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Circulation Dec 1993Adenosine is well known to depress atrioventricular (AV) nodal conduction, but the potential interactions between adenosine and functional AV nodal properties have not... (Comparative Study)
Comparative Study
BACKGROUND
Adenosine is well known to depress atrioventricular (AV) nodal conduction, but the potential interactions between adenosine and functional AV nodal properties have not been explored. The purpose of the present study was to determine (1) whether exogenous adenosine modifies the rate-dependent properties of the AV node, (2) to what extent such changes underlie the actions of adenosine in an in vitro model of AV reentrant tachycardia (AVRT), and (3) the potential role of endogenous adenosine in rate-induced AV nodal responses.
METHODS AND RESULTS
The functional properties of AV nodal recovery (defining the conduction delay of a single premature activation), facilitation (effect of short cycles on subsequent nodal recovery), and fatigue (slowly developing AV nodal delay at a rapid rate) were studied selectively in isolated, superfused rabbit and guinea pig cardiac preparations. Exogenous adenosine increased AV nodal fatigue and attenuated facilitation, resulting in tachycardia-dependent increases in AH interval and AV nodal effective refractory period (AVERP). In experimental AVRT, adenosine caused greater increases in tachycardia cycle length (T) and AVERP as tachycardia rate increased. AVRT was sustained when AVERP/T was < 1, and adenosine suppressed AVRT by increasing the slope of the AVERP/T versus tachycardia rate relation, causing the critical ratio of 1 to be attained at slower rates. A mathematical model incorporating quantitative descriptors of recovery, facilitation, and fatigue accounted for changes in AH interval, AVERP, tachycardia cycle length, and AVERP/T under control conditions and in the presence of adenosine. In the absence of exogenous adenosine, 8-phenyltheophylline (10 mumol/L), an adenosine receptor antagonist, did not alter recovery or facilitation but significantly reduced rate-related fatigue (by 31 +/- 8%, mean +/- SEM, P < .05, in rabbit hearts; 46 +/- 5%, P < .01, in guinea pig hearts). Combined inhibition of adenosine deaminase (with erythro-9-[2-hydroxy-3-nonyl]-adenine hydrochloride, 5 mumol/L) and adenosine uptake (with dipyridamole, 1 mumol/L) increased fatigue in the absence of exogenous adenosine by 57 +/- 20% (P < .05).
CONCLUSIONS
We conclude that (1) exogenously administered adenosine increases AV nodal fatigue and reduces facilitation, without altering AV nodal recovery; (2) these changes cause rate-dependent AV nodal depression, which plays a role in adenosine's actions on experimental AVRT; and (3) endogenous adenosine receptor activation plays a role in physiological AV nodal fatigue. Adenosine's ability to terminate reentrant supraventricular tachycardia may be due, at least in part, to its ability to enhance the physiological conduction slowing that results from sustained increases in AV nodal activation rate.
Topics: Adenosine; Animals; Atrioventricular Node; Cardiac Pacing, Artificial; Disease Models, Animal; Electric Stimulation; Guinea Pigs; Heart Rate; In Vitro Techniques; Models, Cardiovascular; Perfusion; Rabbits; Tachycardia, Atrioventricular Nodal Reentry; Theophylline
PubMed: 8252674
DOI: 10.1161/01.cir.88.6.2632 -
Brain Research Mar 1991Using the hippocampal slice preparation, extracellular recordings of CA3 field excitatory postsynaptic potentials (fEPSPs) were performed to assess the effects of...
Using the hippocampal slice preparation, extracellular recordings of CA3 field excitatory postsynaptic potentials (fEPSPs) were performed to assess the effects of adenosine on the induction of mossy fiber long-term potentiation (LTP). When present during tetanization, adenosine (50 microM) significantly suppressed mossy fiber LTP whereas it failed to inhibit LTP when applied immediately after high-frequency stimulation. Based on the hypothesis that mossy fiber LTP is presynaptic in origin, our data thus provide first evidence that adenosine's presynaptic action alone is sufficiently powerful to interfere with synaptic plasticity.
Topics: Adenosine; Animals; Electric Stimulation; Evoked Potentials; Guinea Pigs; Hippocampus; In Vitro Techniques; Nerve Fibers; Pyramidal Tracts; Synapses
PubMed: 2054670
DOI: 10.1016/0006-8993(91)91061-5 -
Analytical Chemistry Apr 2012S-Adenosyl-L-homocysteine hydrolase (SAHH) catalyzes the reversible conversion of S-adenosyl-L-homocysteine (SAH) to adenosine (ADO) and L-homocysteine, promoting...
