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)

Responses to norepinephrine (NE) before and after treatment with adenosine deaminase (ADA) were examined in anesthetized dogs. In four dogs repeatable changes in coronary blood flow, myocardial oxygen extraction and consumption, left ventricular +dP/dtmax, and heart rate (HR) were demonstrated during two successive intracoronary infusions of 0.13 micrograms.kg-1.min-1 NE. In eight dogs, the NE-induced hyperemia was decreased from +150 to +67%, the change in myocardial oxygen consumption (MVo2) was attenuated from +177 to +101% by ADA, and the increase in HR was reduced from +28 to +16%. In six dogs, the increase in HR caused by NE before ADA was maintained after ADA by atrial pacing. The NE-induced hyperemia and the increase in MVo2 were again decreased by ADA. Similar results were observed in 12 other dogs with hearts paced at a constant, elevated rate during control as well as during both infusions of NE. In all groups, the O2 extraction response to increased MVo2 increased and the flow response decreased after ADA. In six dogs nitroprusside was infused during NE after ADA. When coronary flow was restored to the same level observed before deaminase, MVo2 was not diminished. These results support a role for adenosine in the coronary functional hyperemia accompanying NE activation of the canine myocardium.
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PMID:Adenosine deaminase attenuates norepinephrine-induced coronary functional hyperemia. 334 22

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 +/- 7 to 39 +/- 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5-20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 +/- 6 to 62 +/- 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increase of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.
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PMID:Role of adenosine in coronary vasodilation during exercise. 334 77

Adenosine is an important regulatory molecule that increases in hypoxic and ischemic tissues and has been proposed to mediate blood flow in response to oxygen availability. The current study ascribes another oxygen-responsive role to adenosine, that of regulating synthesis of the erythropoiesis-stimulating hormone, erythropoietin. When perfused through isolated rat kidneys, exogenous adenosine in nanomolar concentrations increased erythropoietin production, whereas inosine, the deaminated nucleoside, had no effect. In addition, an adenosine antagonist, and adenosine deaminase, diminished erythropoietin titers in renal perfusates. In intact rats, adenosine deaminase injections followed by a hypoxic stimulus slightly reduced erythropoietin serum concentrations, whereas an adenosine deaminase inhibitor sharply increased erythropoietin titers. The results suggest that adenosine may function as a mediator to link oxygen supply with erythropoietin production.
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PMID:Modulation of erythropoietin production by adenosine. 339 22

We have determined 15N isotope effects and solvent deuterium isotope effects for adenosine deaminase using both adenosine and the slow alternate substrate 7,8-dihydro-8-oxoadenosine. With adenosine, 15N isotope effects were 1.0040 in H2O and 1.0023 in D2O, and the solvent deuterium isotope effect was 0.77. With 7,8-dihydro-8-oxoadenosine, 15N isotope effects were 1.015 in H2O and 1.0131 in D2O, and the solvent deuterium isotope effect was 0.45. The inverse solvent deuterium isotope effect shows that the fractionation factor of a proton, which is originally less than 0.6, increases to near unity during formation of the tetrahedral intermediate from which ammonia is released. Proton inventories for 1/V and 1/(V/K) vs percent D2O are linear, indicating that a single proton has its fractionation factor altered during the reaction. We conclude that a sulfhydryl group on the enzyme donates its proton to oxygen or nitrogen during this step. pH profiles with 7,8-dihydro-8-oxoadenosine suggest that the pK of this sulfhydryl group is 8.45. The inhibition of adenosine deaminase by cadmium also shows a pK of approximately 9 from the pKi profile. Quantitative analysis of the isotope effects suggests an intrinsic 15N isotope effect for the release of ammonia from the tetrahedral intermediate of approximately 1.03 for both substrates; however, the partition ratio of this intermediate for release of ammonia as opposed to back-reaction is 14 times greater for adenosine (1.4) than for 7,8-dihydro-8-oxoadenosine (0.1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence from nitrogen-15 and solvent deuterium isotope effects on the chemical mechanism of adenosine deaminase. 342 79

