Journal
CIRCULATION
Volume 117, Issue 15, Pages 1982-1990Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.107.729137
Keywords
endothelium; hemoglobin; hypertension; nitric oxide; vasoconstriction
Funding
- NHLBI NIH HHS [R01 HL042397, R01 HL042397-18, HL-42397] Funding Source: Medline
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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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