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)

In experiments on male albino rats and mice a study is made of the effects of imidazol which is a phosphodiesterase stimulator, papaverine which inhibits phosphodiesterase and histamine which stimulates adenylate cyclase, on the convulsive-seizure reactivity. The substances are introduced intraventricularly and intracerebroventricularly, imidazol also intraperitoneally in different doses and at different intervals before the convulsive agent. Electrical, pentylenetetrazol (Cor) and strychnine convulsion models are used. The effect of imidazol on the spontaneous cortical bioelectrical activity is studied throuth its i. v. administration in rabbits. Imidazol markedly increases the convulsive reactivity, and in large doses it alone results in electrographic and motor convulsions. Paperine slightly lowers the convulsive-seizure reactivity only in pentylenetetrazol convulsions. The results obtained and their comparison with the results of previous experiments of ours with other drugs affecting the cyclic adenosinemonophosphate (cAMP) system, such as lithium, haloperidol, caffeine and theophyline, do not permit to assume a considerable significance of the influence of these substances (in the doses tested) on the cAMP system in the mechanisms of their effects on the convulsive-seizure reactivity.
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PMID:Experimental study of the effects of imidazol, papaverine and histamine on convulsive-seizure reactivity. 101 6

Partially degenerate oligonucleotides based on peptide sequence were used to isolate cDNA to a 63-kDa bovine brain calmodulin-stimulated phosphodiesterase (CaM-PDE) isozyme. A 412-base pair polymerase chain reaction fragment was obtained and used along with the oligonucleotides to isolate several cDNAs each encoding sequence identical to known peptide sequences from the 63-kDa CaM-PDE. The largest cDNA contained a full-length open reading frame (ORF) encoding a 534 amino acid, 61,005-dalton protein. It had 59% amino acid identity to the 61-kDa bovine brain CaM-PDE and included a carboxyl-terminal conserved domain containing the PDE catalytic domain consensus sequences. The NH2-terminal region fits the criteria for a calmodulin-binding domain. When its expression was driven by a cytomegalovirus promoter on a pCDM8 vector in COS-7 cells, the cDNA encoded a catalytically active, calmodulin-stimulated PDE. Northern analysis of RNA from several tissues with a probe containing much of the conserved PDE catalytic domain showed only a single band of 4.0 kilobases. Hybridization was seen in mRNA from several regions of the central nervous system with the greatest signal in basal ganglia. Strong signals also were seen in other tissues including kidney papilla and adrenal medulla. Antisense RNA probes were used in RNase-protection assays to look for evidence of multiple 63-kDa CaM-PDE transcripts. A catalytic domain probe was fully protected by RNA from cerebral cortex, basal ganglia, cerebellum, hippocampus, adrenal medulla, and kidney papilla. However, a probe to the NH2-terminal region was fully protected only by brain and adrenal medullary RNA indicating the likelihood of one or more isozyme(s) divergent in this region in the kidney papilla.
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PMID:Molecular cloning of cDNA encoding a "63"-kDa calmodulin-stimulated phosphodiesterase from bovine brain. 132 31

At the onset of pentylenetetrazole induced convulsions, the adenylate cyclase activity and phosphodiesterase activity were increased. The former was markedly stimulated in the brain stem of rats. In the cerebral cortex and brain stem, the glucose level was significantly decreased, and the concentration of glucose-6-phosphate was increased. However, the definite changes in energy reserve system of the brain could not be observed at the onset of penetylentetrazole induced seizures. The present study revealed some correlation between pentylenetetrazole convulsions and the adenylate cyclase activity and glycometabolism.
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PMID:Biochemical aspects of pentylenetetrazole induced seizure. 629 19

A mechanism is proposed for the RNA-catalyzed reactions involved in RNA splicing and RNase P hydrolysis of precursor tRNA. The mechanism postulates that chemical catalysis is facilitated by two divalent metal ions 3.9 A apart, as in phosphoryl transfer reactions catalyzed by protein enzymes, such as the 3',5'-exonuclease of Escherichia coli DNA polymerase I. One metal ion activates the attacking water or sugar hydroxyl, while the other coordinates and stabilizes the oxyanion leaving group. Both ions act as Lewis acids and stabilize the expected pentacovalent transition state. The symmetry of a two-metal-ion catalytic site fits well with the known reaction pathway of group I self-splicing introns and can also be reconciled with emerging data on group II self-splicing introns, the spliceosome, and RNase P. The role of the RNA is to position the two catalytic metal ions and properly orient the substrates via three specific binding sites.
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PMID:A general two-metal-ion mechanism for catalytic RNA. 834 61

