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)

Caffeine induces a dose-dependent decrease in core body temperature in mice and the hypothermia induced by a 100 mg/kg dose of caffeine was seen to persist for greater than 160 min. Other alkylxanthines including theophylline, enprophylline, isbutylmethylxanthine and 1,3-dipropyl-7-methylxanthine also showed dose-dependent reductions in body temperature. The dose of these drugs required to reduce body temperature by 2 degrees C was calculated and correlated with the affinities for the compounds at adenosine A1 and A2 receptors and their activities in inhibiting calcium dependent and independent phosphodiesterases. Significant relationships were found between the 2 degrees C hypothermic dose (HD2) and soluble and membrane calcium-independent phosphodiesterase inhibiting activity (r2s = 0.950 and 0.940, respectively). No significant relationship was seen between HD2 and soluble calcium-dependent phosphodiesterase inhibiting activity or with A2 adenosine receptor affinity. The relationship between HD2 and A1 adenosine receptor affinity (r2 = 0.739) did however almost reach statistical significance. These results would suggest that phosphodiesterase inhibition, instead of or in addition to adenosine receptor blockade, may play an important role in the effects of alkylxanthines on body temperature.
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PMID:Hypothermic effects of alkylxanthines: evidence for a calcium-independent phosphodiesterase action. 180 62

The intradermal injection of adenosine produces a dose-dependent decrease in mechanical nociceptive threshold in the hindpaw of the rat that is not attenuated by elimination of indirect pathways for the production of hyperalgesia. Adenosine-induced hyperalgesia is mimicked by the A2-agonists, 5'-(N-ethyl)-carboxamido-adenosine and 2-phenylaminoadenosine but not by the A1-agonist, N6-cyclopentyladenosine and antagonized by the adenosine A2-receptor antagonist, PD 081360-0002 but not by the A1-antagonist, 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine. The latency to onset of adenosine and 2-phenylaminoadenosine hyperalgesia is similar to that produced by prostaglandin E2, a directly acting hyperalgesic agent but shorter than that produced by leukotriene B4, which acts indirectly. 2-Phenylaminoadenosine hyperalgesia is prolonged by rolipram, a phosphodiesterase inhibitor. Both 2-phenylaminoadenosine and prostaglandin E2 hyperalgesia are antagonized by the A1-agonist N6-cyclopentyladenosine and the mu-agonist, [D-Ala2, NMe-Phe4, Gly-ol]enkephalin. However, 1-acetyl-2-(8-chloro-10,11-dihydrodibenz[b,f]oxazepine-10-ca rbonyl) hydrazine, a prostaglandin-receptor antagonist, inhibits prostaglandin E2 (Taiwo and Levine, Brain Res. 458, 402-406, 1988) but not 2-phenylamino-adenosine hyperalgesia and PD 081360-0002, the adenosine receptor antagonist, inhibits 2-phenylamino-adenosine but not prostaglandin E2 hyperalgesia. These data suggest that adenosine is a directly acting agent that produces hyperalgesia by an action at the A2-receptor and that this hyperalgesia is mediated by the cAMP second messenger.
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PMID:Direct cutaneous hyperalgesia induced by adenosine. 198 Jan 46

The effects of the A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) on force of contraction were examined in isolated electrically driven auricles and papillary muscles from guinea-pigs in the absence and presence of (-)-N6-phenylisopropyladenosine (PIA) and 5'-N-ethylcarboxamidadenosine (NECA). In auricles DPCPX (30-1000 mmol/l) alone increased force of contraction. DPCPX produced only a minor inhibition of phosphodiesterase I-III activity. PIA and NECA alone exerted concentration-dependent negative inotropic effects and the concentration-response curves for PIA and NECA were shifted competitively to the right by the adenosine receptor antagonist DPCPX with similar potency and efficacy. The pA2-value for the inhibition of the effects of PIA and NECA were 9.1 and 8.8, respectively. In papillary muscles DPCPX alone had no inotropic effect. In the presence of isoprenaline PIA and NECA alone exerted concentration-dependent negative inotropic effects and again DPCPX shifted the concentration-response curves for PIA and NECA competitively to the right with similar potency and efficacy. The pA2-value for the inhibition of the effects of PIA and NECA were 9.3 and 9.0, respectively. It is concluded that DPCPX is a potent competitive A1 adenosine receptor antagonist in guinea-pig atrial and ventricular cardiac preparations. Since PIA and NECA were equally potent the cardiac adenosine receptor may constitute a subtype of A1 adenosine receptors differing from the receptor in other tissues such as fat cells. Furthermore, DPCPX has a positive inotropic effect in atrial tissue which cannot be attributed to the A1 receptor antagonism.
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PMID:Effects of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a highly selective adenosine receptor antagonist, on force of contraction in guinea-pig atrial and ventricular cardiac preparations. 255 51

