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 theophylline, proxyphylline and diprophylline on cAMP-phosphodiesterase (PDE), tracheal smooth muscle tone and cAMP-levels were studied in guinea-pig tracheal preparations, and on contractile force in guinea-pig atria. Theophylline and proxyphylline inhibited tracheal PDE-activity to similar extents (I50 approximately 40 micrograms/ml) whereas diprophylline was about 5 times less effective. Half-maximum relaxation of tracheal smooth muscle was obtained with 25 micrograms/ml theophylline, 100 micrograms/ml proxyphylline and 250 micrograms/ml diprophylline. Marked rises in cAMP-levels were obtained with theophylline and, to a lesser extent with proxyphylline whereas diprophylline was almost ineffective. In combination, the relaxant effect of theophylline was over-additively enhanced by diprophylline plus proxyphylline (combination product of these three methylxanthines: Neobiphyllin) but its cAMP-increasing effect (at lower doses) was not, indicating that the potentiated relaxing action was not due to higher levels of cAMP. Diprophylline in contrast to theophylline or proxyphylline had almost no positive inotropic effect in guinea-pig atria which supports the assumption that the mechanism of tracheal smooth muscle relaxation of diprophylline is different from that of theophylline and proxyphylline and unrelated to cAMP. These findings agree with and explain the favourable anti-asthmatic effects obtained with a combination of theophylline, proxphylline and diprophylline.
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PMID:Overadditive synergism between theophylline, diprophylline and proxyphylline in tracheal smooth muscle relaxation. 631 94

We studied the effects of theophylline and ouabain on isolated intestinal mucosa of the goldfish. From continuous recordings of the intracellular potential difference, we concluded that theophylline has no considerable effect on the Cl- conductance of the apical membrane. Theophylline increased transepithelial conductance and bidirectional Cl- fluxes, while Na+ fluxes did not change appreciably. Both streaming potentials and NaCl dilution potentials were immediately reduced by theophylline. Moreover, we found a striking similarity between the effects of theophylline and ouabain. Ouabain initially increased transepithelial conductance, increased bidirectional Cl- fluxes, and instantly abolished NaCl dilution potentials. Determinations of cellular cAMP levels revealed that both theophylline and ouabain increase cAMP. The phosphodiesterase inhibitor theophylline amplified the ouabain-induced rise in cAMP, suggesting that ouabain stimulates adenylate cyclase. Since elevated extracellular K+ did not affect cAMP levels, it can be ruled out that depolarization of the cell membrane due to ouabain increases cAMP. We conclude that in this epithelium both theophylline and ouabain increase the Cl- permeability of the paracellular pathway by a cAMP-dependent mechanism.
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PMID:cAMP-mediated effects of ouabain and theophylline on paracellular ion selectivity. 632 Jun 77

In contrast to dibutyryl cyclic AMP, the methylxanthine phosphodiesterase inhibitors theophylline and caffeine were found to inhibit the conversion of 25 hydroxyvitamin D3 to 1,25 dihydroxyvitamin D3 in isolated renal tubules from vitamin D deficient chicks. This inhibition occurred at concentrations of methylxanthines which were shown to increase renal tubule cyclic AMP levels. No effect of theophylline or caffeine on 25 hydroxyvitamin D3 metabolism in isolated chick renal mitochondria was detected. Because of a demonstrated inhibitory action of calcium (10 and 20 mumol/l) on renal mitochondrial conversion of 25 hydroxyvitamin D3 to 1,25 dihydroxyvitamin D3, the effect of theophylline and dibutyryl cyclic AMP on cellular calcium-45 efflux and total renal tubule calcium content was estimated. Theophylline 10 mmol/l was found to inhibit renal tubular calcium efflux and to increase total cellular calcium content, while dibutyryl cyclic AMP 1 mmol/l had the reverse effect on both parameters. Divergent actions of the methylxanthines and dibutyryl cyclic AMP on the formation of 1,25 dihydroxyvitamin D3 and renal tubule calcium efflux and content support the hypothesis that intracellular calcium is an important regulator of renal vitamin D metabolism. The results indicate that observed actions of methylxanthines cannot always be ascribed to cyclic AMP accumulation.
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PMID:Opposing actions of methylxanthines and dibutyryl cyclic AMP on 1,25 dihydroxyvitamin D3 production and calcium fluxes in isolated chick renal tubules. 632 99

