Pharmacological and physicochemical factors in the pressor effects of conjugated haemoglobin-based oxygen carriers in vivo.
BACKGROUND
The hypertension induced by haemoglobin-based oxygen carriers could be a result of different pharmacological and physicochemical factors.


OBJECTIVE
To investigate whether production of superoxide anion (O2*-) and release of endothelin could be the factors responsible.


METHODS
We studied the variation in mean arterial pressure (MAP) in guinea pigs by carrying out a 50% isovolaemic exchange transfusion with conjugated oxyhaemoglobin (non-oxidized form) or conjugated methaemoglobin (fully oxidized form) in the presence or absence of BQ-788 (5 nmol/l), an endothelin receptor type B (ETR-B) antagonist. At key timepoints of variation in MAP, the plasma concentrations of O2*- were measured. The presence of conjugated oxyhaemoglobin and increases in ETR-B concentrations inside the vascular wall were investigated in different vessels, using western blotting.


RESULTS
We found that the administration of conjugated oxyhaemoglobin induced a significant increase in MAP, whereas conjugated methaemoglobin had no significant haemodynamic effect. Pretreatment with BQ-788 attenuated the increase in MAP induced by conjugated oxyhaemoglobin. This haemoglobin induced the production of high concentrations of O2*- that declined towards control values after 120 min and decreased in the presence of BQ-788. Western blot analysis showed that the presence of conjugated oxyhaemoglobin inside the vascular wall was time-dependent and correlated with increased ETR-B.


CONCLUSIONS
These results show that the release of O2*- during auto-oxidation of conjugated oxyhaemoglobin is associated with the observed increase in MAP, which may be a result of the vasoconstriction caused by an increase in activation of ETR-B. This activation may be caused by the massive release of endothelin induced by the production of O2*-.
Smani
Younes
Y
Laboratoire d'Hématologie et de Physiologie, EA 3452, Faculté de Pharmacie, Université Henri Poincaré-Nancy I, Université de Nancy, France. younes.smani@pharma.uhp-nancy.fr
Fifre
Alexandre
A
Labrude
Pierre
P
Vigneron
Claude
C
Faivre
Béatrice
B
D000818:Animals; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects*; D001802:Blood Substitutes / Q000494:pharmacology*; D016232:Endothelins / Q000378:metabolism; D006168:Guinea Pigs; D006973:Hypertension / Q000209:etiology; D008297:Male; D008706:Methemoglobin / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D044023:Receptor, Endothelin B / Q000187:drug effects*; D013481:Superoxides / Q000097:blood*
D000959:Antihypertensive Agents; D001802:Blood Substitutes; D016232:Endothelins; D009842:Oligopeptides; D010108:Oxyhemoglobins; D010880:Piperidines; D044023:Receptor, Endothelin B; D013481:Superoxides; C086539:BQ 788; D008706:Methemoglobin