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

Dimethyl adipimidate (DMA) reduces K+ loss from, and dehydration of, red ce lls containing haemoglobin S (HbS cells). Three membrane transporters may c ontribute to these processes: the deoxygenation-induced cation-selective ch annel (P-sickle), the Ca2+-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 Ca2+ loading. Considerable KCC activity was present in oxygenated HbS cells , showing a selective action of DMA on the transporter in deoxygenated cell s, Inhibition of sickling correlated strongly with that of P-sickle and mod erately with that of KCC activity. We conclude that DMA does not inhibit th e K+ pathways directly, but acts mainly by preventing HbS polymerisation an d sickling. These findings are relevant to the development of novel chemoth erapeutic agents for amelioration of sickle cell disease. (C) 2000 Federati on of European Biochemical Societies. Published by Elsevier Science B.V. Al l rights reserved.