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

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibition of platelet adhesion by nitric oxide (NO) and prostacyclin and their mechanism of action was studied. Platelet adhesion to collagen fibrils and endothelial cell matrix was inhibited completely by NO but only partially by prostacyclin. Adhesion of platelets to endothelial cell monolayers was inhibited by bradykinin. This effect of bradykinin was unaffected by aspirin, and was accounted for by the amounts of NO released by the endothelial cells. Inhibition of platelet adhesion by NO and prostacyclin was potentiated by selective inhibitors of cGMP phosphodiesterase, but not of cAMP phosphodiesterase, indicating that elevation of cGMP regulates platelet adhesion.
...
PMID:The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. 282 88

The cyclic GMP content of rat lung mice was increased nearly 50-fold within 4 sec following exposure to nitric oxide. This rapid increase in cyclic GMP accumulation was prevented by 10 mM, but not 1 mM, dithiothreitol which itself caused a slower yet massive (100-fold) increase in the cyclic GMP content of lung mince. Tissue cyclic GMP following nitric oxide exposure declined rapidly even in the presence of the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine. The decline in cyclic GMP was accelerated by the thiol oxidant diamide (1 mM). The cyclic GMP content of lung mince was also increased by norepinephrine, pyruvate and t-butyl hydroperoxide. Diamide blocked cyclic GMP accumulation in response to these other agents as well as that caused by nitric oxide or dithiothreitol. The results suggest that sulfhydryl group modification may be a common pathway for the enhancement of cyclic GMP synthesis in tissues by a variety of stimuli.
...
PMID:Sulfhydryl group involvement in the modulation of guanosine 3',5'-monophosphate metabolism by nitric oxide, norepinephrine, pyruvate and t-butyl hydroperoxide in minced rat lung. 629 1

There is growing evidence that nitric oxide serves as a neurotransmitter released from enteric inhibitory nerves in the gastrointestinal tract. The distribution of nitric oxide synthase suggests that nitric oxide may also be a neurotransmitter within enteric ganglia. Since many actions of nitric oxide are mediated by stimulation of soluble guanylate cyclase and a subsequent increase in 3',5'-cyclic guanosine monophosphate (cGMP) concentration, targets for nitric oxide in the canine proximal colon were investigated by immunohistochemical localization of cGMP. In the presence of phosphodiesterase inhibitors (M&B 22948, 100 microM and 3-isobutyl-1-methyl-xanthine, 1 mM), exogenous nitric oxide and electrical field stimulation caused an accumulation of cGMP-like immunoreactivity in several cell-types including colonic smooth muscle cells. cGMP-like immunoreactivity was also observed in a subpopulation of neurons in both myenteric and submucosal ganglia. Sequential labeling with the NADPH diaphorase technique showed that 94% of neurons that responded to exogenous nitric oxide with an increase in cGMP-like immunoreactivity were NADPH diaphorase negative. None of the myenteric neurons that responded to electrical field stimulation with an increase in cGMP-like immunoreactivity were NADPH diaphorase positive, and only one submucosal neuron with cGMP-like immunoreactivity was also NADPH diaphorase positive. The electrical field-stimulated increase in cGMP-like immunoreactivity was blocked by nitroarginine (100 microM). An increase in cGMP-like immunoreactivity also occurred in interstitial cells located at the submucosal surface of the circular muscle layer. These cells are interposed between nerve varicosities and smooth muscle cells and may partially mediate neuromuscular transmission. Sodium nitroprusside and nitric oxide also caused an accumulation of cGMP-like immunoreactivity in smooth muscle cells of intramural arterioles and venules. The results of this study further support the role of nitric oxide as a neurotransmitter in colonic muscles, and provide support for the hypothesis that interstitial cells are functionally innervated by enteric inhibitory neurons. The data also suggest that nitric oxide may serve as a neurotransmitter in enteric ganglia.
...
PMID:Immunohistochemical localization of 3',5'-cyclic guanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. 750 18

The nitric oxide (NO) synthase/cGMP pathway has been studied in vivo in the adult rat hippocampus by monitoring the levels of extracellular cGMP during microdialysis in conscious unrestrained animals. The basal cGMP efflux was concentration-dependently reduced upon local infusion of the NO synthase inhibitor NG-nitro-L-arginine (NARG; 10 microM to 1 mM). The NO donors hydroxylamine and S-nitroso-N-penicillamine, perfused through the dialysis probe at 1 mM, increased by about 200% the extracellular levels of cGMP. The glutamate receptor agonist NMDA (125-500 microM) produced concentration-dependent cGMP responses that were abolished by the selective receptor antagonist D-2-amino-5-phosphonovaleric acid or by NARG. Local perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX; 1 mM) produced a steady eightfold increase of extracellular cGMP levels. The effect of IBMX was highly sensitive to NARG. The inhibition by NARG of the IBMX-induced cGMP response was reversed when the NO synthase substrate L-arginine was administered. It is concluded that cGMP collected during in vivo microdialysis reflects NO synthase activity in the rat hippocampus. The technique may be utilized to investigate the pathophysiology and the pharmacology of the NO/cGMP pathway in the hippocampus of living animals.
...
PMID:Extracellular cGMP in the hippocampus of freely moving rats as an index of nitric oxide (NO) synthase activity. 750 60

