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 cells containing haemoglobin S (HbS cells). Three membrane transporters may contribute to these processes: the deoxygenation-induced cation-selective channel (Psickle), the Ca2+-activated K+ channel (or Gardos channel) and the K+-CI- 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 cells. Inhibition of sickling correlated strongly with that of Psickle 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.
Gibson
J S
JS
Department of Physiology, St George's Hospital Medical School, University of London, Cranmer Terrace, UK. jsgibson@sghms.ac.uk
Stewart
G W
GW
Ellory
J C
JC
D000755:Anemia, Sickle Cell / Q000097:blood*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002414:Cations, Monovalent; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004119:Dimethyl Adipimidate / Q000494:pharmacology*; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006451:Hemoglobin, Sickle; D006801:Humans; D010100:Oxygen / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D027981:Symporters; D000096922:K Cl- Cotransporters
D002352:Carrier Proteins; D002414:Cations, Monovalent; D004119:Dimethyl Adipimidate; D006451:Hemoglobin, Sickle; D010100:Oxygen; D011188:Potassium; D027981:Symporters; D000096922:K Cl- Cotransporters