Treatment with NS3623, a novel Cl-conductance blocker, ameliorates erythrocyte dehydration in transgenic SAD mice: a possible new therapeutic approach for sickle cell disease

The dehydration of sickle red blood cells (RBCs) through the Ca-activated K channel depends on the parallel movement of CI ions. To study whether CI-c onductance block might prevent dehydration of sickle RBCs, a novel CI-condu ctance inhibitor (NS3623) was characterized in vitro using RBCs from health y donors and sickle cell patients and in vivo using normal mice and a trans genic mouse model of sickle cell disease (SAD mice). In vitro, NS3623 rever sibly blocked human RBC CI conductance (g(Cl)) with an IC50 value of 210 nm ol/L and a maximal block of 95%. In vivo, NS3623 inhibited RBC g(CI) after oral administration to normal mice (ED50 = 25 mg/kg). Although g(CI), at a single dose of 100 mg/kg, was still 70% inhibited 5 hours after dosing, the inhibition disappeared after 24 hours. Repeated administration of 100 mg/k g twice a day for 10 days caused no adverse effects; therefore, this regime n was chosen as the highest dosing for the SAD mice. SAD mice were treated for 3 weeks with 2 daily administrations of 10, 35, and 100 mg/kg NS3623, r espectively. The hematocrit increased, and the mean corpuscular hemoglobin concentration decreased in all groups with a concomitant increase in the in tracellular cation content. A loss of the densest red cell population was o bserved in conjunction with a shift from a high proportion of sickled to we ll-hydrated discoid erythrocytes, with some echinocytes present at the high est dosage, These data indicate feasibility for the potential use of CI-con ductance blockers to treat human sickle cell disease. (Blood, 2001;97:1451- 1457) (C) 2001 by The American Society of Hematology.