This Article Full Text Full Text (PDF) All Versions of this Article: 109/11/1339    most recent 01.CIR.0000124450.07016.1Dv1 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Datta, B. Articles by James, P. Search for Related Content PubMed PubMed Citation Articles by Datta, B. Articles by James, P. Related Collections Congestive Endothelium/vascular type/nitric oxide

(Circulation. 2004;109:1339-1342.)
© 2004 American Heart Association, Inc.

Brief Rapid Communications

Red Blood Cell Nitric Oxide as an Endocrine Vasoregulator

A Potential Role in Congestive Heart Failure

Borunendra Datta, MRCP; Timothy Tufnell-Barrett, BSc; Robert A. Bleasdale, MRCP; Christopher J.H. Jones, FESC, FRCP; Ian Beeton, MRCP; Vincent Paul, MD, MRCP; Michael Frenneaux, MD, FRCP; Philip James, PhD

From the Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Cardiff (B.D., T.T.-B., R.A.B., C.J.H.J., M.F., P.J.) and Department of Cardiology, Ashford and St Peters NHS Trust, Surrey (I.B., V.P.), UK.

Correspondence to Dr P.E. James, Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN UK. E-mail Jamespp{at}Cardiff.ac.uk

Received September 12, 2003; de novo received November 27, 2003; revision received January 26, 2004; accepted February 3, 2004.

Background— A respiratory cycle for nitric oxide (NO) would involve the formation of vasoactive metabolites between NO and hemoglobin during pulmonary oxygenation. We investigated the role of these metabolites in hypoxic tissue in vitro and in vivo in healthy subjects and patients with congestive heart failure (CHF).

Methods and Results— We investigated the capacity for red blood cells (RBCs) to dilate preconstricted aortic rings under various O₂ tensions. RBCs induced cyclic guanylyl monophosphate–dependent vasorelaxation during hypoxia (35±4% at 1% O₂, 4.7±1.6% at 95% O₂; P<0.05). RBC-induced relaxations during hypoxia correlated with S-nitrosohemoglobin (SNO-Hb) (R²=0.88) but not iron nitrosylhemoglobin (HbFeNO) content. Relaxation responses for RBCs were compared with S-nitrosoglutathione across a range of O₂ tensions. The fold increases in relaxation evoked by RBCs were significantly greater at 1% and 2% O₂ compared with relaxations induced at 95% (P<0.05), consistent with an allosteric mechanism of hypoxic vasodilation. We also measured transpulmonary gradients of NO metabolites in healthy control subjects and in patients with CHF. In CHF patients but not control subjects, levels of SNO-Hb increase from 0.00293±0.00089 to 0.00585±0.00137 mol NO/mol hemoglobin tetramer (P=0.005), whereas HbFeNO decreases from 0.00361±0.00109 to 0.00081±0.00040 mol NO/mol hemoglobin tetramer (P=0.03) as hemoglobin is oxygenated in the pulmonary circulation. These metabolite gradients correlated with the hemoglobin O₂ saturation gradient (P<0.05) and inversely with cardiac index (P<0.05) for both CHF patients and control subjects.

Conclusions— We confirm that RBC-bound NO mediates hypoxic vasodilation in vitro. Transpulmonary gradients of hemoglobin-bound NO are evident in CHF patients and are inversely dependent on cardiac index. Hemoglobin may transport and release NO bioactivity to areas of tissue hypoxia or during increased peripheral oxygen extraction via an allosteric mechanism.

Key Words: heart failure • hypoxia • nitric oxide • vasodilation

This article has been cited by other articles:

				M. J. Thomson, M. P. Frenneaux, and J. C. Kaski Antioxidant treatment for heart failure: friend or foe? QJM, May 1, 2009; 102(5): 305 - 310. [Abstract] [Full Text] [PDF]

				Y.-Y. Chen, H.-M. Chu, K.-T. Pan, C.-H. Teng, D.-L. Wang, A. H.-J. Wang, K.-H. Khoo, and T.-C. Meng Cysteine S-Nitrosylation Protects Protein-tyrosine Phosphatase 1B against Oxidation-induced Permanent Inactivation J. Biol. Chem., December 12, 2008; 283(50): 35265 - 35272. [Abstract] [Full Text] [PDF]

				D. L. Diesen, D. T. Hess, and J. S. Stamler Hypoxic Vasodilation by Red Blood Cells: Evidence for an S-Nitrosothiol-Based Signal Circ. Res., August 29, 2008; 103(5): 545 - 553. [Abstract] [Full Text] [PDF]

				A. C. Frei, Y. Guo, D. W. Jones, K. A. Pritchard Jr, K. A. Fagan, N. Hogg, and N. J. Wandersee Vascular dysfunction in a murine model of severe hemolysis Blood, July 15, 2008; 112(2): 398 - 405. [Abstract] [Full Text] [PDF]

				S. C. Rogers, A. Khalatbari, B. N. Datta, S. Ellery, V. Paul, M. P. Frenneaux, and P. E. James NO metabolite flux across the human coronary circulation Cardiovasc Res, July 15, 2007; 75(2): 434 - 441. [Abstract] [Full Text] [PDF]

