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)

The effects of pyrrolo[2,3-d]pyrimidine compounds (7-desazapurines) on cAMP hydrolyzing, calmodulin dependent and calmodulin independent phosphodiesterase were studied. Phosphodiesterase inhibition depended on the chemical nature of substituents attached to the pyrrolo-pyrimidine-nucleus at positions 2, 4, 5, 6 and 7. Among a total of 28 compounds tested, the 4-amino-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dicarbaldehyde (9) was the most potent inhibitor of phosphodiesterase activity (IC50 = 16 microM). In addition to the 5,6-disubstitution, position 2 of the pyrrolo-pyrimidine derivatives had to be unsubstituted and position 4 had to bear an amino-group for an optimal inhibitory effect. Calmodulin dependent and calmodulin independent isozymes were affected to the same extent. Inhibition of PDE activity was reversible upon removal of the pyrrolo-pyrimidine derivative 9 and non-competitive with respect to cAMP (Ki = 27 microM).
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PMID:Pyrrolo[2,3-d]pyrimidines as inhibitors of cAMP-phosphodiesterase. Structure-activity relationship. 253 63

Our studies of mononuclear leukocyte peripheral blood homogenates demonstrate significantly increased cyclic adenosine monophosphate-specific phosphodiesterase activity in patients with atopic dermatitis who were untreated for 1 week, compared with normal adult nonatopic control subjects. Phosphodiesterase activity is not related to the extent or activity of the patient's disease or the presence or absence of allergic respiratory disease. Enzyme kinetic studies showed a triphasic plot in normal mononuclear leukocytes but a biphasic plot in atopic dermatitis. This may be interpreted as an absence of an enzyme with a low (0.080) Michaelis Menton constant (Km) in atopic dermatitis samples. One week of therapy with a topical fluorinated steroid ointment caused a significant reduction in disease activity. Although a slight reduction in mean total phosphodiesterase activity occurred, it did not reach statistical significance. One week's treatment, however, caused the abnormal biphasic kinetic plot to revert to a triphasic plot with return of the low Km enzyme form in those patients who showed a fall in phosphodiesterase activity. This finding suggests that the elevated phosphodiesterase activity in atopic dermatitis may be responsive in a limited degree to topical steroid therapy.
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PMID:Response of mononuclear leukocyte cyclic adenosine monophosphate-phosphodiesterase activity to treatment with topical fluorinated steroid ointment in atopic dermatitis. 254 50

Phosphodiesterase activity was stimulated in myelin membranes in the presence of guanine nucleotide analogues. This activity was reduced in myelin membranes which had been adenosine diphosphate ribosylated in the presence of cholera toxin which ADP-ribosylated three proteins of Mr 46,000, 43,000 and 18,500. Aluminum fluoride treatment of myelin had the same stimulatory effects on phosphodiesterase activity as did the guanine nucleotides.
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PMID:Guanine nucleotides stimulate hydrolysis of phosphatidyl inositol bis phosphate in human myelin membranes. 254 48

Prothoracicotropic hormone (PTTH) stimulates ecdysteroid secretion by the prothoracic glands of Manduca sexta in a cAMP-dependent manner. However, larval and pupal glands differ markedly in the degree to which PTTH stimulates cAMP accumulation, suggesting a stage-specific difference in phosphodiesterase activity. The present study was designed to determine if and when such a difference arose during development, and its effect on PTTH-stimulated ecdysteroid secretion. The results reveal that soluble phosphodiesterase activity in the prothoracic glands changes significantly during the course of the fifth (last) larval instar, with a marked increase in activity occurring at the onset of prepupal development. Phosphodiesterase activity, particularly in the soluble cell fraction, is inversely correlated with PTTH-stimulated cAMP accumulation. Hormone-stimulated ecdysteroid secretion does not require cAMP accumulation, but does appear to require detectable cAMP synthesis as measured in the presence of phosphodiesterase inhibitors. The amount of ecdysteroid secreted, however, is not proportional to the amount of cAMP synthesized but rather is more closely correlated with developmental changes in glandular protein content.
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PMID:Developmental changes in phosphodiesterase activity and hormonal response in the prothoracic glands of Manduca sexta. 254 41

