sodium-cyanate and Anemia--Sickle-Cell

Sodium cyanate (NaOCN) first appeared on the biomedical scene as a potential therapeutic agent for sickle-cell disease. Although it did not fulfill its early promise in the clinic, it proved to be useful as a pharmacological tool in physiological research, particularly in the physiology of oxygen transport. NaOCN has been especially valuable in the area of investigation which is reviewed here: the study of oxygen transport, both in normoxic and in hypoxic conditions, in experimental models in which NaOCN was used to induce a shift to the left of the oxygen dissociation curve. The classical idea is that a low Hb-O2 affinity is of adaptive value for life at high altitudes but it has been challenged by several pieces of evidence. One of them is the demonstration of increased survival in hypoxic hypoxia of animals with a high Hb-O2 affinity induced by NaOCN. We also discuss the advantages and potentially confounding factors which should be taken into consideration when interpreting results of studies in which the oxygen dissociation curve has been modified by administration of NaOCN.

Topics: Altitude; Anemia, Sickle Cell; Animals; Cyanates; Embryonic and Fetal Development; Erythropoiesis; Hemoglobins; Humans; Hypoxia; Pulmonary Ventilation

Topics: Anemia, Sickle Cell; Antisickling Agents; Azacitidine; Cyanates; Erythrocyte Deformability; Erythrocytes, Abnormal; Genetic Engineering; Glyceraldehyde; Hemoglobin, Sickle; Humans; Mechlorethamine; Renal Dialysis

The effects of carbamylation and frozen storage on the autologous 51Cr survival and metabolic features of sickle erythrocytes (S-RBCs) were determined. Red cells from four patients with sickle hemoglobinopathies were treated with 50 mM sodium cyanate for 2 hr (37 degrees C), glycerolized and frozen (-80 degrees C) for 62-153 days. The mean in vitro loss of S-RBCs from the combination of cyanate treatment and cryopreservation was 23.6% ( +/- 3.5 SD). The 2,3-diphosphoglycerate content of the thawed cells did not change significantly. However, ATP levels decreased to about 50% of the corresponding values in fresh, untreated S-RBCs. Despite this decrease in ATP, the mean intravascular survival of the frozen cyanated cells nearly doubled. At the high concentration of cyanate used, the oxygen affinity of S-RBCs increased markedly: Their mean P50 was 13.1 mm Hg ( +/- 1.9SD). The gelation of HbS at zero pO2 was also markedly inhibited in the one sample of cyanate-treated S-RBCs examined. Clinical studies to determine the efficacy of autologous transfusions with extensively carbamylated, cryopreserved S-RBCs should be considered.

Topics: 2,3-Diphosphoglycerate; Adenosine Triphosphate; Adult; Anemia, Sickle Cell; Blood Preservation; Cyanates; Diphosphoglyceric Acids; Erythrocyte Aging; Erythrocytes; Freezing; Humans; Oxygen

Glyceraldehyde reacts with hemoglobin S in the intact erythrocyte to reduce the degree of polymerization, thereby inhibiting sickling of the erythrocyte. Only five of the 24 amino groups per alpha beta dimer react with glyceraldehyde; the adducts are present as ketoamine structures, formed by Amadori rearrangement of the initial Schiff base adducts on the protein. The reactive amino groups are the epsilon-amino group of Lys-16 of the alpha-chain, and the alpha-amino group of Val-1 as well as the epsilon-amino groups Lys-82, Lys-59, and Lys-120 of the beta-chain. Hybrid tetramers were prepared with the modification only on Lys-16 of the alpha-chain or on the reactive lysine residues of the beta-chain. The former derivative gels at a much higher hemoglobin concentration (23 g/dl) than either the latter derivative (16 g/dl) or unmodified deoxyhemoglobin S (15 g/dl). Thus, the modification at Lys-16 of the alpha-chain is a major factor in the inhibition of sickling by glyceraldehyde.

Topics: Anemia, Sickle Cell; Biopolymers; Chemical Phenomena; Chemistry; Cyanates; Erythrocytes, Abnormal; Glyceraldehyde; Hemoglobin, Sickle; Humans; In Vitro Techniques; Oxygen

Topics: Administration, Oral; Adolescent; Adult; Anemia, Sickle Cell; Bilirubin; Body Weight; Carbamates; Chemical Phenomena; Chemistry; Child; Cyanates; Dose-Response Relationship, Drug; Drug Evaluation; Erythrocyte Count; Female; Gastrointestinal Diseases; Hemoglobins; Hemolysis; Humans; Male; Middle Aged; Reticulocytes; Retrospective Studies; Sodium