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Query: CAS:7665-99-8 (cGMP)
 21,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have cloned a 4.2-kilobase pair (kb) cDNA that encodes the cyclic GMP-stimulated phosphodiesterase (cGS PDE) from a bovine adrenal cortex library. The 921-residue polypeptide deduced from the cDNA nucleotide sequence is nearly identical with the complete amino acid sequence of the cGS PDE purified from a soluble bovine heart extract. Moreover, PPD-S49 cells transfected with the cGS PDE cDNA express a soluble cAMP hydrolytic activity that is enhanced by cGMP. Total RNA isolated from several bovine tissues were screened for cGS PDE transcript by Northern blot analysis. The cGS PDE cDNA appears to hybridize to a single 4.5-4.6-kb mRNA species. Although the cGS PDE mRNA is most abundant in the adrenal cortex, it is also concentrated in the adrenal medulla and heart and in anatomically distinct regions of the brain and kidney. A mRNA species encoding a putative variant cGS PDE isoform was detected by RNase protection. Total RNA isolated from adrenal cortex, adrenal medulla, liver, kidney, trachea, lung, spleen, and T-lymphocytes completely protected a 452-base riboprobe encoding 100 residues of the adrenal cortex cGS PDE amino terminus. In contrast, RNAs isolated from brain (cerebral cortex, hippocampus, and basal ganglia) protected only 268 bases of this riboprobe. The RNase protection pattern of this same probe using heart RNA showed major bands at both 268 and 452 bases, suggesting that two different cGS PDE mRNA species are expressed. These results indicate that the cGS PDE is widely expressed in a variety of tissues. Moreover, these studies suggest that at least one different cGS PDE isoform having a structurally distinct amino-terminal domain is expressed in brain and heart.
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PMID:Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase cDNA. Identification and distribution of isozyme variants. 165 33

Many of newly developed positive inotropic agents are phosphodiesterase inhibitors (PDEI). These are (in contrast to the classical, unselective PDEIs) in most cases selective inhibitors of PDE III which is inhibitable by cGMP. The most important action of PDEIs is a receptor-independent increase in intracellular cAMP, resulting from an inhibition of the degradation of cAMP. An increase in intracellular cAMP levels can also be produced by stimulation of adenylate cyclase, which leads to an increase in cAMP formation. Therefore, the effects of beta-adrenoceptor agonists (e. g., isoprenaline) and PDEIs are rather similar. The main effect of cAMP is to increase the slow Ca inward current during the action potential. This leads to an increase in Ca release from intracellular Ca stores, to an increase in the Ca concentration in the vicinity of the contractile proteins and, hence, to a positive inotropic effect. In addition, PDEIs also produce vasodilatation, which might be of even greater importance than the cardiostimulatory effects of these drugs ("inodilators"). However, two potential disadvantages of PDEIs must also be mentioned: 1) increase in beat frequency and tachyarrhythmias that also result from an increase in intracellular cAMP concentration and 2) decrease in effectiveness or tolerance, which might be due to an increase in inhibitory G proteins.
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PMID:[Mechanism of the positive inotropic effect of phosphodiesterase inhibitors]. 165 18

This article is a review of cyclic nucleotide phosphodiesterase(s) (CN PDE) from the point of view of the relationships between the newer aspects of the complex enzymology of CN PDE and recent major advances in CN PDE pharmacology. A consolidation of isozyme nomenclature to the proposed family designations is recommended. Emphasis is placed on the importance of defining the subcellular localization of isozymes expressed in a given tissue and cyclic GMP substrate and regulatory roles in CN PDE isozyme functions. CN PDE inhibitors that may be useful for experimental and clinical purposes are discussed. Examples of these inhibitors include CGS 9343B, TCV-3B, KW-6, MIMAX, Dihydroisoquinolines, Trequinsin, bipyridine and dihydropyridazinone cardiotonics, Rolipram, SQ 65442, Zaprinast and Dipyridamole.
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PMID:Cyclic nucleotide phosphodiesterases: pharmacology, biochemistry and function. 166 50

The levels of the retinal mRNAs encoding opsin, the alpha subunit of rod transducin (T alpha), S-antigen (S-ag) and the gamma subunit of rod-specific cGMP-phosphodiesterase (cGMP-PDE) were measured in rats reared in cyclic light or darkness and after adaptation for different periods of time to the opposite light environment. We found that rats changed from cyclic light to darkness, gradually increased their retinal content of opsin and T alpha mRNAs but decreased their levels of S-ag mRNA. The reverse results were obtained when rats were changed from darkness to cyclic light. In contrast, the levels of retinal cGMP-PDE gamma mRNA remained unchanged in animals adapted to either of the two rearing light conditions. Our results indicate that some mRNAs encoding proteins associated with the cGMP cascade are responsive to environmental lighting and may be involved in the long term light or dark adaptive processes.
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PMID:Levels of mRNA encoding proteins of the cGMP cascade as a function of light environment. 166 39

