BACKGROUND: Vasoconstriction, an inherent property of Hemoglobin Based Oxygen Carriers (HBOC) potentially due to nitric oxide (NO) scavenging, may increase cardiovascular complications in HBOC resuscitated trauma patients. The purpose of this study was to determine if co-administration of a weak NO donor, intravenous nitroglycerin (NTG), with HBOC-201 during resuscitation from hemorrhagic shock could safely attenuate HBOC-201 vasoconstriction. METHODS AND RESULTS: Hemorrhagic shock was induced in 44 swine randomized to receive fluid resuscitation with HBOC, HBOC+NTG10 mcg/kg/min, HBOC+NTG20 mcg/kg/min, HBOC+NTG40 mcg/kg/min, Hetastarch (HES), HES+NTG20 mcg/kg/min, NTG20 mcg/kg/min and Lactated Ringers (LR). HBOC resuscitation from hemorrhagic shock increased mean arterial pressure (MAP=94+/-33 mmHg), mean pulmonary artery pressure (MPAP=29+/-11 mmHg) and systemic vascular resistance (SVR=2684+/-871 dyns/cm(5)) in comparison to HES. Co-administration of NTG during HBOC resuscitation attenuated vasoconstriction with HBOC+40 mcg/kg/min demonstrating the most robust reduction in vasoconstriction (MAP=59+/-23 mmHg, MPAP=18+/-7 mmHg, and SVR=1827+/-511 dyns/cm(5)), although the effects were transient. Co-administration of NTG with HBOC did not alter base deficit, lactate, methemoglobin levels, nor cause profound hypotension during resuscitation. CONCLUSION: Nitroglycerin attenuates vasoconstrictive properties of HBOC when co-administered during resuscitation in this swine model of hemorrhagic shock. Translational survival studies are required to determine if this strategy of attenuation of the vasoconstriction of HBOC-201 reduces cardiovascular complications and improves outcome with HBOC fluid resuscitation for hemorrhagic shock.