S-Adenosyl-L-homocysteine hydrolase (SAHH) catalyzes the reversible conversion of S-adenosyl-L-homocysteine (SAH) to adenosine (ADO) and L-homocysteine, promoting methyltransferase activity by relief of SAH inhibition. SAH catabolism is linked to S-adenosylmethionine metabolism, and the development of SAHH inhibitors is of interest for new therapeutics with anticancer or cholesterol-lowering effects. We have developed a continuous enzymatic assay for adenosine that facilitates high-throughput analysis of SAHH. This luciferase-based assay is 4000-fold more sensitive than former detection methods and is well suited for continuous monitoring of ADO formation in a 96-well-plate format. The high-affinity adenosine kinase from Anopheles gambiae efficiently converts adenosine to adenosine monophosphate (AMP) in the presence of guanosine triphosphate. AMP is converted to adenosine triphosphate and coupled to firefly luciferase. With this procedure, kinetic parameters (K(m), k(cat)) for SAHH were obtained, in good agreement with literature values. Assay characteristics include sustained light output combined with ultrasensitive detection (10(-7) unit of SAHH). The assay is documented with the characterization of slow-onset inhibition for inhibitors of the hydrolase. Application of this assay may facilitate the development of SAHH inhibitors and provide an ultrasensitive detection for the formation of adenosine from other biological reactions.
Topics: Adenosine; Biological Assay; Limit of Detection; Luciferases; S-Adenosylhomocysteine
PubMed: 22416759
DOI: 10.1021/ac203297z -
Die Pharmazie Sep 1974
Review
Topics: Adenosine; Adenosine Triphosphate; Aminohydrolases; Aminophylline; Animals; Calcium; Carbon Dioxide; Coronary Circulation; Coronary Vessels; Dipyridamole; Dogs; Hydrogen-Ion Concentration; Hypoxanthines; Hypoxia; Inosine; Nitroglycerin; Oxidative Phosphorylation; Oxygen Consumption; Papaverine; Partial Pressure; Prenylamine; Theophylline; Vasodilator Agents; Verapamil
PubMed: 4213610
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Letters Sep 20242'-5'-Adenosine linked nucleic acids are crucial components in living cells that play significant roles, including participating in antiviral defense mechanisms by...
2'-5'-Adenosine linked nucleic acids are crucial components in living cells that play significant roles, including participating in antiviral defense mechanisms by facilitating the breakdown of viral genetic material. In this report, we present a chemical derivatization method employing 5-fluoro-2-pyridinoyl-imidazole as the acylation agent, a strategy that can be effectively combined with advanced analytical tools, including Nuclear Magnetic Resonance spectroscopy and Liquid Chromatography-Mass Spectrometry, to enhance the characterization and detection capabilities. This marks the first instance of a simple method designed to detect 2'-5'-adenosine linked nucleic acids. The new method is characterized by its time-saving nature, simplicity, and relative accuracy compared to previous methods.
Topics: Acylation; Adenosine; Nucleic Acids; Imidazoles; Molecular Structure; Magnetic Resonance Spectroscopy; Mass Spectrometry
PubMed: 38857849
DOI: 10.1016/j.bmcl.2024.129847 -
Circulation Research Nov 1992Adenosine has been shown to protect the ischemic and reperfused myocardium. To examine whether the protective effect of the nucleoside is mediated by modulation of...
Adenosine has been shown to protect the ischemic and reperfused myocardium. To examine whether the protective effect of the nucleoside is mediated by modulation of oxidative stress, isolated rat hearts were perfused for 30 minutes with 100 microM H2O2 or an exogenous free radical-generating system consisting of purine (3.06 mM) and xanthine oxidase (10 units/l) in the presence or absence of drugs acting on adenosine A1 or A2 receptors. H2O2 alone produced a greater than 90% loss in contractility concomitant with a threefold elevation in resting tension, although these effects occurred in the absence of ultrastructural damage. Two A1 receptor agonists N6-cyclopentyladenosine (CPA, 1 microM) and R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA, 1 microM) significantly attenuated the cardiodepressant effects of H2O2 and depressed the elevation in resting tension; however, only the effect of CPA was found to be significant with regard to the latter parameter. A similar concentration of S(+)-N6-(2-phenylisopropyl)adenosine (S-PIA), a markedly less potent A1 receptor agonist, was found to be without beneficial effect. However, a significant protective effect against both the reduction in contractility and the elevation in resting tension was seen with a 10-fold elevation in the concentration of S-PIA (10 microM). The protective effects on functional parameters were associated with preservation of high-energy phosphate and adenine nucleotide contents after 30 minutes of H2O2 treatment. The salutary effects of all drugs were reversed in the presence of the A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (0.5 microM). An A2 receptor agonist 2-[p-(carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine, termed CGS 21680 (1 microM), failed to alter the cardiac response to H2O2 with regard to all parameters studied. Neither a 50% reduction in external CaCl2 concentration nor treatment with 10 microM DL-propranolol exerted salutary effects against H2O2-induced dysfunction. None of the A1 receptor agonists modulated the response to purine plus xanthine oxidase. Our results demonstrate a selective protective effect of adenosine A1 receptor activation against the cardiac toxicity of H2O2 and provide, at least in part, a basis for the cardioprotective actions of adenosine and its analogues.