Metabolism of cGMP is critically important for the functioning of phototransduction in the mammalian retina. In rod and cone photoreceptors, two types of antagonistic enzymes, guanylate cyclases and cGMP phosphodiesterases, carefully balance the available amount of the intracellular messenger. Guanylate cyclase produces cGMP and phosphodiesterase rapidly hydrolyzes cGMP upon bleaching of the photopigment. Regulation of their activity in light and dark, influence of Ca++, and feed-back mechanisms are currently under intense investigation. A molecular analysis on both the gene and protein levels will contribute significantly to our understanding of their respective roles in phototransduction. The two types of enzymes have been characterized molecularly to a very different extent. Rod phosphodiesterase was purified to homogeneity almost fifteen years ago, but photoreceptor guanylate cyclase has evaded all attempts for molecular characterization. Characterization of retinal guanylate cyclase cDNA(s), however, will most likely be achieved in the near future. Cone PDE was shown to be a distinct enzyme, different from, but related to, the rod enzyme. Molecular cloning has provided sequence information of two of the three subunits of rod PDE; the small inhibitory subunit has been expressed in bacterial expression vectors, giving us an elegant tool for exploring mechanisms of activation and inhibition. The gene encoding the alpha subunit was shown to be a member of a large gene family of cyclic nucleotide phosphodiesterases, present in many eucaryotes ranging from unicellular organisms (yeast) to mammals. While much has been achieved, many questions remain to be answered. The beta subunit of rod phosphodiesterase has evaded complete molecular characterization, and its origin (one gene and posttranslational modification of the gene product generating alpha and beta, alternative splicing, or two separate genes with distinct gene products) has not been elucidated. Mechanisms of interaction of subunits, activation and inhibition, the active site(s) of the enzyme are undefined. Virtually nothing is known about the molecular organization of the photoreceptor guanylate cyclase(s). Recent cloning of two apparently unrelated mammalian guanylate cyclases, however, containing a common homologous domain signals increasingly rapid progress in this field.
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PMID:The molecular genetics of retinal photoreceptor proteins involved in cGMP metabolism. 167 36

Effects of Ro 20-1724, a selective inhibitor of soluble cGMP-insensitive type IV phosphodiesterase, on the force and cAMP levels were compared with those of 3-isobutyl-1-methylaxanthine, a non-selective inhibitor, in the rat ventricular myocardium. Ro 20-1724 scarcely affected the basal force of contraction and cAMP levels, whereas it enhanced the positive intropic effect and cAMP accumulation induced by isoproterenol more effectively than 3-isobutyl-1-methylxanthine. These results imply that inhibition of the soluble cGMP-insensitive type IV PDE by Ro 20-1724 may be crucially involved in the regulation of myocardial contractility through the interaction with cAMP generation in the rat ventricular myocardium.
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PMID:Differential effects of Ro 20-1724 and isobutylmethylxanthine on the basal force of contraction and beta-adrenoceptor-mediated response in the rat ventricular myocardium. 168 99

The present investigation was performed to characterize the positive inotropic actions of inhibitors of the cyclic GMP-inhibited cyclic AMP phosphodiesterase (CGI-PDE) on the electrically driven guinea pig left atria. With forskolin added at a concentration (1 x 10(-8)-3 x 10(-8) M) that in itself produced a 10.7% increase of the response to electrical stimulation, the EC50 value of isoproterenol was slightly but significantly (p less than 0.01) reduced from 1.5 to 0.9 nM without modification of the maximal developed tension (delta Emax). The positive inotropic effects of milrinone, piroximone, and SK&F 94120 were significantly enhanced by forskolin (percentage of increase at 3 x 10(-5) M CGI-PDE inhibitors concentration was milrinone 43, piroximone 154, and SK&F 94120 133). With 8-Br-cyclic GMP added (10(-4) M) that in itself exerted a small but significant negative inotropic effect (-0.12 g), the EC50 value of isoproterenol was significantly (p less than 0.01) increased from 1.5 to 3 nM without modification of the delta Emax value. The positive inotropic effects of CGI-PDE inhibitors were significantly depressed by 8-Br-cyclic GMP (percentage of decrease at 3 x 10(-5) M was milrinone 35, piroximone 63, and SK&F 94120 39). In identical conditions, neither forskolin nor 8-Br-cyclic GMP produced any significant alteration of the positive inotropic effects of elevated external Ca2+ or protoveratrine B. Together these results strongly suggest that the positive inotropic effect of CGI-PDE inhibitors is mediated by cyclic AMP in guinea pig left atria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Implication of cyclic AMP in the positive inotropic effects of cyclic GMP-inhibited cyclic AMP phosphodiesterase inhibitors on guinea pig isolated left atria. 169 69

