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)

Theophylline and its derivatives, such as aminophylline, have an established role as bronchodilators, although their mode of action in man is not clear. There is circumstantial evidence that therapeutic doses of theophylline may have a phosphodiesterase inhibiting effect, thus potentiating the effects of cyclic AMP. However, it remains to be established whether this is the primary mode of action of theophylline at the biochemical level. The pathways of theophylline metabolism have been clarified, although most of the enzymes involved have not been characterized. Hepatic microsomal enzyme induction by polycyclic hydrocarbons will increase the rate of theophylline elimination. There are a number of factors which influence theophylline clearance in adults, which is known to be highly variable. These factors include obesity, smoking habit, diet and the presence of such diseases as hepatic cirrhosis, acute pulmonary oedema, cor pulmonale and viral respiratory infection. There is a good correlation between plasma theophylline level and bronchodilator effect. This can be demonstrated at plasma levels as low as 5 microgram/ml, although optimal levels are usually greater than 10 microgram/ml. Unacceptable toxicity usually occurs in association with plasma levels greater than 20 microgram/ml. The maintenance of adequate plasma theophylline levels by the use of a sustained-release aminophylline tablet is discussed.
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PMID:Theophylline: biochemical pharmacology and pharmacokinetics. 22 Jan 19

The glycogen content of fetal rat lung declines coincident with increased pulmonary phospholipid synthesis. Aminophylline, a methylxanthine cyclic adenosine 3',5' monophosphate (AMP) phosphodiesterase inhibitor, and cyclic AMP augment fetal lung phospholipid synthesis. Because lung glycogen breakdown may contribute to pulmonary phospholipid synthesis, the effects of aminophylline and cyclic AMP on glycogen metabolism were studied in explants of 19 day fetal rat lung in organ culture. Treatment with aminophylline or dibutyryl cyclic AMP for 24 hr, resulted in a 25% (P less than 0.025) and 75% (P less than 0.001) decrease, respectively, in the glycogen content of the explants. Glycogen synthase I activity was reduced by 32% in aminophylline treated cultures (P less than 0.025) and 25% in cyclic AMP treated cultures (P less than 0.025). The percent of total synthase in the active form was significantly reduced in all treated cultures. Neither aminophylline nor cyclic AMP treatment resulted in significant changes in glycogen phosphorylase a or total phosphorylase activity.
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PMID:Influence of aminophylline and cyclic AMP on glycogen metabolism in fetal rat lung in organ culture. 23 Apr 47

The mechamism of action of theophylline was studied by investigating the relationship between relaxant effect and inhibition of cyclic nucleotide phosphodiesterase (PDE) and by studying interactions with adenosine actions. Guinea pig tracheal smooth muscle cyclic AMP PDE had two apparent KmS': 0.4 and 70 microM for cyclic AMP. Theophylline and papaverine competetively inhibited the low Km form. Hydrolysis of 2.0 microM cyclic AMP and cyclic GMP was inhibited by several drugs. Some agents (e.g. ZK 62 711, ICI 63,197, Ro 20--1724, dipyridamol) were considerably more potent as inhibitors of cyclic AMP than of cyclic GMP hydrolysis, while other agents (M & B 22.948 and dilazep) selectively inhibited cyclic GMP breakdown, and some (theophylline, papaverine, IBMX and SQ 20,006) showed little selectivity. There was a weak but significant correlation between inhibition of cyclic AMP phosphodiesterase and relaxation of tracheal smooth muscle in vitro. There was also a correlation between the ratio of IC25 cyclic AMP/IC25 cyclic GMP and the smooth muscle relaxation, indicating that inhibition of cyclic AMP rather than cyclic GMP hydrolysis determined relaxation. However, there was a marked tachyphylaxis to the relaxant effect of the cyclic AMP selective PDE-inhibitors, while the nonselective methylxanthines did not show tachyphylaxis. The effect of theophylline was antagonized by low concentrations of adenosine, which by itself caused a weak tracheal contraction. The effect of PDI-inhibitors can be partly explained by decreased cyclic AMP breakdown but other mechanisms, such as antagonism of endogenous adenosine, may contribute to the observed relaxant action.
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PMID:On the mechanism of relaxation of tracheal muscle by theophylline and other cyclic nucleotide phosphodiesterase inhibitors. 23 92

In the mixed venous blood of anaesthetized, heparinized cats prostacyclin de-aggregated platelet thrombi, which were formed on the surface of blood-superfused collagen strips or on the surface of blood-superfused aortic strips from atherosclerotic rabbits. The reversal of platelet aggregation by prostacyclin was still achieved 3 hrs after the formation of platelet clumps. After an intravenous injection of prostacyclin the ID50 for its de-aggregatory action was 7.5 microgram/kg. Theophylline ethyl-diamine (aminophylline), at a dose of 3 mg/kg i.v., did not reverse platelet aggregation but it enhanced the duration of the de-aggregatory action of prostacyclin; it had little effect on the hypotensive action of prostacyclin. It is concluded that prostacyclin disintegrates platelet clumps long after they are formed in heparinized blood in vivo and that its anti-platelet action, but not hypotensive action, is selectively potentiated by a phosphodiesterase inhibitor. The above experimental data indicate the possibility of the combined use of theophylline and prostacyclin in arterial thrombosis.
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PMID:De-aggregatory action of prostacyclin in vivo and its enhancement by theophylline. 35 3

In an earlier study, theophylline was shown to antagonize the morphine-induced inhibition of electrically induced contractions of the longitudinal muscle-myenteric plexus preparation from the guinea pig ileum. In the present study, acetylcholine (ACh) released from the myenteric plexus was measured directly using a radioenzymatic assay. Theophylline antagonized the morphine-induced inhibiton of ACh release. A similar antagonism was also observed with caffeine and 3-isobutyl-l-methylxanthine (IBMX). All three methylxanthines also increased ACh release. The nonxanthine phosphodiesterase (PDE) inhibitors 4-(3-butoxy-4-methoxy)-2-imidazolidinone (Ro 20-1724) and l-ethyl-4-isopropylidenehydrazino-1 H-pyrozolo(3,4-b)-pyridine-5-carboxylate, ethylester, HCl (SQ 20,009) generally did not antagonize the morphine-induced inhibiton of ACh release. The PDE inhibitor SQ 20,009 but not Ro 20-1724, enhanced the release of ACh. Both high calcium concentration and the divalent cation ionophore A23187 antagonized the inhibitory action of morphine on ACh release. These observations suggest that alteration in calcium fluxes rather than the inhibiton of PDE mediate the methylxanthine-induced antagonism of morphine in this preparation.
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PMID:Interactions of methylxanthines, nonxanthine phosphodiesterase inhibitors, and calcium with morphine in the guinea pig myenteric plexus. 49 98

Theophylline, a phosphodiesterase inhibitor, was found to be a potent stimulator of melanogenesis in the RPMI 3460 hamster melanoma cell line. This stimulation was greater than that caused by either dibutyryl cyclic AMP (db-cAMP) or another phosphodiesterase inhibitor, papaverine. Theophylline and db-cAMP treatments also produced strikingly different morphologies in the monolayered cells. The theophylline effect on melanogenesis was diminished by db-cAMP, whereas simultaneous treatment of cells with db-cAMP and papaverine produced greater stimulation of melanotic activity than either agent acting alone. Theophylline, therefore, may have phenotypic effects that are at least partially independent of phosphodiesterase inhibition. Theophylline stimulated melanin biosynthesis, as measured by rates of 2-[2-14C] thiouracil incorporation, and also caused an increase in the level of tyrosinase (EC 1.10.3.1) activity. This melanotic stimulation was prevented by the presence of cordycepin or cycloheximide. Theophylline inhibited DNA synthesis and mitosis in the melanoma cell cultures but stimulated protein synthesis. However, inhibition of proliferation and the first appearance of induced melanotic activity did not bear an immediate direct relationship to one another.
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PMID:Stimulation of melanotic expression in a melanoma cell line by theophylline. 81 64

