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 content of cAMP, cGMP and cAMP phosphodiesterase activity were studied in lymphocytes of bronchial asthma patients and normal persons before and 15 min after euphylline administration in a dose of 4 mg/kg. The cAMP/cGMP ratio was significantly lowered in patients. Euphylline administration led to its significant increase. In normal persons, this ratio remained unchanged. Some patients manifested an elevated activity of cAMP phosphodiesterase. In these cases, administration of euphylline brought about a significant increase in cAMP level in lymphocytes in the presence of the lowered activity of the enzyme phosphodiesterase. In the remaining patients and in normal persons, these indicators did not significantly change. It is suggested that the mechanism of euphylline action is dependent on cAMP phosphodiesterase activity.
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PMID:[Effect of euphylline on the cyclic nucleotide content and cAMP phosphodiesterase activity of the lymphocytes of bronchial asthma patients]. 632 15

The relaxing effect of Amrinone, an inotropic and vasodilating agent, was investigated on the isolated guinea pig tracheal smooth muscle in comparison and in association with Aminophylline. Amrinone (pD2 = 5.02 +/- 0.07) resulted more active than Aminophylline (pD2 = 4.25 +/- 0.08) in relaxing the isolated guinea pig trachea. The interaction curves of the two drugs showed the pattern typical for "competitive synergism", thus suggesting that Amrinone may act on tracheal muscle through inhibition of phosphodiesterase.
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PMID:Amrinone relaxing effect on the isolated guinea pig trachea and its interaction with aminophylline. 686 73

Terbutaline; a beta2-adrenergic agonist, and aminophyllin, a phosphodiesterase inhibitor, were given separately, or in combination, to rabbit fetuses on the 28th day of gestation. The possibility of these drugs causing a release of pulmonary surfactant was evaluated 3 h after i.m. injection directly to the fetus. Lung compliance was studied and lung lavage fluid assessed as regards content to total phospholipid phosphorus, lecithin/sphingomyelin (L/S) ratio, and surface activity. It was found that terbutaline, in a dose of 0.1 mg, had a significant (p less then 0.05) effect on each of the four parameters studied and, when given in a dose of 0.05 mg, significantly affected all except L/S ratio. Aminophyllin, in a dose of 10 mg, resulted in a 40% mortality, but in the surviving fetuses the drug had no significant (p greater than 0.05) effect on any of the four parameters. When 5 mg aminophyllin was given together with 0.05 mg terbutaline, the effect could be attributed to terbutaline.
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PMID:Pulmonary surfactant release in fetal rabbits as affected by terbutaline and aminophyllin. 689 59

The effectiveness of theophylline (aminophylline) in treating asthma may result in part from nonselective inhibition of multiple isozymes of cyclic nucleotide phosphodiesterase (PDE). The roles for inhibition of different PDE isozymes in the pulmonary antiallergic and bronchodilator effects of theophylline were investigated in anesthetized and ventilated guinea pigs by using the PDE-III-selective inhibitor Cl-930, the PDE-IV-selective inhibitor rolipram and the PDE-V-selective inhibitor zaprinast. Aminophylline, Cl-930 and rolipram inhibited aerosol ovalbumin-induced full [leukotriene (LT) + histamine] and LT-dependent bronchoconstriction, but zaprinast was inactive. At doses producing an equieffective inhibition of antigen-induced full bronchoconstriction, aminophylline and Cl-930 produced a similar inhibition of aerosol histamine-induced bronchoconstriction, whereas rolipram produced much less inhibition of histamine-induced bronchoconstriction. At doses producing an equieffective inhibition of antigen-induced LT-dependent bronchoconstriction, aminophylline and Cl-930 produced a similar inhibition of i.v. LTD4-induced bronchoconstriction, whereas rolipram did not inhibit LTD4-induced bronchoconstriction. Acute airway hyperreactivity was evidenced by significant leftward shifts in dose-response curves to i.v. methacholine-induced bronchoconstriction 24 hr after aerosol ovalbumin challenge. Aminophylline and rolipram prevented airway hyperreactivity without causing residual bronchodilation 24 hr after antigen challenge. In contrast, Cl-930 failed to inhibit airway hyperreactivity, but produced substantial residual bronchodilation. The results indicate that PDE-IV inhibition produces pulmonary antiallergic effects in vivo, including the apparent inhibition of LT release, which may contribute to the antiasthmatic actions of theophylline. The results also support previous suggestions that PDE-III inhibition contributes to the bronchodilator effect of theophylline.
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PMID:Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs. 843 12