The involvement of rolipram-sensitive phosphodiesterase (PDE IV) in regulation of cardiac contraction was investigated by studying the effect of selective inhibitors (rolipram, denbufylline, Ro 20-1724) on guinea pig left atria contraction. In contrast to milrinone and SK&F 94120 (inhibitors of the cyclic GMP-inhibited PDE, PDE III), (+/-)-rolipram and denbufylline (0.1-30 microM) did not produce any positive inotropic effect in normal (2.5 mM) or elevated (3-3.2 mM) external CaCl2 concentration. In these conditions, Ro 20-1724 produced only a slight but significant increase of contraction over control levels. In the presence of forskolin (an adenylate cyclase activator) or SK&F 94120 (a PDE III inhibitor), which produced an increase of the response to electrical stimulation of approximately 10%, (+/-)-rolipram, denbufylline, and Ro 20-1724 all exerted concentration-dependent positive inotropic effects (mean EC50 values were 20, 25, and 125 nM, respectively, in the presence of forskolin). Rolipram exhibited stereospecificity: the (-)-enantiomer was 10 times more potent than the (+)-enantiomer. Neither preincubation of the atria with atenolol nor pretreatment of the guinea pigs with reserpine significantly modified the effect of PDE IV inhibitors obtained in the presence of forskolin. These data show that in the presence of cyclic AMP-dependent positive inotropic agents, PDE IV inhibitors exert a positive inotropic effect which probably does not involve enhanced catecholamine release from sympathetic nerve endings. This suggests that PDE IV may play a role in regulation of cardiac contraction in physiologic conditions in which the sympathetic outflow produces a stimulation of adenylate cyclase in cardiac cells.
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PMID:Involvement of rolipram-sensitive cyclic AMP phosphodiesterase in the regulation of cardiac contraction. 170 3

As part of the search for the Huntington disease (HD) gene we have cloned and sequenced 34 kb of genomic DNA containing the full-length gene for the beta-subunit of the human cGMP phosphodiesterase (beta-cGMP PDE). This gene is localized to 4p16.3 about 700 kb proximal to the 4p telomere and represents the most telomeric gene characterized on 4p to date. We show that this gene is comprised of 22 exons spanning approximately 43 kb of genomic DNA. We also provide 400 bp immediately 5' to the putative initiator methionine and 700 bp of 3' flanking sequences. Northern blot analysis of several human tissues revealed a highly abundant 3.5 kb transcript and a minor signal of 4.5 kb in retinal tissue. Alignment of the deduced amino acid sequence to the previously identified beta-subunits of the cGMP PDEs of mouse and cow demonstrates highly significant similarities and, therefore, confirms the identity of the cloned gene. A defect in the beta-subunit of the cGMP PDE gene has been shown recently to be the cause for the retinal degeneration in the rd mouse. The cloning of the human homolog and the knowledge of its genomic organization with exon/intron boundaries will allow rapid assessment of the role of this gene in the causation of human retinopathies.
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PMID:Genomic organization and complete sequence of the human gene encoding the beta-subunit of the cGMP phosphodiesterase and its localisation to 4p 16.3. 172 Feb 39

An adrenal cGMP-stimulated phosphodiesterase (cGS-PDE) has been shown to mediate atrial natriuretic peptide (ANP)-induced reductions in aldosterone secretion and cAMP levels in primary bovine glomerulosa cells. High concentrations of cGS-PDE have been localized to the zona glomerulosa cell layer of the adrenal cortex using biochemical and immunological techniques. Immunoblot analysis using an affinity-purified, isozyme-specific antiserum revealed a single band that comigrated with a purified cGS-PDE (105 kDa) (1) and that was most highly concentrated in the outermost 1-2 mm of the cortex, representing the capsule and zona glomerulosa regions. Greater than 90% of the overall phosphodiesterase activity present in tissue extracts prepared from these regions was immunoprecipitated using a solid-phase monoclonal antibody reagent, indicating the cGS-PDE as the predominant phosphodiesterase isozyme. Immunohistochemical staining experiments of frozen thin sections of intact adrenal tissue revealed that the cGS-PDE present in this region was localized in the glomerulosa cells themselves. The role of this isozyme as a mediator of ANP-induced decreases in intracellular cAMP concentrations and aldosterone production was tested in primary cultures of bovine adrenal glomerulosa cells. In cells stimulated by ACTH, ANP treatment produced dose-dependent reductions in aldosterone secretion and cellular cAMP content over the same concentration range. Increases in aldosterone production elicited by three cell-permeable cAMP derivatives (8-bromo-cAMP, 8-p-chlorophenylthio-cAMP, and N6-2'-O-dibutyryl-cAMP) were antagonized by ANP, indicating a site of action distal to adenylate cyclase for this hormone. Because the relative magnitude of the ANP effect differed depending upon the derivative used, the three derivatives were compared with respect to their relative rates of in vitro hydrolysis by adrenal cGS-PDE. A positive correlation between their rates of hydrolysis and the degree to which the steroidogenic response produced by these derivatives was antagonized by ANP was demonstrated, further suggesting an ANP-induced activation of the cGS-PDE as being responsible for this effect. The possible contribution of an additional pathway mediated by an inhibitory guanine nucleotide binding regulatory protein (Gi) acting on adenylate cyclase was tested by pretreatment of primary glomerulosa cells with pertussis toxin. Levels of pertussis toxin sufficient to inhibit subsequent in vitro ribosylation did not significantly alter the ANP effect on aldosterone production, although a partial reduction in the ANP effect on cAMP levels was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. 184 62


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