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(Circulation. 2008;117:1982-1990.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Inhaled Nitric Oxide Enables Artificial Blood Transfusion Without Hypertension

Binglan Yu, PhD; Michael J. Raher, BS; Gian Paolo Volpato, MD; Kenneth D. Bloch, MD; Fumito Ichinose, MD; Warren M. Zapol, MD

From the Anesthesia Center for Critical Care Research of the Department of Anesthesia and Critical Care (B.Y., M.J.R., G.P.V., K.D.B., F.I., W.M.Z.), and the Cardiovascular Research Center of the Department of Medicine (K.D.B., F.I.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Warren M. Zapol, MD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St, Thier 503, Boston, MA 02114. E-mail wzapol{at}partners.org

Received July 20, 2007; accepted February 15, 2008.

Background— One of the major obstacles hindering the clinical development of a cell-free, hemoglobin-based oxygen carrier (HBOC) is systemic vasoconstriction.

Methods and 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 117: 1909. [Full Text]