluble guanylate cyclase prevents glutamate and NO neurotoxicity. There is a good correlation between inhibition of cGMP formation and neuroprotection. Moreover 8-Br-cGMP, a cell permeable analog of cGMP, induced neuronal death. These results indicate that increased intracellular cGMP is involved in the mechanism of neurotoxicity. Inhibitors of phosphodiesterase increased extracellular but not intracellular cGMP and prevented glutamate neurotoxicity. Addition of cGMP to the medium also prevented glutamate neurotoxicity. These results are compatible with a neurotoxic effect of increased intracellular cGMP and a neuroprotective effect of increased extracellular cGMP.
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PMID:Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death. 1471 72

We examined whether 10 days' in vivo treatment with glyceryl trinitrate (GTN) might reduce cGMP-induced relaxation in the smooth muscle of rabbit mesenteric resistance arteries and, if so, whether protein kinase C (PKC) plays a role in this downregulation. The relaxation responses to GTN and the nitric oxide donor NOC-7 were significantly reduced in endothelium-denuded strips from GTN-treated rabbits. In beta-escin-skinned smooth muscle, the ability of 8-bromoguanosine 3',5' cyclic monophosphate (8-Br-cGMP, a phosphodiesterase-resistant cGMP analogue) to relax the contraction induced by 0.3 microM Ca2+ was significantly reduced in GTN-treated rabbits. In beta-escin-skinned smooth muscle, an inhibitor of conventional and/or novel PKCs, GF109203X (0.6 microM), inhibited the Ca2+ -induced contraction and enhanced the 8-Br-cGMP-induced relaxation. However, since the relaxing ability of 8-Br-cGMP was found to be unchanged by GF109203X when contractions were amplitude-matched (0.2 microM Ca2+ alone vs 0.3 microm Ca2+ + GF109203X), the increase in the 8-Br-cGMP-response seen with GF109203X was probably due to its inhibitory action on the Ca2+ -induced contraction. Furthermore, although the PKC activator phorbol 12,13-dibutyrate (PDBu, 0.1 microM) decreased the 8-Br-cGMP-induced relaxation of the Ca2+ (0.3 microM) contraction, this was probably due to its enhancement of the Ca2+ -induced contraction since no such effect of PDBu was seen when the Ca2+ -induced contractions were amplitude-matched (0.2 microM Ca2+ + PDBu vs 0.3 microM Ca2+ alone). These results suggest that the relaxing response to cGMP is reduced in the smooth muscle of mesenteric resistance arteries in GTN-treated rabbits but that conventional and/or novel PKCs do not play a major role in maintaining this downregulation. British Journal of Pharmacology (2004) 141, 391-398. doi:10.1038/sj.bjp.0705625
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PMID:Role of PKC in the attenuation of the cGMP-mediated relaxation of skinned resistance artery smooth muscle seen in glyceryl-trinitrate-tolerant rabbit. 1471 64