The ED50 value of cyanide as measured by induction of convulsions (tonic seizure) was significantly increased by 80% or 69% when trifluoperazine (TFP) or chlorpromazine (CHP), a specific calmodulin inhibitor was preinjected intracerebroventricularly (i.v.t.) at a dose of 0.09 mumol/body of mice. However, the ED50 of cyanide was not significantly changed by the same dose of promethazine (PMZ), another calmodulin inhibitor. Since it is known that the inhibitory effect of TFP or CHP against calmodulin-dependent enzymes such as phosphodiesterase is 100-400-fold higher compared to PMZ, it is speculated that the inhibitory effect of TFP or CHP against cyanide-induced convulsions may be based on its strong inhibitory properties into calmodulin-dependent enzymes. On the other hand, the LD50 value of cyanide was significantly increased by i.v.t. preadministration of TFP or CHP (0.045 mumol/body). Furthermore, the LD50 value of cyanide was also significantly increased by the same dose of PMZ. These results suggest that there is no positive correlation between mortality and convulsions induced by cyanide.
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PMID:Protective effect of calmodulin inhibitors against acute cyanide-induced lethality and convulsions in mice. 842 23

The biochemistry of visual excitation is kinetically explored by measuring the activity of the cGMP phosphodiesterase (PDE) at light levels that activate only a few tens of rhodopsin molecules per rod. At 23 degrees C and in the presence of ATP, the pulse of PDE activity lasts 4 s (full width at half maximum). Complementing the rod outer segments (ROS) with rhodopsin kinase (RK) and arrestin or its splice variant p44 does not significantly shorten the pulse. But when the ROS are washed, the duration of the signal doubles. Adding either arrestin or p44 back to washed ROS approximately restores the pulse width to its initial value, with p44 being 10 times more efficient than arrestin. This supports the idea that, in vivo, capping of phosphorylated R* is mostly done by p44. When myristoylated (14:0) recoverin is added to unwashed ROS, the pulse duration and amplitude increase by about 50% if the free calcium is 500 nM. This effect increases further if the calcium is raised to 1 microM. Whenever R* deactivation is changed--when RK is exogenously enriched or when ATP is omitted from the buffer--there is no impact on the rising slope of the PDE pulse but only on its amplitude and duration. We explain this effect as due to the unequal competition between transducin and RK for R*. The kinetic model issued from this idea fits the data well, and its prediction that enrichment with transducin should lengthen the PDE pulse is successfully validated.
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PMID:Responses of the phototransduction cascade to dim light. 864 63

beta-Adrenergic stimulation reduces albumin permeation across pulmonary artery endothelial monolayers and induces changes in cell morphology that are mediated by Cl- flux. We tested the hypothesis that anion-mediated changes in endothelial cells result in changes in endothelial permeability. We measured permeation of radiolabeled albumin across bovine pulmonary arterial endothelial monolayers when the extracellular anion was Cl-, Br-, I-, F-, acetate (Ac-), gluconate (G-), and propionate (Pr-). Permeability to albumin (Palbumin) was calculated before and after addition of 0.2 mM of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), which reduces permeability. In Cl-, the Palbumin was 3.05 +/- 0.86 x 10(-6) cm/s and fell by 70% with the addition of IBMX. The initial Palbumin was lowest for Pr- and Ac-. Initial Palbumin was higher in Br-, I-, G-, and F- than in Cl-. A permeability ratio was calculated to examine the IBMX effect. The greatest IBMX effect was seen when Cl- was the extracellular anion, and the order among halide anions was Cl- > Br- > I- > F-. Although the level of extracellular Ca2+ concentration ([Ca2+]o) varied over a wide range in the anion solutions, [Ca2+]o did not systematically affect endothelial permeability in this system. When Cl- was the extracellular anion, varying [Ca2+]o from 0.2 to 2.8 mM caused a change in initial Palbumin but no change in the IBMX effect. The anion channel blockers 4-acetamido-4'-isothiocyanotostilbene-2, 2'-disulfonic acid (0.25 mM) and anthracene-9-carboxylic acid (0.5 mM) significantly altered initial Palbumin and the IBMX effect. The anion transport blockers bumetanide (0.2 mM) and furosemide (1 mM) had no such effects. We conclude that extracellular anions influence bovine pulmonary arterial endothelial permeability and that the pharmacological profile fits better with the activity of anion channels than with other anion transport processes.
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PMID:Role for anions in pulmonary endothelial permeability. 926 60

