Specificity of adenosine uptake into the heart and inhibition by dipyridamole.
TL;DR: It can be concluded from the results that in the case of adenosine and inosine there is a specific uptake mechanism in the cell, which is inhibited by dipyridamole, and this mechanism does not apply to adenine and hypoxanthine.
About: This article is published in European Journal of Pharmacology.The article was published on 1970-03-01. It has received 99 citations till now. The article focuses on the topics: Inosine & Hypoxanthine.
Citations
More filters
TL;DR: Intriguingly, urate prevents oxidative inactivation of endothelial enzymes and preserves the ability of the endothelium to mediate vascular dilatation in the face of oxidative stress, suggesting a particular relationship between the site of urate formation and the need for a biologically potent radical scavenger and antioxidant.
785 citations
TL;DR: It was concluded that Ado and m-ACh receptors link with the same population of K+ channels via GTP-binding proteins Ni and/or No in the atrial cell membrane.
Abstract: The molecular mechanisms underlying activation of a K+ channel by adenosine (Ado) and acetylcholine (ACh) were examined in single atrial cells of guinea-pig. Whole cell clamp and patch clamp techniques were used to characterize the K+ channel. In the whole cell clamp conditions, Ado and ACh increased the K+ channel current in a dose-dependent manner. The maximum responses and the apparent dissociation constants were different for Ado and ACh activations of the current. Theophylline blocked activation of the K+ current by Ado, while atropine blocked ACh-activation, indicating that two different membrane receptors were involved. Measurements of the conductance and kinetic properties of both whole cell and single channel currents indicate that Ado and ACh regulate the same K+ channels. In “inside-out” patch conditions, GTP was required in the intracellular side of the membrane for activation of the K+ channel by agonists (present in the patch electrode). The A protomer of pertussis toxin inhibited the channel activation only when NAD was also present. Furthermore, GTP-γS, a non-hydrolyzable GTP analogue, gradually caused activation of the K+ channel in the absence of agonists. Therefore, it was concluded that Ado and m-ACh receptors link with the same population of K+ channels via GTP-binding proteins Ni and/or No in the atrial cell membrane.
456 citations
Cites background from "Specificity of adenosine uptake int..."
...Dipyridamole 20 ~tM added in the bath solution, which interferes the uptake of Ado into the cells (Kolassa et al. 1970), did not affect the amount of Ado-induced current (not shown)....
[...]
TL;DR: The chapter discusses the importance of the mechanism of permeation of nucleosides, nucleobases, and nucleotides through the cell membranes of eukaryotes and discusses the carrier model for facilitated diffusion and tests for its applicability to nucleoside and base transport.
Abstract: Publisher Summary This chapter discusses the importance of the mechanism of permeation of nucleosides, nucleobases, and nucleotides through the cell membranes of eukaryotes. Some of the reasons of its importance include (1) many anticancer and immunosuppressive agents presently in use or under development are nucleoside, nucleotide, or nucleobase analogs and a clear understanding of their mode of entry into cells and metabolism is important in the assessment of their mode of action, efficacy, and optimal administration, and (2) radioactively labeled nucleosides and nucleic acid bases are widely used as precursors to label specifically the nucleic acids of various types of organisms or of the viruses or plasmids replicating therein as well as to assess the rates of nucleic acid synthesis. An interpretation of the rates of nucleoside and base incorporation into nucleic acids, be it RNA or DNA, depends on a clear understanding of the extent to which these rates may reflect the rates of the conversion of the extracellular substrate to intracellular nucleotides, which are the direct precursors in nucleic acid synthesis. Elimination of the ambiguities inherent in metabolizing cells is of clear advantage to transport studies. Nucleoside and purine transport have been studied successfully in the absence of intracellular metabolism by the use of erythrocytes or of mutant clones of cultured animal cells that are deficient in specific metabolic enzymes and by the use of cell/substrate systems in which substrate metabolism is blocked in some other manner. The chapter also discusses the carrier model for facilitated diffusion and tests for its applicability to nucleoside and base transport.
324 citations
TL;DR: The effect ofadenosine on atrioventricular conduction results from binding to an extracellular receptor that resembles the R site described for other actions of adenosine in different tissues, and the reversal of adenoine-induced increases in atrial-His conduction delay by aminophylline is not due to phosphodiesterase inhibition and/or release of norepinephrine from nerve terminals.