Inducible nitric oxide synthase (iNOS) is expressed in both the fibrotic plaque of Peyronie's disease (PD) in the human, and in the PD-like plaque elicited by injection of TGFbeta1 into the penile tunica albuginea (TA) of the rat. Long-term inhibition of iNOS activity, presumably by blocking nitric oxide (NO)- and cGMP-mediated effects triggered by iNOS expression, exacerbates tissue fibrosis through an increase in: (a) collagen synthesis, (b) levels of reactive oxygen species (ROS), and (c) the differentiation of fibroblasts into myofibroblasts. We have now investigated whether: (a) phosphodiesterase (PDE) isoforms, that regulate the interplay of cGMP and cAMP pathways, are expressed in both the human and rat TA; and (b) L-arginine, that stimulates NOS activity and hence NO synthesis, and PDE inhibitors, that increase the levels of cGMP and/or cAMP, can inhibit collagen synthesis and induce fibroblast/myofibroblast apoptosis, thus acting as antifibrotic agents. We have found by immunohistochemistry, RT/PCR, and Western blot that PDE5A-3 and PDE4A, B, and D variants are indeed expressed in human and rat normal TA and PD plaque tissue, as well as in their respective fibroblast cultures. As expected, in the PD fibroblast cultures, pentoxifylline (non-specific cAMP-PDE inhibitor) increased cAMP levels without affecting cGMP levels, whereas sildenafil (PDE5A inhibitor) raised cGMP levels. Both agents and L-arginine reduced the expression of collagen I (but not collagen III) and the myofibroblast marker, alpha-smooth muscle actin, as determined by immunocytochemistry and quantitative image analysis. These effects were mimicked by incubation with 8-Br-cGMP, which in addition increased apoptosis, as measured by TUNEL. When L-arginine (2.25 g/kg/day), pentoxifylline (10 mg/kg/day), or sildenafil (10 mg/kg/day) was given individually in the drinking water for 45 days to rats with a PD-like plaque induced by TGF beta1, each treatment resulted in a 80-95% reduction in both plaque size and in the collagen/fibroblast ratio, as determined by Masson trichrome staining. Both sildenafil and pentoxiphylline stimulated fibroblast apoptosis within the TA. Our results support the hypothesis that the increase in NO and/or cGMP/cAMP levels by long-term administration of nitrergic agents or inhibitors of PDE, may be effective in reversing the fibrosis of PD, and more speculatively, other fibrotic conditions.
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PMID:L-arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the Peyronie's fibrotic plaque and related fibroblast cultures. 1499 30

The effects of nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine, S-nitroso-l-glutathione, sodium nitroprusside and sodium nitrite were investigated on the activity of the isolated hearts of Achatina fulica and Helix aspersa. NO donors inhibited heart activity in a concentration-dependent manner. The only exception was sodium nitroprusside, which excited H. aspersa heart. The inhibitory effects of these NO donors were reduced by the NO scavenger, methylene blue, the guanylyl cyclase inhibitor, 1H-(1,2,4) Oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), and potentiated by 8-Br-cGMP and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Acetylcholine also inhibited the heart activity, and this inhibition was reduced by methylene blue and ODQ. Positive NADPH-diaphorase staining was located in the outer pericardial layer of the heart of A. fulica. The present results provide evidence that NO may modulate the activity of gastropod hearts, and this modulation may modify the inhibitory action of acetylcholine on heart activity.
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PMID:Evidence for a possible role for nitric oxide in the modulation of heart activity in Achatina fulica and Helix aspersa. 1505 Sep 21

The thrombin-induced platelet shape change was blocked by nitric oxide (NO), as revealed by scanning electron microscopy, light transmission, and resistive-particle volume determination. The inhibitory effect of NO was accompanied by an increase in levels of both cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) and phosphorylation of the vasodilator-stimulated phosphoprotein (VASP). However, the inhibition of the shape change was only mimicked by cAMP analogs (Sp-5,6-DClcBIMPS, 8-AHA-cAMP, and 8-CPT-cAMP) and not by cGMP analogs (8-Br-PET-cGMP, 8-Br-cGMP, and 8-pCPT-cGMP). The effect of NO on the thrombin-induced shape change was prevented by the protein kinase A (PKA) antagonists Rp-8-Br-cAMPS and Rp-cAMPS. The protein kinase G (PKG) antagonist Rp-8-CPT-cGMPS strongly inhibited PKG-mediated 46-kDa VASP Ser239 phosphorylation, but did not inhibit the thrombin-induced shape change or the PKA-mediated VASP Ser157 phosphorylation. Whereas an inhibitor of cyclic nucleotide phosphodiesterase (PDE) 3A (milrinone) mimicked the effect of NO, inhibitors of PDE2 (erythro-9-(2-hydroxy-3-nonyl)adenine) and PDE5 (dipyridamole) were poorly effective. We concluded that (1) NO was a potent and reversible inhibitor of the platelet shape change, (2) the shape change was reversible, (3) the inhibitory effect of NO was mediated through activation of PKA, (4) the onset of the NO effect coincided with VASP Ser157 phosphorylation, and (5) removal of NO and platelet shape change coincided with VASP Ser157 dephosphorylation. These findings are compatible with elevation of cGMP by NO in a compartment close to PDE3A, PKA, and VASP, leading to a local increase of cAMP able to block thrombin-induced shape change.
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PMID:Protein kinase A mediates inhibition of the thrombin-induced platelet shape change by nitric oxide. 1526 92