We previously showed that 8-[(4-bromo-2,3-dioxobutyl)thio]adenosine 3',5'-cyclic monophosphate inactivates cAMP phosphodiesterase (PDE3A); however, millimolar concentrations were needed to inactivate PDE3A because of ongoing hydrolysis. We have now synthesized a nonhydrolyzable reactive cAMP analogue, (S(p))-8-[(4-bromo-2,3-dioxobutyl)thio]adenosine 3',5'-cyclic S-(methyl)monophosphorothioate (S(p)-8-BDB-TcAMPSMe). S(p)-8-BDB-TcAMPSMe inactivates PDE3A in a time-dependent, irreversible manner, exhibiting saturation kinetics with a k(max) of (19.5 +/- 0.3) x 10(-3) min(-1) and a K(I) of 3.5 +/- 0.3 muM. To ascertain whether S(p)-8-BDB-TcAMPSMe reacts in the active site, nonhydrolyzable analogues of the substrate cAMP, or the competitive inhibitor cGMP, were included to protect against the inactivation of PDE3A. The order of effectiveness of protectants in decreasing the rate of inactivation (with K(d) values in micromolar) is as follows: S(p)-cAMPS (18) > R(p)-cGMPS (560) and S(p)-cGMPS (1260) > 5'-AMP (17 660), R(p)-cAMPS (30 110), and 5'-GMP (42 170). We docked S(p)-8-BDB-TcAMPSMe into PDE3A, based on the structural model of PDE3A-cAMP and the kinetic data from site-directed mutants. The S(p)-8-BDB-TcAMPSMe fits into the active site in the model. These results suggest that inactivation of PDE3A by the affinity reagent is a consequence of reaction at the overlap between cAMP and cGMP binding regions in the active site. S(p)-8-BDB-TcAMPSMe has proven to be an effective active site-directed irreversible cAMP affinity label for platelet PDE3A and can be used to identify amino acids in the active site of PDE3A as well as in other cAMP phosphodiesterases.
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PMID:A nonhydrolyzable reactive cAMP analogue, (S(p))-8-[(4-bromo-2,3-dioxobutyl)thio]adenosine 3',5'-cyclic S-(methyl)monophosphorothioate, irreversibly inactivates human platelet cGMP-inhibited cAMP phosphodiesterase at micromolar concentrations. 1186 34

A mathematical model of the vertebrate phototransduction mechanism was designed in a modular fashion, in that increasingly complex behaviors can be turned on and off to evaluate the relative involvement of all elements of the phototransduction cascade. The problem was approached by starting with a minimum model in which the intracellular cGMP concentration ([cGMP]i) was determined by guanylate cyclase (GC), whose activity was assumed not to be regulated by any factor (such as Ca2+) and by phosphodiesterase (PDE), whose activity was assumed to be proportional to the light intensity. All dependences were subsequently introduced, i.e. the equations describing PDE activation in detail, the Ca2+ regulation of GC and the action of intracellular Ca2+ buffers. The simulations and fits show that a high-gain, smooth time- and light-dependent PDE activation, a Ca2+-dependent GC, and a Ca2+-dependent buffer mechanism are required to account for the flash response kinetics in the dark and on dim backgrounds of light, and the effect of exogenous Ca2+ buffers to produce responses characterized by slow and damped oscillations and to enhance the low-frequency noise. However, it was not possible to find any set of parameters able to simultaneously interpolate the waveform of the flash responses (in the dark and on a background of light) and the responses to steps of light. It is therefore concluded that at least one more shut-off mechanism (possibly not Ca-dependent) is necessary to fully account for the phenomenology of the light response in rod photoreceptors.
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PMID:A step-by-step model of phototransduction cascade shows that Ca2+ regulation of guanylate cyclase accounts only for short-term changes of photoresponse. 1471 23

Understanding patient preferences can be important in ensuring full benefit is derived from treatment for erectile dysfunction (ED). They seem to be important in determining whether patients continue treatment in the medium and long term. In clinical practice, discontinuation rates beyond a year are relatively high. Factors such as spontaneity, "naturalness", and onset and duration of action may all influence preference. This article discusses a number of studies looking into patient preferences for a particular class of treatment method over another, and also for individual treatments within classes. In general, patients appear to prefer oral treatments to others such as penile implant surgery, vacuum-pump therapy, apomorphine, and intracavernosal injection. In some studies, men have also shown preferences for particular oral phosphodiesterase-5 (PDE5) inhibitors over others. Providing patients with full information on the pros and cons of treatment options can help ensure patients are treated with a therapy that fits more closely with their wishes, and ensure continuation of treatment for optimal efficacy.
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PMID:Patient preferences in treatment of erectile dysfunction: the continuing importance of patient education. 1615 24


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