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:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the presence of either methyl xanthines or adenosine deaminase, isoproterenol elicited large dramatic increases in accumulation of cyclic AMPP. In contrast, cyclic AMP accumulation in response to epinephrine or norepinephrine was not potentiated by either methyl xanthines or by adenosine deaminase. Blocking the alpha adrenergic activity of norepinephrine and epinephrine with phentolamine established synergism between these catecholamines and methyl xanthines and adenosine deaminase. The activity of the particulate phosphodiesterase was not influenced by norepinephrine suggesting that the lack of synergism between the catecholamines norepinephrine and epinephrine and methyl xanthines is unrelated to this enzyme. The data are interpreted to suggest that the alpha adrenergic activity of catecholamines prevents the potentiation of cyclic AMP accumulation that occurs when the action of endogenously produced adenosine is interfered with, either by its degradation with adenosine deaminase or by receptor blockade with methyl xanthine. Because a major action of adenosine on fat cells is to inhibit adenylate cyclase it is suggested that alpha adrenergic receptor activation limits the extent to which the enzyme adenylate cyclase can be activated in a fashion similar to that of adenosine.
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PMID:Interactions between catecholamines, methyl xanthines and adenosine in regulation of cyclic AMP accumulation in hamster adipocytes. 615 85

The influence of the activation of presynaptic adenosine receptors on nicotinic autofacilitation of electrically evoked [3H]acetylcholine release from rat phrenic motor nerve terminals was investigated. Blocking the adenosine A2A receptor with 3,7-dimethyl-1-propargylxanthine (DMPX, 10 microM) greatly potentiated, whereas the adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 2.5 nM), partially prevented the facilitatory effect of the nicotinic receptor agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP, 1 microM, 3 min), on evoked [3H]acetylcholine release. The adenosine A2A receptor agonist, 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamideadeno sine (CGS 21680C, 3 nM), but not the adenosine A1 receptor agonist, R-N6-phenylisopropyl adenosine (R-PIA, 300 nM), partially blocked the DMPP (1 microM) facilitation. Forskolin (3 microM) mimicked the attenuation caused by CGS 21680C; inhibition of adenylate cyclase with N-(as-2-phenylcyclopentyl)azacyclo-tridecan-2-imine hydrochloride (MDL 12,330A, 10 microM) markedly enhanced the facilitatory effect of DMPP (1 microM). Prolonged exposure to a high concentration of DMPP (10 microM, 15 min) decreased evoked tritium outflow. The decrease in evoked [3H]acetylcholine release following prolonged exposure to DMPP was augmented by pretreatment with CGS 21680C (3 nM) and forskolin (3 microM), and was abolished by inactivating endogenous adenosine with adenosine deaminase (0.5 U/ml). It is concluded that tonic adenosine A2A receptor activation regulates nicotinic acetylcholine autofacilitation. This action is likely to be mediated through an adenylate cyclase/cyclic AMP-dependent mechanism.
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PMID:Tonic adenosine A2A receptor activation modulates nicotinic autoreceptor function at the rat neuromuscular junction. 770 35

