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)

Congestive heart failure is a clinical syndrome with inadequate cardiac output and increased venous pressure, characterized by hyperfunction of the sympatho-neuro-endocrine system, favoring maximal vasoconstriction in non-essential organs and retention of salt and water. Identification of the cause of heart failure and its correction is the best treatment. The suppression of precipitant factors is also essential. Traditionally the treatment of congestive heart failure is based on diuretics, restriction of salt intake, and digitalis. The conventional vasodilators are effective in the short term, but they have a marked tendency to tachyphylaxis. The inhibitors of angiotensin-converting enzyme are, through their specific action on neuro-endocrine dysregulation, the most important advance in recent years. Of the non-glycosidic inotropic agents used in severe heart failure, the new inhibitors of phosphodiesterase need further testing. In certain cases, permanent synchronous pacing has to be considered.
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PMID:[Pathophysiologic aspects and modern treatment of congestive heart failure]. 302 12

Strips of the rabbit pulmonary artery were incubated with 3H-noradrenaline and subsequently superfused. In strips superfused with Ca2+-free solution containing K+ 64.7 mmol/l, tritium overflow was stimulated by introduction of Ca2+ 1.6 mmol/l; in strips superfused with physiological salt solution, stimulation was carried out with veratridine 30 mumol/l, acetylcholine 1 mmol/l (in the presence of atropine 1 mumol/l) or tyramine 100 mumol/l. The Ca2+-, veratridine- or acetylcholine-induced tritium overflow was facilitated by forskolin, AH 21-132 (a cAMP phosphodiesterase inhibitor) and/or 8-Br-cAMP, i.e. compounds which increase intraneuronal cAMP content. In contrast, the Ca2+-independent tyramine-evoked tritium overflow was not affected by these drugs. It is concluded that cAMP is involved in the regulation of stimulation-evoked Ca2+-dependent noradrenaline release, and that the sympathetic nerve terminals are endowed with an adenylate cyclase system. Facilitation of release may be caused by an alteration of Ca2+ influx or utilization.
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PMID:Further evidence for the involvement of cyclic AMP in Ca2+-dependent, but not Ca2+-independent, noradrenaline release in the rabbit pulmonary artery. 303 Feb 8

Attempts to optimize the recovery of light-stimulated phosphodiesterase activity following reassociation of the hypotonically extractable proteins derived from retinal rod segments with hypotonically stripped disc membranes lead to the following observations: the best reassociations were obtained by mixing proteins and stripped disc membranes under hypotonic conditions and slowly increasing the salt concentration; the binding of G-protein and phosphodiesterase to stripped disc membrane occurs in less than 5 minutes and the recovery of light-stimulated phosphodiesterase activation in response to subsaturating stimulus levels requires 2-3 h to plateau. Stripped disc membranes and proteins were reassociated in 'isotonic' buffers containing KCl/NaCl, KCl/NaCl plus Mg2+, or KCl/NaCl plus Ca2+. Large fractional rhodopsin bleaches produced nearly identical light-stimulated phosphodiesterase activities in each of these samples and in the control rod outer segment membranes. Rod outer segment membranes and reassociated stripped disc membrane samples containing divalent cations showed similar phosphodiesterase activities in response to low fractional rhodopsin bleaches (e.g. less than or equal to 0.1%), however, samples devoid of divalent cations during reassociation required rhodopsin bleaches up to 10-fold larger to elicit comparable phosphodiesterase activities. These results suggest that not all phosphodiesterase and/or G-protein molecules bound to the disc membrane surface are equivalent with regard to their efficiency of activation by bleached rhodopsin and that divalent cations can modulate the distribution of G-protein and/or phosphodiesterase between these populations.
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PMID:Binding and activation of rod outer segment phosphodiesterase and guanosine triphosphate binding protein by disc membranes: influence of reassociation method and divalent cations. 303 Apr 22

