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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1451-1457
RED CELLS
Treatment with NS3623, a novel Cl-conductance blocker,
ameliorates erythrocyte dehydration in transgenic SAD mice: a possible
new therapeutic approach for sickle cell disease
Poul Bennekou,
Lucia de Franceschi,
Ove Pedersen,
Lurong Lian,
Toshio Asakura,
Greg Evans,
Carlo Brugnara, and
Palle Christophersen
From the August Krogh Institute, University of
Copenhagen, and NeuroSearch A/S, Copenhagen, Denmark; Department of
Clinical and Experimental Medicine, University of Verona, Verona,
Italy; Division of Hematology, Children's Hospital of Philadelphia,
Philadelphia, PA; Sickle Cell Disease Scientific Research Group,
National Heart, Lung, and Blood Institute, Bethesda, MD; and Department
of Laboratory Medicine and Pathology, Children's Hospital, Harvard
Medical School, Boston, MA.
The dehydration of sickle red blood cells (RBCs) through the
Ca-activated K channel depends on the parallel movement of Cl ions. To
study whether Cl-conductance block might prevent dehydration of sickle
RBCs, a novel Cl-conductance inhibitor (NS3623) was characterized in
vitro using RBCs from healthy donors and sickle cell patients and in
vivo using normal mice and a transgenic mouse model of sickle cell
disease (SAD mice). In vitro, NS3623 reversibly blocked human RBC
Cl-conductance (gCl) with an IC50 value of 210 nmol/L and a maximal block of 95%. In vivo, NS3623 inhibited RBC gCl after oral administration to normal mice
(ED50 = 25 mg/kg). Although gCl, 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/kg twice a day for 10 days caused no adverse effects; therefore,
this regimen 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, respectively. The hematocrit increased, and the
mean corpuscular hemoglobin concentration decreased in all groups with
a concomitant increase in the intracellular cation content. A loss of
the densest red cell population was observed in conjunction with a
shift from a high proportion of sickled to well-hydrated discoid
erythrocytes, with some echinocytes present at the highest dosage.
These data indicate feasibility for the potential use of Cl-conductance
blockers to treat human sickle cell disease.
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