The feasibility of pharmacological volume control of sickle cells is dependent on the quantization of the transport pathways. A model study

Normal erythrocytes are under physiological conditions characterized by low cation and high anion conductance. However, in the case of sickle cell ane mia the erythrocytes contain a modified hemoglobin, HbS, which under low ox ygen tension gives rise to sickling. This condition is preceded by an incre ase in cation conductance, especially due to the Ca2+-activated K+-channels , leading to net-efflux of KCl and thereby decreased cellular volume, which is part of the pathological condition. A possible symptomatic treatment could be application of conductance blocke rs, targeting the Ca2+-activated K+-channel or the anion conductance, in or der to minimize the passive transport of ions and solvent. It has been argu ed, that due to the high anion conductance, solute loss depended at moderat ely increased cation conductances on the cation only. Consequently the Ca2-activated K+-conductance should be the target for attempts to modify solut e loss. It is shown that: knowledge of mean conductances (time averages) for pathwa ys showing fluctuations are insufficient to predict the quantitative effect of conductance inhibitors, since inhibition is strongly dependent on the k inetics of the mechanisms mediating the translocation and a block of the hi gh conductance anion pathway can be as effective as inhibition of the Ca2+- activated K+-conductance with regard to net salt loss. (C) 1999 Academic Pr ess.