Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:7665-99-8 (cGMP)
 21,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With several notable exceptions, interest in the area of multiple molecular forms of phosphodiesterase remained relatively dormant during the decade following Thompson's discovery of more than one phosphodiesterase in brain in 1971. Within the last several years, however, over 20 novel agents have been identified that exert selective inhibitory effects on the various molecular forms of phosphodiesterase present within different cells. In addition, several studies have documented that such agents can produce discrete changes in cyclic AMP and cyclic GMP, an action that is not shared by "first generation" phosphodiesterase inhibitors such as theophylline. The purpose of this Perspective is to provide some clarity to this rapidly evolving area of selective phosphodiesterase inhibitors. Thus, we have attempted to characterize the different forms of phosphodiesterase present in various tissues and cells according to their kinetic properties, substrate specificity, etc. and also to characterize those major classes of agents that have been shown to inhibit phosphodiesterase activity, whether selectively or nonselectively. In addition, we have described several therapeutic areas wherein selective phosphodiesterase inhibitors might prove efficacious, paying particular attention to those areas in which selective phosphodiesterase inhibitors have already been shown to exert beneficial effects, namely, stimulation of myocardial contractility, inhibition of mediator release, and inhibition of platelet aggregation. Although focusing on these three areas, it is obvious that the potential therapeutic utility of selective phosphodiesterase inhibitors could conceivably extend to several other areas in which modulation of cyclic nucleotides can have desirable effects, including cancer chemotherapy, analgesia, the treatment of depression, Parkinson's disease, and learning and memory disorders. For example, the selective type III phosphodiesterase inhibitor rolipram has been shown to antagonize reserpine-induced hypothermia and also to potentiate yohimbine lethality, two tests that are indicative of antidepressant activity. In addition, microinjection of the selective PDE III inhibitor Ro 20-1724 into the rat brain stem has been shown to produce analgesia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. 298 81

Under the total blockade of PDE1 and the presence of endogeneous ATP and MgCl2, the inhibitory effect of cAMP on HD activity could be demonstrated as low as 8.7 X 10(-8) M concentration in a 20,000 g supernatant of a sustained homogenate of rat hypothalamus. A total reverse of this action and also a partial release of the cAMP-induced inhibition of HD, occurred at higher concentrations of cAMP, and ATP could be achieved by an endogeneous inhibitor of cAMP-dependent protein kinase or by cyclic GMP. The reversal of cAMP action by PKI seems to serve a strong evidence for the role of cAMP-dependent protein kinase (EC 2.7.37: ATP-protein phosphotransferase) in this action and emphasized the involvement of a direct or an indirect phosphorylation in the regulation of HD activity. The stimulatory effect of cyclic GMP on cAMP-induced inhibition of HD or its 'direct' effect on histamine formation is asserted, probably through the activation of PDE, or through independent stimulatory machinery, coupled to the cyclic GMP system.
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PMID:Evidence for the role of cAMP-dependent protein kinase in the down-regulation of hypothalamic HD: reversal of cAMP-(ATP) induced inhibition of HD activity by the 'Walsh' inhibitor of cAMP-dependent protein kinase and by cyclic GMP. 299 Jan 78

The effects of fluoride on ROS phosphodiesterase and G-protein have been studied using membrane-free extracts. When G-protein was present NaF, at millimolar concentrations, stimulated PDE activity however, in a G-protein free extract, cGMP hydrolysis was inhibited by high fluoride concentrations. Fluoride was also found to profoundly inhibit the ability of G-protein to bind a GTP analogue, GTP gamma S, both in the presence and absence of rhodopsin. Aluminium greatly modified these effects of fluoride on PDE and G-protein. The possibility that fluoride activates PDE through its effect on G-protein is discussed.
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PMID:Effects of fluoride on retinal rod outer segment cGMP phosphodiesterase and G-protein. 299 45

