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)

Infusion of adenosine into the coronary arteries of isolated guinea pig hearts produced a dose-dependent inhibition of dP/dtmax caused by bolus injections of isoproterenol (4 X 10(-11) moles). Threshold concentration of adenosine was 10(-7) M and maximal inhibition (90%) occurred at 10(-5) M. Coronary dilation induced by papaverine did not influence the contractile response to catecholamines. In addition to its influence on cardiac performance, adenosine (10(-5) M) effectively inhibited the isoproterenol (10(-7)M) induced initial rise in myocardial levels of cyclic 3'5'-AMP, glucose-1-phosphate and glucose-6-phosphate. Adenosine also antagonized the effect of isoproterenol on adenylate cyclase activity in a crude membrane preparation from guinea pig ventricles; it was without effect on the activity of the membrane phosphodiesterase. Theophylline inhibited the actions of adenosine both on adenylate cyclase activity and on contractile force development. Upon infusion of isoproterenol (3 X 10(-7)M) into the coronary arteries of the isolated heart (perfusion at constant pressure), the adenosine concentration in the effluent perfusate increased within 45 s from 10(-8) M to about 10(-6) M. It thus appears conceivable that in ventricular myocardium endogenously formed adenosine may serve 2 functions: dilation of the coronary arteries and limitation of the inotropic and metabolic effects of catecholamines.
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PMID:Adenosine as inhibitor of myocardial effects of catecholamines. 20 20

The effects of prostaglandins E on the concentration of cyclic AMP (cAMP) and a possible antagonism of opiates vs. prostaglandins E were studied in homogenates and in slices of rat striata in vitro. In homogenates, PGE1 or PGE2 did not affect the synthesis of cAMP. Morphine slightly lowered the cAMP synthesis, in presence or absence of PGE1 or PGE2. In slices, PGE2 significantly elevated the cAMP concentrations, either in presence or in absence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Morphine, met-enkephalin and levorphanol, but not dextrorphan, antagonized this rise of cAMP. The effect of morphine was antagonized by naloxone. Adenosine or an elevation of K+-ions raised the cAMP concentrations, and PGE2 induced a further increase. In presence of elevated K+-ions or adenosine, however, morphine did not antagonize the PGE2-induced rise of cAMP concentration. It is suggested that under some experimental conditions described in the literature, endogenous activators of cAMP formation, e.g. adenosine, might mask the inhibitory effect of opiates on stimulation of opiates on stimulation of cAMP synthesis induced by prostaglandins E.
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PMID:Interactions of opiates and prostaglandins E with regard to cyclic AMP in striatal tissue of rats in vitro. 20 43

Adenosine has been shown to stimulate cyclic AMP accumulation in guinea pig atrial and ventricular slice preparations in a rapid and dose-dependent manner. Response to adenosine was inhibited by therophylline, potentiated by several other phosphodiesterase inhibitors and unaffected by alpha- or beta-adrenergic blocking agents. Agonist action required free hydroxyl groups at 2', 3', and 5' positions on the ribosyl moiety, retention of one proton on the 6-amino group, N at position 7, and unsubstituted C at position 8 on the purine moiety. The combined action between adenosine and isoproterenol was the sum of the individual stimulations. The alpha-agonist action of epinephrine and norepinephrine reduced cyclic AMP levels stimulated by beta-agonist or by adenosine; this action was mimicked by methoxamine. The effect of an alpha-agonist was particularly pronounced when cyclic AMP levels were elevated by adenosine.
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PMID:Effect of adenosine and catecholamines on cyclic AMP levels in guinea pig heart. 20 84

Adenosine 3':5'-cyclic phosphorothioate, Sp-diastereomer was hydrolyzed by cyclic phosphodiesterase from beef heart in the presence of [18O]water to [18O]adenosine 5'-phosphorothioate. This was phosphorylated by myokinase and pyruvate kinase to [18O]adenosine 5'-(1-thiotriphosphate),Sp-diastereomer. The position of 18O was determined to be in a nonbridging position. This result indicates that the hydrolysis proceeded with inversion of configuration at phosphorus.
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PMID:Stereochemistry of hydrolysis of adenosine 3':5'-cyclic phosphorothioate by the cyclic phosphodiesterase from beef heart. 22 49

