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Differential oxygen sensitivity of the K⁺-Cl^- cotransporter in normal and sickle human red blood cells

J. S. Gibson, P. F. Speake and J. C. Ellory *

1. K⁺ influx and efflux were measured in normal (HbA) and sickle (HbS) red blood cells to investigate the interaction of swelling, H⁺ ions and urea with O₂ (0 to 150 mmHg O₂) in the presence of ouabain and bumetanide (both 100 µM).

2. In HbA cells, K⁺-Cl^- cotransport was O₂ dependent. At low oxygen tensions (P_O2s) the transporter was inactive and refractory to low pH, swelling or urea.

3. Cl^--independent K⁺ influxes in sickle cells were elevated at low P_O2s, as previously reported. Cl^--dependent K⁺ influxes were large at both high and low P_O2s, whether stimulated by swelling, H⁺ ions or urea. In the absence of O₂, Cl^--dependent K⁺ influxes were similar in magnitude to those measured at high P_O2s. The minimum for Cl^--dependent K⁺ influx was observed at P_O2s of about 40-70 mmHg.

4. K⁺ efflux from HbS cells was stimulated by the addition of urea (500 mM). The rate constants were of similar magnitude whether measured at high P_O2 or in the absence of O₂, and were predominantly Cl^- dependent under both conditions.

5. In HbS red blood cells, reduction of extracellular Ca²⁺, addition of 1 mM Mg²⁺ or nitrendipine (10 µM) to the saline had no effect. Inhibitors of K⁺-Cl^- cotransport, [(dihydroindenyl)oxy] alkanoic acid (DIOA; 100 µM) or calyculin A (0·1 µM), inhibited influxes by a similar magnitude to Cl^- substitution.

6. Results are significant for the pathophysiology of sickle cell disease. Low pH and urea are able to stimulate KCl loss from sickle cells, leading to cellular dehydration, even in regions of low P_O2.

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