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 free extracellular concentration of theophylline in the brain was estimated from microdialysis samples. Two different methods were used to estimate extracellular concentrations by microdialysis, the perfusion rate method and the difference method. Theophylline 20 mg/kg (s.c.) gave a sufficiently stable level of theophylline in the brain 60 min after injection and lasting over the observation period to allow application of the two methods in vivo. The relation between dose and dialysate concentration was linear. It was found that doses of 20-24 mg/kg theophylline corresponded to a free extracellular concentration of 60-90 microM. The behaviour of theophylline-treated rats was assessed in parallel experiments by means of a holeboard apparatus. Behavioural activation was observed in the dose-range 3-30 mg/kg. It is concluded that behavioural effects of theophylline can be induced at a concentration well below that required to inhibit phosphodiesterase but within the range in which adenosine receptor blockade may be observed, suggesting that the latter mechanism is responsible for the behavioural effects of theophylline.
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PMID:Theophylline concentration in the extracellular space of the rat brain: measurement by microdialysis and relation to behaviour. 225 93

Previously we have shown that the improvement of cold tolerance by theophylline is due to antagonism at adenosine receptors rather than inhibition of phosphodiesterase. Since theophylline is a nonselective adenosine receptor antagonist for both A1 and A2 receptors, the present study investigated the adenosine receptor subtype involved in theophylline's action. Acute systemic injection of selective A1 receptor antagonists (1,3-dialkyl-8-aryl or 1,3-dialkyl-8-cyclopentyl xanthine derivatives) significantly increased both the total and maximal heat production as well as cold tolerance. In contrast, injection of a relatively selective A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (compound No. 19), failed to significantly alter the thermogenic response of the rat under cold exposure. Further, the relative effectiveness of these compounds in increasing total thermogenesis was positively correlated with their potency in blocking the A1 adenosine receptor (r = .52, p less than 0.01), but not in A2 adenosine receptor (r = .20, p less than 0.2). It is likely that the thermally beneficial effects of adenosine A1 antagonists are due to their attenuation of the inhibitory effects of endogenously released adenosine on lipolysis and glucose utilization, resulting in increased substrate mobilization and utilization for enhanced thermogenesis.
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PMID:Improvement of cold tolerance by selective A1 adenosine receptor antagonists in rats. 226 50

A variety of xanthines cause tracheal relaxation, an activity predictive of antiasthmatic potential. Structural analogs of caffeine, theophylline, and enprofylline were examined for their abilities to relax carbamylcholine-stimulated guinea pig trachea in vitro. All caffeine analogs tested were more potent than caffeine (EC50 = 551 +/- 81 microM) except the 8-p-sulfophenyl analog. 1,3,7-Tripropylxanthine and 1,3,7-tripropargylxanthine were among the more potent analogs with EC50 values of 12 +/- 1.3 and 65 +/- 11 microM respectively. Increasing the polarity at the 1- or 3-position by substituting a propargyl group for an n-propyl group decreased relaxant activity, an effect not observed at the 7-position. The 8-cyclohexyl-, 8-cyclopentyl- and 8-phenyl-derivatives of caffeine were relatively potent (EC 50 = approximately 75 microM). The theophylline analog 1,3-di-n-propylxanthine was approximately two times more active than theophylline (EC50 = 162 +/- 17 microM). 3-Isobutyl-1-methylxanthine (EC50 = 7.1 +/- 1.8 microM) and 1-isoamyl-3-isobutylxanthine (EC50 = 37 +/- 4.2 microM) were among the most potent tracheal relaxants. The 8-substituted theophylline analogs were weak or inactive relaxants except for 8-cyclopentyl- and 8-cyclohexyltheophylline, which were more potent or as potent as theophylline. In contrast to enprofylline (EC50 = 56 +/- 9 microM), 8-substituted enprofylline analogs were weak or inactive as relaxants with the exception of the 8-cyclohexyl analog. The potency of xanthines as tracheal relaxants was unrelated to potency as adenosine receptor antagonists and may reflect activity as phosphodiesterase inhibitors.
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PMID:Activities of caffeine, theophylline, and enprofylline analogs as tracheal relaxants. 235 33

