Hemodynamic responses to a hemoglobin bis-tetramer and its polyethylene glycol conjugate

Transfusion. 2012 May;52(5):974-82. doi: 10.1111/j.1537-2995.2011.03421.x. Epub 2011 Nov 9.

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.

Study design and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hemodynamics / drug effects*
  • Hemoglobins / analysis
  • Hemoglobins / chemistry
  • Hemoglobins / pharmacology*
  • Male
  • Methemoglobin / analysis
  • Mice
  • Mice, Inbred C57BL
  • Polyethylene Glycols / pharmacology*

Substances

  • Hemoglobins
  • Polyethylene Glycols
  • Methemoglobin