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Query: EC:3.5.4.17 (adenosine deaminase)
 5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Adenosine and adenosine 5'-triphosphate (ATP) have been reported to cause relaxation of the rat colon longitudinal muscle preparation; the purinoceptors mediating this effect were investigated by use of a series of agonists and antagonists. 2. The tissue was precontracted with carbachol (1 microM), and the purines induced reversible relaxations with a potency order of 5'-N-ethylcarboxamidoadenosine (NECA) greater than N6-cyclopentyladenosine (CPA) = adenosine 5'-(alpha, beta-methylene) triphosphonate (AMPCPP) greater than adenosine = adenylyl 5'-(beta, gamma-methylene) disphosphonate (AMPPCP) = ATP. The P1-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (3 microM) shifted to the right the log concentration-response curves of all these agonists except for AMPCPP, indicating that they all act via P1-purinoceptors. The order of potency of the adenosine analogues and the relatively high concentrations of the antagonist required indicated that these receptors are of the A2 subtype. The P2-selective antagonist suramin (300 microM) inhibited responses to AMPCPP, but not to the other agonists. 3. The dephosphorylation of the nucleotides was studied by high performance liquid chromatography following incubation with the longitudinal muscle preparation for up to 30 min. ATP was rapidly degraded, largely to adenosine, and AMPPCP and AMPCPP were also degraded, although more slowly, to adenosine and adenosine 5'-(alpha, beta-methylene) diphosphonate (AMPCP) respectively. AMPCP, like AMPCPP, caused relaxations by acting on P2-purinoceptors, as it was also inhibited by suramin (300 microM). Incubation of the tissue with adenosine deaminase abolished responses to adenosine, reduced those to ATP and AMPPCP, but had no effect on those to AMPCPP.ATP and AMPPCP therefore appear to be acting on the A2 receptors in this tissue largely via their degradation product adenosine.4. The longitudinal muscle of the rat colon therefore contains both P.- and P2-purinoceptors, which both mediate relaxation. The P,-purinoceptors are of the A2 subtype and the P2-purinoceptors are probably of the P2Y subtype, although the rapid degradation of the nucleotides means that it is difficult to classify them with certainty.
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PMID:Effects of purines on the longitudinal muscle of the rat colon. 150 17

Fat-cells were isolated from patients of body-mass indices (BMIs) ranging from 17.9 to 83.9 kg/m2. Isoprenaline-stimulated cyclic AMP accumulation in cells prepared from obese subjects as compared with normal-weight subjects, was less sensitive to inhibition by the adenosine agonist N6-(phenylisopropyl)adenosine (PIA) (P = 0.047). The inhibition of 7 beta-desacetyl-7 beta-[gamma-(N-methylpiperazino) butyryl]-forskolin-stimulated adenylate cyclase by PIA in the presence of adenosine deaminase was also much attenuated in crude plasma membranes of adipocytes prepared from massively obese patients as compared with lean controls (P = 0.0143). This difference was probably not due to different cell size, because adenylate cyclase of crude plasma membranes of large adipocytes was actually more sensitive to PIA than was adenylate cyclase of membranes of smaller fat-cells co-isolated from the same individual. The stimulatory effect of PIA on glucose uptake in the presence of adenosine deaminase was depressed in adipocytes prepared from obese subjects and correlated with BMI at r = -0.626 (P = 0.007) at 100 nM-PIA. The adenosine receptors were studied by using the adenosine antagonist 1,3-[3H]dipropyl-8-cyclopentylxanthine. The binding was rapid and proportional to protein concentration. There was no difference in the affinities of receptors in membranes of obese and normal-weight subjects; Kd values of all patients averaged 3.3 nM. Bmax values were 54 and 130 fmol/mg of protein in membranes prepared from seven obese and five control patients respectively. The Bmax values calculated per mg of protein correlated with BMI at r = -0.539 (P = 0.047). The adenosine content of adipose tissue was higher in obese than in control subjects. These results demonstrate an attenuated response of cyclic AMP accumulation, adenylate cyclase and glucose uptake to adenosine in fat-cells prepared from obese subjects, and suggest that this change is at least partly due to changes in the amount of adenosine receptors, but not their affinity. The decreased receptor number could be due to higher adenosine content. A higher adenosine concentration in adipose tissue could explain why lipolysis is inhibited in situ in obesity, and the desensitization could explain the diminished response to adenosine analogues in isolated fat-cells.
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PMID:Attenuated adenosine-sensitivity and decreased adenosine-receptor number in adipocyte plasma membranes in human obesity. 165 38