Our previous observations that serum cyclic 3',5'-nucleotide phosphodiesterase activity varied in thyroid disorders and was positively correlated with thyroid function stimulated us to investigate the phosphodiesterase levels in sera of patients with pituitary and adrenal disorders, and the response to glucagon in normal subjects. Both serum cyclic AMP phosphodiesterase (cyclic AMP-PDE) and cyclic GMP phosphodiesterase (cyclic GMP-PDE) activities were measured at a low substrate concentration. Serum cyclic AMP-PDE activity was elevated in five patients with phaeochromocytoma and was not elevated in patients with Cushing's syndrome or acromegaly, compared to the level in normal subjects. Increased enzyme activities returned to normal after resection of the tumours. Intramuscular injection of glucagon to five healthy subjects elevated cyclic AMP levels and cyclic AMP-PDE activity in plasma. These results imply that the increased cyclic AMP level by the activation of cyclase may have induced cyclic AMP-PDE in the target organ and the soluble cyclic AMP-PDE may leak into blood vessels from target organs.
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PMID:High activity of cyclic 3',5'-nucleotide phosphodiesterase in sera of patient with phaeochromocytoma. 301 9

ATP has important roles in the vertebrate rod outer segment (ROS) physiological response to light. One of them is the quench of light-activated cGMP-phosphodiesterase activity. How ATP quenches PDE is not established; however, leading hypotheses favor the intervention of a 48-kDa ATP-binding protein and/or an ATP-utilizing rhodopsin kinase in this reaction. We have investigated the binding of [alpha 32P]8-azido-ATP to rat ROS proteins in the presence and absence of various divalent cations and competitive nucleotides. An event we have detected which might further clarify the role of ATP in PDE inactivation is a zinc-induced binding of azido-ATP to rhodopsin. Manganese is also effective in inducing this binding, while magnesium and calcium are not. The azido-ATP binding is eliminated by the addition of ATP, but not GTP, UTP, cGMP, or cAMP. A nucleotide-binding site on the rim protein is also suggested from these studies.
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PMID:8-Azido-ATP (alpha 32P) binding to rod outer segment proteins. 313 34

Leukosuspensions from 217 patients with bronchial asthma and 73 normal subjects were examined for alterations in the levels of cAMP and cGMP under the effect of incubation with adrenaline, propranolol, acetylcholine. A study was also made of the activity of cAMP PDE and glycogen metabolism. Simultaneous measurement of the basal and stimulated levels of cyclic nucleotides and their ratios revealed a decrease in cell adrenoreactivity and a rise in cholinoreactivity. Variation of the beta-adrenoblocking action of propranolol typical for the atopic mechanism of bronchial asthma was demonstrated. Comparison of the adrenodependent glycogenolysis and alterations in the cAMP level, analysis of the action of analgin on these characteristics allowed the conclusion about the secondary nature of alterations in cAMP metabolism dependent on the features of prostaglandin metabolism. A significant decrease in the adrenodependent glycogenolysis was revealed in lymphocytes, with that decrease induced by drug, dust and pollen allergens. It was demonstrated that in verified viral infection, cAMP PDE was significantly reduced.
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PMID:[Disorders of cellular regulation systems as a basis for changed bronchial reactivity in bronchial asthma]. 609 46

The present work deals with the content of cyclic nucleotides and PDE activity in spleen T-lymphocytes of young and old animals. The cAMP/cGMP ratio is shown to increase with age chiefly owing to the reduction in cGMP level and in PDE activity which induces inhibition of proliferation and 3/1-thymidine incorporation in lymphocyte DNA in response to mitogens concanavalin A (Con A) and phytohemagglutinin (PHA). Isoproterenol, biogenic amines, theophylline, dibutyryl cAMP influence less effectively the level of cyclic nucleotides and PDE activity of T-lymphocytes from old animals than those from young mice. The data suggest that the change in the intracellular content of cyclic nucleotides leads to the reduction in proliferation and immunologic response to one or another antigen.
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PMID:Age-associated changes in content of cyclic adenosine-3', 5'-monophosphate (cAMP), cyclic guanosine-3',5'-monophosphate (cGMP) and in activity of phosphodiesterase-cAM (pDE-cAM) in spleen T-lymphocytes from C3HA mice. 609 7

