TREATMENT WITH ORAL CLOTRIMAZOLE BLOCKS CA2-ACTIVATED K+ TRANSPORT AND REVERSES ERYTHROCYTE DEHYDRATION IN TRANSGENIC SAD MICE - A MODEL FOR THERAPY OF SICKLE-CELL DISEASE()

Prevention of red cell K+ and water loss is a therapeutic strategy for sickle cell disease. We have investigated in vitro and in vivo the ef fects of clotrimazole (CLT) and miconazole (MIC) on transgenic mice re d cells expressing hemoglobin SAD. CLT blocked the Gardos channel (ID5 0 75+/-22 nM; n = 3) and the A23187-induced dehydration of Hbb(s)/Hbb( thal) SAD 1 mouse erythrocytes in vitro. Oral treatment with CLT (160 mg/kg per d) and MIC (100 mg/kg per d) inhibited the Gardos channel in both SAD 1 and control (Hbb(s)/Hbb(thal)) mice. In the SAD 1 mice onl y, cell K+ content increased, and mean corpuscular hemoglobin concentr ation and cell density decreased. After 7 d of treatment, the hematocr it of SAD 1, CLT-treated animals also increased. All changes were full y reversible. Longterm treatments of SAD 1 mice with oral CLT (80 mg/k g per d for 28 d) lead to sustained increases in cell K+ content and h ematocrit and sustained decreases in mean corpuscular hemoglobin conce ntration and cell density, with no changes in animals treated with veh icle alone. Thus, CLT and MIC can reverse dehydration and K+ loss of S AD 1 mouse erythrocytes in vitro and in vivo, further supporting the p otential utility of these drugs in the treatment of sickle cell anemia .