Although adenosine contributes importantly to the regulation of renin release, renal vascular resistance and renal tubular reabsorption, the metabolic pathways that control the intrarenal production rate of adenosine remain ill defined. The objective of this study was to determine whether extracellular metabolism of cyclic AMP to AMP by extracellular phosphodiesterase and hence to adenosine by ecto-5'-nucleotidase can occur in the intact kidney. To test this hypothesis, five experimental series were conducted in kidneys from male Sprague-Dawley rats perfused in a nonrecirculating system (5 ml/min) in vitro with oxygenated Tyrode's solution at 37 degrees C. In each experimental series, cyclic AMP was added to the Tyrode's solution and the renal secretion rates (i.e., the renal venous concentration of purine x the perfusion flow rate) of AMP, adenosine and inosine were determined using high-performance liquid chromatography. In the first experimental series, only cyclic AMP was added to the perfusate. In the second, third, fourth and fifth experimental series, kidneys were perfused with Tyrode's solution containing both cyclic AMP and either 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor), alpha,beta-methyleneadenosine-5'-diphosphate (an ecto-5'-nucleotidase inhibitor), dilazep (an adenosine transport inhibitor) or 1,3-dipropyl-8-p-sulfophenylxanthine (a xanthine that is restricted to the extracellular compartment). In the first experimental series (n = 8), addition of cyclic AMP to the perfusate resulted in significant concentration-related increases in the renal secretion rates of AMP, adenosine and inosine, with the increase in AMP secretion being significantly greater than the increases in adenosine or inosine secretions (delta adenosine secretion/delta AMP secretion = 0.38 +/- 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolism of exogenous cyclic AMP to adenosine in the rat kidney. 753 80

1. In the absence of adenosine uptake inhibition, adenosine produced a concentration-dependent (threshold 30 microM) relaxation of the 5-methylfurmethide pre-contracted guinea-pig taenia caecum. The relaxation was not blocked by 8-phenyltheophylline (8-PT, 3 microM) or 1,3-dipropyl, 8-cyclopentylxanthine (DPCPX, 30 microM). 2. In the presence of the adenosine uptake inhibitor, dipyridamole (Dip, 3 microM), a biphasic adenosine concentration-effect curve was obtained (threshold 0.3 microM). The time course of the responses to adenosine in the absence of Dip was similar to that of the second phase responses in the presence of Dip and occurred over the same adenosine concentration-range. 5'-(N-ethyl) carboxamido-adenosine (NECA) concentration-effect curves (in the absence of Dip) were also biphasic. Only the first phases of the concentration-effect curves obtained with NECA and adenosine (plus Dip) were inhibited by 8-PT. The pA2 values for 8-PT of 6.7 and 7.0 versus adenosine and NECA, respectively, were consistent with actions at P1-purinoceptors. There was a trend towards an increase in the upper asymptote of the first phase of the NECA curve in the presence of increasing concentrations of 8-PT. The A1-purinoceptor selective antagonist, DPCPX, also blocked only the first phase of the NECA concentration-effect curve and produced a significant increase in the upper asymptote. The pA2 value (6.8) obtained was consistent with activation of A2-subtype P1-purinoceptors by the low concentrations of NECA. 3. There was no correlation between A1-purinoceptor affinity and the propensity to cause the increase in the upper asymptote of the first phase of the NECA concentration-effect curves amongst a series of 9-methyl adenine analogues, suggesting that the amplification was not due to inhibition of an underlying A1-purinoceptor-mediated contractile response.4. DPCPX (10 microM) produced a significant increase in the upper asymptote of the NECA concentration effect curve, but had no effect on isoprenaline curves whereas the phosphodiesterase inhibitor Ro20-1724 (30 microM) produced a significant increase in the upper asymptote of both NECA and isoprenaline concentration-effect curves. Therefore the amplification of the first phase responses by DPCPX did not appear to be due to phosphodiesterase inhibition.5. It was not possible to conclude whether second phase responses to adenosine and NECA were mediated by intracellular or extracellular sites of action. However, if intracellular sites of action were involved then adenosine did not apparently gain access by the Dip-sensitive uptake system.
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PMID:Pharmacological analysis of the interaction between purinoceptor agonists and antagonists in the guinea-pig taenia caecum. 758 71

