The effect of hemoglobin carbamylation on the survival of human sickle cell erythrocytes in rats.

The in vitro incubation of human sickle cell erythrocytes (SS RBCs) with sodium cyanate results in significant prolongation of their 'Cr intravascular survival (1, 2). This effect appears to be mediated through carbamylation of the amino terminal valine residue in the hemoglobin S molecule which results in inhibition of erythrocyte sickling (3). Initial clinical studies have shown that the oral administration of sodium cyanate to patients with homozygous sickle cell disease also increases erythrocyte survival and leads to improvement in anemia (4, 5). Sickle cell crises, however, continue to occur in the cyanate treated patients (5). This observation raises serious questions regarding the effectiveness of cyanate treatment in the prevention of localized intravascular sickling, and in the overall clinical management of patients with sickle cell disease. Pretreatment of rats with (a) ethyl palmitate (EP) which blocks the reticuloendothelial system and produces acute splenic necrosis, and (b) cobra venom factor (CVF) which inhibits the third component of complement has resulted in the development of an animal system suitable for study of the intravascular survival of human erythrocytes (6). It now has been shown that two important similarities exist between the behavior of SS RBCs in humans and the behavior of SS RBCs transfused into rats which have been pretreated with EP and CVF (7). The first is that SS RBCs have a significantly shorter 5'Cr life span than that of control RBCs. Secondly, exposure of rats which had been breathing 100% O. to a hypoxic environment results in the rapid loss from circulation of from 30-60% of the transfused human SS RBCs. These observations suggest that the rat model might be of value in determining the effectiveness of antisickling drugs in the prevention of accelerated SS RBC loss from circulation during hypoxia. The immediate objectives of our experiments were to determine the effect of cyanate treatment of human SS RBCs on their survival in the rat model and, more importantly, the behavior of carbamylated human SS RBCs in th^ rat during the stress of hypoxia.