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)

This study examined the relative contributions of phosphodiesterase inhibition and adenosine receptor blockade in the respiratory-stimulant effects of selected xanthines. The respiratory effects of caffeine, theophylline, 8-phenyltheophylline (8-PT), 8-cyclopentyltheophylline (8-CPT), 3-isobutyl-1-methylxanthine and enprofylline, as well as the nonxanthine phosphodiesterase inhibitor, rolipram, and the adenosine analogs, N6-cyclopentyladenosine (CPA) and 5'-N-ethylcarboxamide adenosine (NECA), were studied in unanesthetized rhesus monkeys. Ventilation was measured continuously by enclosing the monkey's head in a fitted Lexan helmet while a pressure transducer measured differences in pressure produced by inspirations and expirations against a constant flow of air. Drugs were administered (i.m.) using cumulative-dosing procedures while the subjects breathed air or 5% CO2 mixed in air. All xanthines except 8-PT produced dose-related increases in respiratory frequency and less pronounced changes in tidal volume, both in air and in 5% CO2 mixed in air. 8-PT, an adenosine antagonist with little activity as a phosphodiesterase inhibitor, did not have respiratory effects over the range of doses studied. Enprofylline, a phosphodiesterase inhibitor with little activity as an adenosine antagonist, had effects that were comparable to those of caffeine. Rolipram also had effects on respiration that were similar to those of caffeine, and it was approximately 100 times more potent than caffeine. The adenosine A1/A2 agonist, NECA, produced dose-related increases in respiratory frequency, and both CPA (an A1-selective agonist) and NECA produced dose-related decreases in tidal volume; NECA was 30 to 100 times more potent than CPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Respiratory effects of xanthines and adenosine analogs in rhesus monkeys. 239 11

Methylxanthines are primary agents used in treatment of hypersensitivity disease. Because polymorphonuclear leukocyte (PMN) activation is associated with generation of potent inflammatory mediators, xanthine effects on the PMN respiratory burst were studied. Enprofylline, a xanthine with important therapeutic potential, does not antagonize adenosine and was contrasted with theophylline. Although enprofylline was more potent at low concentrations, both drugs exhibited dose-dependent inhibition of PMN activation at concentrations greater than 10 mumol/L (1.8 micrograms/ml). Oxygen metabolite generation was decreased by 30% to 40% at therapeutic drug concentrations and by 85% at 1 mmol/L of theophylline. Inhibition by isoproterenol or prostaglandin E2 but not dibutyryl cAMP was potentiated by either xanthine. Isoproterenol effects were also increased when isoproterenol was evaluated in whole blood specimens obtained from subjects after a loading dose of aminophylline. Although these results were most compatible with cAMP phosphodiesterase inhibition, other commonly proposed mechanisms of methylxanthine activity were also studied. Theophylline but not enprofylline blocked adenosine inhibition of PMN activation. Neither xanthine shifted the calcium dose-response when PMNs were activated with calcium ionophore. Because oxygen metabolites generated by the FMN are mediators of inflammation and hypersensitivity, direct inhibition of PMN activation as well as potentiation of catecholamine activity may be important therapeutic effects of theophylline and enprofylline.
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PMID:Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation. 243 4

The effects of enprofylline were studied on A1 adenosine receptors of rat fat cells and on A2 adenosine receptors of human platelets and of guinea-pig lung. Enprofylline antagonized the 5'-N-ethylcarboxamidoadenosine (NECA)-induced stimulation of platelet adenylate cyclase activity with a KB of 130 microM. In human platelets, enprofylline did not antagonize but potentiated the NECA-induced inhibition of aggregation. This potentiation was abolished in the presence of the phosphodiesterase inhibitor papaverine. An adenosine antagonistic effect of enprofylline could not be evaluated on A2 receptors of guinea-pig lung because the xanthine enhanced basal and NECA-stimulated cyclic AMP accumulation. Enprofylline antagonized the N6-R-(-)-phenylisopropyladenosine (R-PIA)-induced inhibition of rat fat cell adenylate cyclase with a KB of 32 microM. The Ki value for inhibition of [3H]PIA binding to fat cell membranes was 45 microM. Enprofylline inhibited cyclic AMP phosphodiesterase activity of human platelets, guinea-pig lung and rat fat cells with Ki values of 15, 130 and 110 microM, respectively. The results show that enprofylline was nearly equipotent as antagonist at A1 and A2 adenosine receptors. Mechanisms other than adenosine antagonism or phosphodiesterase inhibition may be involved in the pharmacological effects of enprofylline.
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PMID:Effects of enprofylline on A1 and A2 adenosine receptors. 300 1

