Metabolic flux rates of adenosine in the heart

Abstract

The quantitatively most important source of adenosine under well-oxygenated conditions is 5'-AMP hydrolyzed by cytosolic 5'-nucleotidase N-I. Hydrolysis of S-adenosylhomocysteine and extracellular dephosphorylation of 5'-AMP further contribute to total production. More than 90% of the total production occur intracellularly under well-oxygenated conditions. Besides cardiomyocytes, endothelial cells and smooth muscle contribute significantly to total cardiac adenosine production. Rapid enzymatic conversion of adenosine is provided by adenosine kinase and adenosine deaminase, keeping the cytosolic adenosine concentration in the nanomolar range. Due to the high intracellular rates of adenosine rephosphorylation and deamination the cytosolic is normally below the extracellular adenosine concentration, making the cytosol to a sink rather than a source of adenosine. It is for this reason that blockers of membrane transport enhance the plasma adenosine concentration. With increasing catabolism of adenine nucleotides the rate of intracellular adenosine production exceeds the rate of adenosine deamination and rephosphorylation. Thus, this condition will result in a concentration gradient from intra- to extracellular. Thence, membrane transport blockers would be expected to increase the intracellular adenosine concentration. A considerable insecurity on the importance of experimental data results from species differences of purine metabolism. Cardiac adenosine metabolism has recently been described in quantitative terms using mathematical model analysis. This analysis tool may prove useful in future when (1) clarifying the importance of various regulatory actions described for the different pathways of adenosine metabolism, (2) making quantitative comparisons of different experimental models possible and (3) deepening the insight from experimental data.

The Adenosine Transporter, mENT1, Is a Target for Adenosine Receptor Signaling and Protein Kinase Cϵ in Hypoxic and Pharmacological Preconditioning in the Mouse Cardiomyocyte Cell Line, HL-1

“…However, we have not determined the source of the Ado involved in this process in HL-1 cells. Literature reports suggest that metabolic stress results in an increase in intracellular levels of Ado as ATP hydrolysis exceeds ATP synthesis (Deussen, 2000). This would lead to an increase in intracellular Ado, which would efflux from cells via ENTs once the intracellular concentration exceeds the extracellular concentration.…”

“…The source of Ado produced during hypoxic challenge has been the subject of some controversy, with reports of 5Ј-ectonucleotidases and endothelial cells being responsible for the increase in extracellular Ado concentration in the heart (Deussen, 2000;Mubagwa and Flameng, 2001). ENTs would then be responsible for reuptake of Ado into cells and would contribute to termination of Ado receptor activation.…”

“…Cardiomyocytes possess predominantly or exclusively equilibrative NTs (ENTs), which facilitate diffusion of Ado down its concentration gradient (Chaudary et al, 2002). Ado concentrations in the heart fluctuate enormously depending on cellular metabolic demands and activity of enzymes involved in Ado metabolism (Deussen, 2000). In neural cells, ENTs are involved in modulating extracellular adenosine levels and appear to be subject to regulation by complex signal transduction pathways (Cunha et al, 2000).…”

Shaping of monocyte and macrophage function by adenosine receptors

“…These processes are closely intertwined and strictly regulated. For, example, under hypoxic conditions, the increased intracellular dephosphorylation of adenosine 5′-triphosphate (ATP) to adenosine by the metabolic enzyme 5′-nucleotidase is accompanied by a suppression of the activity of the salvage enzyme adenosine kinase, which prevents the rephosphorylation of adenosine (Deussen, 2000). These processes lead to adenosine reaching high concentrations inside the cell and the release of adenosine into the extracellular space through nucleoside transporters (Hyde et al, 2001;Pastor-Anglada et al, 2001).…”

Control of Adenosine Transport by Hypoxia

“…1 The capacity to take up adenosine from the extracellular space plays a prominent role in adenosine homeostasis. 10 Because adenosine is not lipophilic, release and uptake of adenosine requires nucleoside membrane transport which is conducted by 2 families of unrelated nucleoside transporter proteins. Active sodium-dependent nucleoside transport is found primarily in specialized epithelial tissues and is mediated by members of the concentrative nucleoside transporter family (SLC28).…”