Cyclic AMP phosphodiesterase (PDE) activity was assayed in the plasma membrane, mitochondrial and microsomal fractions of rat brain. The specific activity of the enzyme was highest in the plasma membrane fraction followed by mitochondrial and then the microsomal fraction. Phosphodiesterase activity of all three fractions was reduced after pretreatment with lecithinase C (PCase) from Clostridium perfringens but less markedly affected by the pretreatment with sphingomyelinase (SMase) from human placenta. The PDE activity of the plasma membrane fraction was more sensitive to PCase treatment compared with the other two particulate fractions, which showed only a slight loss of activity. Temperature seemed to affect PDE activity of the plasma membrane. The enzyme was quite stable at 30 degrees C but its activity dropped by approximately 46% at 37 degrees C after 90 min of incubation. Pretreatment of the plasma membrane at 30 degrees C with PCase at a concentration of more than 5 U caused a marked loss of PDE activity and the decrease in activity reached a plateau at concentrations above 10 U.
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PMID:Reduction of cyclic AMP phosphodiesterase activity of several subcellular fractions of rat brain after pretreatment with phospholipase C. 256 41

Isolated rabbit renal papillary collecting tubule cells were used to examine the effects of phosphodiesterase inhibitors on intracellular cyclic AMP and prostaglandin synthesis. Experiments performed on confluent primary tissue cultures demonstrated that bradykinin increases intracellular cyclic AMP by a prostaglandin-dependent mechanism. Phosphodiesterase inhibitors induced a dose-dependent decrease in bradykinin-stimulated prostaglandin synthesis. Fifty percent inhibition occurred with approximately 0.7 mM 3-isobutyl-1-methylxanthine (IBMX). Inhibition was found to be reversible. IBMX did not inhibit bradykinin-induced prostaglandin synthesis as a result of increased intracellular cyclic AMP. The nonmethylxanthine phosphodiesterase inhibitor RO 20-1724 also reduced bradykinin-stimulated prostaglandin synthesis. IBMX inhibited calcium-ionophore-A23187-induced prostaglandin synthesis but did not inhibit arachidonic acid stimulation of prostaglandin synthesis. The data demonstrate that bradykinin increased renal papillary collecting tubule cell cyclic AMP in a prostaglandin-dependent manner. Based on the data presented, phosphodiesterase inhibitors act to decrease arachidonic acid availability for prostaglandin synthesis, independent of changes in cellular cyclic AMP content.
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PMID:Effect of phosphodiesterase inhibitors on bradykinin-mediated prostaglandin E2 and cyclic AMP synthesis in renal papillary collecting tubule cells. 258 85

Conventional pharmacologic therapy for the management of congestive heart failure includes inotropic, vasodilator, and diuretic agents. Phosphodiesterase inhibitors are a new class of inotropic agent that possesses both inotropic and vasodilating capability. Currently, only one of these agents, amrinone (Inocor), has been approved for clinical use in the United States. Nursing management of the patient receiving amrinone requires knowledge of the appropriate vehicle for administration, the recommended dose, and adverse reactions. A thorough understanding of the hemodynamic alterations in CHF, as well as the effect of amrinone on these hemodynamic parameters, is an essential component of nursing care. Amrinone is only available for intravenous administration. Clinical trials, involving several investigational phosphodiesterase inhibitors, are being conducted. These drugs are being administered orally and intravenously. The goal of research is to develop a potent positive inotrope that will be available for both oral and intravenous administration. The focus of current research involving phosphodiesterase inhibitors includes studying the effect of these agents on myocardial ischemia as well as the mortality and morbidity of CHF. Additional knowledge regarding these and other issues is needed before the new inotropes can become a routine component of the pharmacological armamentarium for treatment of CHF.
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PMID:Cardiac drugs: new inotropes. 281 83