Abstract: Adenosine is known to cause atrioventricular block by slowing conduction through the atrioventricular node, thereby lengthening the atria to His (A-H) interval. To test the hypothesis that the increase in atrioventricular conduction delay produced by adenosine is mediated at an extracellular site, the efficacy of nucleoside transport inhibitors in preventing cellular adenosine uptake was correlated with their ability to potentiate the atrioventricular block and prolong the AH interval. The antagonism of aminophylline and adenosine also was examined. Since methylxanthines are known to inhibit cyclic nucleotide phosphodiesterase, to release catecholamines from nerve terminals, and to block adenosine receptors, it was determined whether the ability of aminophylline to reverse the adenosine-induced prolongation of the atrial-His interval and atrioventricular block was associated with an increase in myocardial cyclic AMP and/or release of norepinephrine. The atrial-His conduction time and adenosine uptake and release were determined in isolated perfused guinea pig and rat hearts. The nucleoside transport inhibitors dipyridamole, nitrobenzylthioinosine, and diazepam caused a dose-dependent decrease in the uptake of 14Cadenosine. Nitrobenzylthioinosine was the most and diazepam the least effective in blocking adenosine uptake. Dipyridamole (5 × 10−6 M) inhibited uptake by 97% and increased adenosine levels in the perfusate. These effects were strongly correlated with a potentiation of adenosineinduced atrial-His prolongation (r = 0.99). The oligonucleotide, adenyl (3′-5′)9-adenosine, an agent restricted to the extracellular space as a result of its large molecular size, was found to be 1.8 times more potent per mole than free adenosine. 2′-Deoxyadenosine and N6-methyladenosine, respectively, were found to have either no effect or an effect similar to that of free adenosine on the atrial-His interval. Aminophylline (1 × 10−5 to 3 × 10−5 M) in the presence or absence of propranolol antagonized in a dose-dependent and competitive manner the prolongation of the atrial-His interval and atrioventricular block caused by adenosine. In concentrations up to 10−4 M, aminophylline did not cause any accumulation of myocardial cyclic AMP, nor did it increase the release of norepinephrine. We conclude (1) that the effect of adenosine on atrioventricular conduction results from binding to an extracellular receptor that resembles the R site described for other actions of adenosine in different tissues, and (2) that the reversal of adenosine-induced increases in atrioventricular conduction delay by aminophylline is not due to phosphodiesterase inhibition and/or release of norepinephrine from nerve terminals.
156 citations
TL;DR: The results are compatible with the hypothesis that the specific inhibition of uptake ofadenosine potentiates adenosine or amine-elicited accumulations of cyclic AMP by increasing the effective extracellular concentration of adenoine within the slice.
146 citations
References
More filters
TL;DR: A modification of the naphthalene-dioxane-PPO liquid scintillator has been described which will allow up to 3.0 ml of an aqueous solution to be counted as mentioned in this paper.
7,634 citations
TL;DR: Experiments were performed on isolated cat hearts perfused with Tyrode's solution and intact hearts of open-chest dogs, finding that cardiac hypoxia resulted in a decrease in coronary vascular resistance and a ...
Abstract: Experiments were performed on isolated cat hearts perfused with Tyrode's solution and intact hearts of open-chest dogs. Cardiac hypoxia resulted in a decrease in coronary vascular resistance and a ...
1,017 citations
134 citations
TL;DR: Perfusion of the isolated cat heart with Tyrode's solution containingadenosine, adenosine-8-C14 or ATP induced an increase in coronary flow and in the amount of inosine and hypoxanthine in the per...
Abstract: Perfusion of the isolated cat heart with Tyrode's solution containing adenosine, adenosine-8-C14 or ATP induced an increase in coronary flow and in the amount of inosine and hypoxanthine in the per...
89 citations
01 Jul 1964
TL;DR: Inosin benotigt zur Erzielung eines gleichen Inhibitoreffektes eine mehr als 10000 fache Konzentration as discussed by the authors.
Abstract: 1. 2,6-Bis(diathanolamino)-4,8-dipiperidino-pyrimido-(5,4-d)pyrimidin (RA 8) hemmt den „erleichterten Adenosintransport“ durch die Erythrocytenmembran des Hundes substratkompetitiv. Inosin benotigt zur Erzielung eines gleichen Inhibitor-effektes eine mehr als 10000 fache Konzentration.
55 citations