Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D06103 (Theophylline)
 2,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Adenosine A(1), A(2A), and A(3) receptors (ARs) and extracellular signal-regulated kinase 1/2 (ERK1/2) play a major role in myocardium protection from ischaemic injury. In this study, we have characterized the adenosine receptor subtypes involved in ERK1/2 activation in newborn rat cardiomyocytes. 2. Adenosine (nonselective agonist), CPA (A(1)), CGS 21680 (A(2A)) or Cl-IB-MECA (A(3)), all increased ERK1/2 phosphorylation in a time- and dose-dependent manner. The combined maximal response of the selective agonists was similar to adenosine alone. Theophylline (nonselective antagonist) inhibited completely adenosine-mediated ERK1/2 activation, whereas a partial inhibition was obtained with DPCPX (A(1)), ZM 241385 (A(2A)), and MRS 1220 (A(3)). 3. PD 98059 (MEK1; ERK kinase inhibitor) abolished all agonist-mediated ERK1/2 phosphorylation. Pertussis toxin (PTX, G(i/o) blocker) inhibited completely CPA- and partially adenosine- and Cl-IB-MECA-induced ERK1/2 activation. Genistein (tyrosine kinase inhibitor) and Ro 318220 (protein kinase C, PKC inhibitor) partially reduced adenosine, CPA and Cl-IB-MECA responses, without any effect on CGS 21680-induced ERK1/2 phosphorylation. H89 (protein kinase A, PKA inhibitor) abolished completely CGS 21680 and partially adenosine and Cl-IB-MECA responses, without any effect on CPA response. 4. Cl-IB-MECA-mediated increases in cAMP accumulation suggest that A(3)AR-induced ERK1/2 phosphorylation involves adenylyl cyclase activation via phospholipase C (PLC) and PKC stimulation. 5. In summary, we have shown that ERK1/2 activation by adenosine in cardiomyocytes results from an additive stimulation of A(1), A(2A), and A(3)ARs, which involves G(i/o) proteins, PKC, and tyrosine kinase for A(1) and A(3)ARs, and Gs and PKA for A(2A)ARs. Moreover, the A(3)AR response also involves a cAMP/PKA pathway via PKC activation.
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PMID:Characterization of ERK1/2 signalling pathways induced by adenosine receptor subtypes in newborn rat cardiomyocytes. 1475 70

ABT-702 is a novel and selective non-nucleoside adenosine kinase (AK) inhibitor that produces increases in endogenous extracellular adenosine. Adenosine (ADO) is thought to be an important neuromodulator of sleep, therefore, the effects of ABT-702 and AK inhibition were examined on rat EEG and sleep, and compared to ADO receptor agonists to further evaluate the role of ADO receptor activation on sleep related EEG patterns. ABT-702 (10.0-30.0 micromol/kg, i.p.) increased the amplitude of the 1-4 Hz band (Fast Fourier Transform (FFT) analysis, p<0.05), which is indicative of augmented sleep-related slow waves. Theophylline (5.0 micromol/kg, i.p.), a centrally active, non-selective adenosine receptor antagonist, attenuated the effects of ABT-702 (20.0 micromol/kg, i.p.) on EEG, whereas 8-(p-sulfophenyl)-theophylline (8-PST, 150.0 micromol/kg, i.p.), a peripherally active antagonist, did not, indicating that the EEG effects of ABT-702 are mediated by a central ADO receptor mechanism. The selective A(1) agonist N6-cyclopentyladenosine (CPA, 30.0 micromol/kg, i.p.) also increased the amplitude of 1-4 Hz band, but was not as efficacious as ABT-702. In contrast, the A(2A) agonist CGS-21680 (1.0-10.0 micromol/kg, i.p.) and the non-selective agonist, N(6)-ethylcarboximidoadenosine (NECA, 0.03-0.1 micromol/kg, ip.), lowered 1-4 Hz amplitude for 2 h after injection. Finally, ABT-702 (10.0 micromol/kg, i.p.) was found to significantly increase slow wave sleep and decrease REM sleep in rats implanted with both EEG and EMG electrodes for evaluation of sleep. These studies demonstrate that increased extracellular adenosine through AK inhibition can elicit modulatory effects on EEG slow waves via an interaction with central ADO receptor subtypes.
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PMID:The adenosine kinase inhibitor ABT-702 augments EEG slow waves in rats. 1547 99

