Adenosine formation and release from neonatal-rat heart cells in culture

Meghji, Parviz; Holmquist, C A; Newby, Andrew C.

doi:10.1042/bj2290799

Cited by 73 publications

(41 citation statements)

References 44 publications

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“…Experimental evidence in agreement with the assumption of a symmetric transport has been provided (Meghji et al 1985(Meghji et al , 1988c, although a nonsymmetric membrane transport was postulated by others (Buchwald et al 1987). A recent quantitative mathematical model analysis has indicated that experimental results can be explained without assumption of nonsymmetric transport (Deussen et al 1999).…”

Section: Compartmentalization: Intracellular Vs Extracellularmentioning

confidence: 81%

Metabolic flux rates of adenosine in the heart

Deußen

2000

Naunyn-Schmied Arch Pharmacol

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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: Compartmentalization: Intracellular Vs Extracellularmentioning

confidence: 81%

Metabolic flux rates of adenosine in the heart

Deußen

2000

Naunyn-Schmied Arch Pharmacol

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“…10 Thus, the protective effects of adenosine transport inhibitors could be primarily due to effects on blood flow. Furthermore, in vitro studies using neurons 11 and heart cells 12 have shown that during reduced energy conditions, adenosine transport inhibitors trap adenosine intracellularly. Under low energy conditions, aden-See Editorial Comment, page 2089 osine transport mechanisms may act to extrude adenosine.…”

Section: Dipyridamole Increases Oxygen-glucosementioning

confidence: 99%

Dipyridamole increases oxygen-glucose deprivation-induced injury in cortical cell culture.

Lobner

Choi

1994

Stroke

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Background and Purpose Adenosine transport inhibitors attenuate ischemic central neuronal damage in vivo, but the locus of this protective action is presently unknown. To help address the question of whether adenosine transport inhibitors have a protective effect directly on brain parenchyma, we tested the effect of the adenosine transport inhibitor dipyridamole on neuronal loss induced by oxygen-glucose deprivation in vitro.Methods Murine cortical cultures were exposed to combined oxygen and glucose deprivation, iV-methyl-D-aspartate, or kainate. The extracellular concentrations of glutamate and adenosine were measured by high-performance liquid chromatography; neuronal cell death was assessed by morphological examination and measurement of lactate dehydrogenase release.Results Cultures exposed to oxygen-glucose deprivation for 30 to 75 minutes exhibited an insult-dependent increase in extracellular adenosine, followed shortly by an increase in E xtracellular adenosine levels have been shown to increase during reduced energy conditions both in vivo 1 -2 and in vitro. 3 However, the source of the extracellular adenosine is not known. In vivo studies have shown that inhibition of the adenosine transporter increases extracellular adenosine 45 and attenuates ischemic damage.6 ' 8 These results are consistent with the possibility that adenosine is formed extracellularly (by the breakdown of ATP and other adenine nucleotides released during the ischemic period), and the adenosine transporter serves to remove extracellular adenosine.However, adenosine transport inhibitors are known to have multiple effects. Specifically, dipyridamole has been shown to potentiate hypoxic pial arteriolar vasodilation 9 and increase cerebral blood flow during anoxia.10 Thus, the protective effects of adenosine transport inhibitors could be primarily due to effects on blood flow. Furthermore, in vitro studies using neurons 11 Addition of the Al receptor antagonist 8-cyclopentyltheophylline during oxygen-glucose deprivation enhanced both glutamate release and neuronal damage. Addition of 10 ^.mol/L dipyridamole decreased extracellular adenosine and also enhanced extracellular glutamate and neuronal death. In contrast, dipyridamole increased the levels of extracellular adenosine stimulated by Af-methyl-D-aspartate or kainate.Conclusions These results are consistent with the idea that endogenous adenosine has a neuroprotective effect directly on cortical cells exposed to oxygen-glucose deprivation. However, inhibition of adenosine transport with dipyridamole was surprisingly not an effective strategy for enhancing this protective effect. The beneficial effects of adenosine transport inhibitors observed in vivo may be mediated indirectly-for example, by effects on the vasculature. To help address the question of whether adenosine transport inhibitors have a protective effect directly on brain parenchyma, we tested the effect of dipyridamole on the neuronal loss induced by oxygen-glucose deprivation in murine cortical cell cultures. Material...