Theophylline is thought to act by inhibiting the activity of phosphodiesterase, with a resultant increase in intracellular cyclic AMP. However, this concept is largely based on in vitro studies using concentrations of theophylline which greatly exceed therapeutic plasma concentrations. To investigate the relationship of the cardiovascular and metabolic effects of theophylline to activation of the sympathetic nervous system, i.v. aminophylline was administered to six healthy males under basal conditions. Each subject received four infusions. Mean theophylline concentrations (+/- SEM) of 4.5 +/- 0.2, 10.0 +/- 0.5, 14.0 +/- 0.5 and 20.0 +/- 1.2 micrograms/ml were achieved. Plasma epinephrine increased 262% (from 29 +/- 4 to 105 +/- 14 pg/ml, p less than 0.01) and plasma norepinephrine increased 64% (from 190 +/- 18 to 312 +/- 51 pg/ml, p less than 0.05) during the high-dose infusion. The increases in circulating catecholamines were dose-related (p less than 0.001 by analysis of variance). Dose-related increases in heart rate, systolic blood pressure, plasma glucose, free fatty acids and insulin were also observed (p less than 0.001 by analysis of variance). Although the duration of total electromechanical systole (QS2) and left ventricular ejection time adjusted for heart rate fell during the aminophylline infusions, this positive inotropic response was not influenced by dose, except possibly the high dose. Echocardiographic ejection fraction was not changed by the aminophylline infusions. We conclude that the acute cardiovascular and metabolic effects of theophylline may be mediated in part by stimulation of the sympathetic nervous system.
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PMID:Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. 633 6

The effect of theophylline, an inhibitor of phosphodiesterase, on tyrosine (Tyr) transport across cell membrane was studied using cultured B-16 mouse melanoma cells. 1.5 mM Theophylline in culture medium increased Tyr uptake velocity in linear fashion up to 36 h, after which it reached a plateau at which the cells showed about a 60% increase in Tyr transport velocity. This increase was independent of extracellular Na, essentially unaffected by cell density, and partially inhibited by concomitantly added cycloheximide. These results suggested that biosynthesis of macromolecules, probably acting as System L transporter, was induced by theophylline treatment.
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PMID:Effect of theophylline on the transport of tyrosine in cultured B-16 mouse melanoma cells. 643 10

The existence of a calcium-dependent contractile process in the formation of somites from segmental plate mesoderm was investigated using a Ca2+ agonist and Ca2+ and calmodulin antagonists. The contribution of cell movement and apical constriction in the segmentation process were assessed using SEM of normal and drug-treated somite and segmental plate tissue. Explants that contained segmental plates of stage 14-15 chick embryos were cultured on vitelline membranes in calcium- and magnesium-free (CMF) Hands' solution, liquid culture medium, and medium containing drugs. Ca2+ ionophore A23187 promoted the rapid completion of one new somite pair. CMF halted segmentation. The Ca2+ antagonists verapamil and papaverine reversibly inhibited segmentation. Theophylline did not inhibit segmentation, suggesting that the effects of the Ca2+ antagonists are not due to inhibition of phosphodiesterase activity. These results suggest that somitogenesis is Ca2+-dependent. Two drugs that inhibit the binding of calmodulin, chlorpromazine and trifluoperazine (TFP), halted segmentation. The inhibitory effect of TFP was reversible. The effects of TFP on somites were compared with those of cytochalasin D. The contribution of microtubules to cell shape and movement in somitogenesis was examined by incubation with nocodazole, a reversible inhibitor of tubulin polymerization. Cell elongation and somitogenesis were inhibited.
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PMID:Calcium dependence and contraction in somite formation. 681 26

Insulin (5 to 40 I.U.) produced dose-dependent positive inotropic effect in the isolated rat heart. The responses to insulin were markedly inhibited in the presence of propranolol (1 . 1X10(-6) M). Insulin responses were markedly reduced in reserpine pretreated (5 mg/kg, i.p.) rats. Theophylline (4.4 mM), the phosphodiesterase inhibitor, potentiated the responses to insulin, whereas imidazole (20 mM), the phosphodiesterase stimulator inhibited the responses to insulin. The data suggest that the positive inotropic effects of insulin in rat heart is mediated through the release of cardiac catecholamines which stimulates beta-adrenoceptors. The final mediator of cardiac action seems to be cyclic-AMP.
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PMID:The cardiac inotropic responses to insulin in the rat heart. 701 65