1. It is well documented that cisplatin (CDDP) treatment increases the expression of adenosine A(1) receptors in both kidney and testes. However, the effect of adenosine at these receptors is controversial. Adenosine A(1) receptors have been documented to be involved in either cytoprotection or aggravation of nephrotoxicity. The aim of the present study was to examine the effect of the non-selective adenosine receptor inhibitor theophylline and the phosphodiesterase inhibitor pentoxifylline on CDDP-induced renal and testicular toxicity. 2. Male Wister rats were divided into six groups. Two control groups received plain drinking water and a third control group received theophylline 0.8 mg/mL in the drinking water for 2 weeks. One group of animals drinking plain water was injected intraperitoneally (i.p.) with pentoxifylline 50 mg/kg per day for 2 weeks. The remaining groups were treated in the same manner and received single dose of CDDP 7 mg/kg, i.p., 1 week after starting theophylline and pentoxifylline treatment and all animals were killed 1 week after CDDP treatment. 3. Rats treated with CDDP developed nephrotoxicity, as demonstrated by increased kidney and testes weight as a percentage of total bodyweight, blood urea nitrogen and serum creatinine levels and decreased serum calcium and albumin levels. In addition, CDDP treatment resulted in an increase in the production of malondialdehyde (MDA) and decreases in total nitrate/nitrite levels, as well as depletion of reduced glutathione (GSH) content and glutathione peroxidase (GPX) activity in both the kidney and testes. Administration of theophylline in the drinking water to CDDP-treated rats resulted in exacerbation of the indices of nephrotoxicity, depletion of GSH content and GPX activity levels, with increased MDA production and platinum accumulation in both the kidney and testes. However, pentoxifylline administration reduced CDDP-induced biochemical changes and reduced platinum accumulation in both organs. Histopathological examination of the kidney revealed that CDDP treatment produced multifocal tubular atrophy, atypical reparative changes of the tubular epithelium and marked tubular necrosis. Animals treated with the theophylline/CDDP combination showed extensive widespread damage with intratubular calcification. However, pentoxifylline treatment ameliorated the overt changes induced by CDDP treatment. 4. Theophylline exacerbates the deleterious effects of CDDP on rat kidney and testes. However, pentoxifylline alleviates CDDP-induced renal and testicular toxicity.
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PMID:Role of non-selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats. 1565 50

In this study, the effect of adenosine receptor agents on nicotine induced antinociception, in formalin test, has been investigated. Intraperitoneal (i.p.) administration of different doses of nicotine (0.1, 1, 10 and 100 microgkg(-1)) induced a dose-dependent antinociception in mice, in the both first and second phases of the test. Adenosine receptor antagonist, theophylline (5, 10, 20 and 80 mgkg(-1), i.p.) also induced antinociception in the both phases, while a dose of the drug (40 mgkg(-1), i.p.) did not induce any response. Theophylline reduced antinociception induced by nicotine in both phases of formalin test. The A(2) receptor agonist, 5'-N-ethylcarboxamide adenosine (NECA; 1 and 5 microgkg(-1), i.p.) also produced antinociception, which was reversed with different doses of theophylline (5, 10, 20 and 40 mgkg(-1), i.p.). But administration of the adenosine receptor agonist, NECA did not potentiate the response of nicotine. It is concluded that adenosine system may be involved in modulation of antinociception induced by nicotine.
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PMID:Adenosine receptor mediates nicotine-induced antinociception in formalin test. 1566 68

