Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Nov;82(5):1694–1699. doi: 10.1172/JCI113782

Metabolic and functional consequences of inhibiting adenosine deaminase during renal ischemia in rats.

M E Stromski 1, A van Waarde 1, M J Avison 1, G Thulin 1, K M Gaudio 1, M Kashgarian 1, R G Shulman 1, N J Siegel 1
PMCID: PMC442739  PMID: 3263396

Abstract

The concentrations of renal ATP have been measured by 31P-nuclear magnetic resonance (NMR) before, during, and after bilateral renal artery occlusion. Using in vivo NMR, the initial postischemic recovery of ATP increased with the magnitude of the residual nucleotide pool at the end of ischemia. ATP levels after 120 min of reflow correlated with functional recovery at 24 h. In the present study the effect of blocking the degradation of ATP during ischemia upon the postischemic restoration of ATP was investigated. Inhibition of adenosine deaminase by 80% with the tight-binding inhibitor 2'-deoxycoformycin led to a 20% increase in the residual adenine nucleotide pool. This increased the ATP initial recovery after 45 min of ischemia from 52% (in controls) to 62% (in the treated animals), as compared to the basal levels. The inhibition also caused an accelerated postischemic restoration of cellular ATP so that at 120 min it was 83% in treated rats vs. 63% in untreated animals. There was a corresponding improvement in the functional recovery from the insult (increase of 33% in inulin clearance 24 h after the injury). Inhibition of adenosine deaminase during ischemia results in a injury similar to that seen after a shorter period of insult.