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“…12 The local role of adenosine within the cardiovascular system is evident from the findings that adenosine is synthesized by vascular fibroblasts, 13 cardiomyocytes, 14 and both vascular 15 and cardiac 16 endothelial cells. Moreover, we recently showed that vascular SMCs and cardiac fibroblasts also synthesize adenosine 17,18 and that SMC-derived as well as cardiac fibroblastderived adenosine inhibits serum-induced SMC and cardiac fibroblast growth.…”

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confidence: 99%

Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Dubey¹,

Mi²,

Gillespie³

et al. 2001

ATVB

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Abstract-The objective of this investigation was to determine whether the regulation of extracellular adenosine levels by smooth muscle cells (SMCs) from conduit arteries (aorta) and resistance microvessels (renal arterioles) is different in spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto (WKY) rats. Basal extracellular adenosine levels were decreased in cultured aortic and arteriolar SHR SMCs, and the increase in extracellular adenosine levels induced by stimulation of the cAMP-adenosine pathway was less in aortic and arteriolar SHR SMCs. Extracellular adenosine levels were lower in SHR SMCs, however, even when the cAMP-adenosine pathway was inhibited with 3-isobutyl-1-methylxanthine. Inhibition of adenosine kinase with iodotubercidin and inhibition of adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl) adenine increased extracellular adenosine; however, only inhibition of adenosine deaminase equalized extracellular adenosine levels in SHR versus WKY SMCs. Membrane-disrupted SHR SMCs metabolized exogenous adenosine faster than WKY SMCs did, and this difference was abolished by inhibition of adenosine deaminase but not adenosine kinase. SHR SMCs demonstrated a greater proliferative response than WKY SMCs. This enhanced proliferative response was not blocked by adenosine per se or inhibition of adenosine kinase but was blocked by inhibition of adenosine deaminase and by 2-chloroadenosine (adenosine deaminase-resistant adenosine analogue). We conclude that dysregulation of extracellular adenosine levels exists in SHR SMCs, that this dysregulation is not due to a defect in the cAMP-adenosine pathway but rather to enhanced activity of adenosine deaminase, and that the dysregulation of extracellular adenosine mediates the enhanced proliferative response of SHR SMCs. Key Words: adenosine deaminase Ⅲ adenosine kinase Ⅲ hypertension Ⅲ proliferation Ⅲ vascular disease S mooth muscle cells (SMCs) within conduit and resistance arteries are importantly involved in the pathophysiology of vascular remodeling induced by hypertension. 1 In this regard, SMC growth, both hypertrophic 1 and hyperplastic, 2,3 contributes to pathological structural changes within the vessel wall in spontaneously hypertensive rats (SHR). SMC growth is regulated by multiple factors. 1 Under normal conditions, vascular SMC quiescence is maintained by a balance between vessel wall-derived and circulating growth inhibitors and growth promoters. 1 Disruption of the balanced generation of growth promoters and growth inhibitors under pathological conditions triggers a cascade of events leading to increased proliferation of SMCs and enhanced deposition of extracellular matrix proteins by SMCs. Therefore, endogenous factors that are generated by cells within the vessel wall and that inhibit SMC growth may play a major vasoprotective role, and decreased vascular levels of growth-inhibitory factors may contribute to vascular disease in hypertension.In this regard, it is conceivable that dysregulation of vascular adenosine levels in hyp...

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Adenosine formation and release from neonatal-rat heart cells in culture

Cited by 73 publications

References 44 publications

Metabolic flux rates of adenosine in the heart

Metabolic flux rates of adenosine in the heart

Dipyridamole increases oxygen-glucose deprivation-induced injury in cortical cell culture.

Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

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