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

Abstract

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 (g(Cl)) with an IC(50) value of 210 nmol/L and a maximal block of 95%. In vivo, NS3623 inhibited RBC g(Cl) after oral administration to normal mice (ED(50) = 25 mg/kg). Although g(Cl), 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.

• Authors: P Bennekou, L de Franceschi, O Pedersen, L Lian, T Asakura, G Evans, C Brugnara, P Christophersen
• Journal: Blood (Blood) Vol. 97 Issue 5 Pg. 1451-7 (Mar 01 2001) ISSN: 0006-4971 [Print] United States
• PMID: 11222393 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chloride Channels
• Hemoglobin, Sickle
• Hemoglobins
• NS 3623
• Oxyhemoglobins
• Phenylurea Compounds
• Tetrazoles
• Water
• oxyhemoglobin S

Topics

• Anemia, Sickle Cell (blood, drug therapy, pathology)
• Animals
• Chloride Channels (antagonists & inhibitors)
• Dehydration (drug therapy)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Erythrocytes (drug effects, metabolism, pathology)
• Hematocrit
• Hemoglobin, Sickle (drug effects, metabolism)
• Hemoglobins (drug effects, metabolism)
• Humans
• Mice
• Mice, Transgenic
• Oxyhemoglobins (drug effects, metabolism)
• Phenylurea Compounds (pharmacology, therapeutic use, toxicity)
• Tetrazoles (pharmacology, therapeutic use, toxicity)
• Time Factors
• Water (metabolism)