Adenosine (ADO) is a well-known regulator of a variety of physiological functions in the heart. In stress conditions, like hypoxia or ischemia, the concentration of adenosine in the extracellular fluid rises dramatically, mainly through the breakdown of ATP. The degradation of adenosine in the ischemic myocytes induced damage in these cells, but it may simultaneously exert protective effects in the heart by activation of the adenosine receptors. The contribution of ADO to stimulation of protective effects was reported in human and animal hearts, but not in rat hearts. The aim of this study was to evaluate the role of adenosine A1 and A3 receptors (A1R and A3R), in protection of isolated cardiac myocytes of newborn rats from ischemic injury. The hypoxic conditions were simulated by exposure of cultured rat cardiomyocytes (4-5 days in vitro), to an atmosphere of a N2 (95%) and CO2 (5%) mixture, in glucose-free medium for 90 min. The cardiotoxic and cardioprotective effects of ADO ligands were measured by the release of lactate dehydrogenase (LDH) into the medium. Morphological investigation includes immunohistochemistry, image analysis of living and fixed cells and electron microscopy were executed. Pretreatment with the adenosine deaminase considerably increased the hypoxic damage in the cardiomyocytes indicating the importance of extracellular adenosine. Blocking adenosine receptors with selective A1 and A3 receptor antagonists abolished the protective effects of adenosine. A1R and A3R activation during the hypoxic insult delays onset of irreversible cell injury and collapse of mitochondrial membrane potential as assessed using DASPMI fluorochrom. Cardioprotection induced by the A1R agonist, CCPA, was abolished by an A1R antagonist, DPCPX, and was not affected by an A3R antagonist, MRS 1523. Cardioprotection caused by the A3R agonist, Cl-IB-MECA, was antagonized completely by MRS 1523 and only partially by DPCPX. Activation of both A1R and A3R together was more efficient in protection against hypoxia than by each one alone. Our study indicates that activation of either A1 or A3 adenosine receptors in the rat can attenuate myocyte injury during hypoxia. Highly selective A1R and A3R agonists may have potential as cardioprotective agents against ischemia or heart surgery.
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PMID:Cardioprotective effects of adenosine A1 and A3 receptor activation during hypoxia in isolated rat cardiac myocytes. 1126 59

Adenosine is a potent anti-inflammatory agent that modulates the function of cells involved in the inflammatory response. Here we show that it inhibits lipopolysaccharide (LPS)-induced formation of reactive oxygen intermediates (ROI) in both freshly isolated and cultured human monocytes. Blocking of adenosine uptake and inactivation of the adenosine-degrading enzyme adenosine deaminase enhanced the inhibitory action of adenosine, indicating that both pathways regulate the extracellular adenosine concentration. Adenosine-mediated inhibition could be reversed by XAC (xanthine amine congener), an antagonist of the adenosine receptor A(2A), and MRS 1220 [N-9-chloro-2-(2-furanyl)[1, 2, 4]-triazolo[1,5-c]quinazolin-5-benzeneacetamide], an A(3) receptor antagonist, in both cell populations, while DPCPX (1,3-dipropyl-8-cyclopentylxanthine), an A(1) receptor antagonist, had no effect. Similar to what was seen with adenosine, CGS 21680, an A(2A) and A(3) receptor agonist, and IB-MECA, a nonselective A(1) and A(3) receptor agonist, dose dependently prevented ROI formation, indicating the involvement of A(3) and probably also A(2A) in the suppressive effect of adenosine. Pretreatment of monocytes with adenosine did not lead to changes in the LPS-induced increase in intracellular calcium levels ([Ca(2+)](i)). Thus, participation of [Ca(2+)](i) in the action of adenosine seems unlikely. The adenosine-mediated suppression of ROI production was found to be more pronounced when monocytes were cultured for 18 h, a time point at which changes in the mRNA expression of adenosine receptors were observed. Most prominent was the increase in the A(2A) receptor mRNA. These data demonstrate that cultivation of monocytes is accompanied by changes in the inhibitory action of adenosine mediated by A(3) and probably also the A(2A) receptor and that regulation of adenosine receptors is an integral part of the monocyte differentiation program.
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PMID:Regulation of adenosine receptor subtypes during cultivation of human monocytes: role of receptors in preventing lipopolysaccharide-triggered respiratory burst. 1497 38