Methylxanthines (aminophylline and caffeine) and imidazole, substances with an opposite action on phosphodiesterase (PDE), were found to contract the terminal ileum and to potentiate nerve-mediated responses--contractions elicited by electrical stimulation (ES) at 3 Hz and 30 Hz. Imidazole-induced contractions which were partly reduced by atropine, potentiated both responses to ES to about the same extent, and enhanced contractility of the preparation to histamine and potassium. The action of imidazole on the terminal ileum could be related to its influence on PDE in the smooth muscle. The effects of aminophylline and caffeine were found to be more complex, possibly involving some mechanisms other than inhibition of PDE. They produced atropine-sensitive contractions of the terminal ileum, which were potentiated by physostigmine and strongly depressed by hemicholinium. In the presence of atropine, they potentiated ES-induced contractions, particularly those elicited by ES at 30 Hz, which are thought to be of adrenergic origin. Both actions appeared to be due to presynaptic effects -- activation of cholinergic and adrenergic neurons in the intestinal wall, possibly by enhanced influx of calcium, and facilitated release of acetylcholine and noradrenaline. Aminophylline, in concentrations which potentiated nerve-mediated contractions elicited by ES, did not affect direct smooth muscle-contracting action of drugs. Higher concentrations of aminophylline, above 0.1 mM, were found to inhibit histamine- and noradrenaline-induced contractions presumably due to inhibition of PDE in the smooth muscle and subsequent elevation of cAMP levels.
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PMID:Action of methylxanthines and imidazole on the contractility of the terminal ileum of the guinea pig. 83 69

Contractile responses of guinea-pig atria to papaverine were analyzed under different stimulation frequencies. Atria, driven at 2 Hz, showed positive inotropic responses to papaverine which were maximal within 10-15 min. These responses were maintained for 60 min in the presence of low concentrations of papaverine (up to 10(-5) M), but reversed into marked negative inotropic effects under the influence of higher concentrations. The well-known frequency-force relationship was reversed by papaverine. At low stimulation rates papaverine elicited positive inotropic responses, which gradually decreased with increasing frequencies until strong cardiodepression occurred. A frequency-force curve obtained in the presence of both the Ca2+-antagonistic drug D 600 and the inhibitor of the phosphodiesterase theophylline was similar to that obtained under the influence of papaverine. Theophylline alone evoked positive inotropic effects at all frequencies studied and left the character of the ascending staircase unchanged. In contrast, D 600 was ineffective at low, but cardiodepressive at high stimulation frequencies. In the presence of D 600 or papaverine high external Ca2+ could not restore a normal frequency-force relationship. The reversal of the frequency-force relationship as produced by D 600 and papaverine could not be obtained by lowering of the external Ca2+. The present results show that papaverine is able to evoke marked positive inotropic effects at low stimulation frequencies by inhibition of phosphodiesterase. At high frequencies, however, these effects are masked by negative inotropic responses due to the inhibitory action of papaverine on Ca2+-exchange of the cardiac muscle cell.
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PMID:Effect of papaverine on the frequency-force relationship in guinea-pig left atria. 83 71

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

Polyinosinic with polycytidylic acid (poly l with poly C), a double-stranded synthetic RNA, produced in newborn rats a runt syndrome characterized by mortality and retarded growth rates of the total body, thymus, and kidneys. In contrast, it induced a hyperplasia in the epidermis and in the spleen. Within 10 days of treatment, the epidermis became 2 or 3 times thicker and the spleen mass was increased by 50%. The epidermal hyperplasia involved all layers, but hair follicles were excluded. Splenic hyperplasia did not result from accelerated erythropoiesis. Double-stranded RNA was required; single-stranded homopolymers were ineffective. Theophylline, a phosphodiesterase inhibitor, did not potentiate the effects. The uptake of iododeoxyuridine-125 was not enhanced in the hyperplastic epidermis or spleen. Thus we concluded that poly l with poly C can retard the growth of some organs in newborn rats, but that it causes epidermis and spleen to accumulate cells. The cytokinetic mechanisms involved in these contrasting effects were not clear.
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PMID:Runt syndrome induced in the rat by polyinosinic-polycytidylic acid. 107 99


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