title: Red blood cells stored for increasing periods produce progressive impairments in nitric oxide-mediated vasodilation.
abstract: BACKGROUND
  Clinical outcomes in transfused patients may be affected by the duration of blood storage, possibly due to red blood cell (RBC)-mediated disruption of nitric oxide (NO) signaling, a key regulator of vascular tone and blood flow.
  
  
  METHODS
  AS-1 RBC units stored up to 42 days were sampled at selected storage times. Samples were added to aortic rings ex vivo, a system where NO-mediated vasodilation could be experimentally controlled.
  
  
  RESULTS
  RBC units showed storage-dependent changes in plasma hemoglobin (Hb), RBC 2,3-diphosphoglycerate acid, and RBC adenosine triphosphate conforming to expected profiles. When freshly collected (Day 0) blood was added to rat aortic rings, methacholine (MCh) stimulated substantial NO-mediated vasodilation. In contrast, MCh produced no vasodilation in the presence of blood stored for 42 days. Surprisingly, the vasoinhibitory effects of stored RBCs were almost totally mediated by RBCs themselves: removal of the supernatant did not attenuate the inhibitory effects, while addition of supernatant alone to the aortic rings only minimally inhibited MCh-stimulated relaxation. Stored RBCs did not inhibit vasodilation by a direct NO donor, demonstrating that the RBC-mediated vasoinhibitory mechanism did not work by NO scavenging.
  
  
  CONCLUSIONS
  These studies have revealed a previously unrecognized vasoinhibitory activity of stored RBCs, which is more potent than the described effects of free Hb and works through a different mechanism that does not involve NO scavenging but may function by reducing endothelial NO production. Through this novel mechanism, transfusion of small volumes of stored blood may be able to disrupt physiologic vasodilatory responses and thereby possibly cause adverse clinical outcomes.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, the Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Alexander
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, the Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: El-Ali
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, the Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: James L
authors.initials: JL
authors.lastname: Newman
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, the Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Sulaiman
authors.initials: S
authors.lastname: Karatela
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, the Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Predmore
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, the Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, the Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, the Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and the Atlanta Veterans Affairs Medical Center, Atlanta, Georgia.
authors.forename: John D
authors.initials: JD
authors.lastname: Roback
mesh_terms: D000255:Adenosine Triphosphate / Q000097:blood; D000818:Animals; D001793:Blood Preservation; D004912:Erythrocytes / Q000502:physiology*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D016210:Methacholine Chloride / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D006454:Hemoglobins; D016210:Methacholine Chloride; D009569:Nitric Oxide; D000255:Adenosine Triphosphate