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

---

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

The effects of a number of purinoceptor agonists and antagonists on norepinephrine (NE) overflow were examined in the electrically field-stimulated rat vas deferens. The P1 receptor agonists adenosine and 2-chloroadenosine and the P2 receptor agonists ATP and beta, gamma-methylene ATP all reduced the overflow of NE, which was quantified by high-performance liquid chromatography-electrochemical detection techniques. The P1 receptor antagonist 8-(p-sulfophenyl)-theophylline (8-SPT) and the P2 receptor desensitizing agent alpha, beta-methylene ATP blocked the inhibitory effects of both P1 and P2 receptor agonists. The pyrimidine nucleotide UTP also inhibited NE overflow and this effect was antagonized by 8-SPT. The adenosine uptake inhibitor S-p-nitrobenzyl-6-thioguanosine potentiated and adenosine deaminase blocked the inhibitory effect of adenosine on NE overflow but neither had any effect on the ability of the adenine nucleotides to inhibit NE overflow. These results indicate that adenine nucleotides can act per se, without conversion to adenosine, on a prejunctional receptor to inhibit the release of NE. Because the effects of the adenine nucleotides are antagonized by 8-SPT, it appears that they act at the same receptor as the adenine nucleosides. UTP apparently acts at this receptor as well. These findings suggest that prejunctional purinoceptors on the sympathetic nerves of the rat vas deferens differ from P1 or P2 receptors as usually defined and thus may represent a unique class of receptor (P3) as has been suggested for the prejunctional receptors of the rat caudal artery.
...
PMID:Nucleotide modulation of norepinephrine release from sympathetic nerves in the rat vas deferens. 167 77

1. The effect of neonatal monosodium-L-glutamate (MSG) treatment on lipolysis in rat epididymal adipose tissue was studied. A reduction in the basal lipolysis was observed in the MSG-treated rats. 2. This was accompanied by a decrease lipolytic response to isoprenaline, adrenocorticotropic hormone, forskolin, isobutylmethylxanthine and dibutyryl-cAMP. 3. The addition of adenosine deaminase, which inactivates endogenous adenosine in the medium, did not normalize the basal and the hormone stimulated lipolytic responses. 4. The maximal lipolysis stimulated by adenosine deaminase or 8-(p-sulfophenyl)-theophylline (8-SPT), an adenosine antagonist, was significantly lower in the MSG-treated rats. 5. Moreover, there was no change in the sensitivity of adenosine receptors to its antagonist as reflected by the similar potency of 8-SPT in eliciting the lipolytic response in both the control and MSG-treated rats. 6. In conclusion, neonatal MSG treatment in rats induced a general reduction of lipolytic response in the epididymal adipocytes which cannot be explained by an enhancement of the adenosine inhibitory system.
...
PMID:Neonatal monosodium-L-glutamate treatment reduced lipolytic response of rat epididymal adipose tissue. 341 Feb 73

The possible role of brain adenosine in acute ethanol-induced alteration in glucose utilization in the whole brain, as well as in the specific brain areas (cerebellum and brain stem), was investigated. Mice were killed 20-min postethanol, and the fresh tissue slices (300 microns) of brain and/or specific brain areas were incubated for 100 min in a 5.5 mM glucose medium in Warburg flasks using [6-(14)C]glucose as a tracer. Trapped 14CO2 was counted to estimate glucose utilization. Ethanol (2 g/kg, i.p.) markedly increased the glucose utilization in whole brain and in both motor areas of brain. Theophylline (50 mg/kg, i.p.), an adenosine antagonist, significantly reduced ethanol-induced increase in glucose utilization in whole brain, as well as in brain areas. However, adenosine agonist N6-cyclohexyladenosine (CHA; 0.1 mg/kg, i.p.) on the contrary, significantly accentuated ethanol-induced increase in glucose utilization in these tissues that was nearly completely blocked by theophylline pretreatment. Theophylline alone did not produce any significant change in glucose utilization, whereas CHA alone (in vivo and in vitro) significantly increased glucose utilization, as well as ethanol-induced increase in glucose utilization in an additive manner. Relevant supportive data were obtained by experiments in which adenosine deaminase (ADA), p-sulfophenyltheophylline (8-SPT), and CHA were administered in vitro to the slice preparations. Both ADA and 8-SPT were effective in almost completely blocking the ethanol-induced increase in glucose utilization, whereas CHA further enhanced the ethanol-induced increase in glucose utilization in an additive manner.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Possible central adenosinergic modulation of ethanol-induced alterations in [14C]glucose utilization in mice. 757 8

