Recombinant human hemoglobin with reduced nitric oxide-scavenging capacity restores effectively pancreatic microcirculatory disorders in hemorrhagic shock.
BACKGROUND
Scavenging of nitric oxide by hemoglobin-based oxygen carriers could aggravate microcirculatory failure in splanchnic organs after hemorrhagic shock as a consequence of vasoconstrictive side effects. The aim of this study was to compare the effects of two recombinant human hemoglobin solutions, a second-generation product bearing reduced nitric oxide-scavenging properties (rHb2.0) due to site directed mutagenesis of the heme pocket and a first-generation recombinant hemoglobin (rHb1.1) with scavenging capacity similar to native hemoglobin, on the pancreatic microcirculation after hemorrhagic shock.


METHODS
Twenty-eight pentobarbital-anesthetized rats were bled to a mean arterial pressure of 40 mmHg and maintained at this level for 1 h. Using an intravital microscope, the length of erythrocyte-perfused pancreatic capillaries per observation area (functional capillary density) were measured in animals resuscitated by volumes of hydroxyethyl starch, rHb1.1, or rHb2.0 equivalent to the shed blood volume. Animals without shock induction served as control.


RESULTS
As compared with control (438 +/- 10 cm(-1)), animals treated with hydroxyethyl starch (315 +/- 44 cm(-1)) and rHb1.1 (288 +/- 67 cm(-1)) showed a significant reduction of functional capillary density after 2 h of resuscitation. rHb2.0 was able to restore functional capillary density (410 +/- 42 cm(-1)) and mean arterial pressure to baseline values.


CONCLUSIONS
rHb2.0 was effectively able to restore pancreatic microcirculation after hemorrhagic shock. This may be related to the compound's effective lack of nitric oxide-scavenging properties. This hemoglobin solution or ones similar to it might be uniquely valuable for resuscitation from hemorrhagic shock.
von Dobschuetz
Ernst
E
Department of General and Visceral Surgery, Albert-Ludwigs-University, Freiburg, Germany. ernst@von-dubshuetz.de
Hutter
Joerg
J
Hoffmann
Tomas
T
Messmer
Konrad
K
D000818:Animals; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000097:blood*; D006454:Hemoglobins / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood*; D010179:Pancreas / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D010182:Pancreatic Diseases / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D012771:Shock, Hemorrhagic / Q000097:blood / Q000188:drug therapy*
D016166:Free Radical Scavengers; D006454:Hemoglobins; D011994:Recombinant Proteins; D009569:Nitric Oxide