A study was made on the force of spontaneous mechanical activity in the rat portal vein. Prostaglandin inhibitor, sodium meclofenamate, phosphodiesterase inhibitors, aminophylline and dipyridamole, adenosine and blockade of calcium entry by isoptin all reduced the force of spontaneous activity in a concentration-dependent manner, while imidazole enhanced it. Low concentration of aminophylline (10 microM), dipyridamole (6 microM) and meclofenamate (10 microM) depressed the spontaneous contraction of the vein by about 50% without modifying the response to noradrenaline. At higher concentration of these drugs, spontaneous mechanical contraction was reduced further and the response to noradrenaline antagonized. Low concentration of isoptin also reduced the mechanical activity without affecting maximum response to noradrenaline. A common mechanism of action for the drugs tested, namely the limiting of Ca2+ availability for muscular contraction, is discussed. Adenosine markedly reduced the spontaneous mechanical activity of the rat portal vein. Its relaxation effect could be due to the activation of a specific adenosine receptor.
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PMID:Effect of drugs on the force of spontaneous mechanical activity in rat portal vein. 26 64

Adenosine, like catecholamines, inhibits the thyroidal T4 release in vitro, when stimulated by TSH,N,O'-dibutyryl cyclic AMP [(Bu) 2cAMP], and phosphodiesterase inhibitors. Unlike catecholamines, the adenosine-induced inhibition is independent of adrenergic receptors. It is postulated that TSH stimulates thyroidal T4 release through a cAMP activated, adenosine-sensitive, protein kinase.
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PMID:Inhibition by adenosine of thyroidal T4 release in vitro. 74 9

Adenosine has actions on smooth muscle similar to those of prostaglandin (PG) antagonists. Like some PG antagonists it is a phosphodiesterase inhibitor and seems to interfere with calcium effects. It has agonist/antagonist interactions with theophylline, a PG antagonist. In rat mesenteric vascular smooth muscle adenosine blocked responses to noradrenaline which depend on release of intracellular calcium but not those to potassium ions which depend on calcium entry from extracellular fluid. Partial inhibition of endogenous PG synthesis by indomethacin enhanced the adenosine effect. In preparations in which vascular reactivity had been abolished by indomethacin and then partly restored by 1 or 5 ng/ml PG2, adenosine also inhibited responses to noradrenaline: the curve for the 5 ng/ml PG2 concentration was to the right of and parallel to the 1 ng/ml curve consistent with a competitive interaction between adenosine and PG2. Similar interactions between adenosine and PG2 were shown in human lymphocytes in which activation also depends on calcium release. These findings suggest how calcium-dependent metabolic responses may be controlled and indicate further reasons for caution in the interpretation of cyclic AMP experiments.
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PMID:Adenosine as a natural prostaglandin antagonist in vascular smooth muscle. 89 5

Broken cell particulate preparations of adenylate cyclase isolated from the human glioma cell line 132-1N1 were stimulated 2-to 3-fold by 30 muM adenosine. This concentration of adenosine produced a maximal stimulation of the cyclase while 3 to 5 muM adenosine produced half-maximal stimulation. Theophylline, at 40 muM, inhibited the adenosine stimulation of the adenylate cyclase by about 40% while 200 muM produced near complete inhibition. The inhibition by theophylline could be overcome by increasing adenosine to a concentration 10-fold that of theophylline, implying that the inhibition was competitive. Basal activity was not inhibited by even 1.0 mM theophylline, nor was the epinephrine stimulated activity. In contrast, 1.0 muM propranolol essentially completely inhibited the 8-fold stimulation of 1.0 muM epinephrine but had no effect on either basal or adenosine-stimulated activity. Adenosine and 2-chloroadenosine were equipotent in stimulating adenylate cyclase from the 132-1N1 line, whereas neither adenine nor guanosine had any detectable effect. GTP, 10 muM, produced a small variable stimulation of the adenylate cyclase while the GTP analogue, 5'-guanylylimidodiphosphate (Gpp(NH)p), produced a marked stimulation fo the cyclase. Preincubation of the adenylate cyclase preparation with the analogue greatly increased its potency and maximal effect. In contrast, both basal and adenosine-stimulated activity decreased markedly with preincubation. The effects of adenosine or epinephrine in combination with Gpp(NH)p were at least additive and often synergistic in comparison to the effects of the compounds alone. The effects of adenosine on intact and broken cell preparations of the human fibroblast lines WI-38 and VA13-2RA were also examined. In the intact VA13-2RA, adenosine produced rapid and large increases in intracellular and extracellular cyclic adenosine 3':5'-monophosphate (cAMP). In the parental fibroblast line, the WI-38, adenosine slightly elevated basal levels of cAMP, but only produced marked elevations in the presence of non-methylxanthine phosphodiesterase inhibitors. The effect of adenosine on the broken cell particulate preparations of adenylate cyclase from the fibroblasts was similar to its action on the cyclase from the 132-1N1; 30 muM adenosine produced a maximal stimulation of the adenylate cyclase, and the stimulation was inhibited by theophylline.
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PMID:Regulation of adenylate cyclase from cultured human cell lines by adenosine. 93 31