1. The coexistence of both inhibitory A(1) and facilitatory A(2) adenosine receptors in the rat myenteric plexus prompted the question of how adenosine activates each receptor subtype to regulate cholinergic neurotransmission. 2. Exogenously applied adenosine (0.3-300 microm) decreased electrically evoked [(3)H]acetylcholine ([(3)H]ACh) release. Blocking A(1) receptors with 1,3-dipropyl-8-cyclopentylxanthine (10 nm) transformed the inhibitory action of adenosine into a facilitatory effect. Adenosine-induced inhibition was mimicked by the A(1) receptor agonist R-N(6)-phenylisopropyladenosine (0.3 microm), but the A(2A) agonist CGS 21680C (0.003 microm) produced a contrasting facilitatory effect. 3. Increasing endogenous adenosine levels, by the addition of (1) the adenosine precursor AMP (30-100 microm), (2) the adenosine kinase inhibitor 5'-iodotubercidin (10 microm) or (3) inhibitors of adenosine uptake (dipyridamole, 0.5 microm) and of deamination (erythro-9(2-hydroxy-3-nonyl)adenine, 50 microm), enhanced electrically evoked [(3)H]ACh release (5 Hz for 40 s). Release facilitation was prevented by adenosine deaminase (ADA, 0.5 U ml(-1)) and by the A(2A) receptor antagonist ZM 241385 (50 nm); these compounds decreased [(3)H]ACh release by 31+/-6% (n=7) and 37+/-10% (n=6), respectively. 4. Although inhibition of ecto-5'-nucleotidase by alpha,beta-methylene ADP (200 microm) or by concanavalin A (0.1 mg ml(-1)) attenuated endogenous adenosine formation from AMP, analysed by HPLC, the corresponding reduction in [(3)H]ACh release only became evident when stimulation of the myenteric plexus was prolonged to over 250 s. 5. In summary, we found that endogenously generated adenosine plays a predominantly tonic facilitatory effect mediated by prejunctional A(2A) receptors. Extracellular deamination and cellular uptake may restrict endogenous adenosine actions to the neuro-effector region near the release/production sites.
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PMID:Dual effects of adenosine on acetylcholine release from myenteric motoneurons are mediated by junctional facilitatory A(2A) and extrajunctional inhibitory A(1) receptors. 1499 98

Motor nerve terminals possess multiple voltage-sensitive calcium channels operating acetylcholine (ACh) release. In this study, we investigated whether facilitation of neuromuscular transmission by adenosine generated during neuronal firing was operated by Ca(2+) influx via 'prevalent' P-type or via the recruitment of 'silent' L-type channels. The release of [(3)H]ACh from rat phrenic nerve endings decreased upon increasing the stimulation frequency of the trains (750 pulses) from 5 Hz (83 +/- 4 x 10(3) disintegrations per minute per gram (d.p.m. g(-1)); n = 11) to 50 Hz (30 +/- 3 x 10(3) d.p.m. g(-1); n = 5). The P-type Ca(2+) channel blocker, omega-agatoxin IVA (100 nm) reduced (by 40 +/- 10%; n = 6) the release of [(3)H]ACh evoked by 50-Hz trains, while nifedipine (1 microM, an L-type blocker) was inactive. Tetanic depression was overcome (88 +/- 6 x 10(3) d.p.m. g(-1); n = 12) by stimulating the phrenic nerve with 50-Hz bursts (five bursts of 150 pulses, 20 s interburst interval). In these conditions, omega-agatoxin IVA (100 nM) failed to affect transmitter release, but nifedipine (1 microM) decreased [(3)H]ACh release by 21 +/- 7% (n = 4). Inactivation of endogenous adenosine with adenosine deaminase (ADA, 0.5 U ml(-1)) reduced (by 54 +/- 8%, n = 5) the release of [(3)H]ACh evoked with 50-Hz bursts. This effect was opposite to the excitatory actions of adenosine (0.5 mm), S-(p-nitrobenzyl)-6-thioinosine (5 microM, an adenosine uptake blocker) and CGS 21680C (3 nM, a selective A(2A) receptor agonist); as the A(1) receptor agonist R-N(6)-phenylisopropyl adenosine (R-PIA, 300 nM) failed to affect the release of [(3)H]ACh, the results indicate that adenosine generated during 50-Hz bursts exerts an A(2A)-receptor-mediated tonus. The effects of ADA (0.5 U ml(-1)) and CGS 21680C (3 nm) were prevented by nifedipine (1 microM). Blocking tonic A(2A) receptor activation, with ADA (0.5 U ml(-1)) or 3,7-dimethyl-1-propargyl xanthine (10 microM, an A(2A) antagonist), recovered omega-agatoxin IVA (100 nM) inhibition and caused the loss of function of nifedipine (1 microM). Data indicate that, in addition to the predominant P-type Ca(2+) current triggering ACh release during brief tetanic trains, motoneurones possess L-type channels that may be recruited to facilitate transmitter release during high-frequency bursts. The fine-tuning control of Ca(2+) influx through P- or L-type channels is likely to be mediated by endogenous adenosine. Therefore, tonic activation of presynaptic A(2A) receptors operating Ca(2+) influx via L-type channels may contribute to overcome tetanic depression during neuronal firing.
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PMID:Tetanic depression is overcome by tonic adenosine A(2A) receptor facilitation of L-type Ca(2+) influx into rat motor nerve terminals. 1529 71

