Nc. Adragna et Pk. Lauf, QUININE AND QUINIDINE INHIBIT AND REVEAL HETEROGENEITY OF K-CL COTRANSPORT IN LOW K-SHEEP ERYTHROCYTES, The Journal of membrane biology, 142(2), 1994, pp. 195-207
Low K (LK) sheep red blood cells (SRBCs) serve as a model to study K-C
I cotransport which plays an important role in cellular dehydration in
human erythrocytes homozygous for hemoglobin S. Cinchona bark derivat
ives, such as quinine (Q) and quinidine (QD), are effectively used in
the treatment of malaria. In the present study, we investigated in LK
SRBCs, the effect of various concentrations of Q and QD on Cl-dependen
t K efflux and Rb influx (K(Rb)-Cl flux), activated by either swelling
in hyposmotic media, thiol alkylation with N-ethylmaleimide (NEM), or
by cellular Mg (Mg-i) removal through A23187 in the presence of exter
nal chelators. K efflux or Rb influx were determined in Cl and NO3 med
ium and K(Rb)-Cl flux was defined as the Cl-dependent (Cl minus NO3) c
omponent. K(Rb)-Cl flux stimulated by all three interventions was inhi
bited by both Q and QD in a dose-dependent manner. Maximum inhibition
of K(Rb)-Cl flux occurred at Q and QD concentrations greater than or e
qual to 1 mM. The inhibitory effect of Q was manifested in Cl, but not
in NO3, whereas QD reduced K and Rb fluxes both in Cl and NO3 media.
The mean 50% inhibitory concentration (IC50) of Q and QD to inhibit K(
Rb)-Cl flux varied between 0.23 and 2.24 mM. From determinations of th
e percentages of inhibition of the different components of K and Rb fl
uxes, we found that SRBCs possess a Cl-dependent QD-sensitive and a Cl
-dependent QD-insensitive K efflux and Rb influx. These two components
vary in magnitude depending on the manipulation and directional flux,
but in average they are about 50% of the total Cl-dependent flux. Thi
s study raises the possibility that, in SRBCs, the Cl-dependent K(Rb)
fluxes are heterogeneous.