title: Hemodynamic responses to a hemoglobin bis-tetramer and its polyethylene glycol conjugate.
abstract: BACKGROUND
  The design of hemoglobin-based oxygen carriers (HBOCs) poses a significant challenge as clinical trials of many materials have reported adverse side effects that may come from the scavenging of the vasodilator nitric oxide (NO). A compensating reaction, reduction of endogenous nitrite by hemoglobin (Hb) and its derivatives, generates NO. Polyethylene glycol (PEG) conjugation of Hb enhances the rate of the reaction.
  
  
  METHODS
  Hemoglobin bis-tetramers (BT) and their PEGylated derivative (BT-PEG) bind oxygen with a degree of cooperativity and also have significantly enhanced nitrite reductase activity compared to the native protein. Circulatory evaluation will test if the properties of BT and BT-PEG are reflected in their effects in vivo. BT and BT-PEG were evaluated as infusions into healthy wild-type (WT) and diabetic (db/db) mouse models. The effects were compared to infusions of murine Hb.
  
  
  RESULTS
  The materials were found not to cause significant increases in systemic blood pressure in either WT mice or db/db mice. The latter are highly sensitive to NO scavenging. Further hemodynamic measurements in WT mice indicate that while a slight increase in systemic vascular resistance (SVR) was observed after infusion of BT, the extent is not significant. No change in SVR from baseline was observed after infusion of BT-PEG.
  
  
  CONCLUSIONS
  The enlarged Hb derivatives do not evoke unfavorable circulatory responses that have been noted to result from infusion of Hb derivatives. These results suggest that a compromise between the P(50) , n(50) , and nitrite reductase activity of a Hb derivative can serve as the basis for producing HBOCs that can be tested for vasoactivity.
authors: Davenport Chemical Research Laboratories, Department of Chemistry, University of Toronto, Ontario, Canada.
authors: Francine E
authors: FE
authors: Lui
authors: Binglan
authors: B
authors: Yu
authors: David M
authors: DM
authors: Baron
authors: Chong
authors: C
authors: Lei
authors: Warren M
authors: WM
authors: Zapol
authors: Ronald
authors: R
authors: Kluger
mesh_terms: D000818:Animals; D006439:Hemodynamics / Q000187:drug effects*; D006454:Hemoglobins / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008706:Methemoglobin / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000494:pharmacology*
chemical_list: D006454:Hemoglobins; D011092:Polyethylene Glycols; D008706:Methemoglobin