Full text

PDF
1694

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agarwal R. P., Parks R. E. Potent inhibition of muscle 5'-AMP deaminase by the nucleoside antibiotics coformycin and deoxycoformycin. Biochem Pharmacol. 1977 Apr 1;26(7):663–666. doi: 10.1016/0006-2952(77)90046-6. [DOI] [PubMed] [Google Scholar]
  2. Agarwal R. P., Spector T., Parks R. E., Jr Tight-binding inhibitors--IV. Inhibition of adenosine deaminases by various inhibitors. Biochem Pharmacol. 1977 Mar 1;26(5):359–367. doi: 10.1016/0006-2952(77)90192-7. [DOI] [PubMed] [Google Scholar]
  3. Burridge P. W., Paetkau V., Henderson J. F. Studies of the relationship between adenosine deaminase and immune function. J Immunol. 1977 Aug;119(2):675–678. [PubMed] [Google Scholar]
  4. Collins G. M., Green R. D., Carter J. N., Halasz N. A. Adenine nucleotide levels and recovery of function after renal ischemic injury. Transplantation. 1981 Apr;31(4):295–296. doi: 10.1097/00007890-198104000-00012. [DOI] [PubMed] [Google Scholar]
  5. Cunningham S. K., Keaveny T. V., Fitzgerald P. Effect of allopurinol on tissue ATP, ADP and AMP concentrations in renal ischaemia. Br J Surg. 1974 Jul;61(7):562–565. doi: 10.1002/bjs.1800610716. [DOI] [PubMed] [Google Scholar]
  6. Fernando A. R., Armstrong D. M., Griffiths J. R., Hendry W. F., O'Donoghue E. P., Perrett D., Ward J. P., Wickham J. E. Enhanced preservation of the ischaemic kidney with inosine. Lancet. 1976 Mar 13;1(7959):555–557. doi: 10.1016/s0140-6736(76)90356-1. [DOI] [PubMed] [Google Scholar]
  7. Foker J. E., Einzig S., Wang T. Adenosine metabolism and myocardial preservation. Consequences of adenosine catabolism on myocardial high-energy compounds and tissue blood flow. J Thorac Cardiovasc Surg. 1980 Oct;80(4):506–516. [PubMed] [Google Scholar]
  8. Gaudio K. M., Stromski M., Thulin G., Ardito T., Kashgarian M., Siegel N. J. Postischemic hemodynamics and recovery of renal adenosine triphosphate. Am J Physiol. 1986 Oct;251(4 Pt 2):F603–F609. doi: 10.1152/ajprenal.1986.251.4.F603. [DOI] [PubMed] [Google Scholar]
  9. Glazer R. I. Adenosine deaminase inhibitors: their role in chemotherapy and immunosuppression. Cancer Chemother Pharmacol. 1980;4(4):227–235. doi: 10.1007/BF00255266. [DOI] [PubMed] [Google Scholar]
  10. Hems D. A., Brosnan J. T. Effects of ischaemia on content of metabolites in rat liver and kidney in vivo. Biochem J. 1970 Nov;120(1):105–111. doi: 10.1042/bj1200105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Henderson J. F., Brox L., Zombor G., Hunting D., Lomax C. A. Specificity of adenosine deaminase inhibitors. Biochem Pharmacol. 1977 Nov 1;26(21):1967–1972. doi: 10.1016/0006-2952(77)90003-x. [DOI] [PubMed] [Google Scholar]
  12. Hopkinson D. A., Cook P. J., Harris H. Further data on the adenosine deaminase (ADA) polymprphism and a report of a new phenotype. Ann Hum Genet. 1969 May;32(4):361–367. doi: 10.1111/j.1469-1809.1969.tb00087.x. [DOI] [PubMed] [Google Scholar]
  13. Kaufman J. M., Siegel N. J., Hayslett J. P. Functional and hemodynamic adaptation to progressive renal ablation. Circ Res. 1975 Feb;36(2):286–293. doi: 10.1161/01.res.36.2.286. [DOI] [PubMed] [Google Scholar]
  14. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  15. Miller W. L., Thomas R. A., Berne R. M., Rubio R. Adenosine production in the ischemic kidney. Circ Res. 1978 Sep;43(3):390–397. doi: 10.1161/01.res.43.3.390. [DOI] [PubMed] [Google Scholar]
  16. Nelson S. R., Schulz D. W., Passonneau J. V., Lowry O. H. Control of glycogen levels in brain. J Neurochem. 1968 Nov;15(11):1271–1279. doi: 10.1111/j.1471-4159.1968.tb05904.x. [DOI] [PubMed] [Google Scholar]
  17. Paller M. S., Hoidal J. R., Ferris T. F. Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest. 1984 Oct;74(4):1156–1164. doi: 10.1172/JCI111524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Siegel N. J., Avison M. J., Reilly H. F., Alger J. R., Shulman R. G. Enhanced recovery of renal ATP with postischemic infusion of ATP-MgCl2 determined by 31P-NMR. Am J Physiol. 1983 Oct;245(4):F530–F534. doi: 10.1152/ajprenal.1983.245.4.F530. [DOI] [PubMed] [Google Scholar]
  19. Stromski M. E., Cooper K., Thulin G., Avison M. J., Gaudio K. M., Shulman R. G., Siegel N. J. Postischemic ATP-MgCl2 provides precursors for resynthesis of cellular ATP in rats. Am J Physiol. 1986 May;250(5 Pt 2):F834–F837. doi: 10.1152/ajprenal.1986.250.5.F834. [DOI] [PubMed] [Google Scholar]
  20. Stromski M. E., Cooper K., Thulin G., Gaudio K. M., Siegel N. J., Shulman R. G. Chemical and functional correlates of postischemic renal ATP levels. Proc Natl Acad Sci U S A. 1986 Aug;83(16):6142–6145. doi: 10.1073/pnas.83.16.6142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Tedde A., Balis M. E., Schonberg R., Trotta P. P. Effects of 2'-deoxycoformycin infusion on mouse adenosine deaminase. Cancer Res. 1979 Aug;39(8):3044–3050. [PubMed] [Google Scholar]
  22. Trotta P. P., Ahland M. P., Brown G. F., Balis M. E. Studies on the effects of infusion of enzyme inhibitors on mouse adenosine deaminase. Mol Pharmacol. 1978 Jan;14(1):199–209. [PubMed] [Google Scholar]
  23. Vogt M. T., Farber E. On the molecular pathology of ischemic renal cell death. Reversible and irreversible cellular and mitochondrial metabolic alterations. Am J Pathol. 1968 Jul;53(1):1–26. [PMC free article] [PubMed] [Google Scholar]
  24. Ward H. B., Wang T., Einzig S., Bianco R. W., Foker J. E. Prevention of ATP catabolism during myocardial ischemia: a preliminary report. J Surg Res. 1983 Apr;34(4):292–297. doi: 10.1016/0022-4804(83)90074-4. [DOI] [PubMed] [Google Scholar]
  25. Warnick C. T., Lazarus H. M. Recovery of nucleotide levels after cell injury. Can J Biochem. 1981 Feb;59(2):116–121. doi: 10.1139/o81-017. [DOI] [PubMed] [Google Scholar]
  26. Zager R. A., Baltes L. A., Sharma H. M., Jurkowitz M. S. Responses of the ischemic acute renal failure kidney to additional ischemic events. Kidney Int. 1984 Nov;26(5):689–700. doi: 10.1038/ki.1984.204. [DOI] [PubMed] [Google Scholar]
  27. Zager R. A., Jurkowitz M. S., Merola A. J. Responses of the normal rat kidney to sequential ischemic events. Am J Physiol. 1985 Jul;249(1 Pt 2):F148–F159. doi: 10.1152/ajprenal.1985.249.1.F148. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES