Extracellular guanosine regulates extracellular adenosine levels

Abstract

The aim of this investigation was to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels. Rat preglomerular vascular smooth muscle cells were incubated with adenosine, guanosine, or both. Guanosine (30 μmol/l) per se had little effect on extracellular adenosine levels. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) were 0.125 ± 0.020 μmol/l, indicating rapid disposition of extracellular adenosine. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) plus guanosine (30 μmol/l) were 1.173 ± 0.061 μmol/l, indicating slow disposition of extracellular adenosine. Cell injury increased extracellular levels of endogenous adenosine and guanosine, and the effects of cell injury on endogenous extracellular adenosine were modulated by altering the levels of endogenous extracellular guanosine with exogenous purine nucleoside phosphorylase (converts guanosine to guanine) or 8-aminoguanosine (inhibits purine nucleoside phosphorylase). Extracellular guanosine also slowed the disposition of extracellular adenosine in rat preglomerular vascular endothelial cells, mesangial cells, cardiac fibroblasts, and kidney epithelial cells and in human aortic and coronary artery vascular smooth muscle cells and coronary artery endothelial cells. The effects of guanosine on adenosine levels were not mimicked or attenuated by 5-iodotubericidin (adenosine kinase inhibitor), erythro-9-(2-hydroxy-3-nonyl)-adenine (adenosine deaminase inhibitor), 5-aminoimidazole-4-carboxamide (guanine deaminase inhibitor), aristeromycin (S-adenosylhomocysteine hydrolase inhibitor), low sodium (inhibits concentrative nucleoside transporters), S-(4-nitrobenzyl)-6-thioinosine [inhibits equilibrative nucleoside transporter (ENT) type 1], zidovudine (inhibits ENT type 2), or acadesine (known modulator of adenosine levels). Guanosine also increases extracellular inosine, uridine, thymidine, and cytidine, yet decreases extracellular uric acid. In conclusion, extracellular guanosine regulates extracellular adenosine levels.

Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats

“…Together, these data reinforced the idea that the CSF may be a major source of distribution to the brain following IN administration while the purine levels after IP administration reflect blood levels. This hypothesis is reinforced by works of Jiang's group [19,20] that showed, using a mixture of unlabeled and labeled [ H] GUO than was used here), that GUO is promptly and markedly metabolic breakdown after systemic administration reflecting in an increase of GUO metabolites in the brain [25,26].…”

“…Some works in the literature have focused attention on the interplay of extracellular ADO and GUO levels. An experimentally based hypothesis is that GUO caused an increase in extracellular ADO levels by competing with nucleoside transporter [19,20]. In fact, some of GUO's neuroprotective effects, but not all, are ADO receptor dependent [18][19][20][21][22]39].…”

“…A putative binding site for GUO was already described in rat brain membranes [17], but in opposite, several evidences point to an adenosine (ADO) receptors contribution for GUO effects. Indeed, some, but not all of the observed neuroprotective effects of GUO, were blocked by ADO receptor antagonists, suggesting multiple mechanisms of action for GUO [18][19][20][21][22]. Certainly, GUO effects seem to be directly mediated by action on the brain, as intracerebroventricular or intracortical GUO infusion in experimental models of excitotoxicity have demonstrated neuroprotection [8,13].…”

Guanosine prevents nitroxidative stress and recovers mitochondrial membrane potential disruption in hippocampal slices subjected to oxygen/glucose deprivation

“…GUO effects over adenosinergic system are controversial [43], but we have shown that neuroprotective effects of GUO depend on adenosine receptors modulation [33] and on activation of a calcium-dependent potassium channel [14]. It has also recently been shown that GUO may regulate the extracellular disposition of adenosine in some cell types by an unknown mechanism, but this effect seems not to occur in neuronal cells [44]. Therefore, this putative guanosine-adenosine interaction in the brain must be further characterized.…”

Dueling nucleosides: cross-regulation of extracellular adenosine by guanosine. Focus on “Extracellular guanosine regulates extracellular adenosine levels”

“…Thus, despite their critical roles in intracellular signal transduction, guanosine-containing compounds have historically been considered as nonentities in terms of extracellular signaling by nucleotides and nucleosides. However, a new study by Jackson et al (1) in this issue of American Journal of Physiology-Cell Physiology reveals a hitherto unappreciated role for extracellular guanosine (and guanosine nucleotides) in the regulation of extracellular adenosine clearance/metabolism. Thus, these "poor relative" purines may indeed be involved in the complex world of extracellular purinergic signaling.…”