Nitric oxide (NO) has been recently shown to act with a dual action in mouse oocyte meiotic maturation depending on its concentration, but the mechanism(s) through which it influences oocyte maturation has not been fully clarified to date. The purpose of this study was to test the hypothesis that different signaling mechanisms exist for NO-stimulated and NO-inhibited in vitro maturation of meiosis in cumulus cell-enclosed oocytes (CEOs) from PMSG-primed immature female mice. CEOs were cultured in both spontaneous maturation model and hypoxanthine (HX) arrested model to investigate the mechanism(s). Sodium nitroprusside (SNP, an NO donor) at a concentration of 1mM delayed significantly germinal vesical breakdown (GVBD) during the first 5 h of incubation period and further inhibited the formation of first polar body (PB1) at the end of 24 h of incubation. While SNP, at a concentration of 10 microM, stimulated significantly the meiotic maturation of oocytes by overcoming the inhibition of HX. Methinine blue (MB, 10 microM) or 1-H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 microM)), two soluble guanylate cyclase (sGC) inhibitors, could reverse SNP-inhibited spontaneous oocyte maturation, but had no effect on SNP-stimulated meiotic maturation in the presence of HX. 8-Br-cGMP (1mM), a cell-permeating cGMP analogue, demonstrated a significant inhibitory effect on both spontaneous meiotic maturation and HX-arrested meiotic maturation. The delay effect of SNP on GVBD occurrence was similar to that of forskolin (6 microM, an adenylate cyclase stimulator) and rolipram (250 microM, a phosphodiesterase 4 inhibitor), two cAMP elevating reagents. Both forskolin and rolipram reversed significantly the SNP-stimulated meiotic maturation, but did not reverse the SNP-inhibited spontaneous meiotic maturation. Cilostamide (1 microM), the selective inhibitor of phosphodiestrase 3 (PDE3), could mimic the inhibitory effect of HX on the spontaneous meiotic maturation in CEOs and this inhibitory effect could also be reversed by SNP (10 microM). Moreover, sphingosine (3 microM), a protein kinase C (PKC) inhibitor, blocked the SNP-inhibited spontaneous meiotic maturation, but did not block the SNP-stimulated meiotic maturation. Clearly, these results suggest that pathway differences are present between SNP-inhibited spontaneous meiotic maturation and SNP-stimulated meiotic maturation of mouse oocytes.
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PMID:Nitric oxide influences the maturation of cumulus cell-enclosed mouse oocytes cultured in spontaneous maturation medium and hypoxanthine-supplemented medium through different signaling pathways. 1527 14

Nitric oxide (NO) is a neurotransmitter of the autonomic nerves in the urogenital tract, in particular the release of NO in the cavernous tissue is of importance for maintaining erection. However, the regulation of NO formation in neurons of the corpus cavernosum is poorly understood. Here, we report, that upon electrical stimulation of isolated rabbit corpus cavernosum, NO/NO(2-) was formed and released in a reproducible fashion. The NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester decreased the amount of NO/NO(2-) released to 50+/-18% (P<0.05). The neurotoxin tetrodotoxin diminished the nerve-induced release of NO/NO(2-), to 35+/-10% (P<0.001). Blockage of the cholinergic and noradrenergic pathways by application of scopolamine and guanethidin (both 10(-5) M) did not alter the basal or nerve-evoked formation of NO/NO(2-). We also applied modulators of the soluble guanylate cyclase (sGC)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway to study if and to what extent cGMP might affect the release of NO from the erectile tissue. In the presence of the cGMP analog 8-Br-cGMP (10(-4) M), and, the sGC stimulator 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (10(-4) M), the release of NO/NO(2-) was increased to 385+/-120% (P<0.05) and 282+/-78% (P<0.05), respectively. The effect of the phosphodiesterase inhibitor zaprinast (10(-4) M), was not significant (209+/-53%, n.s). In contrast, inhibition of sGC by 1-H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10(-5) M) decreased the release of NO/NO(2-) to 64+/-14% (P<0.05). Our results suggest that NO/NO(2-) is released by nitrergic neurons within the rabbit corpus cavernosum and that the release is subject to modulation by the sGC/cGMP pathway, but not to modulation by acetylcholine or noradrenaline.
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PMID:Nerve-induced release of nitric oxide from the rabbit corpus cavernosum is modulated by cyclic guanosine 3',5'-monophosphate. 1589 40

