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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1375-1382. Prepublished online as a Blood First Edition Paper on May 18, 2004; DOI 10.1182/blood-2004-03-0880. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-0880v1 104/5/1375    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Crawford, J. H. Articles by Patel, R. P. Search for Related Content PubMed PubMed Citation Articles by Crawford, J. H. Articles by Patel, R. P. Related Collections Hemostasis, Thrombosis, and Vascular Biology Red Cells Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Transduction of NO-bioactivity by the red blood cell in sepsis: novel mechanisms of vasodilation during acute inflammatory disease Jack H. Crawford, Balu K. Chacko, Heather M. Pruitt, Barbora Piknova, Neil Hogg, and Rakesh P. Patel From the Department of Pathology and the Center for Free Radical Biology, University of Alabama at Birmingham; and the Department of Biophysics and the Free Radical Research Center, Medical College of Wisconsin, Milwaukee. Sepsis is an acute inflammatory disease characterized by dysfunctional blood flow and hypotension. Nitric oxide (NO) is elevated during sepsis and plays an integral role in the associated vascular pathology. However, precise mechanisms and functions of NO in sepsis remain unclear. In this study, we show that red blood cells (RBCs) are foci for nitrosative reactions during acute inflammation, resulting in the formation of cells that can promote systemic vascular relaxation in an uncontrolled manner. Specifically, using experimental models of endotoxemia and surgical sepsis, NO adducts were found in the RBCs, including S-nitrosohemoglobin (SNOHb). These RBCs, referred to as septic RBCs, spontaneously stimulated vasodilation in a manner consistent with elevated SNOHb concentrations. Moreover, relaxation was cyclic guanosine monophosphate (cGMP) dependent and was inhibited by RBC lysis and glutathione but not by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline 1-oxyl 3-oxide (C-PTIO). The potential mechanism of septic RBC–mediated vasorelaxation is discussed and may involve the intermediate, nitroxyl (HNO). Coupled with data showing that NO adducts in septic RBCs were dependent on the inducible nitric oxide synthase and correlated with plasma nitrite, these findings provide a novel framework to understand mechanisms underlying dysfunctional blood flow responses during sepsis. Specifically, the concept that RBCs directly mediate systemic hypotension through NO-dependent mechanisms is discussed. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. D. Reynolds, G. S. Ahearn, M. Angelo, J. Zhang, F. Cobb, and J. S. Stamler S-nitrosohemoglobin deficiency: A mechanism for loss of physiological activity in banked blood PNAS, October 23, 2007; 104(43): 17058 - 17062. [Abstract] [Full Text] [PDF] E. Bennett-Guerrero, T. H. Veldman, A. Doctor, M. J. Telen, T. L. Ortel, T. S. Reid, M. A. Mulherin, H. Zhu, R. D. Buck, R. M. Califf, et al. 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[Abstract] [Full Text] [PDF] J. H. Crawford, T. S. Isbell, Z. Huang, S. Shiva, B. K. Chacko, A. N. Schechter, V. M. Darley-Usmar, J. D. Kerby, J. D. Lang Jr, D. Kraus, et al. Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation Blood, January 15, 2006; 107(2): 566 - 574. [Abstract] [Full Text] [PDF] T. J. McMahon and A. Doctor Extrapulmonary effects of inhaled nitric oxide: role of reversible s-nitrosylation of erythrocytic hemoglobin. Proceedings of the ATS, January 1, 2006; 3(2): 153 - 160. [Abstract] [Full Text] [PDF] A. Dejam, C. J. Hunter, M. M. Pelletier, L. L. Hsu, R. F. Machado, S. Shiva, G. G. Power, M. Kelm, M. T. Gladwin, and A. N. Schechter Erythrocytes are the major intravascular storage sites of nitrite in human blood Blood, July 15, 2005; 106(2): 734 - 739. [Abstract] [Full Text] [PDF] F. J. Schopfer, P. R. S. Baker, G. Giles, P. Chumley, C. Batthyany, J. Crawford, R. P. Patel, N. Hogg, B. P. Branchaud, J. R. Lancaster Jr., et al. 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