In two groups of Saffan-anaesthetized, spontaneously breathing rats we have attempted to identify the peripheral influences of adenosine in mediating the responses evoked by hypoxia by using an adenosine receptor antagonist, 8-sulphophenyltheophylline (8-SPT, 20 mg kg-1 i.v., Group 1) and adenosine deaminase (ADA, 500 units in 0.04 ml infused into the tail artery for 10 min, Group 2); neither of these drugs crosses the blood-brain barrier. Recordings were made of respiration, heart rate, arterial pressure, blood flow and vascular conductance in the femoral artery, with ankle ligated (FBF and FVC, respectively) and in the carotid artery with all branches except the internal carotid ligated (CBF and CVC, respectively, Group 1 only) in order to indicate responses in skeletal muscle and cerebral vasculature. Hypoxia (breathing 8 or 10% O2 for 10 min) evoked an increase followed by a secondary decrease in respiration, tachycardia followed by secondary bradycardia, a fall in arterial pressure, an increase in FVC and CVC and an increase, followed by a decrease, in CBF. Neither 8-SPT nor ADA had any significant effect on the secondary decrease in respiration. The secondary bradycardia was unaffected by 8-SPT, but abolished by ADA. Both drugs reduced the fall in arterial pressure and the increase in FVC; 8-SPT had no significant effect on the increase in CVC, but CBF no longer fell with arterial pressure. We propose that adenosine contributes to the hypoxia-induced fall in arterial pressure by causing vasodilatation in skeletal muscle and possibly by causing bradycardia by a direct action on the heart; other evidence suggests that adenosine contributes to the secondary decrease in respiration by acting on central respiratory neurones. The possibility that the fall in arterial pressure and the secondary falls in CBF, respiration and heart rate, can become interdependent in a positive feedback manner is discussed.
...
PMID:Differentiation of the peripherally mediated from the centrally mediated influences of adenosine in the rat during systemic hypoxia. 781 67

The purpose of this study was to determine the changes in interstitial fluid (ISF) adenosine and cerebral blood flow (CBF) during inhibition of adenosine kinase or adenosine deaminase. Brain microdialysis was used to (a) measure CBF (H2 clearance), (b) sample cerebral ISF, and (c) deliver drugs locally to the brain. Microdialysis probes were implanted bilaterally in the caudate nucleus of halothane-anesthetized rats (n = 11). One probe was perfused with artificial cerebrospinal fluid (CSF) containing iodotubercidin (IODO), an adenosine kinase inhibitor, while the other probe was perfused with erythro-2-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor. Both probes were subsequently perfused with EHNA+IODO. Finally, 8-(p-sulfophenyl)theophylline (SPT), an adenosine receptor antagonist, was added to EHNA + IODO in one probe, while the other probe continued to receive only EHNA + IODO. CBF and dialysate adenosine levels increased with either EHNA or IODO; however, the increases were greater with IODO. EHNA + IODO further increased CBF and dialysate adenosine. The hyperemia observed with EHNA + IODO was abolished by adenosine receptor blockade. These data suggest that basal adenosine levels are influenced to a greater extent by adenosine kinase than by adenosine deaminase. In addition, the increased CBF observed with inhibition of adenosine metabolism and the attenuation of this vasodilatory response with adenosine receptor blockade support a role for adenosine in CBF regulation.
...
PMID:Increases in interstitial adenosine and cerebral blood flow with inhibition of adenosine kinase and adenosine deaminase. 843 11

The effects of endogenous adenosine release on CA1 neurons in hippocampal slices were studied under normoxic and hypoxic conditions, by using extra-/intracellular and whole-cell recordings. During normoxia, the adenosine antagonist, 8-(p-sulphophenyl) theophylline (8-SPT) or adenosine deaminase (ADA) potentiated both evoked CA1 EPSPs and spontaneous synaptic activity, but not monosynaptic IPSPs; there was a minimal depolarization (by 1 mV), probably caused by the enhanced synaptic activity, but no increase in input conductance. Under voltage-clamp with KCl electrodes (with holding potential (VH) near -70 mV), hypoxia (4-5 min) elicited a rise in input conductance and an outward current that reversed near -90 mV, in keeping with the activation of K conductance. These effects of hypoxia were partly attenuated by 8-SPT (10 microM). The hypoxia-induced outward current and conductance increase were abolished by 1 mM Ba, being replaced by a small inward current and a conductance decrease. These data indicate that adenosine tonically inhibits excitatory, but not inhibitory, synaptic transmission, has no direct effect on input conductance, and contributes to the hyperpolarization and fall in input resistance induced by hypoxia.
...
PMID:Endogenous adenosine on membrane properties of CA1 neurons in rat hippocampal slices during normoxia and hypoxia. 914 54

