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. 1990 Nov;86(5):1768–1771. doi: 10.1172/JCI114904

Role of endothelium-derived nitric oxide in the bleeding tendency of uremia.

G Remuzzi 1, N Perico 1, C Zoja 1, D Corna 1, D Macconi 1, G Viganò 1
PMCID: PMC296932  PMID: 2243146

Abstract

Endothelium-derived relaxing factor, now identified as nitric oxide (NO), is a labile humoral agent formed by vascular endothelial cells from L-arginine. NO mediates the action of substances that induce endothelium-dependent relaxation and plays a role in regulating blood pressure. In this study we investigated whether NO is involved in the pathogenesis of the bleeding tendency associated with renal failure. Rats with extensive surgical ablation of renal mass develop renal insufficiency due to progressive glomerulosclerosis. Like uremic humans, rats with renal mass reduction and uremia have a bleeding tendency that manifests itself by a prolonged bleeding time. We found that N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO formation from L-arginine, completely normalized bleeding time when given to uremic rats. L-NMMA injection also increased ex vivo platelet adhesion but did not affect ex vivo platelet aggregation induced by adenosine diphosphate, arachidonic acid, and calcium ionophore A23187. The shortening effect of L-NMMA on bleeding time was completely reversed by giving the animals the NO precursor L-arginine, but not D-arginine, which is not a precursor of NO. It thus appears that NO is a mediator of the bleeding tendency of uremia.

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Selected References

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

  1. Deykin D. Uremic bleeding. Kidney Int. 1983 Nov;24(5):698–705. doi: 10.1038/ki.1983.214. [DOI] [PubMed] [Google Scholar]
  2. Evans E. P., Branch R. A., Bloom A. L. A clinical and experimental study of platelet function in chronic renal failure. J Clin Pathol. 1972 Sep;25(9):745–753. doi: 10.1136/jcp.25.9.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. FERGUSON J. H., LEWIS J. H., ZUCKER M. B. Bleeding tendency in uremia. Blood. 1956 Dec;11(12):1073–1076. [PubMed] [Google Scholar]
  4. Hellem A. J. Platelet adhesiveness in von Willebrand's disease. A study with a new modification of the glass bead filter method. Scand J Haematol. 1970;7(5):374–382. [PubMed] [Google Scholar]
  5. Hostetter T. H., Olson J. L., Rennke H. G., Venkatachalam M. A., Brenner B. M. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol. 1981 Jul;241(1):F85–F93. doi: 10.1152/ajprenal.1981.241.1.F85. [DOI] [PubMed] [Google Scholar]
  6. Ignarro L. J. Endothelium-derived nitric oxide: actions and properties. FASEB J. 1989 Jan;3(1):31–36. doi: 10.1096/fasebj.3.1.2642868. [DOI] [PubMed] [Google Scholar]
  7. Olson J. L., Hostetter T. H., Rennke H. G., Brenner B. M., Venkatachalam M. A. Altered glomerular permselectivity and progressive sclerosis following extreme ablation of renal mass. Kidney Int. 1982 Aug;22(2):112–126. doi: 10.1038/ki.1982.143. [DOI] [PubMed] [Google Scholar]
  8. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  9. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  10. Palmer R. M., Moncada S. A novel citrulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jan 16;158(1):348–352. doi: 10.1016/s0006-291x(89)80219-0. [DOI] [PubMed] [Google Scholar]
  11. Palmer R. M., Rees D. D., Ashton D. S., Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun. 1988 Jun 30;153(3):1251–1256. doi: 10.1016/s0006-291x(88)81362-7. [DOI] [PubMed] [Google Scholar]
  12. Pfeffer J. M., Pfeffer M. A., Frohlich E. D. Validity of an indirect tail-cuff method for determining systolic arterial pressure in unanesthetized normotensive and spontaneously hypertensive rats. J Lab Clin Med. 1971 Dec;78(6):957–962. [PubMed] [Google Scholar]
  13. Radomski M. W., Palmer R. M., Moncada S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun. 1987 Nov 13;148(3):1482–1489. doi: 10.1016/s0006-291x(87)80299-1. [DOI] [PubMed] [Google Scholar]
  14. Rees D. D., Palmer R. M., Hodson H. F., Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol. 1989 Feb;96(2):418–424. doi: 10.1111/j.1476-5381.1989.tb11833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Rees D. D., Palmer R. M., Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A. 1989 May;86(9):3375–3378. doi: 10.1073/pnas.86.9.3375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Remuzzi G. Bleeding in renal failure. Lancet. 1988 May 28;1(8596):1205–1208. doi: 10.1016/s0140-6736(88)92019-3. [DOI] [PubMed] [Google Scholar]
  17. Remuzzi G., Livio M., Marchiaro G., Mecca G., de Gaetano G. Bleeding in renal failure: altered platelet function in chronic uraemia only partially corrected by haemodialysis. Nephron. 1978;22(4-6):347–353. doi: 10.1159/000181474. [DOI] [PubMed] [Google Scholar]
  18. Salzman E. W., Neri L. L. Adhesiveness of blood platelets in uremia. Thromb Diath Haemorrh. 1966 Jan 31;15(1):84–92. [PubMed] [Google Scholar]
  19. Steiner R. W., Coggins C., Carvalho A. C. Bleeding time in uremia: a useful test to assess clinical bleeding. Am J Hematol. 1979;7(2):107–117. doi: 10.1002/ajh.2830070203. [DOI] [PubMed] [Google Scholar]
  20. Vanhoutte P. M., Shimokawa H. Endothelium-derived relaxing factor and coronary vasospasm. Circulation. 1989 Jul;80(1):1–9. doi: 10.1161/01.cir.80.1.1. [DOI] [PubMed] [Google Scholar]
  21. Zoja C., Perico N., Bergamelli A., Pasini M., Morigi M., Dadan J., Belloni A., Bertani T., Remuzzi G. Ticlopidine prevents renal disease progression in rats with reduced renal mass. Kidney Int. 1990 Mar;37(3):934–942. doi: 10.1038/ki.1990.68. [DOI] [PubMed] [Google Scholar]
  22. Zoja C., Viganò G., Bergamelli A., Benigni A., de Gaetano G., Remuzzi G. Prolonged bleeding time and increased vascular prostacyclin in rats with chronic renal failure: effects of conjugated estrogens. J Lab Clin Med. 1988 Sep;112(3):380–386. [PubMed] [Google Scholar]

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