Leptin resistance leads to obesity and may affect responses to the second messenger cGMP. We tested the hypothesis that the myocardial negative metabolic response to cGMP would be enhanced in leptin-resistant animals. This hypothesis was tested in anesthetized open-chest Zucker obese (n = 16) and age-matched control rats (n = 13). Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) measurements were used to determine myocardial O2 consumption (VO2). Protein phosphorylation by cGMP protein kinase and cAMP phosphodiesterase activity were also determined. Either vehicle (saline) or 8-Br-cGMP (10(-3) M) was topically applied to the left ventricular surface. Body weight was significantly greater in the obese rats (523 +/- 17 versus 322 +/- 12 g). There were no hemodynamic differences between groups. There was no difference in VO2 between lean (52 +/- 13 mL O2/min/100 g) and obese (54 +/- 9) vehicle-treated rats. 8-Br-cGMP significantly lowered VO2 in obese (35 +/- 6) but not lean (45 +/- 7) rats. This was not related to altered protein phosphorylation by the cGMP protein kinase. Cyclic GMP inhibited cAMP phosphodiesterase activity in lean but not obese hearts. Thus, the high myocardial oxygen consumption of lean rats was not significantly affected by cGMP but was reduced in obese hearts. This appeared to be related to a reduced inhibition of cAMP phosphodiesterase activity by cGMP in the Zucker obese rat.
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PMID:Negative metabolic effects of cGMP are enhanced in obese rat hearts. 1589 79

Grasshopper sound production, in the context of mate finding, courtship, and rivalry, is controlled by the central body complex in the protocerebrum. Stimulation of muscarinic acetylcholine receptors in the central complex has been demonstrated to stimulate specific singing in various grasshoppers including the species Chorthippus biguttulus. Sound production elicited by stimulation of muscarinic acetylcholine receptors in the central complex is inhibited by co-applications of various drugs activating the nitric oxide/cyclic guanosine monophosphate (cGMP) signaling pathway. The nitric oxide-donor sodium nitroprusside caused a reversible suppression of muscarine-stimulated sound production that could be blocked by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxaline-1-one (ODQ), which prevents the formation of cGMP by specifically inhibiting soluble guanylyl cyclase. Furthermore, injections of both the membrane-permeable cGMP analog 8-Br-cGMP and the specific inhibitor of the cGMP-degrading phosphodiesterase Zaprinast reversibly inhibited singing. To identify putative sources of nitric oxide, brains of Ch. biguttulus were subjected to both nitric oxide synthase immunocytochemistry and NADPH-diaphorase staining. Among other areas known to express nitric oxide synthase, both procedures consistently labeled peripheral layers in the upper division of the central body complex, suggesting that neurons supplying this neuropil contain nitric oxide synthase and may generate nitric oxide upon activation. Exposure of dissected brains to nitric oxide and 3-(5'hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) induced cGMP-associated immunoreactivity in both the upper and lower division. Therefore, both the morphological and pharmacological data presented in this study strongly suggest a contribution of the nitric oxide/cGMP signaling pathway to the central control of grasshopper sound production.
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PMID:Nitric oxide/cyclic guanosine monophosphate signaling in the central complex of the grasshopper brain inhibits singing behavior. 1592 38


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