The stimulation of excitatory amino acid receptors in the cerebellar cortex results in the Ca2+/calmodulin-dependent activation of nitric oxide synthase. This leads to an increase in tissue levels of cGMP following the interaction of nitric oxide with soluble guanylyl cyclase. The cerebellar cortex has the highest levels of nitric oxide synthase and cGMP in the brain; however, the levels of guanylyl cyclase and cGMP-phosphodiesterase are remarkably low. Thus, the mechanisms regulating cGMP levels in cerebellar cells are unclear. One report has noted that cGMP can be released from cerebellar slices. We have therefore used intracerebellar microdialysis in awake, freely moving rats to test the hypothesis that activation of nitric oxide synthase in the cerebellar cortex results in the release of cGMP. Climbing fibers, which release excitatory amino acids in the cerebellum, were activated with systemic harmaline. This resulted in an immediate increase in extracellular cGMP, which was blocked by TTX or the removal of extracellular Ca2+, and attenuated by prior lesion of the climbing fibers. Blockade of N-type calcium channels with omega-conotoxin also antagonized the harmaline-induced increase. In contrast, blockade of L-type calcium channels, or inhibition of anion transport with probenecid or bromosulfophthalein, potentiated the increase in cGMP seen in response to harmaline. Inhibitors of nitric oxide synthase or guanylyl cyclase prevented the harmaline-induced increase in extracellular cGMP, while phosphodiesterase inhibitors potentiated the increase. Local application of the NMDA antagonist 2-amino-5-phosphonopentanoic acid or the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione attenuated the effect of harmaline.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Nitric oxide-dependent efflux of cGMP in rat cerebellar cortex: an in vivo microdialysis study. 750 65

Nitric oxide (NO) has recently been identified as an intercellular messenger which is involved in the regulation of neurotransmission, vasorelaxation, and cytotoxicity. In cerebellum and endothelium this compound is synthesized by "constitutive" nitric oxide synthases (NOS); these are Ca(2+)-calmodulin (CaM)-dependent enzymes. A potential CaM-binding domain for the CaM-dependent NOS has previously been identified in the gene sequence. In this work, a synthetic 23 residue peptide encompassing the putative CaM-binding domain of rat cerebellar NOS was studied. The constitutive NOS peptide binds to CaM in a calcium-dependent manner with 1:1 stoichiometry as determined by polyacrylamide gel electrophoresis of the peptide-CaM complex in 4 M urea. Circular dichroism studies showed that the peptide binds to CaM in an alpha-helical conformation. Binding of the constitutive NOS peptide inhibits the stimulatory effect of CaM on cyclic nucleotide phosphodiesterase. From competition experiments between the peptide and phosphodiesterase we have determined a Kd of 2.2 nM for the peptide-CaM complex. Two-dimensional NMR and circular dichroism studies were used to determine the structure of the peptide in aqueous solution. In addition, the effect of increasing amounts of trifluoroethanol on the peptide structure was investigated. It was found that the peptide can adopt an alpha-helical structure which bears close resemblance to the structure of the CaM-bound form of the CaM-binding domains of myosin light chain kinases.
...
PMID:Characterization of the calmodulin-binding domain of rat cerebellar nitric oxide synthase. 750 14

