title: Direct sGC activation bypasses NO scavenging reactions of intravascular free oxy-hemoglobin and limits vasoconstriction.
abstract: OBJECTIVE
  Hemoglobin-based oxygen carriers (HBOC) provide a potential alternative to red blood cell (RBC) transfusion. Their clinical application has been limited by adverse effects, in large part thought to be mediated by the intravascular scavenging of the vasodilator nitric oxide (NO) by cell-free plasma oxy-hemoglobin. Free hemoglobin may also cause endothelial dysfunction and platelet activation in hemolytic diseases and after transfusion of aged stored RBCs. The new soluble guanylate cyclase (sGC) stimulator Bay 41-8543 and sGC activator Bay 60-2770 directly modulate sGC, independent of NO bioavailability, providing a potential therapeutic mechanism to bypass hemoglobin-mediated NO inactivation.
  
  
  RESULTS
  Infusions of human hemoglobin solutions and the HBOC Oxyglobin into rats produced a severe hypertensive response, even at low plasma heme concentrations approaching 10 μM. These reactions were only observed for ferrous oxy-hemoglobin and not analogs that do not rapidly scavenge NO. Infusions of L-NG-Nitroarginine methyl ester (L-NAME), a competitive NO synthase inhibitor, after hemoglobin infusion did not produce additive vasoconstriction, suggesting that vasoconstriction is related to scavenging of vascular NO. Open-chest hemodynamic studies confirmed that hypertension occurred secondary to direct effects on increasing vascular resistance, with limited negative cardiac inotropic effects. Intravascular hemoglobin reduced the vasodilatory potency of sodium nitroprusside (SNP) and sildenafil, but had no effect on vasodilatation by direct NO-independent activation of sGC by BAY 41-8543 and BAY 60-2770.
  
  
  CONCLUSIONS
  These data suggest that both sGC stimulators and sGC activators could be used to restore cyclic guanosine monophosphate-dependent vasodilation in conditions where cell-free plasma hemoglobin is sufficient to inhibit endogenous NO signaling.
authors.affiliation: 1 Laboratory of Experimental Anesthesiology, Department of Anesthesiology, Erasmus MC-University Medical Center Rotterdam , Rotterdam, The Netherlands .
authors.forename: Nicolaas J H
authors.initials: NJ
authors.lastname: Raat
authors.forename: D Marcela
authors.initials: DM
authors.lastname: Tabima
authors.forename: Patricia A C
authors.initials: PA
authors.lastname: Specht
authors.forename: Jesús
authors.initials: J
authors.lastname: Tejero
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Kim-Shapiro
authors.forename: Jeff
authors.initials: J
authors.lastname: Baust
authors.forename: Egbert G
authors.initials: EG
authors.lastname: Mik
authors.forename: Mariana
authors.initials: M
authors.lastname: Hildesheim
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Becker
authors.forename: Hubert
authors.initials: H
authors.lastname: Truebel
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010108:Oxyhemoglobins / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; C450679:BAY 41-8543; D001565:Benzoates; D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D006845:Hydrocarbons, Fluorinated; D009025:Morpholines; D010108:Oxyhemoglobins; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase