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)

Coronary autoregulation appears to be closely coupled to myocardial oxidative metabolism. Recent data suggest that coronary autoregulation depends on the prevailing balance between myocardial oxygen supply and demand. It seems likely that pO2 within a critical range may be the initial metabolic stimulus for coronary autoregulation. Whether adjustments in vascular resistance result from changes in myocardial pO2 directly or indirectly through changes in vasoactive metabolites remains unclear. The observation that intracoronary infusion of adenosine deaminase in concentrations sufficient to attenuate myocardial reactive hyperemia has no effect on coronary autoregulation strongly suggests that adenosine is not essential for autoregulation in the blood-perfused dog heart. This is supported by the recent finding that the interstitial concentration of adenosine (estimated from epicardial exudate) remained unchanged during autoregulation. Prostaglandins may play a role in autoregulation in buffer-perfused rabbit hearts but do not appear to be involved in blood-perfused dog hearts. Potassium is probably not involved in autoregulation. It is also unlikely that changes in tissue pressure can account for coronary autoregulation. The role of adenine nucleotides, hydrogen ion, carbon dioxide, and intermediate metabolites of the citric acid cycle, in coronary autoregulation has not been examined. The possibility that a myogenic mechanism contributes to coronary autoregulation has not been directly tested. Finally, it is entirely possible that coronary autoregulation may result from the concerted interaction of several different mediators or mechanisms. In this regard, it should be emphasized that blocking or destroying one mediator could elicit a compensatory increase in the contribution of another.
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PMID:Autoregulation of the coronary circulation. 380 16

In potassium-depolarized guinea-pig left atria treated with isoproterenol, calcium entry blocking activities of adenosine and its potentiating compounds, dipyridamole, lidoflazine and dilazep were studied and compared to verapamil and diltiazem. pA2 values for various drugs were calculated using concentration-response curves for calcium (parallel shift to the right). The order of potency for the calcium entry blocking effect was: verapamil greater than diltiazem greater than adenosine greater than lidoflazine = dilazep greater than dipyridamole. Adenosine caused negative inotropic effects in depolarized left atria. The negative inotropic effect of adenosine was very quick in onset and was potentiated by erythro-6-amino-9(2-hydroxy-3-nonyl)-purine hydrochloride (EHNA), an adenosine deaminase inhibitor, suggesting that adenosine was being degraded. The effect of adenosine was quickly abolished by adenosine deaminase (ADA) and antagonized by 8-phenyltheophylline (8-PT), suggesting that the action of adenosine was most likely through the surface membrane receptor sites. The negative inotropic effects of dilazep and dipyridamole were only partially reversed by ADA and 8-PT, while that of lidoflazine was not affected by these agents. These findings suggest that the mechanism(s) of negative intotropic effect of lidoflazine was different from that of dilazep and dipyridamole. These data suggest that the negative intropic effect of dilazep is most likely due to a direct calcium entry blocking effect and in part due to its adenosine potentiating effect. However, the calcium entry blocking effect of lidoflazine is independent of adenosine.
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PMID:Calcium entry blocking activity of dilazep and other adenosine potentiating compounds in guinea-pig atria. 395 77

The present study was undertaken to demonstrate and characterize potentiation of ventricular overdrive suppression by adenosine. To substantiate that adenosine has an enhanced effect on overdrive suppression, it would be necessary to demonstrate that adenosine increases pause duration independent of slowing spontaneous pre-drive rate. In isolated perfused guinea pig hearts with surgically induced complete atrioventricular block, the effect of adenosine (2-20 microM) on pause duration was compared to two alternative means of slowing the pre-drive rate, i.e., hypothermia (28.0 degrees C to 34.0 degrees C) and cesium chloride (0.3-1.0 mM). The slope value of the linear regression line describing the relationship between pre-drive cycle length and pause duration for adenosine (15.8) was significantly greater than control (1.7), hypothermia (1.7), and cesium chloride (5.4). The competitive adenosine antagonist, aminophylline (60 microM), when infused at the initiation of overdrive during adenosine administration, significantly reduced the effect of adenosine on pause duration by 72.9 +/- 4.2% (mean +/- SEM). The reduction in pause duration by aminophylline was specific for adenosine and did not occur under control conditions or during cesium chloride administration. During hypoxia, aminophylline and adenosine deaminase, when infused at the initiation of overdrive, caused 72.3 +/- 5.6 and 63.3 +/- 6.1% reductions in pause duration, respectively. Endogenous adenosine levels rose significantly with hypoxia (1,687 +/- 202 vs. 36 +/- 4 pmol/min per g during normoxia) and increased significantly further during hypoxic overdrive (3,004 +/- 323 pmol/min per g). In isolated guinea pig Purkinje fibers (n = 4), adenosine (20 microM) increased pause duration by 73.6 +/- 9.9% while only minimally affecting the pre-drive cycle length (7.6 +/- 3.8%). These fibers, when stimulated at 1.5 Hz, also displayed an adenosine-induced reduction in action potential duration at 90% repolarization (16 +/- 2 msec). In addition, we demonstrated that adenosine had an enhanced effect on pause duration in the presence of ouabain (1 microM)-induced attenuation of overdrive suppression. Thus, in isolated Purkinje fibers, it is unlikely that the potentiating effect of adenosine on pause duration, which is independent of its chronotropic effect, is mediated via an enhancement of sodium potassium adenosine triphosphatase pump activity. The effect of adenosine is likely to be secondary to a direct action on outward potassium conductance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of adenosine on ventricular overdrive suppression in isolated guinea pig hearts and Purkinje fibers. 404 82

The synthesis of fluorescent derivatives of nucleosides and nucleotides, by reaction with isatoic anhydride in aqueous solution at mild pH and temperature, yielding their 3'-O-anthraniloyl derivatives, is here described. The N-methylanthraniloyl derivatives were also synthesized by reaction with N-methylisatoic anhydride. Upon excitation at 330-350 nm these derivatives exhibited maximum fluorescence emission at 430-445 nm in aqueous solution with quantum yields of 0.12-0.24. Their fluorescence was sensitive to the polarity of the solvent; in N,N-dimethylformamide the quantum yields were 0.83-0.93. The major differences between the two fluorophores were the longer wavelength of the emission maximum of the N-methylanthraniloyl group and its greater quantum yield in water. All anthraniloyl derivatives, as well as the N-methylanthraniloyl ones, had virtually identical fluorescent properties, regardless of their base structures. The ATP derivatives showed considerable substrate activity as a replacement of ATP with adenylate kinase, guanylate kinase, glutamine synthetase, myosin ATPase and sodium-potassium transport ATPase. The ADP derivatives were good substrates for creatine kinase and glutamine synthetase (gamma-glutamyl transfer activity). The GMP and adenosine derivatives were substrates for guanylate kinase and adenosine deaminase, respectively. All derivatives had only slightly altered Km values for these enzymes. While more fluorescent in water, the N-methylanthraniloyl derivatives were found to show relatively low substrate activities against some of these enzymes. The results indicate that these ribose-modified nucleosides and nucleotides can be versatile fluorescent substrate analogs for various enzymes.
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PMID:New ribose-modified fluorescent analogs of adenine and guanine nucleotides available as substrates for various enzymes. 613 22

The concept of limiting irreversible damage due to ischemic arrest by inhibiting nucleoside breakdown was tested in the isolated perfused rat heart. Functional recovery measurements were combined with continuous high-energy phosphate measurements by means of 31P nuclear magnetic resonance (NMR) and with nucleoside release measurements in the reperfusion period. The adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and 2'-deoxycoformycin (DCF) were given 5 min before ischemia and for the first 5 min of reperfusion. These treated groups were compared with a control, untreated group. These were further compared with a group of hearts arrested with potassium and to a group combining potassium arrest and EHNA. It was found that all treated groups recovered mechanical function significantly better than the untreated group. DCF, K+, and K+ + EHNA slowed ATP decline and resulted in better ATP recovery than untreated or EHNA-treated, and all treatments decreased nucleoside base release. Intracellular pH fell equally in all groups and recovered to preischemic values. Thus, these adenosine deaminase inhibitors improve functional recovery following ischemia, although this improvement was not well correlated with purine losses observed during reperfusion.
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PMID:Effect of adenosine deaminase inhibitors on the heart's functional and biochemical recovery from ischemia: a study utilizing the isolated rat heart adapted to 31P nuclear magnetic resonance. 619 52

