Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1842-1848
Volume control in sickle cells is facilitated by the novel anion
conductance inhibitor NS1652
Poul Bennekou,
Ove Pedersen,
Arne Møller, and
Palle Christophersen
From the August Krogh Institute, University of Copenhagen; and
NeuroSearch A/S, Pederstrupvej, Denmark.
A low cation conductance and a high anion conductance are
characteristic of normal erythrocytes. In sickle cell anemia, the polymerization of hemoglobin S (HbS) under conditions of low oxygen tension is preceded by an increase in cation conductance. This increase
in conductance is mediated in part through
Ca++-activated K+ channels. A net efflux
of potassium chloride (KCl) leads to a decrease in intracellular
volume, which in turn increases the rate of HbS polymerization.
Treatments minimizing the passive transport of ions and solvent to
prevent such volume depletion might include inhibitors targeting either
the Ca++-activated K+ channel or the
anion conductance. NS1652 is an anion conductance inhibitor that has
recently been developed. In vitro application of this compound lowers
the net KCl loss from deoxygenated sickle cells from about 12 mmol/L cells/h to about 4 mmol/L cells/h, a value similar
to that observed in oxygenated cells. Experiments performed in
mice demonstrate that NS1652 is well tolerated and decreases red
cell anion conductance in vivo.