We developed a model of ischemia and reperfusion (I and R) in human ventricular myocytes (CM). CM injury and metabolics were studied after various interventions: endogenous preconditioning (PC) with anoxia, hypoxia, and anoxic or hypoxic supernatants; endogenous PC with or without SPT or adenosine deaminase; and exogenous adenosine PC before, during, or after I or continuously, with or without SPT. To assess the clinical implications of PC and the possible mediating effects of adenosine, patients undergoing elective coronary bypass surgery (CABG) received either a high or low dose of adenosine. Patients not receiving adenosine served as controls. Adenosine levels, high-energy phosphate levels, the metabolic parameters were evaluated from blood samples and left ventricular biopsy samples. Our cellular model studies indicated that preconditioning conferred protection to human CM via an adenosine-mediated pathway. Adenosine simulated PC without a fall in ATP. Adenosine administered to patients during CABG stimulated myocardial metabolism while preventing the degradation of high energy phosphates. A prospective randomized trial of adenosine administered to high-risk patients for myocardial protection is required.
...
PMID:Optimal myocardial preconditioning in humans. 1041 42

By pharmacological manipulation of endogenous adenosine, using chemically distinct methods, we tested the hypothesis that endogenous adenosine tempers proinflammatory cytokine responses and oxyradical-mediated tissue damage during endotoxemia and sepsis. Rats were pretreated with varying doses of pentostatin (PNT; adenosine deaminase inhibitor) or 8-sulfophenyltheophylline (8-SPT; adenosine receptor antagonist) and then received either E. coli endotoxin (lipopolysaccharide; 0.01 or 2.0 mg/kg) or a slurry of cecal matter in 5% dextrose in water (200 mg/kg). Resultant levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 were measured in serum and in liver and spleen. Untreated, 2 mg/kg lipopolysaccharide elevated serum TNF-alpha, IL-1beta, and IL-10. PNT dose dependently attenuated, without ablating, the elevation in serum TNF-alpha and IL-1beta and raised liver and spleen IL-10. PNT also attenuated elevation of TNF-alpha in serum, liver, and spleen at 4 and 24 h after sepsis induction, and 8-SPT resulted in higher proinflammatory cytokines. Modulating endogenous adenosine was also effective in exacerbated (8-SPT) or diminished (PNT) tissue peroxidation. Survival from sepsis was also improved when PNT was used as a posttreatment. These data indicate that endogenous adenosine is an important modulatory component of systemic inflammatory response syndromes. These data also indicate that inhibition of adenosine deaminase may be a novel and viable therapeutic approach to managing the systemic inflammatory response syndrome without ablating important physiological functions.
...
PMID:Inhibiting adenosine deaminase modulates the systemic inflammatory response syndrome in endotoxemia and sepsis. 1195 72

Adenosine is a multifaceted signaling molecule mediating key aspects of innate and immune lung defenses. However, abnormally high airway adenosine levels exacerbate inflammatory lung diseases. This study identifies the mechanisms regulating adenosine elimination from the apical surface of human airway epithelia. Experiments conducted on polarized primary cultures of nasal and bronchial epithelial cells showed that extracellular adenosine is eliminated by surface metabolism and cellular uptake. The conversion of adenosine to inosine was completely inhibited by the adenosine deaminase 1 (ADA1) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). The reaction exhibited Km and Vmax values of 24 microM and 0.14 nmol x min(-1) x cm(-2). ADA1 (not ADA2) mRNA was detected in human airway epithelia. The adenosine/mannitol permeability coefficient ratio (18/1) indicated a minor contribution of paracellular absorption. Adenosine uptake was Na+-dependent and was inhibited by the concentrative nucleoside transporter (CNT) blocker phloridzin but not by the equilibrative nucleoside transporter (ENT) blocker dipyridamole. Apparent Km and Vmax values were 17 microM and 7.2 nmol x min(-1) x cm(-2), and transport selectivity was adenosine = inosine = uridine > guanosine = cytidine > thymidine. CNT3 mRNA was detected throughout the airways, while CNT2 was restricted to nasal epithelia. Inhibition of adenosine elimination by EHNA or phloridzin raised apical adenosine levels by >3-fold and stimulated IL-13 and MCP-1 secretion by 6-fold. These responses were reproduced by the adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA) and blocked by the adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline (8-SPT). This study shows that adenosine elimination on human airway epithelia is mediated by ADA1, CNT2, and CNT3, which constitute important regulators of adenosine-mediated inflammation.
...
PMID:Adenosine deaminase 1 and concentrative nucleoside transporters 2 and 3 regulate adenosine on the apical surface of human airway epithelia: implications for inflammatory lung diseases. 1769 52

---