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)

Cardiac effects of thio-xanthine derivatives, S-caffeine and S-theophylline, were studied on isolated guinea-pig atria and on partially purified cardiac cAMP phosphodiesterase enzymes. Theophylline and caffeine were taken as reference compounds. On electrically driven left atria S-caffeine (0.01-1 mmol/l) decreased contractile tension in a concentration dependent manner. On spontaneously beating atria, the same concentrations of S-caffeine showed negative inotropic as well as negative chronotropic effects. On electrically driven left atria, S-theophylline (0.01-1 mmol/l) increased heart contractile tension but, at higher concentrations, a reversal of the stimulating effect was observed. Both S-caffeine and S-theophylline inhibited bovine heart cAMP phosphodiesterase activity to a comparable extent. Their inhibitory potencies were about three and nine times higher than those of theophylline or caffeine but consistently lower than that of IBMX. The results show that the replacement of O with S in the methylxanthine molecule drastically modifies the effects induced by the drugs on cardiac function without changing those on cAMP phosphodiesterase.
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PMID:A caffeine analogue (1,3,7-trimethyl-6-thioxo-2-oxopurine) with a negative inotropic and chronotropic effect. 299 29

Bovine pulmonary artery endothelial cells in culture were used to assess the influence of cyclic nucleotides, isoproterenol (beta adrenergic agonist), and theophylline (phosphodiesterase inhibitor) on angiotensin-I-converting enzyme (ACE) activity of the cells and culture medium. Dibutyryl cAMP (10(-3) M) but not cAMP or dibutyryl cGMP stimulated angiotensin-I-converting enzyme (ACE) activity of cells in culture approximately 50-100% but had little influence on ACE activity of the medium. Theophylline at 10(-3) M concentration produced a three- to fourfold stimulation of both cellular and medium ACE activity. Isoproterenol by itself had no effect on cellular ACE activity but produced a stimulatory effect at 10(-7)-10(-5) M concentration after pretreatment of cells for 24 hr with 10(-4) M theophylline. The results support the concept that ACE activity of endothelial cells is influenced by the cyclic AMP system. ACE activity in cells and that released into medium may be under different regulatory controls.
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PMID:Stimulation of bovine endothelial cell angiotensin-I-converting enzyme activity by cyclic AMP-related agents. 302 84

Theophylline, a phosphodiesterase inhibitor, was applied to the arterially perfused cat eye in vitro. At a concentration of 850 microM, theophylline abolished the light peak of the DC-ERG and led to a 20% increase in perfusate flow to the eye. The effects were reversible. An experimentally-induced increase in flow per se by 20% resulted in a slight enhancement of the light peak. The data suggest the involvement of cyclic nucleotides in the generation of the light peak. Theophylline also caused a decrease in the standing potential of the eye, an increase in the b-wave amplitude, and a decrease in the c-wave amplitude in a dose-dependent and reversible manner.
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PMID:Theophylline abolishes the light peak in perfused cat eyes. 303 Sep 61

Activation of white cells, including the neutrophil, eosinophil, basophil, and mast cell, has long been known to be suppressed by high, nonphysiological levels of E-prostaglandins (PGE). In contrast, PGE at levels consistent with an interaction with the PGE receptor (5 X 10(-9) M) have recently been shown to suppress leukotriene (LT) and prostaglandin (PG) production by neutrophils and eosinophils. This occurs by cyclic AMP-dependent inhibition of release of substrate arachidonic acid (AA) from phospholipid pools. The additional observation that indomethacin (10(-9) M) enhances release of eicosanoids by suppressing endogenous PGE2 acting to increase cAMP levels in these cells. Theophylline and other phosphodiesterase inhibitors precisely duplicate the action of PGE2, and the combined effects of such phosphodiesterase inhibitors and adenylate cyclase stimulators are synergistic. The mechanism of action of theophylline in asthma is not know, although it is generally agreed that its effect is a direct one on the bronchial smooth muscle. The findings described in this report now permit the bronchial smooth muscle, but is primarily one of suppressing mediator release from relevant white cells by inhibition of cAMP phosphodiesterase, an action that is enhanced by the presence of inflammatory prostaglandins in the lung.
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PMID:Cyclic AMP-dependent regulation of lipid mediators in white cells. A unifying concept for explaining the efficacy of theophylline in asthma. 303 56

