In the final two years, June 1991 to June 1993, of the Letterman Army Institute of Research, a variety of cell, tissue, organ, and animal systems were used to explore the toxicities of model
hemoglobin (Hb) solutions produced in the sterile Hb production facility. Human mononuclear cells release
TNF alpha and
Il-8 when exposed to chromatographically purified human Hb (
HbA0). Mixed cultures of fetal mouse neurons and glial cells exhibit neuronal death with exposure to
HbA0 in a dose and time dependent manner while the glial cells are not injured. Isolated perfused rabbit hearts were used to explore the reversibility of coronary vasoconstriction after Hb and cyanomet-Hb administration, and
deferoxamine was shown to partially protect that reversibility. In rabbits
HbA0 and human Hb cross-linked with bis(3,5-dibromosalicyl)
fumarate (
alpha alpha Hb) caused
hypertension and pulmonary
arteritis. In swine,
HbA0 and
alpha alpha Hb caused systemic and
pulmonary hypertension and a doubling of the vascular resistance that was equivalent to that seen with inhibition of
nitric oxide synthesis. Elevations of
creatine kinase and lactic
dehydrogenase activity were observed after Hbs were infused, but not after blockade of
nitric oxide synthesis.
Acute renal failure seen after administration
HbA0, did not appear after
alpha alpha Hb. Infusion of cyanomet-
alpha alpha Hb did not cause the increased vascular resistance seen after
alpha alpha Hb. The infusion of 1-arginine or nitroglycerine with
alpha alpha Hb did not prevent the increased vascular resistance and decreased cardiac output or allow the increased
oxygen carrying capacity provided by Hb in the plasma from translating into improved
oxygen delivery or improved oxygen consumption.