Artificial Red Cells : Physiological Importance of the Ligand Reaction Dynamism and the New Application for Ligand Therapy

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Chemically modified hemoglobin (Hb) solutions as artificial O_2 carriers show vasoconstriction and hypertension presumably due to the high affinity for endogenous NO and CO as vasorelaxation factors, and due to the faster O_2-release that induces autoregulatory vasoconstriction. On the other hand, cellular-type Hb-vesicle (HbV) does not induce such side effects. Herein we analyzed the reactions of ligand gaseous molecules by physicochemical techniques, and found out that HbV shows much slower reactions and it is due to the intracellular gas diffusion barrier induced by a concentrated Hb solution, and the retarded lateral diffusion of HbV when it flows in a narrow tube. In addition, we tested HbV as an exogenous CO carrier because endogenous CO is cytoprotective. After inducing hemorrhagic shock, rats were resuscitated with CO-bound HbV. It showed cytoprotective effect at reperfusion, and CO was dissociated rapidly and exhaled through the lung. No symptom related to toxicity of CO was detected. The results imply the possibility of artificial red cells for a new ligand therapy.