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

Administration of theophylline has been shown to enhance gastric acid secretion in humans. Because theophylline has been reported to be a poor inhibitor of phosphodiesterase but a better adenosine receptor antagonist, we tested the hypothesis that there are inhibitory "R site" adenosine receptors on parietal cells. Utilizing isolated dispersed canine parietal cells, we measured acid secretion by the [14C]aminopyrine accumulation technique. We tested the effect of increasing concentrations of 2-chloroadenosine (10(-7), 10(-6), 10(-5) M) and L-N6-phenylisopropyl adenosine (L-PIA) (10(-7), 10(-6), and 10(-5) M), stable analogs of adenosine with specificity for the R sites, on aminopyrine uptake produced by submaximal stimulating concentrations of histamine (1 microM) plus isobutyl methylxanthine (3 microM) or carbachol (1 microM). Histamine-stimulated parietal cell aminopyrine uptake was 4.3- +/- 0.4-fold above basal; 2-chloroadenosine inhibited this response in a dose-dependent fashion with a 57 +/- 6% inhibition at 10(-5) M.L-PIA also inhibited histamine-stimulated aminopyrine uptake with a 67 +/- 11% inhibition at 10(-5) M. Carbachol-stimulated aminopyrine uptake was 5.8- +/- 1.6-fold above basal, but 2-chloroadenosine had no significant effect on this response. Theophylline, 300 microM, and 8-phenyltheophylline, 10 microM, reduced the inhibitory effect of 2-chloroadenosine. 8-Phenyltheophylline was inactive in inhibiting the parietal cell phosphodiesterase activity and the IC50 of theophylline for phosphodiesterase was 1 mM. Because prostaglandins inhibit parietal cell uptake of aminopyrine in a pattern similar to 2-chloroadenosine, we also tested the possibility that prostaglandins are involved in the 2-chloroadenosine response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptors on canine parietal cells modulate gastric acid secretion to histamine. 240 69

The aim of the present study was to characterize the positive inotropic effect of the Ca2+ channel activator Bay K 8644. In isolated guinea-pig papillary muscles we investigated whether adenosine and the R site adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA) were able to antagonize the positive inotropic effect of Bay K 8644. The effect of Bay K 8644 and adenosine or PIA on myocardial cAMP content was also measured. The influence of adenosine and PIA on the positive inotropic effect of the beta-adrenoceptor agonist isoprenaline and of the phosphodiesterase inhibitor amrinone was studied for comparison. Adenosine and PIA antagonized the positive inotropic effects of isoprenaline and amrinone in a concentration-dependent manner. In contrast, adenosine or PIA did not affect the positive inotropic effect of Bay K 8644. The positive inotropic effect of Bay K 8644 was not accompanied by a change in the cAMP content of the papillary muscles. Additionally applied adenosine or PIA also failed to affect the cAMP content. It is concluded that an increased myocardial cAMP content is not involved in the positive inotropic effect of Bay K 8644. Moreover, the results support the view that adenosine and PIA only antagonize the positive inotropic effects of drugs known to increase myocardial cAMP content and that an increased myocardial cAMP content is a prerequisite for the manifestation of a negative inotropic effect of the nucleosides in ventricular cardiac muscle.
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PMID:Positive inotropic effect of Bay K 8644: cAMP-independence and lack of inhibitory effect of adenosine. 241 40

Differentiation of 3T3-L1 adipocytes, monitored by accumulation of neutral lipid and by increase in alpha-glycerophosphate dehydrogenase activity, is accelerated by incubation of confluent 3T3-L1 fibroblasts in media containing insulin, dexamethasone and isobutylmethylxantine (IBMX). IBMX inhibits cyclic nucleotide phosphodiesterases as well as the binding of adenosine to its receptor. Agents with relatively specific effects were utilized to examine the role of IBMX in differentiation. Ro 20-1724, a selective inhibitor of soluble cAMP phosphodiesterase activities, was as effective as IBMX in increasing alpha-glycerophosphate dehydrogenase activity and fat deposition. Neither cilostamide, which inhibits particulate but not soluble cAMP phosphodiesterase activities, 8-phenyltheophylline, an adenosine receptor antagonist with little inhibitory effect on phosphodiesterase activities, nor N6-(R phenyl-isopropyl) adenosine (PIA), a potent adenosine receptor agonist, were effective in promoting differentiation. In addition, we find that maximal increases in alpha-glycerophosphate dehydrogenase activity and lipid accumulation were observed when differentiation was initiated in the presence of 10 nM dexamethasone. These data suggest that inhibition of soluble cAMP phosphodiesterase activity and subsequent alterations in cAMP may play an important role in the mechanism whereby IBMX enhances differentiation of 3T3-L1 cells.
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PMID:A role for soluble cAMP phosphodiesterases in differentiation of 3T3-L1 adipocytes. 241 50