This study investigated the interactive effects of acute exercise and adenosine receptor agonist and antagonist on antioxidant enzyme activities, glutathione and lipid peroxidation in the heart of the rat. Male Fisher-344 rats were divided into six groups and treated as follows: (1) saline control; (2) acute exercise (100% VO2max); (3) R-Phenyl isopropyl adenosine (R-PIA) (3.46 micromol/kg, i.p.); (4) theophylline (1.70 micromol/kg, i.p.) plus acute exercise; (5) theophylline plus R-PIA; and (6) theophylline. Animals were sacrificed 1 h after treatments; hearts were isolated and analyzed. The results show that acute exercise as well as adenosine receptor agonist R-PIA significantly enhanced cardiac superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activity by 36-135% and 16-51%, respectively. Adenosine receptor agonist R-PIA significantly decreased cardiac GSSG concentration and enhanced GSH/GSSG ratio by 22 and 30%, respectively. Whereas theophylline treatment blocked the activation of antioxidant enzyme activities enhanced by acute exercise and R-PIA. Theophylline treatment significantly increased lipid peroxidation by 43% in the heart of exercised rats. The study concluded that the adenosine receptors are involved in the upregulation of cardiac antioxidant defense system and attenuation of lipid peroxidation due to acute exercise in rats.
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PMID:Interaction of exercise and adenosine receptor agonist and antagonist on rat heart antioxidant defense system. 1579 69

Although theophylline has side effects when used in bronchodilator doses, increasing evidence shows that it has significant antiinflammatory effects in chronic obstructive pulmonary disease at lower plasma concentrations. These antiinflammatory effects are unlikely to be accounted for by phosphodiesterase inhibition or adenosine receptor antagonism, which require higher concentrations. There is now evidence that theophylline at low therapeutic concentrations is an activator of histone deacetylases and that this activation enhances the antiinflammatory effect of corticosteroids. There appears to be a marked reduction in histone deacetylase-2 in macrophages and peripheral lung of patients with chronic obstructive pulmonary disease, which accounts for amplified inflammation and steroid resistance. Theophylline has been shown to restore steroid sensitivity in vitro. The effect of theophylline on histone deacetylase activity appears to be enhanced by oxidative stress. The mechanism whereby theophylline activates histone deacetylase is not yet known, but it does not involve other known actions of theophylline that account for its side effects. Better understanding of the molecular basis for the action of theophylline might lead to the development of novel drugs.
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PMID:Theophylline in chronic obstructive pulmonary disease: new horizons. 1626 58

Several previous studies have demonstrated a beneficial effect of the adenosine receptor (AdoR) antagonist theophylline in different forms of acute renal failure in laboratory animals and in humans. Therefore, we wanted to test whether theophylline can also improve impaired allograft function following ischemia reperfusion injury in experimental kidney transplantation (KT). Orthotopic transplantation of the left kidney was performed from Fisher 344 into Lewis rats. All transplanted rats received daily cyclosporine (5 mg/kg). The effect of theophylline treatment (10 mg/kg) on graft function was compared with appropriate controls on day 5 after KT by assessment of glomerular filtration rate (GFR) (inulin clearance). On day 5, GFR of allografts in control rats was 0.23 +/- 0.05 ml/min/g kidney weight (n = 10) compared with 0.50 +/- 0.09 ml/min/g in rats receiving theophylline (n = 9, p < 0.01), representing a 2-fold increase in GFR. Renal AdoR A(1) mRNA content was significantly increased in both KT groups compared with their respective control groups, whereas mRNA of AdoR A(2a), A(2b), and A(3) were found to be unchanged. Theophylline did not affect significantly interstitial infiltration of the graft by monocytes/macrophages and T-cells. Likewise, serum cytokines [interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor-alpha] and erythropoietin plasma levels were not different among the allograft groups. The present study demonstrates that theophylline remarkably improved early renal allograft function in rats undergoing KT without influencing cytokine serum patterns or tissue inflammation. Since theophylline is a commonly used medication in humans, clinical studies in patients undergoing KT are warranted.
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PMID:Theophylline improves early allograft function in rat kidney transplantation. 1641 Apr 6

