Formation and release of nucleosides in the ischemic myocardium. Is the guinea-pig the exception?

Belle, H. Van; Wynants, J.; Goossens, F.

doi:10.1007/bf01907864

Cited by 30 publications

(11 citation statements)

References 11 publications

(9 reference statements)

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“…The figure emphasizes the potential of mathematical model analysis to obtain realistic concentration-effect relationships and transmembranous and tissue concentration gradients are beginning to emerge (Kroll et al 1992;Kroll and Stepp 1996;Stepp et al 1996;Decking et al 1997b;Deussen et al 1999;Schwartz et al 1999). A sigificant problem in adenosine metabolism research arises from large species differences (van Belle et al 1985). In medicine the ultimate importance of experimental results is measured against the applicability to human physiology.…”

Section: Future Directionsmentioning

confidence: 97%

Metabolic flux rates of adenosine in the heart

Deußen

2000

Naunyn-Schmied Arch Pharmacol

101

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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.

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Section: Future Directionsmentioning

confidence: 97%

Metabolic flux rates of adenosine in the heart

Deußen

2000

Naunyn-Schmied Arch Pharmacol

101

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“…The nucleotidase generates adenosine, a cardioprotectant and precursor for 'salvage' adenylate biosynthesis, whereas AMPD irreversibly converts AMP into IMP [2]. Thus AMPD may influence myocardial adenine nucleotide metabolism during ischaemia through both substrate availability to 5'-nucleotidase and net utilization of tissue adenine nucleotides [3].…”

Section: Introductionmentioning

confidence: 99%

Oxidative modulation and inactivation of rabbit cardiac adenylate deaminase

Janero¹,

Yarwood²

1995

Biochemical Journal

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Oxidative stress and adenine nucleotide catabolism occur concomitantly in several disease states, such as cardiac ischaemia-reperfusion, and may act as synergistic determinants of tissue injury. However, the mechanisms underlying this potential interaction remain ill-defined. We examined the influence of oxidative stress on the molecular, kinetic and regulatory properties of a ubiquitous AMP-catabolizing enzyme, adenylate deaminase (AMPD) (EC 3.5.4.6). To this intent, rabbit heart AMPD and an H2O2/ascorbate/iron oxidation system were employed. Enzyme exposure to the complete oxidation system acutely impaired its catalytic activity, lowered the Vmax. by 7-fold within 5 min, and rendered the enzyme unresponsive to nucleotide effectors. Irreversible AMPD inactivation resulted within about 15 min of oxidative insult and was not prevented by free-radical scavengers. Oxidative stress did not affect the molecular mass, tetrameric nature, Km, immunoreactivity or trypsinolytic pattern of the enzyme; nor did it induce carbonyl formation, Zn2+ release from the holoenzyme or net AMPD S-thiolation. This injury pattern is inconsistent with a radical-fragmentation mechanism as the basis for the oxidative AMPD inactivation observed. Rather, the sensitivity of the enzyme to both S-thiolation and thiol alkylation and the significant (3 of 9/mol of denatured enzyme) net loss of DTNB-reactive thiols on exposure to oxidant strongly implicate the conversion of essential thiol moieties into stable higher-oxidation states in the oxidative inactivation of cardiac AMPD. The altered thiol status of the enzyme on oxidative insult may prohibit a catalytically permissible conformation and, in so doing, increase AMP availability to 5'-nucleotidase in vivo.

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“…Upon reperfusion, the nucleosides and purine bases accumulated during ischaemia are released very rapidly in the eMuate (usually within 2 min.). In a study by Van Belle et a/. (1985), the mean concentrations of adenosine, inosine and hypoxanthine in 4 min.…”

Section: Discussionmentioning

confidence: 99%

Lidocaine Interactions with Exogenous and Endogenous Adenosine in the Isolated Rat Heart

Schjøtt

Brurok

Jynge

1994

Pharmacology & Toxicology

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We examined whether pretreatment with lidocaine could influence the cardiac kinetics of adenosine and thereby strengthen the physiologic responses of the nucleoside, either exogenously administered or endogenously produced. Isolated rat hearts perfused with lidocaine, 0.05 microM to 500 microM, were subjected to 6 min. of adenosine infusion followed by 30 min. of perfusion. The hearts were then subjected to 6 min. of total global ischaemia and then perfused for 30 min. Effects on cardiac kinetics and physiologic responses of adenosine were based on a comparison of uptake or release of adenosine in effluate (kinetics), and the effects of adenosine on aortic pressure and left ventricular developed pressure (physiologic responses), to a lidocaine-free control group. A low concentration of lidocaine, 0.05 microM, increased the uptake of exogenously administered adenosine. A high concentration of lidocaine, 50 and 500 microM was associated with a reduced release of endogenously produced adenosine. However, these effects on cardiac kinetics of adenosine were not associated with any increase of the physiologic responses to the nucleoside. The results failed to support the hypothesis that lidocaine increases the physiologic responses of adenosine in the isolated rat heart by a kinetic interaction.

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Formation and release of nucleosides in the ischemic myocardium. Is the guinea-pig the exception?

Cited by 30 publications

References 11 publications

Metabolic flux rates of adenosine in the heart

Metabolic flux rates of adenosine in the heart

Oxidative modulation and inactivation of rabbit cardiac adenylate deaminase

Lidocaine Interactions with Exogenous and Endogenous Adenosine in the Isolated Rat Heart

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