Comprehensive model of transport and metabolism of adenosine and S-adenosylhomocysteine in the guinea pig heart.

Kroll, Keith; Deußen, Andreas; Sweet, Ian R.

doi:10.1161/01.res.71.3.590

Cited by 49 publications

(37 citation statements)

References 33 publications

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“…Furthermore, SAH contents after 20-minute step inputs of 200 mol/L homocysteine were predicted reasonably well for all conditions without any further adjustment of model parameters. This parameter set also fitted the adenosine release rate and the tissue SAH content of the previous study 10 within 10%. Figure 5 shows measured coronary flows plotted versus calculated adenosine concentrations of capillary and interstitial regions, respectively.…”

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confidence: 67%

“…10 As a starting point for the present analyses, the published parameter set was used. 10 The general modeling strategy was to fit measured venous adenosine concentrations by constraining the flow term by the measurements and using adenosine production terms as free parameters. To obtain parameter values that fitted the venous concentrations determined under various experimental conditions equally well, several iterations of parameter adjustment were necessary.…”

Section: Model Analysismentioning

confidence: 99%

“…Starting with a previously published parameter set, 10 the effects of transport inhibition were simulated by setting the parameter values of the membrane permeability-surface area products to 2% of the starting values 10 (98% inhibition of transport at basal adenosine concentrations) and flow rate to the measured value. An interstitial adenosine production term of 185 pmol ⅐ min Ϫ1 ⅐ g Ϫ1 fitted the mean measured release rate within 3%.…”

Section: Model Calculationsmentioning

confidence: 99%

“…A previous limitation in discerning between these alternative explanations has been the inability to measure the adenosine concentration on both sides of the membrane. However, because of the invention of the S-adenosylhomocysteine (SAH) technique 9 and formulation of a related comprehensive mathematical model, 10 it has become possible to quantify cytosolic adenosine concentrations. The present study was designed to determine the adenosine concentrations for the different tissue regions and thereby to assess the net transmembranous concentration gradient.…”

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confidence: 99%

“…Measurements were made before and after blocking of the facilitative membrane transporter in the absence and presence of blockers of adenosine metabolism. In a second stage, the experimental results were analyzed with a mathematical model 10 to calculate the adenosine production of different tissue regions and predict net transport between regions. The interstitial adenosine concentration was related to the measured changes of coronary flow.…”

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confidence: 99%

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Quantification of Extracellular and Intracellular Adenosine Production

et al. 1999

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Background-Inhibitors of adenosine membrane transport cause vasodilation and enhance the plasma adenosine concentration. However, it is unclear why the plasma adenosine concentration rises rather than falls when membrane transport is inhibited. We tested the hypothesis that the cytosolic adenosine concentration exceeds the interstitial concentration under well-oxygenated conditions. Methods and Results-In isolated, isovolumically working guinea pig hearts (nϭ50), the release rate of adenosine and accumulation of S-adenosylhomocysteine (after 20 minutes of 200 mol/L homocysteine), a measure of the free cytosolic adenosine concentration, were determined in the absence and presence of specific and powerful blockers of adenosine membrane transport (nitrobenzylthioinosine 1 mol/L), adenosine deaminase (erythro-9-hydroxy-nonyladenine 5 mol/L), and adenosine kinase (iodotubericidine 10 mol/L). Data analysis with a distributed multicompartment model revealed a total cardiac adenosine production rate of 2294 pmol ⅐ min Ϫ1 ⅐ g Ϫ1 , of which 8% was produced in the extracellular region. Because of a high rate of intracellular metabolism, however, 70.3% of extracellularly produced adenosine was taken up into cellular regions, an effect that was effectively eliminated by membrane transport block. The resulting Ϸ2.8-fold increase of the interstitial adenosine concentration evoked near-maximal coronary dilation. Conclusions-We rejected the hypothesis that the cytosolic adenosine concentration exceeds the interstitial. Rather, there is significant extracellular production, and the parenchymal cell represents a sink, not a source, for adenosine under well-oxygenated conditions. (Circulation. 1999;99:2041-2047.)

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confidence: 67%

Section: Model Analysismentioning

confidence: 99%

Section: Model Calculationsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Quantification of Extracellular and Intracellular Adenosine Production

et al. 1999

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Role of adenosine kinase and AMP deaminase in the regulation of cardiac purine release

Decking

Schrader

1998

Drug Dev. Res.

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To analyze the relation between cardiac energy status, adenosine formation, and purine release, reliable measurements of the cytosolic concentrations of ATP, ADP, AMP, and adenosine are required. Based on the creatine kinase and myokinase equilibrium, ADP and AMP are determined by 31P nuclear magnetic resonance spectroscopy, whereas free cytosolic adenosine is measured by the S‐adenosyl‐homocysteine (SAH) technique. Combining these methods with efflux measurements, selective enzyme blockade and a comprehensive model analysis enables a description of both concentrations and flux rates in purine metabolism. In the well‐oxygenated heart, adenosine is predominantly formed intracellularly from AMP, but also from S‐adenosyl‐homocysteine. Net adenosine formation (2.3 nmol/min per g) exceeds coronary venous release (0.07 nmol/min per g) more than 30‐fold, because most of the adenosine formed is rephosphorylated by adenosine kinase. This enzyme maintains a low intracellular adenosine and limits both adenosine release and deamination to inosine. In fact, inosine is mainly formed from IMP (1.8 nmol/min per g) the product of AMP deaminase. Inosine, hypoxanthine, xanthine, and uric acid (1.1, 0.4, 0.2, 1.4 nmol/min per g) are the main purine catabolites released. In the oxygen‐limited heart, energy status is impaired and AMP increased. Under these conditions, a linear relation between AMP (200–3,000 nmol/liter), net adenosine formation, as well as net inosine formation is observed. It is, thus, the AMP substrate concentration that directly controls adenosine formation by cytosolic 5′‐nucleotidase and most likely flux through AMP deaminase. Hypoxia‐induced inhibition of adenosine kinase shunts adenosine from the salvage pathway to venous release and causes the amplification of small changes in AMP into a major rise in adenosine. This mechanism plays an important role in the high sensitivity of the cardiac adenosine system to impaired oxygenation. Drug Dev. Res. 45:295–303, 1998. © 1998 Wiley‐Liss, Inc.

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