Based on the fact that nitric oxide (NO) production is associated with changes in intracellular cGMP levels and is selectively inhibited by N omega-methyl L-arginine (L-NME), we investigated the shear stress dependency of NO production in endothelial cells (ECs) from its cGMP responses to various shear stress loads. Cultured fetal bovine aortic ECs treated with a phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX; 1 mM), were exposed to a laminar flow of Krebs buffer solution for 5 minutes in a parallel-plate flow chamber and examined for changes in intracellular cGMP levels by radioimmunoassay using an [125I] cGMP kit. Application of flow increased the cGMP levels. The increase was significant in the presence of extracellular ATP (1 microM)(control, 286.1 +/- 43.6; flow, 506.5 +/- 44.9 fmol/10(7) cells; p < 0.001), but not in its absence (control, 256.6 +/- 60.6; flow, 301.5 +/- 91.4 fmol/10(7) cells; N.S.). The cGMP levels increased significantly as the magnitude of shear stress applied increased. Treatment of ECs with a specific inhibitor of NO production, L-NMA (200 microM), completely inhibited the flow-induced increase in cGMP, and L-arginine reversed the L-NMA-induced inhibition, indicating that the increase in cGMP was due to NO produced by the flow. The flow-induced increase in NO production was markedly suppressed when extracellular Ca++ was chelated by adding EGTA to the perfusate. These findings suggest that flow stimulates NO production to increase cGMP levels shear stress-dependently in ECs and that extracellular Ca++ and ATP modulate the effects of flow.
...
PMID:Laminar flow stimulates ATP- and shear stress-dependent nitric oxide production in cultured bovine endothelial cells. 750 19

We have identified a putative cGMP-gated cation conductance in rat retinal ganglion cells. Both in situ hybridization and polymerase chain reaction amplification detected transcripts in ganglion cells that were highly homologous to the cGMP-gated cation channel expressed in rod photoreceptors. Whole-cell patch-clamp recordings detected a current stimulated by cGMP due to activation of nonselective cation channels. This current had a reversal potential near 0 mV, showed some outward rectification, and could be blocked by Cd2+. The current could also be activated by a phosphodiesterase inhibitor and the nitric oxide donors sodium nitroprusside and S-nitrosocysteine. We propose that nitric oxide released from an identified subpopulation of amacrine cells may activate this channel to modulate ganglion cell activity.
...
PMID:Retinal ganglion cells express a cGMP-gated cation conductance activatable by nitric oxide donors. 750 37

The nitric oxide synthase/cyclic GMP pathway has been studied in vivo in the adult rat cerebellum by monitoring the levels of extracellular cyclic GMP during microdialysis in conscious unrestrained animals. The basal cyclic GMP efflux was concentration-dependently reduced upon local infusion of the nitric oxide synthase inhibitor NG-nitro-L-arginine (10 microM-1 mM). The nitric oxide donor S-nitroso-N-penicillamine, perfused through the dialysis probe at 1 mM, increased by about 200% the extracellular levels of cyclic GMP. The glutamate receptor agonist N-methyl-D-aspartate (500 microM) produced a cyclic GMP response which was abolished by the selective receptor antagonist D-2-amino-5-phosphonovaleric acid (500 microM) or by NG-nitro-L-arginine (10 microM). The elevation of cyclic GMP levels caused by local infusion of 500 microM N-methyl-D-aspartate was also abolished by parenteral administration of the N-methyl-D-aspartate channel blocker dizocilpine (0.4 mg/kg, i.p.). Local perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (1 mM) increased by about 150% the extracellular levels of cyclic GMP. It is concluded that cyclic GMP collected during in vivo microdialysis reflects nitric oxide synthase activity in the rat cerebellum. The technique may be utilized to investigate the pathophysiology and the pharmacology of the nitric oxide/cyclic GMP pathway in the cerebellum of living animals.
...
PMID:Monitoring of cyclic GMP during cerebellar microdialysis in freely-moving rats as an index of nitric oxide synthase activity. 750 75

The influence of interferon (IFN)-gamma on vasodilation was examined in bovine isolated mesenteric arteries. Arterial rings were incubated with IFN-gamma (100 U ml-1) for 20 hr and subsequently the response to vasodilators was determined isometrically in an organ bath. Treatment with IFN-gamma markedly inhibited endothelium-dependent relaxation to bradykinin and impaired vasodilation to nitroprusside, which was endothelium-independent. The decrease in relaxation was correlated with a decrease in bradykinin- and nitroprusside-induced cGMP production. Relaxation to the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine or zaprinast was not altered after IFN-gamma, which suggests that the IFN-gamma effect is specific for guanylate cyclase-activating agonists. Nitrite concentration in the incubation medium was increased after IFN-gamma, which indicates the induction of nitric oxide release during the incubation period. Inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine during the 20-hr incubation with IFN-gamma completely prevented the decrease in relaxation and cGMP elevation to nitroprusside. We conclude that IFN-gamma induces a marked increase in release of arterial-derived nitric oxide resulting in a desensitization of guanylate cyclase, which contributes to a decrease in relaxation to bradykinin and nitroprusside. These results may implicate the existence of an important adaptive process in the regulation of vascular tone during pathological situations associated with the induction of nitric oxide synthesis.
...
PMID:Induction of nitric oxide release by interferon-gamma inhibits vasodilation and cyclic GMP increase in bovine isolated mesenteric arteries. 750 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---