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)

When rat fat cells were incubated with ACTH, epinephrine, or theophylline for 2 to 10 min, cyclic AMP phosphodiesterase (3':5'-cyclic-AMP 5'-nucleotidohydrolase, E.C. 3.1.4.17) activity (K(m) about 0.39 muM) in the 100,000 x g sediment fraction of homogenates was increased 35 to 50%. The effects of epinephrine and ACTH were concentration dependent and maximal increases were produced with concentrations similar to those that maximally stimulate lipolysis. Theophylline (0.5 mM) similarly increased phosphodiesterase activity but did not enhance the effects of maximally effective concentrations of the hormones. The changes in phosphodiesterase activity following addition of ACTH or theophylline paralleled changes in cell cyclic AMP content; both reached a maximum within 5 min and then declined, approaching basal levels after 20 or 30 min. The increased phosphodiesterase activity in cells incubated for 5 min with epinephrine reverted to basal levels within 2.5 min after the addition of propranolol. Our data are consistent with the view that there is a component of the fat-cell phosphodiesterase, perhaps localized in the plasma membrane, whose activity can be acutely modified by the concentration of its substrate, cyclic AMP. As previously reported (J. Biol. Chem.248, 7164-7170, 1973), exposure of fat cells to insulin increases the activity of a low K(m) phosphodiesterase also localized in the 100,000 x g sediment fraction of fat cell homogenates. In the presence of insulin, however, phosphodiesterase remained elevated for at least 40 min and there was no significant change in fat-cell cyclic AMP content. When phosphodiesterase activity was elevated and cyclic AMP content maintained at a high level by incubation of cells with ACTH plus theophylline, insulin produced a further increase in enzyme activity. Whether or not insulin and ACTH (or epinephrine or theophylline) affect the same phosphodiesterase, there seems little doubt that the underlying mechanisms are different.
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PMID:Effects of epinephrine, adrenocorticotrophic hormone, and theophylline on adenosine 3', 5'-monophosphate phosphodiesterase activity in fat cells. 436 58

We postulated that methyl xanthines stimulate hydrochloric acid production in the isolated frog gastric mucosa by inhibiting the phosphodiesterase that destroys adenosine-3',5'-monophosphate (cyclic AMP). In support of this theory, several criteria were satisfied. Exogenously supplied cyclic AMP stimulated hydrogen and chloride transport in the spontaneously secreting mucosa and in the non-acid secreting mucosa in a similar fashion as did the methyl xanthines. Methyl xanthines increased the mucosal content of cyclic AMP, and the increase preceded the secretory response; thereafter, the magnitude of these two quantities paralleled each other. A correspondence was found between the concentration of methyl xanthines that affected acid secretion and the concentration of methyl xanthines that affected the tissue content of cyclic AMP. Theophylline was more effective than caffeine in increasing cyclic AMP content, which is in accord with the previously reported differences in their effect on acid secretion and phosphodiesterase activity.
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PMID:Adenosine-3',5'-monophosphate: intracellular mediator for methyl xanthine stimulation of gastric secretion. 437 47

1. Dose response curves for noradrenaline were determined before, during and after pretreatment with a variety of agents. The inhibitory response to noradrenaline on the isolated rat uterus was measured according to its ability to inhibit an acetylcholine induced contraction.2. Theophylline, an agent that inhibits phosphodiesterase and increases cyclic AMP levels in the rat, potentiated the response to noradrenaline.3. Pretreatment with cocaine had no significant effect on the potentiation of the noradrenaline response by theophylline.4. Theophylline potentiated the inhibitory response to nitroglycerine.5. Pretreatment with nitroglycerine also potentiated the inhibitory response to noradrenaline.6. Theophylline appears to produce a potentiation of the inhibitory effect of noradrenaline on the rat uterus by means of a non-specific mechanism.
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PMID:The potentiation of rat uterine inhibitory responses to noradrenaline by theophylline and nitroglycerine. 497 19