1. The aim of this study was to determine the effects of inhibitors of phosphodiesterase (PDE) on the early and late phase bronchoconstriction in sensitized, conscious guinea-pigs and the subsequent development of acute airway hyperreactivity to the inhaled thromboxane mimetic, U46619, and leukocyte infiltration following ovalbumin (OvA) challenge. 2. Following an inhalation challenge with OvA, there was an early bronchoconstriction which peaked at 15 min with recovery after 3-4 h. A late phase bronchoconstriction occurred between 17 and 24 h after challenge. The PDE 4 inhibitors, Ro 20-1724 (3 mg kg-1, i.p.) and rolipram (1 mg kg-1, i.p.) administered 30 min before and 6 h after antigen challenge (double dosing regimen), did not affect the development of the early or late phase responses. 3. Seventeen to twenty four hours following an acute OvA or saline challenge, a consistently greater bronchoconstrictor response to inhaled U46619 was observed in the OvA challenged group. This increase in responsiveness was significantly attenuated by the administration of Ro 20-1724 and rolipram 30 min before and 6 h after antigen challenge (P < 0.05); this was not attributable to a residual bronchodilator effect of these compounds. There was a trend towards inhibition of the hyperreactivity to U46619 by aminophylline but not by the PDE3 inhibitors, siguazodan or SKF 95654. 4. Aminophylline, rolipram and Ro 20-1724 when administered as the double dose regimen attenuated the rise in macrophages, eosinophils and neutrophils recovered in bronchial lavage fluid 17 to 24 h after antigen challenge. 5. The dose of Ro 20-1724 given at 6 h post challenge was essential for attenuation of airway hyperreactivity and to protect against leukocyte influx. 6. In summary, aminophylline, rolipram and Ro 20-1724 have anti-inflammatory effects against antigen-induced airway leukocyte infiltration. Rolipram and Ro 20-1724 additionally attenuated the development of acute airway hyperreactivity, effects which are probably mediated through inhibition of PDE type 4. A dose of PDE inhibitor 6 h after the antigen challenge appears to be essential to achieve this protection. Inhibitors of PDE type 3 were generally without effect. However, there was no effect of rolipram or Ro 20-1724 on the development of either the early or late phase type responses.
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PMID:Effects of inhibitors of phosphodiesterase, on antigen-induced bronchial hyperreactivity in conscious sensitized guinea-pigs and airway leukocyte infiltration. 911 22

Endothelial cell contraction plays a pivotal role in vascular leakage. It increases the extravasation of fluid and macromolecules from the lumen into the interstitium. This is also true for bronchial edema. Previous studies have indicated that an elevation of intracellular adenosine-3',5'-cyclic monophosphate (cAMP) or guanosine-3',5'-cyclic monophosphate (cGMP), respectively, can counteract this vascular leakage by improving the endothelial barrier function in analogy to the relaxation of smooth muscle cells. To investigate the potential antiedemateous effects of ularitide acetate (CAS 115966-23-9), isoproterenol hemisulfate (CAS 6078-56-4), sodium nitroprusside (CAS 13755-38-9, SNP), aminophylline (CAS 317-34-0), and combinations of these compounds, their effects on thrombin-induced macromolecular permeability raise in relation to cGMP- or cAMP-levels, respectively, in a model of human umbilical vein endothelial cells (HUVECs) were examined. Ularitide acetate, isoproterenol hemisulfate, and SNP all increased the amount of cyclic nucleotides and decreased the raise in permeability in the following order of potency: isoproterenol hemisulfate > ularitide acetate > SNP. Aminophylline raised both cGMP- and cAMP-levels in a weaker amount and was not able to decrease the thrombin-induced permeability raise on its own. By way of contrast, preincubation of HUVECs with aminophylline resulted in a more than additive potentiation of the cGMP-levels and the permeability lowering induced by ularitide-acetate. These in vitro-data indicate that ularitide-acetate, especially in combination with phosphodiesterase (PDE) inhibitors, could probably have beneficial effects in bronchial permeability edema.
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PMID:Comparison of the effects of ularitide acetate and other bronchorelaxing substances on the thrombin-induced permeability raise of human endothelial cell monolayers. 955 82