The 13C NMR spectra of [2-13C]- and [6-13C]purine ribosides have been obtained free in solution and bound to the active site of adenosine deaminase. The positions of the resonances of the bound ligand are shifted relative to those of the free ligand as follows: C-2, -3.7 ppm; C-6, -73.1 ppm. The binary complexes are in slow exchange with free purine riboside on the NMR time scale, and the dissociation rate constant is estimated to be 13.5 s-1 from the slow exchange broadening of the free signal. In aqueous solution, protonation of purine riboside at N-1 results in changes in 13C chemical shift relative to those of the free base as follows: C-2, -4.9 ppm; C-6, -7.9 ppm. The changes in chemical shift that occur when purine riboside binds to the enzyme indicate that the hybridization of C-6 changes from sp2 to sp3 in the binary complex with formation of a new bond to oxygen or sulfur. A change in C-2 hybridization can be eliminated as can protonation at N-1 as the sole cause of the chemical shift changes. The kinetic constants for the adenosine deaminase catalyzed hydrolysis of 6-chloro- and 6-fluoropurine riboside have been compared, and the reactivity order implies that carbon-halogen bond breaking does not occur in the rate-determining step. These observations support a mechanism for the enzyme in which formation of a tetrahedral intermediate is the most difficult chemical step. Enzymic stabilization of this intermediate may be an important catalytic strategy used by the enzyme to lower the standard free energy of the preceding transition state.
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PMID:Adenosine deaminase converts purine riboside into an analogue of a reactive intermediate: a 13C NMR and kinetic study. 344 68

The possibility that endogenously released adenosine, a potent vasodilator, is involved in the increase in cerebral blood flow (CBF) response to hypercapnia has been investigated in an anesthetized, paralyzed rat model. The left retroglenoid vein was cannulated and cerebral venous blood flow measured with a drop counter. Animals were ventilated with a 40% oxygen, 60% nitrogen gas mixture. At 20 min intervals, at a constant rate of flow, the inspired gas mixture was altered to 10% carbon dioxide, 40% oxygen, 50% nitrogen for periods of between 30-90 sec. This brief hypercapnic challenge induced a rapid increase in CBF in the absence of any change in MABP. An involvement of adenosine in this response was demonstrated using an adenosine antagonist, caffeine, an uptake inhibitor, dipyridamole and an adenosine deaminase inhibitor, deoxycoformycin. Caffeine (10 and 20 mg/kg i.p.) 15 min prior to hypercapnic challenges significantly decreased the peak increases in CBF. Dipyridamole (0.1 mg/kg) and deoxycoformycin (0.1 microgram/kg) enhanced the peak increases in flow. These results are consistent with an important role for adenosine in coupling PCO2 to cerebral blood flow.
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PMID:An involvement of adenosine in cerebral blood flow regulation during hypercapnia. 349 49

A study was designed to test the hypothesis that endogenous adenosine concentration may increase during episodes of rapid ventricular pacing and, by virtue of its negative chronotropic effects, contribute to the transient suppression of automaticity that follows the period of overdrive. Isolated, perfused, rat ventricular preparations were subjected to periods of 6.0 Hz overdrive stimulation while adenosine release, oxygen consumption, and subsequent suppression of automaticity were measured. At the end of a 1 min episode of overdrive oxygen consumption and adenosine release were significantly increased, and the initial beating rate after 1 min overdrive was suppressed. At the end of 10 min overdrive oxygen consumption was still increased but adenosine release had returned to control values. Suppression of automaticity after 10 min overdrive was similar to that after 1 min overdrive. The relative magnitude of suppression after 1 min overdrive was decreased by theophylline (10(-4) mol.litre-1), and increased by the adenosine deaminase inhibitor, EHNA (10(-5) mol.litre-1). Neither theophylline nor EHNA had any discernible influence on suppression after 10 min overdrive. It its therefore concluded that endogenous adenosine may contribute to the suppression of ventricular automaticity that follows a 1 min episode of overdrive, but because of the transient nature of the increase in adenosine during overdrive endogenous adenosine does not contribute to the suppression that follows prolonged overdrive.
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PMID:Transient increase in release of adenosine during rapid cardiac pacing; transient effects on overdrive suppression of ventricular automaticity. 365 5

