Inosine: Alternative or Adjunct to Regional Hypothermia in the Prevention of Post-Ischemic Renal Failure?

Marberger, Michael; Günther, Rolf W.; Alken, P.; Rumpf, W; Ranc, M

doi:10.1159/000473299

Cited by 20 publications

(6 citation statements)

References 9 publications

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“…The model of ischaemic renal failure which was used in the present study permitted to demonstrate a partial but significant protective effect of inosine in the 48-hour series, which is consistent with earlier work from this [I I] and other [12][13][14] laboratories. This effect was clear-cut with respect to plasma creatinine (figure 1).…”

Section: Discussionsupporting

confidence: 90%

Failure of Verapamil to Protect from Ischaemic Renal Damage

Bock¹,

Brunner²,

Torhorst³

et al. 1991

Nephron

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To reassess the reported protective effects of verapamil in renal ischaemia, we perfused the left kidney of uninephrectomized female Wistar rats with verapamil (0.1 and 1.0 mg/kg) immediately prior to clamping the renal artery for 60 min. When compared to controls, both doses of verapamil failed to afford protection with respect to urine flow, plasma creatinine, creatinine clearance or histology 24 and 48 h after ischaemia, whereas the purine nucleotide inosine (200 mg/kg) was partially protective: mean plasma creatinine 48 h after ischaemia ( ± SEM) was 547 ± 54 μmol/l in controls, 686 ± 38 μmol/l with 0.1 mg/kg verapamil, 491 ± 68 μmol/l with 1.0 mg/kg verapamil and 374 ± 45 μmol/l with inosine (p < 0.05 vs. controls). Using the same model, the effect of verapamil 1.0 mg/kg on renal blood flow, creatinine clearance, urine flow and arterial pressure was studied in the first 2 h after ischaemia. Although significant amounts of verapamil were present in the kidney during ischaemia as evidenced by decreases in systemic blood pressure and in renal vascular resistance after unclamping the renal artery, the early course of renal failure was not altered when compared to controls. In conclusion, we have been unable to confirm earlier reports of a protective effect of verapamil in this rat model of ischaemic renal failure. If there is such an effect, its demonstration appears to depend on very specific experimental circumstances. Based on the results of this and other studies, verapamil is unlikely to afford an impressive overall benefit in the clinical setting of ischaemic renal failure.

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Section: Discussionsupporting

confidence: 90%

Failure of Verapamil to Protect from Ischaemic Renal Damage

Bock¹,

Brunner²,

Torhorst³

et al. 1991

Nephron

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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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“…Various agents, like mannitol [4,5], inosine [6,7], ATP-MgCh [8], tf-propanolol [5,9], renin antagonists [10] as well as salt-loading [11] and systemic alkalinization [./. Fitzpatrick and J.E.A.…”

Section: Introductionmentioning

confidence: 99%