Formation of dense erythrocytes in SAD mice exposed to chronic hypoxia: Evaluation of different therapeutic regimens and of a combination of oral clotrimazole and magnesium therapies

We have examined the effect of hydroxyurea (HU), clotrimazole (CLT), magnes ium oxide (Mg), and combined CLT+Mg therapies on the erythrocyte characteri stics and their response to chronic hypoxia in a transgenic sickle mouse (S AD) model. SAD mice were treated for 21 days with 1 of the following regime ns (administered by gavage): control (n = 6), HU (200 mg/d; n = 6), CLT (80 mg/kg/d, n = 5), Mg (1,000 mg/kg/d, n = 5), and CLT+Mg (80 and 1,000 mg/kg /d, respectively, n = 6). Nine normal mice were also treated as controls (n = 3), HU (n = 3), and CLT+Mg (n = 3). Treatment with HU induced a signific ant increase in mean corpuscular volume and cell K content and a decrease i n density in SAD mice. Treatment with the CLT and Mg, either alone or in co mbination, also increased cell K and reduced density in SAD mice. After 21 days of treatment, the animals were exposed to hypoxia (48 hours at 8% O-2) maintaining the same treatment. In the SAD mice, hypoxia induced significa nt cell dehydration. These hypoxia-induced changes were blunted in either H U- or Mg-treated SAD mice and were completely abolished by either CLT or CL T+Mg treatment, suggesting a major role for the Gardos channel in hypoxia-i nduced dehydration in vivo. (C) 1999 by The American Society of Hematology.