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 anemia the erythrocytes contain a modified haemoglobin, HbS, which under low oxygen tension gives rise to sickling. This condition is preceded by an increase in cation conductance, especially due to the Ca2+-activated K+-channels, leading to net-efflux of KCI and thereby decreased cellular volume, which is part of the pathological condition.A possible symptomatic treatment could be application of conductance blockers, targeting the Ca2+-activated K+-channel or the anion conductance in order to minimize the passive transport of ions and solvent. It has been argued, that due to the high anion conductance, solute loss depended at moderately increased cation conductances on the cation only. Consequently the Ca2+-activated K+-conductance should be the target for attempts to modify solute loss.It is shown that: knowledge of mean conductances (time averages) for pathways showing fluctuations are insufficient to predict the quantitative effect of conductance inhibitors, since inhibition is strongly dependent on the kinetics of the mechanisms mediating the translocation and a block of the high conductance anion pathway can be as effective as inhibition of the Ca+-activated K+-conductance with regard to net salt loss.
Bennekou
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The August Krogh Institute-LCMF, University of Copenhagen, Universitetsparken 13, DK 2100. pbennekou@aki.ku.dk
D000755:Anemia, Sickle Cell / Q000097:blood / Q000628:therapy*; D020013:Calcium Signaling; D004910:Erythrocyte Membrane / Q000502:physiology*; D004912:Erythrocytes / Q000473:pathology; D006801:Humans; D007473:Ion Channels; D008954:Models, Biological; D015221:Potassium Channels / Q000187:drug effects*
D007473:Ion Channels; D015221:Potassium Channels