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. 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.