Adenosine and gamma-aminobutyric acid (GABA) are both major inhibitory neuromodulators/neurotransmitters in the CNS. We now investigated if endogenous GABA modulates adenosine A(1)-mediated action on synaptic transmission in the hippocampus. Field excitatory postsynaptic potentials (fEPSP) were recorded from the CA(1) area of rat hippocampal slices. The adenosine analogue 2-chloroadenosine (0.15-1 microM) inhibited synaptic transmission with an EC(50) of 398 nM. Blocking GABA(A) receptors with the specific antagonists, bicuculline (10 microM) or picrotoxin (10 microM) potentiated the inhibitory effect of 2-chloroadenosine. The concentration-response curve for 2-chloroadenosine was displaced to the left by a factor of 2 (EC(50)=210 nM) in the presence of bicuculline (10 microM). GABA(A) receptor blockade also potentiated the action of N(6)-cyclopentyladenosine (CPA, 10 nM), a specific adenosine A(1) receptor agonist. Prevention of adenosine accumulation with adenosine deaminase (1 U/ml) did not influence bicuculline-induced potentiation of the effect of 2-chloroadenosine. The potentiation of adenosine A(1)-mediated response by bicuculline was abolished when nitric oxide (NO) synthase was inhibited with nitroarginine (100 microM), and when guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 20 microM). The NO donors, (+/-)-S-nitroso-N-acetylpencillamine (SNAP, 300 microM) and diethylamine NONate diethylammonium salt (DEA/NO, 100 microM), significantly enhanced the inhibitory action of 2-chloroadenosine (150 nM). It is concluded that the blockade of GABA(A) receptors induces a potentiation of adenosine A(1) receptor-mediated inhibitory action, an effect that involves NO acting through guanylyl cyclase. Therefore, endogenous GABA might exert an inhibitory effect over adenosine A(1)-mediated responses in the hippocampus, which may represent a physiologic regulatory mechanism between the two inhibitory mediators.
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PMID:Nitric oxide mediates interactions between GABAA receptors and adenosine A1 receptors in the rat hippocampus. 1683 16

The high requirement of O2 in the renal proximal tubule stems from a high rate of Na(+) transport. Adenosine A1 receptor (A1R) activation regulates Na(+) transport in this nephron segment. Thus, the effect of the acute activation and the mechanisms of A1R on the rate of O2 consumption were evaluated. The A1R-antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX) and adenosine deaminase (ADA), which metabolize endogenous adenosine, reduced O2 consumption (40-50%). Replacing Na(+) in the buffer reversed the ADA- or CPX-mediated reduction of O2 consumption. Blocking the Na/H-exchanger activity, which decreases O2 usage per se, did not enhance the ADA- or CPX-induced inhibition of O2 consumption. These data indicate that endogenous adenosine increases O2 usage via the activation of Na(+) transport. In the presence of endogenous adenosine, A1R was further activated by the A1R-agonist N(6)-cyclopentyladenosine (CPA); CPA inhibited O2 usage (30%) and this effect also depended on Na(+) transport. Moreover, a low concentration of CPA activated O2 usage in tissue pretreated with ADA, whereas a high concentration of CPA inhibited O2 usage; both effects depended on Na(+). Protein kinase C signaling mediated the inhibitory effect of A1R, while adenylyl cyclase mediated its stimulatory effect on O2 consumption. In summary, increasing the local concentrations of adenosine can either activate or inhibit O2 consumption via A1R, and this mechanism depends on Na(+) transport. The inhibition of O2 usage by A1R activation might restore the compromised balance between energy supply and demand under pathophysiological conditions, such as renal ischemia, which results in high adenosine production.
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PMID:Dual Effect of Adenosine A1 Receptor Activation on Renal O2 Consumption. 2601 Feb 90

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