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), magnesium oxide (Mg), and combined CLT+Mg therapies on the erythrocyte characteristics and their response to chronic hypoxia in a transgenic sickle mouse (SAD) model. SAD mice were treated for 21 days with 1 of the following regimens (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 significant increase in mean corpuscular volume and cell K content and a decrease in density in SAD mice. Treatment with the CLT and Mg, either alone or in combination, 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 significant cell dehydration. These hypoxia-induced changes were blunted in either HU- or Mg-treated SAD mice and were completely abolished by either CLT or CLT+Mg treatment, suggesting a major role for the Gardos channel in hypoxia-induced dehydration in vivo.
De Franceschi
L
L
Department of Internal Medicine, University of Verona, Verona, Italy.
Brugnara
C
C
Rouyer-Fessard
P
P
Jouault
H
H
Beuzard
Y
Y
D000284:Administration, Oral; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002908:Chronic Disease; D003022:Clotrimazole / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D006131:Growth Inhibitors / Q000008:administration & dosage*; D000860:Hypoxia; D008274:Magnesium / Q000008:administration & dosage*; D051379:Mice
D006131:Growth Inhibitors; D003022:Clotrimazole; D008274:Magnesium