The Guanosine-Adenosine Interaction Exists In Vivo

Abstract

In cultured renal cells and isolated perfused kidneys, extracellular guanosine augments extracellular adenosine and inosine (the major renal metabolite of adenosine) levels by altering the extracellular disposition of these purines. The present study addressed whether this "guanosine-adenosine mechanism" exists in vivo. In rats (n 5 15), intravenous infusions of adenosine (1 mmol/kg per minute) decreased mean arterial blood pressure (MABP) from 114 6 4 to 83 6 5 mm Hg, heart rate (HR) from 368 6 11 to 323 6 9 beats/min), and renal blood flow (RBF) from 6.2 6 0.5 to 5.3 6 0.6 ml/min). In rats (n 5 15) pretreated with intravenous guanosine (10 mmol/kg per minute), intravenous adenosine (1 mmol/kg per minute) decreased MABP (from 109 6 4 to 58 6 5 mm Hg), HR (from 401 6 10 to 264 6 20 beats/min), and RBF (from 6.2 6 0.7 to 1.7 6 0.3). Two-factor analysis of variance (2F-ANOVA) revealed a significant interaction (P , 0.0001) between guanosine and adenosine for MABP, HR, and RBF. In control rats, the urinary excretion rate of endogenous inosine was 211 6 103 ng/30 minutes (n 5 9); however, in rats treated with intravenous guanosine (10 mmol/kg per minute), the excretion rate of inosine was 1995 6 300 ng/30 minutes (n 5 12; P , 0.0001 versus controls). Because adenosine inhibits inflammatory cytokine production, we also examined the effects of intravenous guanosine on endotoxemia-induced increases in tumor necrosis factor-a (TNF-a). In control rats (n 5 7), lipopolysaccharide (LPS; Escherichia coli 026:B6 endotoxin; 30 mg/kg) increased plasma TNF-a from 164 6 56 to 4082 6 730 pg/ml, whereas in rats pretreated with intravenous guanosine (10 mmol/kg per minute; n 5 6), LPS increased plasma TNF-a from 121 6 45 to 1821 6 413 pg/ml (2F-ANOVA interaction effect, P 5 0.0022). We conclude that the guanosine-adenosine mechanism exists in vivo and that guanosine may be a useful therapeutic for reducing inflammation.

Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway

“…Additionally, consistent with our findings, Jackson and Mi showed that guanosine inhibited the LPS-induced production of TNF-α and IL-1β in an in vivo experimental model [46]. Our group recently demonstrated in the C6 astroglial cell line that the HO-1 pathway was involved in the anti-inflammatory activity of guanosine under azide exposure and that its glioprotective effects were associated with decreased neuroinflammation and oxidative stress [30].…”

“…Because some effects of guanosine have been shown to be mediated by adenosinergic system [44][45][46], the role of adenosine and/or caffeine (adenosine receptor antagonist) in LPSinduced inflammatory response was also evaluated. Interestingly, adenosine (100 and 1000 μM) did not prevent the increase in cytokine release that occurred after LPS exposure (Table 1).…”

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].…”