Chronic ingestion of caffeine by mice caused a marked reduction in locomotor exploratory activity. At least 4 days of withdrawal were required to restore activity to normal levels. Stimulatory effects of injected caffeine were lower in chronically treated mice and the biphasic dose-response (stimulatory followed by depressant) curve for injected caffeine was left shifted. Seven days of withdrawal were required before the dose-response curve to caffeine was identical to that of control mice. The depressant effects of a potent xanthine phosphodiesterase inhibitor, 1,3-dipropyl-7-methylxanthine, were blunted in caffeine-treated mice. The depressant effects of A1- and A2-selective adenosine analogs were enhanced after chronic caffeine. There was little or no effect of chronic caffeine on the stimulatory effects of dopaminergic agents (amphetamine, caffeine), while both depressant and stimulatory effects of cholinergic agents (nicotine, oxotremorine, scopolamine) were reduced. The results indicate that chronic caffeine affects functions of adenosine and cholinergic receptors related to regulation of locomotor exploratory activity.
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PMID:Locomotor activity in mice during chronic treatment with caffeine and withdrawal. 767 19

The pharmacological actions of methylxanthines such as theophylline and caffeine may be due to blockade of adenosine receptors and/or inhibition of phosphodiesterase (PDE) activities. In the last years, potent xanthines have been developed that display some selectivity for A1 and A2 adenosine receptors. Little is known about the PDE inhibitory potency of these xanthines. The aim of the present study was to determine the potencies of A1 and A2 receptor selective xanthines as inhibitors of several PDE isozymes, the PDE I-V subtypes. The IC50 values of 8-phenyl- and 8-cycloalkyl-1,3-dialkylxanthines for inhibition of PDE isozymes from different sources are up to 10,000-fold higher than their antagonistic potencies at adenosine receptors. However, the A1 receptor selective antagonists 1,3-diethyl-8-phenylxanthine and 1,3-dipropyl-8-cyclopentylxanthine are comparatively potent inhibitors of PDE IV activity with IC50 values in the 10 microM range and are, therefore, nearly as potent as the PDE IV selective inhibitor, rolipram. The A2 receptor selective 1,3-dipropyl-7-methylxanthine is about 10-300-fold more potent as an adenosine receptor antagonist than as a PDE inhibitor. The results indicate that some of these novel xanthines can be used as selective adenosine receptor antagonists without interference due to inhibitory effects on PDEs.
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PMID:Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes. 768 Aug 59

The role of prejunctional purinoceptors (P1-subtype) in the control of ATP-release from inhibitory motoneurons was investigated electrophysiologically, by studying fast purinergic inhibitory junction potentials (IJPs) in guinea-pig ileal circular muscle. Pressure ejections of adenosine and ATP (but not of alpha,beta-methylene ATP) onto circular muscle depressed the amplitude of fast IJPs, indicating the presence of prejunctional P1-purinoceptors. An adenosine (A1/2)-receptor antagonist, theophylline (10(-8)-10(-4) M), increased the amplitude of fast IJPs in a dose-related manner (EC50 = 17.5 microM), suggesting the existence of a basal 'adenosine tone' that regulated ATP-release from ileal motoneurons. However, three methylxanthine derivatives, caffeine (10(-8)-10(-4) M), 3-isobutyl-1-methylxanthine (IBMX; 10(-8)-10(-4) M) and the potent A1-receptor antagonist 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (DPCPX; 10(-8)-10(-4) M), failed to potentiate fast IJPs and placed in doubt the existence of this inhibitory adenosine tone. Caffeine and IBMX, but not DCPCX, hyperpolarised ileal circular muscle in a dose-related manner and reduced IJP-amplitude; DPCPX did not alter the amplitude of IJPs. The non-specific inhibitor of phosphodiesterases, Ro-20-1724 (5 x 10(-7)-5 x 10(-5) M), increased the amplitude of fast IJPs, mimicking the actions of theophylline. To this extent, facilitation of inhibitory transmission appeared to involve phosphodiesterase inhibition and modification of intra-axonal cAMP levels and phosphorylation of intra-axonal protein kinases. The phenomenon of IJP rundown, presumed to be a manifestation of prejunctional autoinhibition, was studied using theophylline and DPCPX as A1-receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prejunctional autoinhibition of purinergic transmission in circular muscle of guinea-pig ileum; a mechanism distinct from P1-purinoceptor activation. 802 18

