Effect of dimethyl adipimidate on K + transport and shape change in red blood cells from sickle cell patients

Abstract

Dimethyl adipimidate (DMA) reduces K + loss from, and dehydration of, red cells containing haemoglobin S (HbS cells). Three membrane transporters may contribute to these processes: the deoxygenation-induced cation-selective channel (P sickle), the Ca 2+-activated K + channel (or Gardos channel) and the K +-Cl − cotransporter (KCC). We show that DMA inhibited all three pathways in deoxygenated HbS cells. The Gardos channel could be activated following Ca 2+ loading. Considerable KCC activity was present in oxygenated HbS cells, showing a selective action of DMA on the transporter in deoxygenated cells. Inhibition of sickling correlated strongly with that of P sickle and moderately with that of KCC activity. We conclude that DMA does not inhibit the K + pathways directly, but acts mainly by preventing HbS polymerisation and sickling. These findings are relevant to the development of novel chemotherapeutic agents for amelioration of sickle cell disease.