Cyclic adenosine monophosphate-phosphodiesterase is the enzyme responsible for cyclic adenosine monophosphate degradation. We investigated the kinetic behavior of this enzyme in the myometrium of women who were nonpregnant, pregnant at term not in labor, and pregnant at term in active labor. Phosphodiesterase activity was measured in the 100,000 g supernatant by the two-step isotopic procedure. The Km (Michaelis constant) value remains essentially unchanged from the nonpregnant to the pregnant state and subsequent labor in both the low and the high affinity enzymes. During pregnancy the V max (maximum velocity) is 75% less than in the nonpregnant state (p less than 0.005) and remains unchanged during labor. This is true for both the high and the low affinity enzymes. These changes in the kinetic characteristics of the cyclic adenosine monophosphate-phosphodiesterase are indicative of noncompetitive inhibition. We conclude that this inhibition may be interpreted as part of the mechanism for uterine smooth muscle relaxation and pregnancy maintenance.
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PMID:Changes in cyclic adenosine monophosphate-phosphodiesterase activity in nonpregnant and pregnant human myometrium. 282 Feb 29

This study examines the pattern and regulatory properties of cyclic nucleotide phosphodiesterases in a human lymphoblastoid B-cell line (RPMI 8392) established from a patient with acute lymphocytic leukaemia. In this cell line, phosphodiesterase activity measured at 0.25 microM-cyclic AMP is approx. 7-fold greater than that in isolated human peripheral-blood lymphocytes, and 16% of the phosphodiesterase activity in RPMI 8392 cells is associated with particulate fractions. Phosphodiesterase activity in crude fractions of this cell line is reproducibly stimulated by about 60-80% by Ca2+-calmodulin. In the presence of 20 nM-calmodulin, half-maximal stimulation occurs at 0.7 microM-Ca2+. The cytosolic phosphodiesterase activity of RPMI 8392 cells is separated into two forms by DEAE-Sephacel chromatography. The first form is eluted at approx. 0.2 M-sodium acetate, catalyses the hydrolysis of both cyclic AMP and cyclic GMP, and is stimulated 3-fold by Ca2+-calmodulin. This form exhibits non-linear kinetics for cyclic AMP in the absence of calmodulin, with extrapolated Km values of 0.8 and 4 microM, and non-linear kinetics in the presence of calmodulin, with extrapolated Km values of 0.5 and 1 microM. The Vmax. values are increased approx. 3-fold by calmodulin. The second form is eluted at approx. 0.6 M-sodium acetate, is specific for cyclic AMP, and insensitive to stimulation by Ca2+-calmodulin. The Ca2+-calmodulin-sensitive phosphodiesterase from the DEAE-Sephacel column can be adsorbed to a calmodulin-Sepharose affinity column and eluted with EGTA. This enzymic activity can also be immunoprecipitated by a monoclonal antibody directed against a calmodulin-bovine heart phosphodiesterase complex. This study documents the existence of Ca2+-calmodulin-sensitive phosphodiesterase in a cultured lymphoblastoid cell line derived from a leukaemic patient.
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PMID:Identification and characterization of a Ca2+-calmodulin-sensitive cyclic nucleotide phosphodiesterase in a human lymphoblastoid cell line. 282 Mar 85

The effects of aging and of food restriction at different times during life on rat adipocyte responses to glucagon and epinephrine were explored by studying hormone-stimulated lipolysis, hormone binding, and phosphodiesterase activity. The times of food restriction were: (a) from 6 weeks of age, (b) limited to early life, and (c) beginning in young adult life. Hormone-sensitive lipolysis is lost with age. Food restriction from 6 weeks of age prevents this loss, and food restriction started in adult life causes the recovery of this lipolysis. Hormone binding studies reveal that: (a) changes in glucagon-stimulated lipolysis parallel changes in glucagon binding; (b) glucagon binding and glucagon-stimulated lipolysis correlate inversely with cell size; (c) changes in epinephrine-stimulated lipolysis are not due to changes in beta-adrenergic binding; and (d) neither beta-adrenergic binding nor epinephrine-promoted lipolysis correlate with fat cell size. Phosphodiesterase activity is not influenced by diet, making it unlikely to be a postreceptor component lost with age.
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PMID:Action of food restriction on age-related changes in adipocyte lipolysis. 282 98


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