In the majority of patients one of the primary features of bronchial asthma is the occurrence of nocturnal symptoms. There are significant bioperiodicities for hormonal, neural, cellular and humoral factors and for mediators, which are all in favour of reducing bronchial patency during the night. In the morning hours between 2 and 6 a.m. the histamine concentration shows a peak, the adrenaline and cyclic AMP have their minimum, while the cortisol secretion with its delayed onset of action is already ascending. The kallikrein kinin system is activated by histamine. Circadian variations have also been found for the receptor density of beta-receptors, cAMP, adenylcyclase and phosphodiesterase. While circadian rhythms are not known for the platelet activating factor (PAF) at the present time, the known nocturnal peak of thromboxane A2 may influence PAF-liberation as well. The bronchodilating metabolite of the cyclooxygenase pathway, PGE2, was found to have depressed levels during the night. Total plasma, total protein as well as IgA, IgM, IgG and IgE have a minimum during the night, cellular elements like T11-, T4-, B-lymphocytes and Leu8 have a maximum. Slow release theophylline is today the most important drug for nocturnal asthma. Theophylline is known to interfere with histamine release from mast cells, mediator release of arachidonic acid metabolites, the cyclic AMP concentration and suppressor cell activity. Important work remains to be done to clarify the therapeutic and immunological role of theophylline in nocturnal asthma and to identify the subgroups of patients having the greatest benefit of theophylline treatment.
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PMID:Biochemical and cellular basis for circadian rhythms in obstructive lung disease and implications for theophylline therapy. 305 28

This study examined the effects of caffeine, theophylline and rolipram on the acquisition of conditioned responses in the rabbit and their ability to antagonize the retardant effects of the adenosine analog N6-(L-phenylisopropyl)adenosine (L-PIA) on acquisition. Pavlovian conditioning of nictitating membrane extension was accomplished by pairing the offset of a 800-msec tone- and light-conditioned stimulus with the onset of a 100-msec shock unconditioned stimulus to the skin just lateral to the outer canthus of the eye. L-PIA (5 mumol/kg) retarded the acquisition of conditioned responses to the tone- and light-conditioned stimuli, although theophylline (50-200 mumol/kg), caffeine (3-100 mumol/kg) and rolipram (0.03-3.0 mumol/kg) had no effect. The highest dose of caffeine used (300 mumol/kg) produced a small but significant enhancement of conditioned response acquisition in two of four experiments. The two adenosine antagonists theophylline (200 mumol/kg) and caffeine (300 mumol/kg) completely blocked the retardant effects of L-PIA on acquisition, although the phosphodiesterase inhibitor rolipram (3.0 mumol/kg) did not. In previously trained animals, L-PIA (5 mumol/kg) also increased the intensity threshold of a tone-conditioned stimulus for eliciting conditioned responses by more than 10 db. Theophylline (200 mumol/kg) and caffeine (300 mumol/kg) had no effect on the intensity threshold of the tone-conditioned stimulus but completely antagonized the effects of L-PIA. It was suggested that the depressant effects of the adenosine analog L-PIA on both the acquisition of conditioned responses and on the ability of a conditioned stimulus to elicit conditioned responses as soon as learning had occurred were mediated by adenosine receptors.
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PMID:Effects of N6-(L-phenylisopropyl)adenosine, caffeine, theophylline and rolipram on the acquisition of conditioned responses in the rabbit. 357 86

Topically administered salbutamol was extremely effective in suppressing immediate allergic conjunctivitis in the guinea pig; a dose as low as 0.1% elicited 98% inhibition. Topical pretreatment with 1% propranolol completely blocked the suppressant action of 0.1% salbutamol. This was also the case after systemic propranolol (1 mg/kg SC); the beta-adrenoceptor antagonist itself has no effect on antigen-induced inflammation. The effect of 0.1% salbutamol was unaltered by pretreatment with the specific beta 1-adrenoceptor antagonist betaxolol (1 mg/kg SC). In marked contrast, the suppressant action of 0.1% salbutamol was profoundly inhibited by pretreatment with the selective beta 2-adrenoceptor antagonist ICI-118,551 (0.5 mg/kg SC). The experiments employing beta-adrenoceptor antagonists unequivocally demonstrate that the salbutamol suppression of immediate allergic conjunctivitis in the guinea pig is mediated via the activation of beta 2-adrenoceptors. The methylxanthine phosphodiesterase inhibitor theophylline was active after oral administration, 50 mg/kg eliciting an 80% inhibition. Theophylline was inactive topically at 1% and 5%, but this could be due to the fact that the compound was insoluble at these concentrations. Thus, procedures that elevate cyclic-AMP levels suppress immediate hypersensitivity reactions in the guinea pig conjunctiva. Whether or nor this offers an alternative approach to treat allergic conjunctivitis in humans remains to be determined.
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PMID:The ability of salbutamol and theophylline to suppress immediate allergic conjunctivitis in the guinea pig. 366 75

