Inhibition of K+ efflux and dehydration of sickle cells by [(dihydroindenyl)oxy]alkanoic acid: an inhibitor of the K+ Cl- cotransport system.
[(Dihydroindenyl)oxy]alkanoic acid (DIOA) was recently introduced as a potent inhibitor of the K+Cl- cotransport system without side effects on other cation transport systems [Garay, R. P., Nazaret, C., Hannaert, P.A. & Cragoe, E. J., Jr. (1988) Mol. Pharmacol. 33, 696-701]. In sickle cells, an abnormal activation of this K+Cl- cotransport system was proposed to be involved in cell K+ loss and dehydration. We found that DIOA inhibited the abnormal sickle cell K+ loss and specifically reduced sickle cell density upon stimulation of the net outward K+Cl- cotransport--i.e., low pH, hypoosmolarity, and activation by N-ethylmaleimide. DIOA opens another therapeutic approach to sickle cell disease by inhibiting cell dehydration, which favors HbS polymerization and reduces erythrocyte deformability.
Vitoux
D
D
Institut National de la Santé et de la Recherche Médicale U91, Centre National de la Recherche Scientifique UA 607, Hôpital H. Mondor, Crétiel, France.
Olivieri
O
O
Garay
R P
RP
Cragoe
E J
EJ
Galacteros
F
F
Beuzard
Y
Y
D000755:Anemia, Sickle Cell / Q000097:blood*; D002264:Carboxylic Acids / Q000494:pharmacology*; D002352:Carrier Proteins / Q000097:blood*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005033:Ethylmaleimide / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007192:Indenes / Q000494:pharmacology*; D007700:Kinetics; D011188:Potassium / Q000097:blood*; D012016:Reference Values; D027981:Symporters; D000096922:K Cl- Cotransporters
D002264:Carboxylic Acids; D002352:Carrier Proteins; D005033:Ethylmaleimide; D007192:Indenes; D011188:Potassium; D027981:Symporters; D000096922:K Cl- Cotransporters; C059990:((dihydroindenyl)oxy)alkanoic acid