To test the hypothesis that adenosine is required to mediate the coronary vasodilative response to acute hypoxia haemodynamic indices, regional myocardial blood flow, and oxygen and lactate metabolism were measured in nine closed chest anaesthetised domestic swine at control, after 3-5 min of 100% nitrogen inhalation, at second control, and after 3-5 min of 100% nitrogen inhalation plus adenosine deaminase infusion in the left anterior descending coronary artery. Cardiac lymph adenosine deaminase concentration was also measured in a separate group of four animals previously reported on. Heart rate was held constant by atrial pacing during the study. Aortic mean pressure did not change. Changes in arterial and anterior interventricular vein pH, PO2, PCO2, and oxygen content were similar for each intervention. Transmural left anterior descending artery zone flow increased significantly (p less than 0.01) compared with control (1.22(0.23) ml.min-1.g-1; mean(SD)) in response to hypoxia (2.73(0.92)). Intracoronary adenosine deaminase infusion (167 nmol.s-1), however, failed to blunt the flow response to hypoxia (1.33(0.30) to 2.79(1.32); second control to hypoxia plus adenosine deaminase respectively, p less than 0.01). Mean adenosine deaminase activity (nmol.s-1) in cardiac lymph was 105(85) at the end of 10 min of intracoronary infusion (167 nmol.s-1) and 203 (148) nmol.s-1 at the end of 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of adenosine in mediating the coronary vasodilative response to acute hypoxia. 366 45

This study examined the role of adenosine in regulating coronary arteriolar tone under basal conditions in the normal coronary circulation. Measurements of hemodynamics and flow (microspheres) were made in eight closed-chest, sedated pigs at 1) control and 2) after 10 min of infusion of adenosine deaminase (ADA, 10 U X kg-1 X min-1) into the left anterior descending (LAD) coronary artery. Heart rate was held constant by atrial pacing. Transmural flow in the distal LAD zone did not change versus control (1.81 +/- 0.36) with ADA (1.78 +/- 0.46). However, in comparison with control the distal LAD:circumflex zone transmural flow ratio (0.96 +/- 0.04) declined (P less than 0.01) during ADA infusion (0.93 +/- 0.04). Similarly, the distal LAD:circumflex zone transmural flow resistance ratio increased significantly (P less than 0.01) versus control (1.04 +/- 0.05) in response to intracoronary ADA infusion (1.08 +/- 0.04). Regional myocardial oxygen consumption in the distal LAD zone did not change versus control (16.9 +/- 3.3 3.3 ml X min-1 X 100 g-1) during ADA (16.9 +/- 4.5). Additional studies in 15 open-chest swine given intracoronary infusion of ADA demonstrated that 1) the enzyme penetrates the interstitial fluid (ISF) and 2) attains ISF levels which are adequate to reduce basal adenosine concentration 10 fold even if substantial increase in adenosine production occurs in response to ADA. Thus, since destruction of adenosine by ADA caused only very modest relative reduction in regional flow, it is likely that the nucleoside plays only a limited role in regulation of arteriolar tone under basal conditions in the normal coronary circulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine's role in regulating basal coronary arteriolar tone. 371 57

To test the hypothesis that adenosine is required to mediate the sustained increase in myocardial flow evoked by isoproterenol haemodynamic indices, myocardial blood flow (microspheres), and regional myocardial oxygen consumption were measured in eight closed chest, sedated pigs at control, after isoproterenol (6.9(2.8) ng X kg-1 X min-1 (mean (SD)) infused into the left anterior descending coronary artery, repeat control, and after a simultaneous infusion of the same dose of isoproterenol and adenosine deaminase (10 U X kg-1 X min-1). Data were acquired at one and 10 minutes after each infusion and compared with control measurements. Heart rate was held constant by atrial pacing. Peak left ventricular dP/dt (mm Hg X s-1) increased significantly (control 2190(32) mean (SD)) at both one (2900(302)) and 10 minutes (3010(391)) of isoproterenol infusion alone. At one minute of simultaneous infusion there was no change (control 1970(447)) in left ventricular dP/dt (2290(521)), although dP/dt was significantly increased at 10 minutes of simultaneous infusion (2790(483)). Transmural flow (ml X min-1 X g-1) increased significantly (control 1.49(0.46)) in the distal left anterior descending zone at one (1.94(0.48)) and 10 minutes (2.07(0.27)) of isoproterenol infusion alone. In contrast, flow failed to increase (control 1.65(0.27)) during the first minute of simultaneous infusion (1.73(0.38)), although it did increase significantly by 10 minutes (1.91(0.21). Finally, although myocardial oxygen consumption (ml X min-1 X 100 g-1) increased significantly (control 16.4(4.7)) at both one (20.1(4.7)) and 10 minutes (19.4(3.6)) of isoproterenol infusion alone, it failed to increase (control 18.2(3.8)) at one (19.3(4.6)) and 10 minutes (19.1(3.8)) of simultaneous infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of adenosine in mediating myocardial blood flow response to isoproterenol: observations in closed chest, sedated, domestic swine. 377 47


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