Topics: Adenosine; Animals; Energy Metabolism; Heart; Hydrogen Peroxide; Male; Myocardial Contraction; Myocardium; Phenylisopropyladenosine; Rats; Rats, Sprague-Dawley; Receptors, Purinergic
PubMed: 1394872
DOI: 10.1161/01.res.71.5.1101 -
Texas Heart Institute Journal 2007
Topics: Adenosine; Cardiac Surgical Procedures; Dose-Response Relationship, Drug; Drug Administration Schedule; Heart Arrest, Induced; Humans; Injections, Intravenous; Myocardial Contraction; Vascular Surgical Procedures
PubMed: 17622386
DOI: No ID Found -
Medizinische Klinik (Munich, Germany :... Jul 1998
Topics: Adenosine; Anti-Arrhythmia Agents; Electrocardiography; Humans; Tachycardia, Supraventricular
PubMed: 9711062
DOI: 10.1007/BF03042645 -
Nucleosides, Nucleotides & Nucleic Acids 2015Several methods for the preparation of some N(6)-substituted adenosines based on selective 1-N-alkylation with subsequent Dimroth rearrangement were developed. The...
Several methods for the preparation of some N(6)-substituted adenosines based on selective 1-N-alkylation with subsequent Dimroth rearrangement were developed. The proposed methods seem to be effective for the preparation of natural N(6)-isopentenyl- and N(6)-benzyladenosines, which are known to possess pronounced biological activities. Direct 1-N-alkylation of 2',3',5'-tri-O-acetyladenosine and 3',5'-di-O-acetyl-2'-deoxyadenosine with alkyl halides in N,N-dimethylformamide (DMF) in the presence of BaCO3 and KI gave 1-N-substituted derivatives with quantitative yields, whereas 1-N-alkylation of adenosine was accompanied by significant O-alkylation. Moreover, the reaction of trimethylsilyl derivatives of N(6)-acetyl-2',3',5'-tri-O-acetyladenosine and N(6)-acetyl-3',5'-di-O-acetyl-2'-deoxyadenosine with alkyl halides leads to the formation of the stable 1-N-substituted adenosines. Dimroth rearrangement of 1-N-substituted adenosines in aqueous ammonia yields pure N(6)-substituted adenosines.
Topics: Adenosine; Alkylation; Deoxyadenosines
PubMed: 26158567
DOI: 10.1080/15257770.2015.1016169 -
Journal of Thrombosis and Haemostasis :... Oct 2013Ticagrelor, a P2Y12 antagonist, is an antiplatelet agent approved for the treatment of acute coronary syndromes; it also inhibits adenosine uptake by erythrocytes and...
BACKGROUND
Ticagrelor, a P2Y12 antagonist, is an antiplatelet agent approved for the treatment of acute coronary syndromes; it also inhibits adenosine uptake by erythrocytes and other cells.
OBJECTIVE
To test whether ticagrelor inhibits platelet aggregation (PA) in whole blood (WB) by increasing the extracellular levels of adenosine, which inhibits PA via the A2A receptor.
METHODS
Collagen-induced PA was measured in WB or platelet-rich plasma (PRP) from 50 healthy subjects and two patients with inherited P2Y12 deficiency, in presence/absence of adenosine concentrations that by themselves marginally affected PA in WB, and ZM241385 (A2A antagonist). The effects of ticagrelor, the active metabolite of prasugrel (PAM) (P2Y12 antagonist), and dipyridamole (adenosine uptake inhibitor) on PA and on adenosine clearance in WB were compared.
RESULTS
For PA in WB, adenosine contributed to drug-induced inhibition of PA; the adenosine contribution was similar for dipyridamole and ticagrelor but was significantly greater for ticagrelor than for PAM (P < 0.01). For PA in PRP (no adenosine uptake by erythrocytes), adenosine contributed to inhibition of PA in the presence/absence of all tested drugs. ZM241385 reversed the inhibition by adenosine in WB and PRP. Similar results were obtained with WB and PRP from P2Y12 -deficient patients. Adenosine (7.1 μmol L(-1) ) added to WB, was detectable for 0.5 min in the presence of vehicle or PAM, for 3-6 min in the presence of ticagrelor, and for > 60 min in the presence of dipyridamole.
CONCLUSION
This study provides the first evidence of an additional antiplatelet mechanism by ticagrelor, mediated by the induced increase of adenosine levels.
Topics: Adenosine; Adult; Aged; Female; Humans; Hypoxanthine; Male; Middle Aged; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Ticagrelor; Young Adult
PubMed: 23890048
DOI: 10.1111/jth.12360