Studies on the vasoocclusive crisis of sickle cell disease. III. In vitro and in vivo effect of the pyrimido-pyrimidine derivative, RA-233: studies on its mechanism of action.
Red cell deformability was found to be impaired in SS- and SC-genotype and to a lesser extent SA-genotype red blood cells as compared with those of AA-genotype. RA-233 in vitro improved deformability according to a bell-shaped dose-response curve. RA-233 also prevented experimental vasoocclusive crisis in Macaca arctoides. Deoxygenation of SS-genotype red cells resulted in sickle shape transformation, ATP depletion, potassium efflux, and attachment of hemoglobin molecules to the membrane. These changes were prevented by RA-233. Suspending SS-genotype red blood cells in potassium rich tris-buffer also prevented potassium efflux during deoxygenation and also decreased cellular deformability. RA-233 had no effect on osmotic fragility of SS-genotype red blood cells.
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy*; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004907:Erythrocyte Deformability / Q000187:drug effects; D005260:Female; D005838:Genotype; D006801:Humans; D008251:Macaca; D008297:Male; D009012:Mopidamol / Q000494:pharmacology / Q000627:therapeutic use*; D009996:Osmotic Fragility / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*
D000986:Antisickling Agents; D011743:Pyrimidines; D009012:Mopidamol; D011188:Potassium