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
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
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DOI：
10.1172/jci117149
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发表时间：
1994-04-01
影响因子：
15.9
通讯作者：
BEUZARD, Y
中科院分区：
文献类型：
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作者：
DEFRANCESCHI, L;SAADANE, N;BEUZARD, Y
预防红细胞K+和水分流失是镰状细胞病的一种治疗策略。我们在体外和体内研究了克霉唑（CLT）和咪康唑（MIC）对表达血红蛋白SAD的转基因小鼠红细胞的影响。CLT阻断Gardos通道（ID50 75+/-22 nM; n = 3）和a23187诱导的体外Hbb(s)/Hbb(thal) SAD 1小鼠红细胞脱水。口服CLT （160 mg/kg / d）和MIC （100 mg/kg / d）可抑制SAD 1和对照组(Hbb（s)/Hbb(thal)）小鼠的Gardos通道。仅在SAD 1小鼠中，细胞K+含量升高，平均红细胞血红蛋白浓度和细胞密度降低。治疗7 d后，SAD - 1、clt治疗动物的红细胞压积也有所增加。所有的变化都是完全可逆的。长期口服CLT （80 mg/kg / d，持续28 d）治疗SAD 1小鼠，导致细胞K+含量和红细胞压积持续增加，平均红细胞血红蛋白浓度和细胞密度持续下降，而单独给药的动物没有变化。因此，CLT和MIC可以在体内体外逆转小鼠红细胞SAD 1的脱水和K+丢失，进一步支持这些药物在治疗镰状细胞性贫血中的潜在效用。
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 effects of clotrimazole (CLT) and miconazole (MIC) on transgenic mice red cells expressing hemoglobin SAD. CLT blocked the Gardos channel (ID50 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 only, cell K+ content increased, and mean corpuscular hemoglobin concentration and cell density decreased. After 7 d of treatment, the hematocrit of SAD 1, CLT-treated animals also increased. All changes were fully reversible. Longterm treatments of SAD 1 mice with oral CLT (80 mg/kg per d for 28 d) lead to sustained increases in cell K+ content and hematocrit and sustained decreases in mean corpuscular hemoglobin concentration and cell density, with no changes in animals treated with vehicle alone. Thus, CLT and MIC can reverse dehydration and K+ loss of SAD 1 mouse erythrocytes in vitro and in vivo, further supporting the potential utility of these drugs in the treatment of sickle cell anemia.