Reactive oxygen-derived free radical species have been implicated in the pathogenesis and pathophysiology of inflammatory lung diseases. In a guinea pig model of aerosolized endotoxin-induced bronchial hyperresponsiveness to substance P, a possible involvement of oxidative lung injury was assessed by measuring the changes in membrane-bound neutral endopeptidase activity in the airway tissues and the level of lipid peroxides in the plasma. Vehicle-treated animals developed a neutrophilic airway inflammation, bronchial hyperresponsiveness to substance P associated with neutral endopeptidase hypoactivity, and elevation of lipid peroxides at 18 to 24 h after an exposure to endotoxin (75 microgram/ml, 40 min). A nonselective phosphodiesterase inhibitor, aminophylline, and selective phosphodiesterase isoenzyme inhibitors, SDZ-ISQ-844 (type III/IV) and SDZ-MKS-492 (type III), attenuated the neutrophilic airway inflammation induced by endotoxin. Aminophylline, SDZ-MKS-492, and a superoxide anion-generating NADPH-oxidase inhibitor apocynin inhibited bronchial hyperresponsiveness to substance P with attenuation of neutral endopeptidase inactivation induced by endotoxin. SDZ-ISQ-844, SDZ-MKS-492, and apocynin attenuated the elevation of lipid peroxides. The generation of hypochlorite (OCl-) from whole blood leukocytes was attenuated by aminophylline, SDZ-ISQ-844, SDZ-MKS-492, and apocynin at 1 to 2 h after exposure. These results suggest that reactive oxygen-derived free radical species-mediated oxidative lung injury may play an important role in endotoxin-induced bronchial hyperresponsiveness to substance P, and that phosphodiesterase isoenzyme inhibitors may be potentially useful as anti-inflammatory drugs.
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PMID:A possible involvement of oxidative lung injury in endotoxin-induced bronchial hyperresponsiveness to substance P in guinea pigs. 970 1

Ovalbumin (OvA) inhalation by sensitized guinea-pigs caused a pronounced rise in interleukin (IL)-5 in bronchoalveolar lavage (BAL) fluid at both 3 and 24 h after antigen exposure. The increased levels at 24 h were attenuated by the phosphodiesterase inhibitors Ro 20-1724 and aminophylline and by dexamethasone, all of which also attenuated the concurrent lung eosinophilia. The rise in IL-5 at 3 h was additionally attenuated by the PDE3 inhibitor, siguazodan, which failed to attenuate the eosinophilia at 24 h. These results suggest a pivotal action of these compounds on the later rise in IL-5. Ro 20-1724, aminophylline, siguazodan and dexamethasone attenuated a rise in IL-8 levels in BAL fluid at 3 h and the subsequent neutrophilia at 24 h. There was no increase in plasma ACTH at 3 and 24 h after OvA challenge but cortisol levels were elevated at 3 h. This was inhibited by Ro 20-1724, siguazodan and dexamethasone. Thus, elevation of plasma cortisol does not explain the anti-inflammatory actions of these compounds. Aminophylline, however, did raise plasma cortisol at both 3 and 24 h after antigen challenge which may be an important further mechanism of action for this compound.
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PMID:The potential roles of cytokines, IL-5 and IL-8, and plasma cortisol in the anti-inflammatory actions of phosphodiesterase inhibitors in sensitized guinea-pig airways. 977 91

In the present study, the possible role of free radicals in aminophylline-induced seizures was evaluated in albino rats. Aminophylline (theophylline in ethylene diamine; 50 - 300 mg/kg) induced convulsions in rats in a dose-dependent manner, and both incidence of seizure and mortality were maximum at 300 mg/kg. Conventional anti-epileptics, diphenylhydantoin and dizocilpine, as well as adenosine agonists were ineffective in antagonizing these seizures. On the other hand, phosphodiesterase inhibitors, pentoxyphylline and rolipram, showed insignificant seizurogenic effects. Pretreatment with antioxidants (ascorbic acid, alpha-tocopherol, and melatonin) showed differential attenuating effects on aminophylline seizures and lethality. Further, prior administration of 1-buthionine sulfoxamine (BSO, glutathione depletor) and triethyltetramine (TETA, superoxide dismutase inhibitor), precipitated seizures and enhanced lethality in response to subthreshold doses of aminophylline. The present results suggested of the possible involvement of oxidative stress during aminophylline-induced seizures.
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PMID:Pharmacological studies on mechanisms of aminophylline-induced seizures in rats. 1623 15

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


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