Renal preservation with inosine

Maggio, August J.; D.A.S., Sakti; Kaufman, Joseph J.

doi:10.1016/0090-4295(80)90134-x

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…There is overwhelming evidence that adenosine and inosine protect against acute kidney injury (AKI; Maggio et al. ; Marberger et al. ; Fitzpatrick et al.…”

Section: Discussionmentioning

confidence: 99%

Guanosine regulates adenosine levels in the kidney

Jackson

Cheng

et al. 2014

Physiol Rep

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In cell culture, extracellular guanosine increases extracellular adenosine by attenuating the disposition of extracellular adenosine (American Journal of Physiology – Cell Physiology 304: C406–C421, 2013). The goal of this investigation was to determine whether this “guanosine–adenosine mechanism” is operative in an intact organ. Twenty‐seven isolated, perfused mouse kidneys were subjected to metabolic poisons (iodoacetate plus 2,4‐dinitrophenol) to cause energy depletion and thereby stimulate renal adenosine production. Adenosine levels in the renal venous perfusate increased from a baseline of 36 ± 8 to 499 ± 96, 258 ± 50, and 71 ± 13 nmol/L at 15, 30, and 60 min, respectively, after administering metabolic poisons (% of basal; 1366 ± 229, 715 ± 128, and 206 ± 33, respectively). Changes in renal venous levels of guanosine closely mirrored the time course of changes in adenosine: baseline of 15 ± 2 to 157 ± 13, 121 ± 8, and 50 ± 5 nmol/L at 15, 30, and 60 min, respectively (% of basal; 1132 ± 104, 871 ± 59, and 400 ± 51, respectively). Freeze‐clamp experiments in 12 kidneys confirmed that metabolic poisons increased kidney tissue levels of adenosine and guanosine. In eight additional kidneys, we examined the ability of guanosine to reduce the renal clearance of exogenous adenosine; and these experiments revealed that guanosine significantly decreased the renal extraction of adenosine. Because guanosine is metabolized by purine nucleoside phosphorylase (PNPase), in another set of 16 kidneys we examined the effects of 8‐aminoguanine (PNPase inhibitor) on renal venous levels of adenosine and inosine (adenosine metabolite). Kidneys treated with 8‐aminoguanine showed a more robust increase in both adenosine and inosine in response to metabolic poisons. We conclude that in the intact kidney, guanosine regulates adenosine levels.

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“…There is overwhelming evidence that adenosine and inosine protect against acute kidney injury (AKI; Maggio et al. ; Marberger et al. ; Fitzpatrick et al.…”

Section: Discussionmentioning

confidence: 99%

Guanosine regulates adenosine levels in the kidney

Jackson

Cheng

et al. 2014

Physiol Rep

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“…There is now an overwhelming body of evidence in support of the conclusion that adenosine (Okusa et al, 1999(Okusa et al, , 2000(Okusa et al, , 2001Emala, 2000, 2002;Okusa, 2002;Day et al, 2003Day et al, , 2005Lee et al, 2004aLee et al, ,b, 2007Grenz et al, 2007aGrenz et al, ,b, 2008Grenz et al, , 2011Grenz et al, , 2012Kim et al, 2009;Haskó et al, 2011) and inosine (Maggio et al, 1980;Marberger et al, 1980;Fitzpatrick et al, 1981;Rothwell et al, 1981;Mathur and Ramsey, 1983) protect the kidneys from acute injury. Less well known is the fact that guanosine is also renoprotective (Kelly et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

The Guanosine-Adenosine Interaction Exists In Vivo

Jackson

2014

J Pharmacol Exp Ther

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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.

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“…Indeed, several recent studies have demonstrated that administration of inosine can be protective against various forms of ischemic conditions (7–10). The current results may provide a mechanistic explanation to the previously reported protective effect of inosine in vitro as an adjuvant to organ storage solutions (47) or in vivo as a protective agent in a rat model of hepatic reperfusion injury (48) and can stimulate further studies to explore whether inosine has the potential to improve cellular bioenergetics and to protect hepatocytes in various forms of liver injury, including various forms of warm ischemia or cold ischemia associated with liver transplantation.…”

Section: Discussionmentioning

confidence: 55%

Adenosine and inosine exert cytoprotective effects in an in vitro model of liver ischemia-reperfusion injury

Módis

Gerö

Stangl

et al. 2012

International Journal of Molecular Medicine

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Liver ischemia represents a common clinical problem. In the present study, using an in vitro model of hepatic ischemia-reperfusion injury, we evaluated the potential cytoprotective effect of the purine metabolites, such as adenosine and inosine, and studied the mode of their pharmacological actions. The human hepatocellular carcinoma-derived cell line HepG2 was subjected to combined oxygen-glucose deprivation (COGD; 0-14-24 h), followed by re-oxygenation (0-4-24 h). Adenosine or inosine (300–1,000 μM) were applied in pretreatment. Cell viability and cytotoxicity were measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and lactate dehydrogenase methods, respectively. The results showed that both adenosine and inosine exerted cytoprotective effects, and these effects were not related to receptor-mediated actions, since they were not prevented by selective adenosine receptor antagonists. On the other hand, the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA, 10 μM) markedly and almost fully reversed the protective effect of adenosine during COGD, while it did not influence the cytoprotective effect of inosine in the same assay conditions. These results suggest that the cytoprotective effects are related to intracellular actions, and, in the case of adenosine also involve intracellular conversion to inosine. The likely interpretation of these findings is that inosine serves as an alternative source of energy to produce ATP during hypoxic conditions. The protective effects are also partially dependent on adenosine kinase, as the inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, 2HCl (ABT 702, 30 μM) significantly reversed the protective effect of both adenosine and inosine during hypoxia and re-oxygenation. Collectively, the current results support the view that during hypoxia, adenosine and inosine exert cytoprotective effects via receptor-independent, intracellular modes of action, which, in part, depend on the restoration of cellular bioenergetics. The present study supports the view that testing of inosine for protection against various forms of warm and cold liver ischemia is relevant.

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Renal preservation with inosine

Cited by 6 publications

References 5 publications

Guanosine regulates adenosine levels in the kidney

Guanosine regulates adenosine levels in the kidney

The Guanosine-Adenosine Interaction Exists In Vivo

Adenosine and inosine exert cytoprotective effects in an in vitro model of liver ischemia-reperfusion injury

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