Three phenothiazines with similar structure; chlorpromazine (CPZ), triflupromazine (TFPZ), and trifluoperazine (TFP), were compared for the potency of swelling of normal red cells and antisickling effect of red cell from patients with sickle cell disease. 2. Normal erythrocytes treated with the phenothiazines became swollen within 60 min, and the percent increase in mean cell volume (MCV) was dose-dependent and varied according to the agent used. 3. The cell swelling was hematocrit-dependent, and pH-dependent. A greater swelling potency was seen at lower hematocrits and higher pH values. 4. The swelling was also dependent on the pKa values of these chemicals. TFP with the lowest pKa induced the highest degree of swelling while CPZ with the highest pKa induced the lowest. 5. The un-ionized fraction of the phenothiazines at a given pH was directly related to potency of the swelling. 6. The cell swelling was directly related to the binding affinities of the phenothiazines to calmodulin. 7. The antisickling effect of these compounds using sickle red cells, numerically estimated by an automated image analysis system, was found in the same order as that of swelling potency: TFP > TFPR > CPZ.