Theophylline has emerged as a major prophylactic agent for controlling the symptoms of chronic asthma, but it provides little if any relief of pulmonary symptoms caused by irreversible chronic airways obstruction. Although in vitro it inhibits phosphodiesterase and antagonizes adenosine receptors, theophylline's mechanism of action in asthma is unknown. Often, 10 to 20 micrograms/ml is used as the range of serum concentrations where there is the greatest likelihood of obtaining maximal benefit safely. Slow-release products have the potential to provide more stable serum concentrations with longer dosing intervals. However, clinically important differences in rate and sometimes extent of absorption exist between the 15 formulations sold under 29 brand names in this country. In patients with more rapid elimination, few products have sufficiently slow absorption to allow twice-daily use. Often these formulations must be administered every eight hours to prevent breakthrough in asthmatic symptoms despite promotional claims to the contrary. In patients with slower elimination, differences among products are unlikely to be clinically important with 12-hour dosing intervals. Current products approved for "once-a-day" dosing are clinically inadequate because of erratic absorption or excessive serum concentration fluctuations. Moreover, food induces dose dumping of potentially toxic amounts of theophylline from Theo-24, greatly increases the extent of absorption of theophylline from Uniphyl, decreases extent of absorption from Theo-dur-Sprinkle capsules, but has no clinically important effect on Theo-Dur tablets, Theobid, Slo-Bid, or Somophyllin-CRT. The effects of food or other factors that alter gastrointestinal physiology on theophylline absorption are unknown for most other products.
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PMID:Update on the pharmacodynamics and pharmacokinetics of theophylline. 389 22

Prostaglandins E(1) and E(2) (PGE(1) and PGE(2)) stimulate adenyl cyclase activity in broken cell preparations of normal human leukocytes, whereas prostaglandin F(1a) produces no effect. PGE(1) and PGE(2) also cause increased accumulation of cyclic 3',5'-adenosine monophosphate-(3)H ((3)H-labeled AMP) in intact leukocytes which have been preincubated with adenine-(3)H in vitro. Theophylline inhibits leukocyte phosphodiesterase activity and potentiates the stimulatory effect of the prostaglandins on intracellular accumulation of cyclic 3',5'-AMP-(3)H. The ability of human granulocytes in vitro to kill Candida albicans was consistently inhibited by PGE(1) and theophylline. This effect was reproduced by dibutyryl cyclic 3',5'-AMP, a lipid-soluble analogue of the endogenous nucleotide. The inhibition of candidacidal activity could not be accounted for by drug effects on phagocytosis, oxygen consumption, or hexose monophosphate shunt activity. These results are consistent with the hypothesis that increased intracellular concentrations of cyclic 3',5'-AMP impair the granulocyte's ability to kill C. albicans, but the precise mechanism of inhibition has not yet been defined.
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PMID:Cyclic 3',5'-adenosine monophosphate in the human lukocyte: synthesis, degradation, andeffects n neutrophil candidacidal activity. 432 28

1. The mechanism of the positive inotropic responses to theophylline and to iminazole has been examined in the frog heart.2. Both theophylline and iminazole caused positive inotropic effects which declined to control amplitude with time despite continued exposure to the drugs. The duration of the response to iminazole was always longer than that to theophylline.3. On washout of theophylline and iminazole the amplitude of heart beat slowly decreased to a value below that in the control period.4. The theophylline response was not prevented by phentolamine or by propranolol given separately or in combination.5. Theophylline potentiated the staircase and prolonged the post-stimulation potentiation phenomena when its own inotropic activity had subsided but iminazole reduced the staircase effect at this time.6. Theophylline, iminazole and 3 x [Ca(2+)](o) all increased the influx of (45)Ca into isolated ventricles. Theophylline increased but iminazole and 3 x [Ca(2+)](o) slightly reduced (45)Ca efflux.7. Total cell calcium changes were only detected in ventricles exposed for 15 min to 3 x [Ca(2+)](o) or theophylline (5 x 10(-3)M). After 60 min exposure to theophylline the total cell calcium was not significantly different from controls.8. It is concluded that the positive inotropic responses to theophylline and iminazole can be interpreted in terms of the increased calcium influx which they produce and that interpretation of effects in terms of their action on phosphodiesterase should be treated with reservation.
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PMID:The nature of the positive inotropic response of the isolated frog heart to theophylline and to iminazole. 434 Feb 15


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