Trypsin-treated Ca2+/calmodulin-dependent phosphodiesterase (CA2+-PDE), which had lost its sensitivity to Ca2+-calmodulin, was inhibited by various calmodulin antagonists, trifluoperazine, chlorpromazine, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and aminoalkyl chain analogues of W-7 (A-3, A-4, A-5, I-240, A-6, A-7). These inhibitory effects were less than those on calmodulin-activated Ca2+-PDE. The ability of these compounds to inhibit trypsin-treated Ca2+-PDE correlated well with the inhibitory effect on calmodulin-activated Ca2+-PDE. W-7 inhibited trypsin-treated Ca2+-PDE in a competitive fashion with respect to cyclic GMP and the Ki value was 300 microM. The inhibition of trypsin-treated Ca2+-PDE by W-7 (300 microM) or A-7 (100 microM) was overcome by the addition of excess calmodulin. Trypsin-treated Ca2+-PDE can bind to W-7-coupled cyanogen bromide-activated Sepharose 4B in the presence of 1 mM EGTA. These results suggest that Ca2+-PDE possesses a binding site for calmodulin antagonists and that the binding site for these antagonists on this enzyme may be structurally similar to the binding site on calmodulin itself.
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PMID:Direct interaction of calmodulin antagonists with Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase. 609 52

Effect of a novel compound, 14-ethoxycarbonyl-(3 alpha, 16 alpha-ethyl)-14,15-eburnamenine (vinpocetine, TCV-3B), on the cyclic nucleotide metabolism and in vitro response of a vascular strip was investigated. The concentration of vinpocetine producing relaxation of the canine basilar arterial strip induced by 30 microM arachidonate peroxide was 3 microM. Cyclic GMP content in the vascular strip increased dose-dependently by addition of vinpocetine, and 2.5-fold elevation of cyclic GMP content in the vascular strip was observed by 10 microM vinpocetine. Administration of vinpocetine concentrations ranging from 1 to 100 microM did not produce a significant increase in cyclic AMP of the vascular strip. Vinpocetine did not stimulate guanylate cyclase, but selectively inhibited Ca2+-calmodulin dependent phosphodiesterase (Ca2+-PDE). Increase in cyclic GMP by vinpocetine is due to inhibition of Ca2+-PDE because Ca2+-PDE is known to hydrolyze cyclic GMP preferentially. Our results suggest that vinpocetine, a selective Ca2+-PDE inhibitor, produces relaxation of the vascular strip by the increase in cyclic GMP.
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PMID:[Effect of vinpocetine (TCV-3B), a vasodilator agent, on cyclic nucleotide metabolism]. 613 34

A series of 26 compounds belonging to the chemical class of (1,2,4)triazolo(4,3-a)-quinoxaline-1,4-diones have been investigated for their antiallergic activities in 3 in vitro models of anaphylaxis. Effects of these and other known antiallergic agents on cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells have also been investigated. 18 compounds were potent (I50 less than or equal to 45 microM) inhibitors of antigen-induced release of histamine (AIR) from rat mast cells (RMC), 3 compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 25 microM) and none of the compounds significantly affected AIR from guinea pig lung slices. 13 of the compounds were more potent than theophylline as inhibitors of cyclic AMP-PDE and/or cyclic GMP-PDE from RMC. Parallel concentration-response curves for the inhibition of cyclic AMP-PDE and cyclic GMP-PDE indicated that these compounds probably interact with enzyme in the same manner. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC by these compounds revealed no statistically significant correlation between the inhibition of AIR and inhibition of cyclic AMP-PDE or cyclic GMP-PDE. We conclude: (1) some of these compounds are potent inhibitors of immunologic release of histamine from RMC with an in vitro activity profile similar to that of DSCG, and (2) inhibition of cyclic AMP or cyclic GMP hydrolysis by cNUD-PDE by these compounds, DSCG, and 6 known antiallergic agents is not the biochemical mechanism by which they inhibit AIR from RMC.
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PMID:Antiallergic activity profiles in vitro of RHC 3164 and related compounds. I. A lack of correlation between inhibition of cyclic nucleotide phosphodiesterases and antigen-induced release of histamine from rat mast cells. 619 87


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