Adenosine and ATP depressed resting O2 uptake in frog sartorius. This action was blocked by low levels of caffeine and by 8-phenyltheophylline. It was mimicked by a polymer of adenosine. Adenosine also decreased radioactive calcium uptake in muscles. Potassium and magnesium content were increased while sodium and calcium content were decreased by adenosine. Adenosine did not decrease oxygen uptake in muscles from frogs sacrificed in winter months. However, adenosine deaminase, which inactivates adenosine by removing the amino group, increased oxygen uptake, calcium content and lactate release of these muscles. Our results suggest that adenosine reduces resting metabolism, possibly through reducing passive leaks of electrolytes.
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PMID:Effect of adenosine on oxygen uptake and electrolyte content of frog sartorius muscle. 697 47

The change in transmembrane potential of rat adipocytes was measured using the fluorescent probe 3,3'-diethylthiadicarbocyanine iodide, diS-C2-(5). The method was calibrated by altering the potassium ion concentration while keeping the sum of potassium and sodium ions at a constant concentration of 153 mM (Bailey et al: Bioelectrochem. Bioenergetics 21:333-42, 1989). Two insulin-mimetic agents, phospholipase C from Clostridium perfringens and concanavalin A, induced a dose dependent hyperpolarization of rat epididymal adipocytes, like insulin. Removal of endogenous adenosine with adenosine deaminase or adenosine receptor blockade with isobutylmethylxanthine following the initiation of insulin-induced hyperpolarization resulted in depolarization. These same agents induced hyperpolarization of -6 to -8 mV when added without insulin. The replacement of adenosine with its analogue, N6-phenylisopropyladenosine, plus insulin depolarized the cells toward the transmembrane potential established by insulin, -2.0 mV. These studies suggest that adenosine receptor occupancy is required to maintain insulin-induced hyperpolarization.
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PMID:Membrane potential of rat adipocytes: effect of phospholipase C, concanavalin A, and adenosine. 751 7

Short-term hibernating myocardium is characterized by reduced contractile function during persistent ischemia, the recovery of metabolism over time, a recruitable inotropic reserve, and the lack of necrosis. The mechanisms underlying myocardial hibernation are unclear. The present study addressed the role of endogenous adenosine and that of activation of ATP-dependent potassium (KATP) channels. In 22 enflurane-anesthetized swine, coronary inflow was reduced to decrease regional myocardial work (W, measured by sonomicrometry) by 60-70% at 5 min of ischemia; this flow reduction has previously been shown to be compatible with the development of myocardial hibernation. Systemic hemodynamics, W, subendocardial blood flow (measured by microspheres), and the myocardial creatine phosphate content (measured by biopsies, mumol/g wet wt) were measured under control conditions and during 90 min of ischemia, with an intracoronary dobutamine infusion during the last 5 min of ischemia. The impact of endogenous adenosine was eliminated by infusion of intracoronary adenosine deaminase (ADA), and the impact of activation of KATP channels by glibenclamide. Creatine phosphate content recovered in the placebo-treated swine (n = 8, 3.8 +/- 1.9 to 5.8 +/- 2.0 mumol/g wet wt) as well as in swine receiving ADA (n = 7, 4.1 +/- 1.2 to 6.0 +/- 1.7 mumol/g wet wt) or glibenclamide (n = 7, 2.8 +/- 1.3 to 6.7 +/- 1.6 mumol/g wet wt) when ischemia was prolonged from 5 to 85 min. At the end of 90 min of ischemia, W increased during intracoronary dobutamine in all three groups to a comparable extent, and myocardial necrosis was absent in all three groups of swine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regional short-term myocardial hibernation in swine does not involve endogenous adenosine or KATP channels. 761 80