The widely used phosphodiesterase inhibitor MIX (1-methyl 3-isobutyl xanthine) blocked insulin antagonism of cAMP-stimulated glycogenolysis in rat hepatocytes but other phosphodiesterase inhibitors including Ro 20-1724 had no effect. Dose-response curves for MIX potentiation of cAMP-stimulated glycogenolysis and for MIX inhibition of the effects of insulin on cAMP-stimulated glycogenolysis suggested that at higher concentrations (250 microM) MIX may act at a site other than phosphodiesterase inhibition. MIX, at 250 microM, attenuated the insulin antagonism of glucose release stimulated by 8-bromo-cAMP, an extremely poor substrate for phosphodiesterase; other phosphodiesterase inhibitors did not. The possibility that MIX acts as an adenosine antagonist interfering with a postulated role for adenosine in insulin action was examined using N6-phenylisopropyladenosine (PIA), an Ra adenosine receptor agonist which increases hepatic cAMP levels. MIX inhibited insulin antagonism of PIA-stimulated glycogenolysis under conditions where it did not act as an adenosine antagonist (MIX and Ro 20-1724 both increased the response to PIA equally). The effect of concanavalin A on cAMP-stimulated glycogenolysis was antagonized by MIX, suggesting a post-receptor site of action for MIX. MIX paradoxically increased lactate production in the presence of 8-bromo-cAMP, reminiscent of the reported actions of calcium mobilizing hormones on lactate formation in fed hepatocytes. Cytosolic free Ca2+, as measured in Quin 2-loaded cells, was increased by MIX. In cells depleted of calcium, MIX no longer blocked insulin antagonism of 8-bromo-cAMP-stimulated glucose release, suggesting that MIX may function through an insulin-insensitive release of calcium. MIX greatly potentiated the stimulation of glycogenolysis by phenylephrine but did not alter the response to vasopressin. The relationship of this effect of MIX to the mechanism of insulin action and the ability of insulin to antagonize only alpha-adrenergic responses and not those of vasopressin is discussed.
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PMID:Methylisobutylxanthine blocks insulin antagonism of cAMP-stimulated glycogenolysis at a site distinct from phosphodiesterase. Evidence favoring an insulin-insensitive calcium release mechanism. 241 37

Adenosine uptake by cultured rabbit coronary microvascular endothelial cells was studied. Radiolabeled [2-3H]-adenosine, present initially in the extracellular space at 10(-6) mol/l, was incorporated into the cell cultures at a steady rate during 30 s-3 h incubations. Incorporated 3H was found mostly (83%) in adenine nucleotides. Incorporation of [3H]-adenosine was attenuated by an adenosine deaminase inhibitor (EHNA) but only at adenosine concentrations of 10(-5) mol/l or higher. Adenosine transport inhibitors (dipyridamole, nitrobenzylthioinosine) attenuated 3H incorporation. Adenosine uptake was also diminished by certain structural analogues of adenosine (e.g., 2-chloroadenosine), by several alkylxanthine drugs (theophylline, isobutylmethylxanthine, enprofylline and 8-phenyltheophylline), and by certain calcium antagonists (verapamil, nifedipine and trifluoperazine). The mechanisms of actions of these agents on adenosine uptake do not appear to be related to phosphodiesterase inhibition, adenosine receptor antagonism or calcium antagonism. The effects of varying adenosine metabolism may contribute to the pharmacologic actions of these agents.
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PMID:Effects of alkylxanthines and calcium antagonists on adenosine uptake by cultured rabbit coronary microvascular endothelium. 244 79

1. A series of related methylxanthines were studied for their effects on the kinetics of decay of end-plate currents (e.p.c.s) and miniature end-plate currents (m.e.p.c.s) at motor end-plates of the frog. 2. Isobutyl methylxanthine (IBMX, 50 microM-3 mM) produced a concentration-dependent depression of the peak e.p.c. and m.e.p.c. amplitude and a change in the kinetics of e.p.c. and m.e.p.c. decay from the normal single-exponential to a double-exponential function. Drug effects of this nature are generally attributed to open-channel blockade. 3. After wash-out of IBMX, the decay of the e.p.c. or m.e.p.c. was restored to a single-exponential function but with a significantly prolonged time constant. 4. Caffeine or theophylline derivatives (0.1-4 mM), during exposure to drug, produced effects similar to those observed after the application of IBMX; namely a prolongation of the time course of e.p.c.s and m.e.p.c.s without changing the single-exponential nature of the function. 5. Computer simulations were made of the m.e.p.c.s in IBMX. The effects of IBMX could be fitted to the sequential model of channel block only if the prolonged time constant observed upon wash-out was used for the rate constant of channel closure. Independent calculations of the rate constant of channel closure during IBMX application were in agreement with those measured during wash-out. 6. The theophylline derivative 8-phenyltheophylline, a selective adenosine receptor blocker with minimal effects on phosphodiesterase (PDE), increased the time constant of e.p.c. decay in a manner similar to theophylline and caffeine. Non-xanthine PDE inhibitors, either had no effect on m.e.p.c. decay (papaverine) or decreased the time constant of decay (RO 20-1724). It is thus unlikely that PDE inhibition is responsible for the post-junctional effects of IBMX. 7. IBMX (50 microM-2 mM) increased quantal ACh release in the virtual absence of extracellular calcium and also increased the efficacy of adenosine derivatives in inhibiting ACh release. Adenosine (10-100 microM) or 2-chloroadenosine (1-10 microM) had no effect on the time constant of e.p.c. decay nor did these adenosine receptor agonists alter the post-junctional actions of IBMX. The effects of IBMX on end-plate channel kinetics are thus not due to the blockade of adenosine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Independent control of channel closure and block of open channels by methylxanthines at acetylcholine receptors in frog. 245 Sep 93


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