				P. Sonveaux, I. I. Lobysheva, O. Feron, and T. J. McMahon Transport and Peripheral Bioactivities of Nitrogen Oxides Carried by Red Blood Cell Hemoglobin: Role in Oxygen Delivery Physiology, April 1, 2007; 22(2): 97 - 112. [Abstract] [Full Text] [PDF]

				A. Doctor, B. Gaston, and D. B. Kim-Shapiro Detecting physiologic fluctuations in the S-nitrosohemoglobin micropopulation: triiodide versus 3C. Blood, November 1, 2006; 108(9): 3225 - 3227. [Full Text] [PDF]

				J. M. Zimmet and J. M. Hare Nitroso-Redox Interactions in the Cardiovascular System Circulation, October 3, 2006; 114(14): 1531 - 1544. [Full Text] [PDF]

				B. W. Allen and C. A. Piantadosi How do red blood cells cause hypoxic vasodilation? The SNO-hemoglobin paradigm Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1507 - H1512. [Abstract] [Full Text] [PDF]

				J.-P. Bin, A. Doctor, J. Lindner, E. M. Hendersen, D. E. Le, H. Leong-Poi, N. G. Fisher, J. Christiansen, and S. Kaul Effects of Nitroglycerin on Erythrocyte Rheology and Oxygen Unloading: Novel Role of S-Nitrosohemoglobin in Relieving Myocardial Ischemia Circulation, May 30, 2006; 113(21): 2502 - 2508. [Abstract] [Full Text] [PDF]

				A. Godecke On the impact of NO-globin interactions in the cardiovascular system Cardiovasc Res, February 1, 2006; 69(2): 309 - 317. [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]

				B. Piknova, M. T. Gladwin, A. N. Schechter, and N. Hogg Electron Paramagnetic Resonance Analysis of Nitrosylhemoglobin in Humans during NO Inhalation J. Biol. Chem., December 9, 2005; 280(49): 40583 - 40588. [Abstract] [Full Text] [PDF]

				T. J. McMahon, G. S. Ahearn, M. P. Moya, A. J. Gow, Y.-C. T. Huang, B. P. Luchsinger, R. Nudelman, Y. Yan, A. D. Krichman, T. M. Bashore, et al. A nitric oxide processing defect of red blood cells created by hypoxia: Deficiency of S-nitrosohemoglobin in pulmonary hypertension PNAS, October 11, 2005; 102(41): 14801 - 14806. [Abstract] [Full Text] [PDF]

				S. C. Rogers, A. Khalatbari, P. W. Gapper, M. P. Frenneaux, and P. E. James Detection of Human Red Blood Cell-bound Nitric Oxide J. Biol. Chem., July 22, 2005; 280(29): 26720 - 26728. [Abstract] [Full Text] [PDF]

				A. J. Gow Nitric Oxide, Hemoglobin, and Hypoxic Vasodilation Am. J. Respir. Cell Mol. Biol., June 1, 2005; 32(6): 479 - 482. [Full Text] [PDF]

				P. Sonveaux, A. M. Kaz, S. A. Snyder, R. A. Richardson, L. I. Cardenas-Navia, R. D. Braun, J. R. Pawloski, G. M. Tozer, J. Bonaventura, T. J. McMahon, et al. Oxygen Regulation of Tumor Perfusion by S-Nitrosohemoglobin Reveals a Pressor Activity of Nitric Oxide Circ. Res., May 27, 2005; 96(10): 1119 - 1126. [Abstract] [Full Text] [PDF]

				A. Doctor, R. Platt, M. L. Sheram, A. Eischeid, T. McMahon, T. Maxey, J. Doherty, M. Axelrod, J. Kline, M. Gurka, et al. Hemoglobin conformation couples erythrocyte S-nitrosothiol content to O2 gradients PNAS, April 19, 2005; 102(16): 5709 - 5714. [Abstract] [Full Text] [PDF]

				J. R. Pawloski, D. T. Hess, and J. S. Stamler Impaired vasodilation by red blood cells in sickle cell disease PNAS, February 15, 2005; 102(7): 2531 - 2536. [Abstract] [Full Text] [PDF]

				J. M. Hare Nitroso-Redox Balance in the Cardiovascular System N. Engl. J. Med., November 11, 2004; 351(20): 2112 - 2114. [Full Text] [PDF]

				P. E. James, T. Tufnell-Barret, A. B. Milsom, M. P. Frenneaux, and D. Lang Red Blood Cell-Mediated Hypoxic Vasodilatation: A Balanced Physiological Viewpoint Circ. Res., July 23, 2004; 95(2): e8 - e9. [Full Text] [PDF]

				M. W. Foster and J. S. Stamler New Insights into Protein S-Nitrosylation: MITOCHONDRIA AS A MODEL SYSTEM J. Biol. Chem., June 11, 2004; 279(24): 25891 - 25897. [Abstract] [Full Text] [PDF]