Quantitative autoradiography was used to investigate the effects of Mg2+ on agonist and antagonist binding to A1 receptors in rat striatum. A1 receptors were labelled with the selective agonist N6-[3H]cyclohexyladenosine ([3H]CHA) or the selective antagonist 1,3-[3H]dipropyl-8-cyclopentylxanthine ([3H]DPCPX). Mg2+ had no significant effect on equilibrium binding constants for [3H]CHA [control: KD (95% confidence interval) of 0.34 (0.15-0.80) nM and Bmax of 267 +/- 8 fmol/mg of gray matter; with 10 mM Mg2+: KD of 0.8 (0.13-4.9) nM and Bmax of 313 +/- 8.9 fmol/mg of gray matter] or [3H]DPCPX [control: KD of 0.54 (0.30-0.99) nM and Bmax of 256 +/- 2.3 fmol/mg of gray matter; with 10 mM Mg2+: KD of 1.54 (0.2-11.0) nM and Bmax of 269 +/- 35.7 fmol/mg of gray matter]. In contrast, Mg2+ slowed the apparent association rate for both ligands; this was observed as a shift from a one-component to a two-component model for [3H]DPCPX. Mg2+ also affected the dissociation rates of both ligands; for [3H]CHA, dissociation in the presence of Mg2+ was not detected. Mg2+ produced a concentration-dependent inhibition of [3H]CHA binding only prior to equilibrium. HPLC was performed on untreated sections, sections preincubated with adenosine deaminase (ADA), and sections preincubated with ADA and incubated with ADA in the absence or presence of Mg2+. Adenosine was found in measurable quantities under all conditions, and the concentration was not influenced by Mg2+ or by the inclusion of GTP in the preincubation medium. From these data, we conclude the following: (a) adenosine is present and may be produced continuously in brain sections; (b) ADA is not capable of completely eliminating the produced adenosine; (c) Mg2+ apparently does not influence adenosine production or elimination; (d) A1 receptor-guanine nucleotide binding protein coupling is maximal in this preparation; and (e) Mg2+ decreases the dissociation rate of bound endogenous adenosine from A1 receptors, thus limiting the access of [3H]CHA and [3H]DPCPX to the receptors. Thus, enhancement of endogenous adenosine binding to A1 receptors by Mg2+ is a complicating factor in receptor autoradiography and may be so in other preparations as well.
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PMID:Magnesium-dependent enhancement of endogenous agonist binding to A1 adenosine receptors: a complicating factor in quantitative autoradiography. 173 1

The effects of 5-amino-4-imidazolecarboxamide riboside (rAICA) on coronary adenosine efflux were examined in blood-free perfused working rat heart preparations subjected to mild (70% O2) and severe hypoxia (45% O2). Under these hypoxic conditions, no significant increase of coronary adenosine effluxes was observed in the presence of 300 microM rAICA alone. However, rAICA-induced augmentation of coronary adenosine efflux during hypoxia was revealed in the presence of an adenosine deaminase inhibitor, erythro-(2-hydroxy-3-nonyl)adenine hydrochloride, indicating that the failure to note the increase in coronary adenosine efflux was due to a rapid deamination of adenosine to inosine. A depression in heart rate during mild and severe hypoxia was significantly exacerbated by rAICA. These effects on heart rate were mediated by adenosine, since they were effectively blocked by 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine, a selective adenosine A1-receptor antagonist. These results suggest that rAICA elevates adenosine efflux during hypoxia.
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PMID:5-Amino-4-imidazolecarboxamide riboside raises adenosine in perfused hypoxic rat heart. 180 58

This study was designed to evaluate the role of adenosine and adenosine receptors in the reactive (RH) and functional hyperemia (FH) in rat gut. Experiments were performed on anesthetized rats. Mesenteric blood flow was measured with a pulsed Doppler flowmeter. We also determined the duration of reactive hyperemia, excess volume of blood flow above control value and maximal increase in mesenteric vascular conductance during both hyperemic responses. Data were collected following release from occlusions lasting 30, 60 and 120 sec. Functional hyperemia was induced by perfusion of the gut with a solution. Studied parameters were obtain before and after adenosine deaminase (ADA) and two adenosine receptor antagonists: 8-phenyltheophylline (8-PT) and 1.3-dipropyl-7-methyl-xanthine (DPMX). In fasted rats ADA and 8-PT reduced of RH after each period of occlusion and DPMX was ineffective in reducing any parameter of RH. In fed rats control mesenteric blood flow was increased. ADA, 8-PT, and DPMX were more effective inhibitors of RH and FH. Above findings suggest that adenosine play a role in the modulation of RH and FH acting on A2 subtype receptors.
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PMID:[Role of adenosine in functional and reactive intestinal hyperemia]. 184 31

Adenosine has been shown in vitro to be a potent antilipolytic agent and an inhibitor of insulin-stimulated glucose utilization in skeletal muscle. To test whether endogenously produced adenosine (e.g., from ATP hydrolysis) shares these deleterious effects on substrate mobilization and utilization and thus limits maximum thermogenesis in vivo, adenosine deaminase (converts adenosine to inosine) was given to rats 15 min before cold exposure. Significant (P less than 0.05) increases in thermogenesis were observed under both well-fed (100 units/kg ip) and food-rationed (200 units/kg ip) states. Significant (P less than 0.05) increases in thermogenesis and cold resistance were also observed after pretreatment with selective adenosine receptor antagonists [8-cyclopentyltheophylline (1 microgram/kg ip) greater than 1,3-dipropyl-8-p-sulfophenylxanthine (1.25 mg/kg ip) greater than aminophylline (18.7 mg/kg ip)], indicating an A1-receptor-mediated effect. These results indicate that endogenously released adenosine can indeed attenuate the thermogenic capacity in severe cold and that adenosine antagonists, especially those selective for A1-receptor, are useful in improving cold resistance under varying nutritional states.
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PMID:Enhancement of maximal thermogenesis by reducing endogenous adenosine activity in the rat. 231 70

The purpose of this study was to test the hypothesis that endogenous adenosine functions to restrain the renin release response to pharmacological and pathophysiological stimuli. To achieve this objective, we examined the effects of an adenosine receptor antagonist, 1,3-dipropyl-8-(p-sulfophenyl)xanthine (DPSPX), on the renin release response induced by acute administration of hydralazine or by chronic clipping of the left renal artery (renovascular hypertensive rats). In conscious, unrestrained rats, DPSPX significantly increased plasma renin activity (PRA) in control rats, in rats treated with hydralazine, and in renovascular hypertensive rats. The effect of DPSPX on PRA was significantly greater in rats treated with hydralazine or in renovascular hypertensive rats compared with control rats. DPSPX did not influence arterial blood pressure in any group, did not affect the measurement of PRA, and did not alter the elimination of renin activity from the circulation. Additional experiments were performed in the in situ autoperfused kidney so that the effects of DPSPX on renal hemodynamics and renal excretory function could be assessed. In this experimental model, DPSPX also increased PRA in hydralazine-treated rats and in renovascular hypertensive rats without affecting arterial pressure, renal blood flow, or sodium excretion. In a final set of studies in conscious, unrestrained rats, adenosine deaminase increased PRA in a dose-dependent manner in hydralazine-treated rats and significantly increased the slope of the relation between PRA and the depressor response to hydralazine. We conclude: 1) Although the kidney has both A1 and A2 adenosine receptors mediating inhibitory and stimulatory actions, respectively, on renin release, the dominant effect of endogenous adenosine on renin release is inhibitory. 2) Even under basal physiological conditions, endogenous adenosine tonically inhibits renin release. 3) This inhibitory effect is augmented whenever the renin-angiotensin system is stimulated regardless of the approach used to activate renin release. 4) Endogenous adenosine negatively modulates renin release by a direct effect on juxtaglomerular cells.
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PMID:Endogenous adenosine restrains renin release in conscious rats. 240 69