The molecular and pharmacological properties of adenosine receptors in the T24 human bladder epithelial carcinoma cell line were assessed by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), Ca2+ Flux, cAMP production and interleukin-8 measurements. RT-PCR experiments detected the presence of transcripts for the adenosine A1, A2A and A2B receptors but not for the adenosine A3 subtype. Application of specific adenosine receptor ligands resulted in concentration-dependent increases in intracellular calcium ([Ca2+]i) with the following order of potency and EC50 values: 5'-N-Ethylcarboxamidoadenosine (NECA) (1153+/-214)>5'-(N-Cyclopropyl)carboxamidoadenosine (CPCA) (1436+/-186)>adenosine (4823+/-932). This rank order of potency is typical of adenosine A2B receptors. In addition, select adenosine receptor antagonists N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6 dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS 1706), 8-[4-[((4-Cyano[2,6-]-phenyl)carbamoylmethyl)oxy]phenyl]-1,3-di(n-propyl)-xanthine (MRS 1754), 1,3-Diethyl-8-phenylxanthine (DPCPX), 1,3-Diethyl-8-phenylxanthine (DPX), Alloxazine, 8-(3-Chlorostyryl)caffeine (CSC), and Theophylline blocked the NECA-induced calcium responses. Additionally, NECA, CPCA, and adenosine stimulated cAMP formation with a rank order of potency characteristic of adenosine A2B receptors. The select adenosine A2A antagonist, 5-amino-7-(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (SCH 58261) failed to antagonize the NECA response, whereas the potent and highly selective adenosine A2B antagonists MRS 1754 and MRS 1706 inhibited NECA-stimulated cAMP production. Lastly, NECA-induced interleukin-8 secretion was inhibited by MRS 1754. Taken together, these data indicate that [Ca2+]i accumulation and cAMP production as well as interleukin-8 secretion is mediated through the adenosine A2B receptor in the T24 cell line.
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PMID:Characterization of adenosine receptors in the human bladder carcinoma T24 cell line. 1658 Oct 66

1. Theophylline and aminophylline have been widely used as inhibitors of phosphodiesterase when examining the role of cAMP in regulating cell function. In reality, however, these phosphodiesterase inhibitors may have additional sites of action that could complicate the interpretation of the results. These additional sites of action could include antagonism of inhibitory adenosine autoreceptors and release of intracellular calcium. The purpose of the present study was to determine which of the above three is the primary mechanism by which theophylline and aminophylline affect transmitter release at the mammalian neuromuscular junction. 2. Quantal release measurements were made using intracellular recording techniques. A variety of drugs were used to elucidate this pathway. Isoproterenol, an adenylate cyclase activator, was first used to establish the effect of enhanced levels of cAMP. Theophylline application on its own or in the presence of a drug combination that blocked the adenosine receptor and phosphodiesterase pathways caused significant release depression, opposite to what is expected if it was functioning to enhance cAMP levels. However, when applied in the presence of a drug combination that blocked the adenosine receptor, phosphodiesterase and intracellular ryanodine calcium pathways, theophylline was unable to depress release. Therefore, it was concluded that the major mechanism of action of theophylline is depression of transmitter release by causing the release of intracellular calcium. 3. Aminophylline application alone resulted in a significant enhancement of release. However, when coupled with an adenosine receptor blocker, the ability of aminophylline to enhance transmitter release was blocked, suggesting that its dominant mechanism of action is adenosine receptor inhibition. 4. Taken together, these results indicate that the use of theophylline and aminophylline is inappropriate when examining the role of cAMP at the mammalian neuromuscular junction.
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PMID:Effect of theophylline and aminophylline on transmitter release at the mammalian neuromuscular junction is not mediated by cAMP. 1670 Aug 79

Theophylline has been relegated to a second- or even third-line therapy in the treatment of asthma and chronic obstructive pulmonary disease (COPD), behind glucocorticosteroids and beta2-agonists, although recent findings have suggested that theophylline possesses anti-inflammatory and immunomodulatory effects in addition to its well-recognized effects as a bronchodilator. In part, theophylline has fallen out of favor because of its adverse side-effect profile, and this has led to the search for more effective and safer drugs based on the knowledge that theophylline is orally active and that it is a nonselective phosphodiesterase (PDE) inhibitor. This has led to the development of selective PDE4 inhibitors, originally designed for depression, for the treatment of both COPD and asthma. Such drugs have shown clinical efficacy in the treatment of respiratory disease while having a considerably safer side-effect profile in comparison with theophylline, particularly because there are no reported drug interactions with PDE4 inhibitors, a feature that complicates the use of theophylline. In addition, it is also becoming increasingly apparent that theophylline is not working solely through PDE inhibition, as formerly assumed, and that this drug has other relevant pharmacologic activities that are likely to contribute to its efficacy, such as adenosine receptor antagonism and induction of histone deacetylase. Thus, the introduction of PDE4 inhibitors represents an entirely new class of drugs for the treatment of respiratory disease.
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PMID:Are phosphodiesterase 4 inhibitors just more theophylline? 1675 Sep 81


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