Human diploid lung fibroblasts (IMR-90) were used to investigate the reported increase in beta-adrenergic-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) levels in fibroblasts aged in culture. Under basal conditions cellular cAMP was 34.2 +/- 5.6 and 38.4 +/- 9.1 pmol/mg protein in early (PDL 22-24) and late (PDL 47-52) passage fibroblasts, respectively. Net release of cAMP from fibroblasts was 67.8 +/- 8.6 and 18.5 +/- 7.0 pmol/30 min/mg protein in early and late passage cultures, respectively. In confluent, early passage fibroblasts, cellular cAMP and net release of cAMP increased by 2.7-fold and 3.8-fold, respectively, after a 30 min incubation in 2 microM isoproterenol. In confluent late passage fibroblasts, isoproterenol incubation increased cellular cAMP and net release of cAMP by 7.8-fold and 26.1-fold, respectively. Adenosine failed to inhibit isoproterenol-induced stimulation of cAMP in early or late passage fibroblasts. There was no passage-related difference in basal, isoproterenol, or forskolin-stimulated adenylyl cyclase activity in crude fibroblast membrane preparations. The activity of cAMP-phosphodiesterase in sonicates of early and late passage IMR-90 was 9.61 +/- 1.15 and 5.81 +/- 1.11 pmol/min/mg protein respectively. Measurements of cAMP in subconfluent early passage fibroblasts indicated that mechanisms related to the reduced cell density in confluent late passage IMR-90 may, in part, account for the enhanced isoproterenol-induced cAMP levels observed in these cultures. The results suggest that the remainder of the enhanced cAMP response to isoproterenol of in vitro aged fibroblasts may be due to a lower cAMP phosphodiesterase activity in these cells.
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PMID:Mechanism of enhanced cyclic AMP stimulation by isoproterenol in aged human fibroblasts. 132 20

A method for the separation of cyclic AMP from adenosine and polyvalent adenine nucleotides is described. The method consists of the sequential elution of adenosine and cyclic AMP from a single column of acidic aluminum oxide (alumina) with dilute hydrochloric acid and ammonium acetate. Adenosine, adenine, xanthine, and hypoxanthine are rapidly eluted with the application of 0.005 N hydrochloric acid while cyclic AMP remains adsorbed to the alumina. A subsequent application of 0.1 M ammonium acetate elutes more than 90% of the cyclic AMP. Under these conditions, polyvalent nucleotides (AMP, ADP, and ATP) remain adsorbed to the alumina. The method permits the measurement of adenylylcyclase activity using [3H]ATP as the labeled substrate. The same technique can be used to measure the accumulation of cyclic AMP in intact cells after labeling the ATP pool with [3H]adenine. With slight modification, the technique can be used to measure the activity of cyclic-AMP phosphodiesterase using [3H]cyclic AMP as the substrate. The proposed technique provides rapid, highly reproducible assays using inexpensive, disposable columns.
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PMID:A separation method for the assay of adenylylcyclase, intracellular cyclic AMP, and cyclic-AMP phosphodiesterase using tritium-labeled substrates. 132 36


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