Intracellular recordings were performed on hippocampal CA3 neurons in vitro to investigate the inhibitory tonus generated by endogenously produced adenosine in this brain region. Bath application of the highly selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine at concentrations up to 100 nM induced both spontaneous and stimulus-evoked epileptiform burst discharges. Once induced, the 1,3-dipropyl-8-cyclopentylxanthine-evoked epileptiform activity was apparently irreversible even after prolonged superfusion with drug-free solution. The blockade of glutamatergic excitatory synaptic transmission by preincubation of the slices with the amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM), but not with the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid (50 microM), prevented the induction of epileptiform activity by 1,3-dipropyl-8-cyclopentylxanthine. The generation of the burst discharges was independent of the membrane potential, and the amplitude of the slow component of the paroxysmal depolarization shift increased with hyperpolarization, indicating that the 1,3-dipropyl-8-cyclopentylxanthine-induced bursts were synaptically mediated events. Recordings from tetrodotoxin-treated CA3 neurons revealed a strong postsynaptic component of endogenous adenosinergic inhibition. Both 1,3-dipropyl-8-cyclopentylxanthine and the adenosine-degrading enzyme adenosine deaminase produced an apparently irreversible depolarization of the membrane potential by about 20 mV. Sometimes, this depolarization attained the threshold for the generation of putative calcium spikes, but no potential changes resembling paroxysmal depolarization shift-like events were observed. At the concentrations used in electrophysiological experiments (30-100 nM), 1,3-dipropyl-8-cyclopentylxanthine displayed only a negligible inhibitory action on total cyclic nucleotide phosphodiesterase activity measured by means of a radiochemical assay in a homogenate of the rat cerebral cortex. Furthermore, even high concentrations of the selective phosphodiesterase inhibitor rolipram (10 microM), which displays no affinity to adenosine receptors, did not mimic the electrophysiological actions of 1,3-dipropyl-8-cyclopentylxanthine, thus excluding the possibility that the effects of the A1 receptor antagonist on neuronal discharge behavior can be ascribed to an inhibition of phosphodiesterases. The present data demonstrate that endogenously released adenosine exerts a vigorous control on the excitability of hippocampal CA3 neurons on both the pre- and postsynaptic sites. The long-lasting disinhibition following a transient suppression of adenosinergic inhibition strongly suggests that, besides its well-known short-term effects on neuronal activity, adenosine might also contribute to the long-term control of hippocampal excitability.
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PMID:Disinhibition of hippocampal CA3 neurons induced by suppression of an adenosine A1 receptor-mediated inhibitory tonus: pre- and postsynaptic components. 830 25

In this study we determined whether cAMP is metabolized to adenosine in vascular smooth muscle cells and whether cAMP-derived adenosine modulates vascular smooth muscle cell growth. Confluent smooth muscle cells were exposed to cAMP (0.01 to 30 mumol/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol/L; an inhibitor of both extracellular and intracellular phosphodiesterase), alpha, beta-methyleneadenosine 5'-diphosphate (AMP-CP, 100 mumol/L; an ecto-5'-nucleotidase inhibitor), and 1,3-dipropyl-8-p-sulfophenyl-xanthine (DPSPX, 100 mumol/L; a xanthine that can inhibit extracellular phosphodiesterase) for 0 to 60 minutes. Medium was then sampled and assayed for AMP, adenosine, and inosine. cAMP increased the amount of AMP, adenosine, and inosine in the medium in a time- and concentration-dependent manner. The conversion of cAMP to adenosine and inosine was inhibited by blockade of phosphodiesterase with IBMX, of ecto-phosphodiesterase with DPSPX, and of ecto-5'-nucleotidase with AMP-CP. To evaluate the physiological relevance of cAMP-derived adenosine in vascular smooth muscle cell proliferation, we studied the inhibitory effects of cAMP (10(-4) mol/L) and 8-bromo-cAMP (10(-4) mol/L) on fetal calf serum-induced DNA synthesis ([3H]thymidine incorporation) in the presence and absence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, an inhibitor of adenosine deaminase), dipyridamole (a blocker of adenosine transport), KF17837 (a selective A2 adenosine receptor antagonist), and DPSPX (a nonselective adenosine receptor antagonist). cAMP inhibited DNA synthesis, and both EHNA and dipyridamole enhanced this effect. Both KF17837 and DPSPX significantly reduced the inhibitory effects of cAMP on DNA synthesis; however, they did not reduce the inhibitory effects of 8-bromo-cAMP on DNA synthesis. These results indicate that vascular smooth muscle cells metabolize cAMP to adenosine via the sequential action of ecto-phosphodiesterase and ecto-5'-nucleotidase and provide the first evidence that cAMP-derived adenosine can inhibit vascular smooth muscle cell growth. Hence, this cAMP-adenosine pathway may importantly contribute to the regulation of vascular biology.
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PMID:Cyclic AMP-adenosine pathway inhibits vascular smooth muscle cell growth. 890 21


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