1. The effects of several drugs, including antagonists of vasoactive intestinal peptide (VIP), and antisera to VIP or peptide histidine isoleucine (PHI), on relaxation responses of guinea-pig isolated trachea to electrical field stimulation (EFS) have been examined. 2. beta-Adrenoceptor blockade with propranolol only partially blocked the inhibitory response to EFS, but had no effect in tissues from animals pretreated with 6-hydroxydopamine or reserpine. 3. Neither adenosine deaminase, in the presence of dipyridamole, nor the potent adenosine antagonist NPC205 (1,3-n-dipropyl-8-(4-hydroxyphenyl)-xanthine) had any effect on the inhibitory response to EFS. 4. The VIP antagonists, [Ac-Tyr1, D-Phe2]-GRF(1-29)-NH2 and [4-Cl-D-Phe6, Leu17]-VIP had no effect on the inhibitory response to EFS. Moreover, they were without effect on responses to exogenous VIP or PHI. 5. Overnight incubation with VIP antisera markedly reduced the inhibitory response to EFS. PHI antisera had a similar, but smaller effect. 6. In the presence of a concentration of VIP that is maximal for its relaxant effect, inhibitory responses to electrical stimulation were greatly inhibited. 7. Naloxone and reactive blue 2 each had no effect on inhibitory responses indicating that endogenous opioids and adenosine 5'-triphosphate (ATP) respectively are not involved. 8. The results suggest that VIP and PHI, but not adenosine, contribute to non-adrenergic, noncholinergic inhibitory nerve responses of guinea-pig trachea. Moreover, the surprising lack of effect of both VIP antagonists on these responses, and in particular, on responses to exogenous VIP, suggests that the receptors mediating VIP-induced tracheal relaxation are different from those that mediate pancreatic secretion.
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PMID:The effects of vasoactive intestinal peptide (VIP) antagonists, and VIP and peptide histidine isoleucine antisera on non-adrenergic, non-cholinergic relaxations of tracheal smooth muscle. 272 Feb 90

The effects of intracarotid (i.c.) infusions of the adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and of the adenosine uptake blocker, dipyridamole on spontaneous ventilation were studied in rats anaesthetized with sodium pentobarbitone. Both EHNA and dipyridamole mimicked the excitatory effect of adenosine on respiration increasing in a dose-dependent manner respiratory ventilation determined as increases in tidal volume (VT), respiratory frequency (f) and minute volume (VE). These excitatory effects were abolished after section of the carotid sinus nerves. The excitatory effect of EHNA on respiration was prevented by adenosine deaminase and antagonized by 1,3-dipropyl-8(p-sulfophenyl)xanthine (DPSPX). DPSPX also antagonized the excitatory effect of dipyridamole on respiration. Both EHNA and dipyridamole in doses virtually devoid of effect on respiration potentiated the excitatory effect of exogenous adenosine on respiration. Two different effects on respiration were observed during i.c. infusions of cumulative doses of DPSPX: one inhibitory, not present in glomectomized animals and another, excitatory, present in both glomectomized and non-glomectomized animals. It is concluded that endogenous adenosine could be involved in respiration mediated through carotid body chemoreceptors and that the nucleoside is inactivated at this level by deamination and uptake.
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PMID:Adenosine deaminase and adenosine uptake inhibitions facilitate ventilation in rats. 281 35

Previous studies have shown that activation of A1 and A2 adenosine receptors leads to inhibition and stimulation respectively of renin secretion by rat renal cortical slices. In the present studies, rat renal cortical slices were incubated in the presence of adenosine deaminase, to destroy any adenosine released from the preparation. N6-cyclohexyladenosine (CHA) had a biphasic effect on renin secretion: submicromolar concentrations inhibited concentration-dependently, and there was an inflection in the dose-response curve near 1 microM CHA such that higher concentrations produced a concentration-dependent relative stimulation, which became an absolute stimulation (i.e., secretory rate was higher than control) at 50 microM. These findings are consistent with A1 and A2 adenosine receptor-mediated inhibition and stimulation of renin secretion, respectively. Xanthine amine congener ["XAC," 8-(4-((2-aminoethyl)-aminocarbonylmethyloxy)phenyl-1,3-dipropyl xant hine] has been shown by others to be a very potent adenosine receptor antagonist with selectivity for A1 receptors. It antagonized both CHA-induced inhibition (Ki approximately 2 x 10(-9) M) and CHA-induced stimulation (Ki approximately 5 x 10(-8) M) of renin secretion. Thus, XAC exhibited a 25-fold selectivity for CHA-induced inhibition of renin secretion in comparison with CHA-induced stimulation. In comparison with previous results, XAC is approximately 3 orders of magnitude more potent than theophylline. In conclusion, occupation of adenosine receptors can lead either to inhibition (A1 receptor-mediated) or stimulation (A2 receptor-mediated) of renin secretion, and XAC is a very potent and selective antagonist of CHA-induced changes in renin secretion.
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PMID:XAC, a functionalized congener of 1,3-dialkylxanthine, antagonizes A1 adenosine receptor-mediated inhibition of renin secretion in vitro. 332 70


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