Four cyclic nucleotide phosphodiesterase (PDE) activities were separated from low-speed supernatants of homogenates of human cardiac ventricle by DEAE-Sepharose chromatography, and designated PDE I-PDE IV in order of elution with an increasing salt gradient. PDE I was a Ca2+/calmodulin-stimulated activity, and PDE II was an activity with a high Km for cyclic AMP which was stimulated by low concentrations of cyclic GMP. Human ventricle PDE III had Km values of 0.14 microM (cyclic AMP) and 4 microM (cyclic GMP), and showed simple Michaelis-Menten kinetics with both substrates. PDE IV is a previously unrecognized activity in cardiac muscle, the human enzyme having Km values of 2 microM (cyclic AMP) and 50 microM (cyclic GMP). PDE III and PDE IV were not activated by cyclic nucleotides or calmodulin. Four PDE activities were also isolated from guinea-pig ventricle, and had very similar kinetic properties. By gel filtration, the Mr of PDE III was 60,000, and that of PDE IV 45,000. The drug SK&F 94120 selectively and competitively inhibited PDE III with a Ki value of 0.8 microM (human), showing simple hyperbolic inhibition kinetics. Rolipram (Schering ZK 62711) and Ro 20-1724 (Roche), which have previously been reported to inhibit PDE III-like activities strongly, were shown to be weak inhibitors of human and guinea-pig PDE III enzymes (Ki values greater than 25 microM), but potent inhibitors of PDE IV [Ki values 2.4 microM (Rolipram) and 3.1 microM (Ro 20-1724) with human PDE IV]. The inhibition in all cases demonstrated simple hyperbolic competition. These observations suggest that the previously reported complex inhibition of PDE III-type activities from cardiac muscle was caused by incomplete separation of the PDE III from other enzymes, particularly PDE IV.
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PMID:The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. 303 66

Experiments were designed to study the interaction of rat peritoneal neutrophils with the vascular smooth muscle of the rat aorta. Rings of aorta, suspended in 10-ml organ chambers containing a physiologic salt solution, were precontracted with phenylephrine. Neutrophils (1 X 10(5) -4 X 10(7) cells/organ chamber) caused a cell number-dependent relaxation of the rat aorta that was augmented by superoxide dismutase (100 U/ml) or changing the oxygen content from 95 to 21%. The neutrophil-induced smooth muscle relaxation occurred in rings with and without endothelium and in rings precontracted with increasing concentrations of phenylephrine, prostaglandin F2 alpha or KCI. Catalase (1000 U/ml) and mannitol (1 X 10(-3) M) did not block the neutrophil-induced relaxation, whereas phenazine methosulfate (1 X 10(-5) M), hydroquinone (3 X 10(-5) M) and methylene blue (1 X 10(-5) M) reversed the neutrophil-induced relaxation. Pre-exposure of endothelium-rubbed rings to neutrophils (2 X 10(7) cells/organ chamber; 15 min) depressed the subsequent concentration-response curve to phenylephrine but augmented the relaxation induced by the phosphodiesterase inhibitor zaprinast (1 X 10(-5) M). The effluent from a column restraining the neutrophils induced a relaxation of endothelium-rubbed aortic rings that was prevented by methylene blue (1 X 10(-5) M). These results demonstrate that rat neutrophils release a factor that has a pharmacologic profile similar to that previously reported for the relaxing factor released from the vascular endothelium.
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PMID:Interaction of neutrophils with vascular smooth muscle: identification of a neutrophil-derived relaxing factor. 312 47

