Inhaled nitric oxide enables artificial blood transfusion without hypertension.
BACKGROUND
One of the major obstacles hindering the clinical development of a cell-free, hemoglobin-based oxygen carrier (HBOC) is systemic vasoconstriction.


RESULTS
Experiments were performed in healthy mice and lambs by infusion of either murine tetrameric hemoglobin (0.48 g/kg) or glutaraldehyde-polymerized bovine hemoglobin (HBOC-201, 1.44 g/kg). We observed that intravenous infusion of either murine tetrameric hemoglobin or HBOC-201 induced prolonged systemic vasoconstriction in wild-type mice but not in mice congenitally deficient in endothelial nitric oxide (NO) synthase (NOS3). Treatment of wild-type mice by breathing NO at 80 ppm in air for 15 or 60 minutes or with 200 ppm NO for 7 minutes prevented the systemic hypertension induced by subsequent intravenous administration of murine tetrameric hemoglobin or HBOC-201 and did not result in conversion of plasma hemoglobin to methemoglobin. Intravenous administration of sodium nitrite (48 nmol) 5 minutes before infusion of murine tetrameric hemoglobin also prevented the development of systemic hypertension. In awake lambs, breathing NO at 80 ppm for 1 hour prevented the systemic hypertension caused by subsequent infusion of HBOC-201.


CONCLUSIONS
These findings demonstrate that HBOC can cause systemic vasoconstriction by scavenging NO produced by NOS3. Moreover, in 2 species, inhaled NO administered before the intravenous infusion of HBOC can prevent systemic vasoconstriction without causing methemoglobinemia.
Yu
Binglan
B
Anesthesia Center for Critical Care Research of the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Raher
Michael J
MJ
Volpato
Gian Paolo
GP
Bloch
Kenneth D
KD
Ichinose
Fumito
F
Zapol
Warren M
WM
D000280:Administration, Inhalation; D000818:Animals; D001802:Blood Substitutes / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D001803:Blood Transfusion; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control*; D007262:Infusions, Intravenous; D008708:Methemoglobinemia / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D011292:Premedication; D012756:Sheep; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D014851:Wakefulness
D001802:Blood Substitutes; D006454:Hemoglobins; D014665:Vasodilator Agents; C096798:HBOC 201; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D012977:Sodium Nitrite