1. An eye-cup preparation in anaesthetized rabbits was used to examine opioid modulation of acetylcholine (ACh) release from cholinergic neurones in the retina. 2. The mu-opioid receptor agonist, [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO), when applied locally to the retina at concentrations between 1-30 microM significantly increased the light-evoked release of ACh. The effect of DAMGO was completely blocked by the selective mu-receptor antagonist CTOP but the kappa-receptor antagonist nor-binaltorphimine (norBNI) did not affect the action of DAMGO on ACh release indicating that the opioid produced its effect by activation of mu-receptors (the rabbit retina has negligible delta-receptors). 3. Blockade with bicuculline and strychnine of GABAergic and glycinergic inputs to the cholinergic neurones did not affect the action of DAMGO on ACh release. Also DAMGO did not reduce the potassium-evoked release of either GABA or glycine from rat isolated retinas. 4. Exposure of the rabbit retina to a combination of an A1-adenosine receptor antagonist, 8-cyclopentyl-1,3 dipropylxanthine (DPCPX), and adenosine deaminase did not affect the enhancing action of DAMGO on the light-evoked release of ACh. 5. When the retina in the rabbit eye-cup was exposed to kainate, the release of ACh was increased by approximately three times the resting release. In the presence of DAMGO the kainate-evoked release of ACh was enhanced by 44%. 6. These experiments show that activation of mu-opioid receptors by DAMGO increases the release of ACh elicited by physiological stimulation (flickering light). Since we could find no evidence thatDAMGO reduces inhibitory inputs to the cholinergic neurones, it seems that the enhancing action ofDAMGO on the light-evoked release of ACh involves a direct excitatory effect rather than disinhibition.This conclusion is supported by the enhancing action of DAMGO on the kainate-evoked release of ACh because kainate is thought to act directly on the cholinergic neurones.
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PMID:Enhancement of retinal acetylcholine release by DAMGO: possibly a direct opioid receptor-mediated excitatory effect. 785 68

We previously reported that adenosine A1 receptor activation protects against the cardiodepressant effects of hydrogen peroxide in isolated rat hearts. The present study examined whether a transient ischemic period of 5 min duration, which preconditions the heart against ischemic and reperfusion-induced dysfunction, can bestow protection against 30-min exposure to hydrogen peroxide in isolated rat hearts. Transient ischemia on its own failed to alter the cardiac response to hydrogen peroxide. However, when transient ischemia was carried out in the presence of the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thioguanosine and the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-nonyl)adenine, a significant attenuation of the hydrogen peroxide-induced loss in contractility was evident and this was associated with significant preservation of tissue glycogen content. The protective effect of the transient ischemia/drug combination on both functional changes and glycogen levels was abolished by the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine as well as by glibenclamide, a blocker of the ATP-sensitive potassium channel (KATP). To further assess the role of glycogen in the protection against hydrogen peroxide, we compared the effects of the adenosine A1 agonist N6-cyclopentyl adenosine (CPA) and insulin. While both treatments protected against hydrogen peroxide the effect of insulin was superior to any other treatment. Moreover, while all protective modalities preserved glycogen stores after hydrogen peroxide treatment, the protection afforded by insulin was also associated with significantly elevated glycogen levels prior to hydrogen peroxide administration. No protection by either CPA or insulin was evident in the absence of exogenous glucose. Taken together, our results demonstrate that a brief period of ischemia with concomitant administration of agents which increase interstitial adenosine levels protects against hydrogen peroxide toxicity. The effect is mediated by activation of adenosine A1 receptors and is linked to KATP stimulation. Moreover, our results are strongly suggestive of an important role of glycogen preservation in bestowing protective effects against hydrogen peroxide cardiotoxicity.
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PMID:Transient ischemia in the presence of an adenosine deaminase plus a nucleoside transport inhibitor confers protection against contractile depression produced by hydrogen peroxide. Possible role of glycogen. 876 52


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