In order to study interrelationships between the components of the interferon enzyme system and the cyclic AMP system, NIH 3T3 cells were incubated in the presence of theophylline or adrenaline that cause a rise of intracellular cAMP, respectively, through inhibition of phosphodiesterase of cAMP and activation of adenylate cyclase. In doses that caused a transient, 2-to 3-fold elevation of the cAMP level, theophylline and adrenaline elicited about 2.5-fold elevation of 2',5'-oligoadenylate synthetase (2-5A synthetase) activity. This increase could be prevented by actinomycin D. This suggests that the elevation of the enzyme activity in the cells was due to a transcription-dependent induction process. Theophylline and adrenaline treatment of the cell cultures also led to a 2-to 3-fold fall of the activity of the phosphodiesterase of 2',5'-oligoadenylate (2'-phosphodiesterase). This effect of adrenaline was prevented by propanolol but not by actinomycin D. In the case of adrenaline, the fall of 2'-phosphodiesterase activity was accompanied by at least 5-fold increase in the enzyme activity which did not occur if actinomycin D was present in the culture. Similarities and differences between these effects and those induced by interferon are discussed. It is concluded that cAMP is an important regulator of the enzyme system of the 2',5'-oligoadenylate metabolism. 2',5'-Oligoadenylate, in turn, was found to act on the activity of phosphodiesterase of cyclic AMP. The cAMP phosphodiesterase activity in the NIH 3T3 cell lysates was activated 2- to 2.5-fold at physiological concentrations (10(-9) to 10(-7) M) of both the phosphorylated form of oligoisoadenylate, ppp(5'A2'p)n5'A2'OH, and the dephosphorylated form, HO(5'A2'p)25'A2'OH. The phosphorylated form of oligoisoadenylate also activated partially purified preparations of cAMP phosphodiesterase. The data obtained in this study allow us to consider cAMP and 2',5'-oligoadenylate as the key metabolites that may be used in the cells to form a complex, interconnected, multifunctional circuit that involves the interferon enzyme system and the system of cyclic AMP metabolism and governs essential cell functions, as regulation of RNA metabolism and protein synthesis, cell growth and differentiation.
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PMID:A study on the relationship between the interferon enzyme system and the system of cyclic nucleotide metabolism. 608 24

Theophylline and other methylxanthines display a large number of biological effects, some of which are clinically important. The effects of these compounds are commonly ascribed to an inhibition of cyclic AMP breakdown. However, it becomes actually evident that another mechanism, namely adenosine receptor antagonism, could be responsible for certain methylxanthine effects. It could be of interest to find new compounds displaying only one of these mechanisms, either phosphodiesterase inhibition or adenosine receptor antagonism. We have studied several synthetic imidazol[1,2a]pyrazines, some of which display theophylline-like pharmacological properties at lower doses than theophylline. We showed that some of these compounds inhibited mitogen-induced [3H]-thymidine uptake by human lymphocytes, which is consistent with increases in cyclic AMP levels: the most efficient compounds were those which were better phosphodiesterase inhibitors than theophylline and poorer adenosine receptor antagonists.
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PMID:Theophylline-like properties of xanthine analogs. 608 21

1 Cyclic adenosine 3',5'-monophosphate (cyclic AMP)- and cyclic guanosine 3',5'-monophosphate (cyclic GMP)-phosphodiesterase activities from rat lung were selectively inhibited by ZK 62711 and M & B 22948, respectively. Theophylline and papaverine inhibited both activities. 2 Rat lung strips contracted by carbachol were relaxed by 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 26711, EC25 = 7 x 10(-8)M) and 2-O-propoxyphenyl-8-azapurin-6-one (M & B 22948, EC25 = 5 x 10(-7)M) indicating relaxant properties of both cyclic AMP and cyclic GMP. 3 The antigen-induced histamine release from human basophils was inhibited by ZK 62711 (IC25 = 8 x 10(-7)M), whereas M & B 22948 had no effect. On the contrary, the release from rat mast cells was inhibited by M & B 22948 (IC25 = 10(-6)M), while ZK 62711 had no effect. 4 These data show an inhibitory effect of cyclic AMP on histamine release to be involved with basophils, whereas cyclic GMP is predominantly involved with mast cells. Is is suggested that the antianaphylactic properties of cyclic nucleotide phosphodiesterase inhibitors are mainly linked to the increase of cyclic GMP.
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PMID:Effects of cyclic AMP- and cyclic GMP- phosphodiesterase inhibitors on immunological release of histamine and on lung contraction. 616 23

Addition of IgG-sensitized human erythrocytes to peripheral blood monocytes elicit a transient increment in monocyte cAMP levels. This increase in cAMP was facilitated when monocytes were preincubated with the phosphodiesterase inhibitors, isobutylmethylxanthine (IBMX) and theophylline, and the adenylate cyclase agonists, isoproterenol and prostaglandin E1 (PGE1). Although these cAMP elevating agents were able to inhibit monocyte ADCC, the degree of inhibition could not be anticipated from the cAMP levels achieved by these drugs since theophylline inhibited monocyte ADCC in doses not elevating cAMP and PGE1, isoproterenol and IBMX were less effective inhibitors of monocyte ADCC than theophylline when comparing their effects on cAMP levels. Both PGE1-induced elevation of cAMP levels and the further increments of cAMP after addition of IgG-sensitized erythrocytes to PGE1-treated monocytes were significantly correlated to the inhibition of beta-glucuronidase release during ADCC. Theophylline in doses of 0.5 mM did not elevate basal levels of monocyte cAMP but facilitated the ADCC-induced cAMP increment concomitant with inhibition of monocyte ADCC and degranulation. Possibly, facilitation of cAMP increments during ADCC by an inhibitory feedback mechanism may be responsible for the inhibition caused by cAMP-elevating agents.
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PMID:Facilitation of cAMP increments during ADCC mediated by monocytes pretreated with cAMP-elevating agents. 619 93