The recently developed xanthine derivate, enprofylline, was studied in an in vitro system with human pregnant myometrium, in particular its effect on spontaneous myometrial contraction, cyclic adenosine monophosphate content, cyclic adenosine monophosphate protein kinase, and cyclic adenosine monophosphate-and cyclic guanosine monophosphate-dependent phosphodiesterase activity. Enprofylline was shown to be a rather potent smooth muscle relaxant [inhibitory concentration that decreases response by 50% (IC50) = 3 X 10(-5) mol/L] and an almost equally potent cyclic adenosine monophosphate-dependent phosphodiesterase inhibitor (IC50 = 10(-4) mol/L), whereas it was a less potent cyclic guanosine monophosphate-dependent phosphodiesterase inhibitor. Enzyme kinetic studies revealed that enprofylline is a competitive cyclic adenosine monophosphate phosphodiesterase inhibitor. Enprofylline increased the cyclic adenosine monophosphate content in a dose-dependent way with subsequent increased activity of cyclic adenosine monophosphate-dependent protein kinase. It is suggested that enprofylline relaxes myometrial smooth muscles and that this is at least partly the result of interference with the cyclic adenosine monophosphate system.
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PMID:Effects of enprofylline, a new xanthine derivate, on human pregnant myometrium. 303 59

Dipyridamole inhibits platelet aggregation in whole blood at lower concentrations than in plasma. The blood cells responsible for increased effectiveness in blood are the erythrocytes. Using the impedance aggregometer we have carried out a series of pharmacological studies in vitro to elucidate the mechanism of action of dipyridamole in whole blood. Adenosine deaminase, an enzyme breaking down adenosine, reverses the inhibitory action of dipyridamole. Two different adenosine receptor antagonists, 5'-deoxy-5'-methylthioadenosine and theophylline, also partially neutralize the activity of dipyridamole in blood. Enprofylline, a phosphodiesterase inhibitor with almost no adenosine receptor antagonistic properties, potentiates the inhibition of platelet aggregation by dipyridamole. An inhibitory effect similar to that of dipyridamole can be obtained combining a pure adenosine uptake inhibitor (RE 102 BS) with a pure phosphodiesterase inhibitor (MX-MB 82 or enprofylline). Mixing the blood during preincubation with dipyridamole increases the degree of inhibition. Lowering the haematocrit slightly reduces the effectiveness. Although we did not carry out direct measurements of adenosine levels, the results of our pharmacological studies clearly show that dipyridamole inhibits platelet aggregation in whole blood by blocking the reuptake of adenosine formed from precursors released by red blood cells following microtrauma. Its slight phosphodiesterase inhibitory action potentiates the effects of adenosine on platelets.
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PMID:Mechanism of the antiplatelet action of dipyridamole in whole blood: modulation of adenosine concentration and activity. 370 98

Extracts from purified human basophils revealed activity of cAMP-phosphodiesterase with a km-value of 0.59 microM. The enzyme was not activated by Ca-ions. Enprofylline and theophylline inhibited the enzyme in a competitive manner. Enprofylline was more potent than theophylline. These drugs did also inhibit the anti-IgE-induced histamine release from the basophils. These results favour the hypothesis that inhibition of histamine release of enprofylline is caused by an inhibition of phosphodiesterase. Although accumulating data have indicated that theophylline, at therapeutic concentrations, is a weak inhibitor of cAMP-phosphodiesterase activity, there is reason to believe that enprofylline, at therapeutic concentrations, may act at least partly as a phosphodiesterase inhibitor.
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PMID:Effects of enprofylline and theophylline on purified human basophils. 620 6

In awake, male rats, oral theophylline (TH) or enprofylline (EN; 3-propyl xanthine), 10 to 50 mg/kg b.wt., similarly increased urinary prostaglandin (PG)E2 excretion, by 2- to 3-fold; urinary PGF2 alpha excretion was increased to a lesser extent (50%), while excretion of a PGI2 metabolite, 6-keto-PGF1 alpha, was not altered. In rat renal high-speed supernatant, neither TH nor EN inhibited activity of 15-hydroxyprostaglandin dehydrogenase, an intrarenal PG catabolizing enzyme, suggesting that the increased urinary PG excretion was due to increased synthesis. TH, at all doses that increased urinary PGE2 excretion, also caused dose-related 2-to 4-fold increases in urine volume and urinary excretion of sodium and potassium. In contrast, at low doses EN increased urinary PGE2 excretion without altering urine volume or electrolyte excretion; at the highest dose tested, EN produced a modest diuresis and natriuresis. Pretreatment of rats with indomethacin or meclofenamate (10 mg/kg b.wt., p.o.), chemically dissimilar PG synthesis inhibitors, prevented effects of TH and EN on urinary PG excretion, and also blocked their diuretic and natriuretic effects. Thus, increased renal PGs may be permissive and requisite for the diuretic and natriuretic effects of xanthines, but not sufficient to cause those effects. Enprofylline has been reported (Persson et al., Life Sci. 30: 2181, 1982) to be more active than theophylline as a phosphodiesterase inhibitor, but inactive as an adenosine antagonist, suggesting that the latter action is not required for xanthine stimulation of urinary PG excretion but may be a factor in the diuretic and natriuretic effects.
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PMID:Dissociation of effects of xanthine analogs on renal prostaglandins and renal excretory function in the awake rat. 658 Dec 88

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