Therapeutic strategies for prevention of sickle cell dehydration.

The intracellular concentration of Hb S is an important determinant of the kinetic of polymer formation and cell sickling. A variable fraction of dense, dehydrated erythrocytes with high Hb S concentration is seen in the blood of patients with sickle cell disease; these dense cells play an important role in the pathophysiology of the vasoocclusive events of sickle cell disease, due to their higher tendency to polymerize and sickle. Sickle cell dehydration is due to loss of K+, Cl-, and water: the two major determinant pathways of dehydration of sickle erythrocytes are the Ca2+-activated K+ channel (IK1 or Gardos channel) and the K-Cl cotransport (KCC). Specific inhibitors of these pathways being tested in patients with sickle cell disease are Mg2+ pidolate, which inhibits KCC by increasing the sickle cell content of Mg2+, and clotrimazole and derivatives of clotrimazole metabolites, which specifically block the Gardos channel. An inhibitor of Cl- conductance has been shown to reduce dehydration in a transgenic mouse model of sickle cell disease but has not been tested in humans. If clinical efficacy and benefit are demonstrated, an inhibitor of cell dehydration could be used in patients as a single agent or in combination with existing therapies, such as hydroxyurea.