Therapeutic response to theophylline in asthma is generally attributed to its effect in increasing intracellular 3',5' cyclic adenosine monophosphate (cAMP) by competitive inhibition of cAMP phosphodiesterase. However, because of discrepancies between therapeutic serum theophylline concentration achieved clinically and those required for in vitro phosphodiesterase inhibition, we explored the possibility that theophylline may act through adrenomedullary secretion of catecholamines. Five healthy, nonasthmatic male and female adults were studied with a double-blind, randomized, crossover protocol. Theophylline (5 mg/kg) and placebo were administered in a capsule dosage form. Plasma catecholamines epinephrine (E), norepinephrine (NE), and dopamine (DA) were measured by a radioenzymatic assay at baseline and after administration of theophylline at 1, 2, and 3 hr. Significant differences between theophylline- and placebo-treated groups (p less than 0.05) were seen at 3 hr for mean percentage increase over baseline with E (120% +/- 25.3%) and NE (48.02% +/- 17.94%) after theophylline therapy (mean peak level 7.2 +/- 0.48 micrograms/ml). Epinephrine plasma concentration was significantly greater (p less than 0.001) at 3 hr compared with baseline (105 +/- 16 vs 56 +/- 18 pg/ml), while NE (448 +/- 52 vs 320 +/- 36 pg/ml) did not attain significance (p = 0.136). A significant correlation (p less than 0.05) was found between the percentage increase over basal for E (r = 0.58) and NE (r = 0.66) and serum theophylline levels. DA was not significantly increased at any time period. Thus theophylline in clinically relevant concentration appears to stimulate adrenomedullary secretion of catecholamine. Whether this is an important mechanism of action in asthma or explains some side effects of theophylline remains to be determined.
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PMID:Stimulation of endogenous catecholamine release by theophylline: a proposed additional mechanism of action for theophylline effects. 713 May 53

The present investigation was undertaken to study effects of methylxanthine derivatives on rotational behaviour produced by dopamine receptor stimulating drugs and properties of methylxanthine-induced rotation in mice with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the striatum. L-Dopa 10mg/kg, i.p., produced contralateral turning which lasted for about 40 min. When L-dopa 10mg/kg was given to mice in combination with theophylline 25 mg/kg, total turns for 2 hr were significantly higher than those of L-dopa and theophylline alone. Caffeine and theophylline in doses of 25 and 50 mg/kg, i.p., respectively, produced marked increase in contralateral rotation in a dose-dependent manner in mice with lesions. Theobromine 100 mg/kg, i.p., also produced a moderate contralateral rotation. Total turns of ipsilateral rotation produced by methylxanthine derivatives were less than 10% of those of contralateral circling. Theophylline-induced contralateral rotation was reduced to nearly 30% of the control by alpha-methyl-p-tyrosine (alpha-MPT). It was also suppressed by spiroperidol, at a dose higher than that to apomorphine or methamphetamine. These results suggest that methylxanthine derivatives produce contralateral rotational behaviour due to not only phosphodiesterase inhibition but also dopamine receptor stimulation.
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PMID:Properties of rotational behaviour produced by methylxanthine derivatives in mice with unilateral striatal 6-hydroxydopamine-induced lesions. 719 46

The effect of theophylline (a non-selective phosphodiesterase (PDE) inhibitor), dosed intratracheally (it) as a dry powder, on histamine- and platelet activating factor (Paf)-induced bronchospasm and antigen (ovalbumin, OA)-, histamine- and Paf-induced microvascular leakage (MVL) in the airways, was studied in the anaesthetized guinea-pig. Bronchospasm was measured as the increase in pulmonary inflation pressure (PIP). MVL was assessed by fluorometric assay of fluorescein isothiocyanate dextran (FITC-dextran) content in airway tissues and tracheobronchial lavage fluid. OA (200 micrograms), histamine (60 nmol) and Paf (4 nmol), all given it, significantly increased MVL by up to 350% over levels in undosed unchallenged animals. Theophylline (50-500 micrograms it, n = 5-6) inhibited histamine-induced bronchospasm (30% inhibitory dose, ID30: 258 +/- 30 micrograms), and Paf-induced bronchospasm (ID30: 190 +/- 80 micrograms). An inhibition of 40-50% of maximal bronchospasm was the largest attained. Theophylline, at approximately the bronchospasm ID30 dose (200 micrograms it, n = 4-8), inhibited MVL induced by all agents by 30-80% in airway tissues and in lavage fluid samples. Theophylline (50-500 micrograms it, n = 3) produced plasma drug levels of 0.13 +/- 0.07 to 0.83 +/- 0.39 microgram/ml 10 min after dosing. Plasma levels were the same 60 min after dosing, suggesting retention of theophylline in the airways. The local concentration of theophylline retained in the airways should be sufficient to inhibit PDE activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of theophylline administered intratracheally as a dry powder formulation on bronchospasm and airway microvascular leakage in the anesthetized guinea-pig. 754 9


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