Endothelial dysfunction enhances vasoconstriction due to scavenging of nitric oxide by a hemoglobin-based oxygen carrier.
BACKGROUND
To date, there is no safe and effective hemoglobin-based oxygen carrier (HBOC) to substitute for erythrocyte transfusion. It is uncertain whether a deficiency of endothelial nitric oxide bioavailability (endothelial dysfunction) prevents or augments HBOC-induced vasoconstriction.


METHODS
Hemodynamic effects of infusion of PolyHeme (1.08 g hemoglobin/kg; Northfield Laboratories, Evanston, IL) or murine tetrameric hemoglobin (0.48 g hemoglobin/kg) were determined in awake healthy lambs, awake mice, and anesthetized mice. In vitro, a cumulative dose-tension response was obtained by sequential addition of PolyHeme or tetrameric hemoglobin to phenylephrine-precontracted murine aortic rings.


RESULTS
Infusion of PolyHeme did not cause systemic hypertension in awake lambs but produced acute systemic and pulmonary vasoconstriction. Infusion of PolyHeme did not cause systemic hypertension in healthy wild-type mice but induced severe systemic vasoconstriction in mice with endothelial dysfunction (either db/db mice or high-fat fed wild-type mice for 4-6 weeks). The db/db mice were more sensitive to systemic vasoconstriction than wild-type mice after the infusion of either tetrameric hemoglobin or PolyHeme. Murine aortic ring studies confirmed that db/db mice have an impaired response to an endothelial-dependent vasodilator and an enhanced vasoconstrictor response to HBOC.


CONCLUSIONS
Reduction in low molecular weight hemoglobin concentrations to less than 1% is insufficient to abrogate the vasoconstrictor effects of HBOC infusion in healthy awake sheep or in mice with reduced vascular nitric oxide levels associated with endothelial dysfunction. These findings suggest that testing HBOCs in animals with endothelial dysfunction can provide a more sensitive indication of their potential vasoconstrictor effects.
Yu
Binglan
B
Anesthesia Center for Critical Care Research, Department of Anesthesia, Wellman Center of Photomedicine, Boston, Massachusetts, USA.
Shahid
Mohd
M
Egorina
Elena M
EM
Sovershaev
Mikhail A
MA
Raher
Michael J
MJ
Lei
Chong
C
Wu
Mei X
MX
Bloch
Kenneth D
KD
Zapol
Warren M
WM
D000280:Administration, Inhalation; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001802:Blood Substitutes / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D003432:Cross-Linking Reagents; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006454:Hemoglobins / Q000494:pharmacology*; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D010100:Oxygen / Q000097:blood*; D012756:Sheep; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D001802:Blood Substitutes; D003432:Cross-Linking Reagents; D006454:Hemoglobins; C509893:PolyHeme; D009569:Nitric Oxide; D010100:Oxygen