The effects of aralkylation of selected oligonucleotides by a bulky chemical carcinogen, 7,12-dimethylbenz(a)anthracene (after activation) have been studied. The aralkylation involves the base adenine, designated A* at the modification site, in the center of synthetic heptameric, nonameric and pentadecameric oligonucleotides; complementary strands lacking any modification were also synthesized. The products were studied by UV melting curves and CD spectral techniques. Duplex formation was modified by such aralkylation of a central base in the oligomers. The extent of duplex formation was found to depend on chain length as follows: no evidence was found for duplex formation of the heptamer d(GTCA*GAC) + d(GTCTGAC); the nonamer, d(GTGCA*ATCC) + d(GGATTGCAC), appears to form a duplex at high salt concentrations and reduced temperature; the pentadecamer, d(CCGCT-GCGA*TCCGGC) + d(GCCGGATCGCAGCGG), forms a duplex at low salt concentration and room temperature, but its melting temperature is lower than that of the nonalkylated parent system. CD-spectra for the duplexes formed by the nonamer or pentadecamer are indicative of a right-handed helical conformations. On phosphordiesterase digestion it appears that the aralkylated adenine and the base on its 5'-side act as "stops" for enzymatic digestion from either direction. We suggest, from model building, that this inhibition of phosphodiesterase activity is the result of the steric bulk and disposition of the polycyclic aromatic hydrocarbon. We further suggest that unusual base pairing (mismatching), such as A...A, which would lead to an AT transversion, may be favored by the bulkiness of the aromatic group.
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PMID:Preparation and characterization in solution of oligonucleotides alkylated by activated carcinogenic polycyclic aromatic hydrocarbons. 315 57

Titin and nebulin are two major protein components of a cytoskeletal matrix that coexists with thick and thin filaments within the sarcomere of a wide range of striated muscles. Purified titin and nebulin from mouse diaphragm muscle are similar in size, in relative abundance, and in amino acid composition to analogous proteins from other mammals or avians. Phosphate analysis of these nucleic-acid-free proteins indicated that both proteins contain substantial amounts of protein-bound phosphate: about 12 mol of phosphate per mole of titin subunit and 11 mol of phosphate per mole of nebulin subunit. Incubation of intact, excised mouse diaphragm with radioactive inorganic phosphate resulted in significant incorporation of radiophosphate into titin and nebulin. The identification of titin and nebulin phosphorylation was facilitated by a simple salt fractionation and nuclease digestion procedure that effectively separated titin and nebulin from radiolabeled nucleic acids. Such in vivo phosphorylation studies indicated that approximately 2 mol of phosphate per titin subunit and 5 to 7 mol of phosphate per nebulin subunit were incorporated within 5 h of incubation. The incorporation nearly doubled when the beta-adrenergic agonist, isoproterenol, or a phosphodiesterase inhibitor, theophylline, was present in the medium. For both proteins, phosphorylation occurred mainly on serine residues. Nebulin also appears to possess a smaller number of threonine sites. Taken together, our data indicate that a small proportion (20 to 40%) of the steady-state titin phosphates are rapidly turning over. In contrast, most of the nebulin phosphates (50 to 100%) are readily exchanged. The modulation of turnover by external stimuli that increase cytosolic cAMP raises the possibility that at least a portion of the multiple phosphorylation sites of titin and nebulin may be involved in the functional regulation of the sarcomere matrix.
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PMID:Sarcomere matrix of striated muscle: in vivo phosphorylation of titin and nebulin in mouse diaphragm muscle. 335 62

Treatment of heart failure comprises the use of diuretics, vasodilators and inotropic substances. Unloading of the heart and the circulation in hydropic states is classically achieved with diuretics. The retention of salt and water in chronic heart failure requires chronic treatment with diuretics. This mode of treatment is basic to all forms of hydropic heart failure. Inotropic substances such as digitalis glycosides, sympathomimetic amines or phosphodiesterase inhibitors have certain disadvantages: Inotropic stimulation increases energy demand of the working heart muscle. Most of the substances used today increase energy consumption inordinately, thereby decreasing economy of myocardial contraction. This aspect calls for caution in the application of these substances in chronic heart failure, although they seem indispensable (sympathomimetic amines) in acute hypotensive failure and shock. Digitalis glycosides, basically suited for longterm treatment, exert only mild inotropic effects. In addition inotropic stimulation brings with it arrhythmogenic effects. All inotropic substances can induce ventricular arrhythmias already at therapeutic levels. Vasodilating substances have found increasing acceptance as a particularly useful and safe group of drugs for the treatment of heart failure. Nitrates: With the different nitrate compounds and nitrate preparations an effective venodilation with preload reduction can safely be achieved. At higher doses, arteriolar also dilatation can be induced. Although tolerance may be a problem with chronic application, this can be avoided with prudent dosing. The strong venodilating property makes these drugs together with their rapid onset of action ideally suited for the treatment of acute heart failure with pulmonary congestion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Treatment of heart failure: status of therapy with vasodilator agents]. 343 15