The response of the plasmodial levels of cyclic AMP and cyclic GMP in Physarum polycephalum to several putative phosphodiesterase inhibitors and to ionizing radiation has been measured. Isobutylmethylxanthine (2 mM) induces a rapid transient threefold elevation of cyclic AMP alone, with maximum response in about 10 min and return to the base line in about 30 min. Theophylline (2 mM) induces a rapid, sustained twofold elevation of cyclic GMP only. Caffeine (2 mM) and Ro-20-1724 (18 microM) both elicit a rapid transient rise in cyclic AMP, resembling the isobutylmethylxanthine response, and a slow transient elevation of the cyclic GMP level. Of particular interest is the rapid threefold transient elevation of the cyclic AMP, but not of the cyclic GMP, level by gamma radiation. These results (1) emphasize the organism and agent specificity of cyclic nucleotide responses, (2) indicate that the kinetics and apparent refractory response are compatible with the function of previously identified membrane receptor systems, i.e., a blue light receptor and a choleragen receptor mediating cyclic AMP responses, and (3) suggest a relationship between the agent-specific cyclic nucleotide responses and the modification of gamma-radiation-induced delay of mitosis by the same agents, i.e., a decrease in the delay by those which elevate cyclic GMP levels and an increase in the delay by those which elevate only cyclic AMP levels.
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PMID:Cyclic nucleotide responses and radiation-induced mitotic delay in Physarum polycephalum. 619 72

(Bu)2cAMP inhibits the action of testicular Mullerian inhibiting substance (MIS) in vitro, but it is unknown whether the intracellular nucleotide diminishes production of MIS by the testis or interferes with its action at the Mullerian duct. When added to the 14 1/2-day old rat embryo Mullerian duct in organ culture, (Bu)2cAMP (0.1 or 1.0 mM) inhibited regression caused by biologically active exogenous MIS fractions, as well as that produced by the fetal testis (1.0 mM). Dibutyryl cyclic guanosine 3',5'-monophosphate was ineffective against exogenous MIS fractions or the fetal testis. The phosphodiesterase inhibitor, methyl-isobutyl-xanthine, had the same inhibitory effect on the MIS-fraction (0.1 or 1.0 mM), as well as against MIS secreted from the fetal testis (1.0 mM). Theophylline at 1.0 mM inhibited the action of the MIS fraction. The presence of (Bu)2cAMP in the medium was required for at least the first 24 h of the 72-h incubation to significantly inhibit MIS action. These results indicate that intracellular cAMP inhibits the action of MIS at the Mullerian duct itself by a potentially reversible change in the cells. We speculate that cAMP may act by altering the state of differentiation in the cells, perhaps by mediating phosphorylation of intracellular (and extracellular) proteins.
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PMID:Cyclic adenosine 3',5'-monophosphate modulation of mullerian duct regression. 620 48

In anaesthetized, open-chest dogs N,N-diethyl-5-methyl[1,2,4]triazolo[1,5-alpha]pyrimidine-7-amine (trapidil) in doses of 0.3--3 mg/kg i.v. produced increases in coronary sinus outflow and heart rate and decreases in systemic blood pressure and coronary resistance in a dose-dependent manner. Trapidil produced an increase in myocardial oxygen consumption but virtually no change in coronary arteriovenous oxygen difference. At 1.8 mg/kg i.v. of the drug coronary resistance fell to half of the pre-drug value and coronary sinus outflow almost doubled, and so did myocardial oxygen consumption. In isolated, blood-perfused dog heart preparations, trapidil produced coronary vasodilator and positive inotropic and chronotropic effects. Theophylline produced similar effects. Trapidil was a more positive inotropic than positive chronotropic agent, and so was theophylline but to a lesser degree than trapidil. In producing vasodilator and positive inotropic effects trapidil was about 3 times more effective than theophylline. Trapidil and theophylline inhibited the cyclic AMP phosphodiesterase (PDE) activity in crude extracts prepared from the dog ventricular muscle. In this respect trapidil was nearly 3 times more potent than theophylline. It is suggested that PDE inhibition would be a fundamental mechanism of action of trapidil.
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PMID:Mechanism of cardiovascular action of trapidil. 625 46


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