Continued exposure of many beta-adrenoceptor-coupled adenylate cyclase systems to high doses of agonist causes diminished responsiveness, a phenomenon called desensitization. After exposure of isolated guinea pig tracheae to a high concentration of isoproterenol for 30 min, relaxation produced by subsequent challenge by a lower concentration was attenuated, as expected. However, potentiation of isoproterenol-induced relaxation by aminophylline was greater after desensitization as compared to that prior to desensitization. This observation was further investigated using a graphical method that allows quantitative and statistical evaluation of combinations of synergistically acting drugs. Concentration-relaxation curves (CRC) for isoproterenol alone and in the presence of a fixed concentration of aminophylline were determined in isolated rat trachea. A theoretical additive curve was constructed from the data obtained, and the displacement of the isoproterenol CRC from the theoretical additive curve caused by aminophylline in tracheae desensitized by 2.5 hr of exposure to 2 X 10(-5) M isoproterenol (DESN) was compared to that in tracheae equilibrated for a similar period in physiologic salt solution (CON). Desensitization had no significant effect on aminophylline-induced relaxation but caused a marked depression and right-shift of the isoproterenol CRC. In the CON group aminophylline shifted the isoproterenol CRC upward and to the left indicating that the synergistic interaction between the two agents was greater than additive. The left-shift and elevation of the ceiling effect of the isoproterenol CRC caused by aminophylline were significantly greater in the DESN group vs the CON group. These observations from intact tissue are compared with published data from biochemical and broken cell studies. The possibility of increased phosphodiesterase activity as an explanation for the observations reported is discussed.
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PMID:Potentiation of isoproterenol-induced relaxation of isolated trachea by aminophylline: modulation by desensitization. 361 5

1. Supernatant proteins from rat brain were separated into two fractions containing phosphatidylinositol phosphodiesterase activity by chromatography on DEAE-Sephadex A-50. 2. The first fraction sediments in linear sucrose density gradients in two bands corresponding to molecular weights of 66000 and 36000. There was presumptive evidence that the lighter protein constituted the monomeric form of the enzyme. The second fraction sediments predominantly as a single protein of molecular weight 86000. 3. Treatment of rat brain supernatant with [(3)H]colchicine abolished the second DEAE-Sephadex peak and removed the lighter protein from the first peak. These proteins emerged in the same position as the protein binding [(3)H]colchicine at high salt concentration; phospholipase activity was recovered from linear sucrose density gradients in positions corresponding to molecular weights 88000 and 43000, together with an aggregate of molecular weight 140000. Electrophoresis on sodium dodecyl sulphate-urea-polyacrylamide gels of this fraction revealed only three proteins: the alpha and beta-subunits of microtubular protein, of molecular weights 56000 and 52000 respectively, and a protein of molecular weight 38000. 4. A sample of microtubular protein from mouse, labelled in vivo with [(3)H]proline and (32)P(i), was added to rat brain supernatant together with an equal amount of the same microtubular protein treated with cyclic AMP and [gamma-(32)P]ATP and the mixture subsequently characterized by ion-exchange chromatography. Some phospholipase activity characteristic of the second peak from DEAE-Sephadex was associated with one fraction of added microtubular protein. This fraction was identified on the basis of the (3)H:(32)P ratio as the beta subunit of the protein treated with ATP and cyclic AMP. The subunit of added microtubular protein untreated with nucleotides was not associated with phospholipase activity.
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PMID:The association between phosphatidylinositol phosphodiesterase activity and a specific subunit of microtubular protein in rat brain. 435 36


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