Dipyridamole inhibits sickling-induced cation fluxes in sickle red blood cells.
Sickling-induced cation fluxes contribute to cellular dehydration of sickle red blood cells (SS RBCs), which in turn potentiates sickling. This study examined the inhibition by dipyridamole of the sickling-induced fluxes of Na(+), K(+), and Ca(++) in vitro. At 2% hematocrit, 10 microM dipyridamole inhibited 65% of the increase in net fluxes of Na(+) and K(+) produced by deoxygenation of SS RBCs. Sickle-induced Ca(++) influx, assayed as (45)Ca(++) uptake in quin-2-loaded SS RBCs, was also partially blocked by dipyridamole, with a dose response similar to that of Na(+) and K(+) fluxes. In addition, dipyridamole inhibited the Ca(++)-activated K(+) flux (via the Gardos pathway) in SS RBCs, measured as net K(+) efflux in oxygenated cells exposed to ionophore A23187 in the presence of external Ca(++), but this effect resulted from reduced anion conductance, rather than from a direct effect on the K(+) channel. The degree of inhibition of sickling-induced fluxes was dependent on hematocrit, and up to 30% of dipyridamole was bound to RBC membranes at 2% hematocrit. RBC membrane content of dipyridamole was measured fluorometrically and correlated with sickling-induced flux inhibition at various concentrations of drug. Membrane drug content in patients taking dipyridamole for other clinical indications was similar to that producing inhibition of sickling-induced fluxes in vitro. These data suggest that dipyridamole might inhibit sickling-induced fluxes of Na(+), K(+), and Ca(++) in vivo and therefore have potential as a pharmacological agent to reduce SS RBC dehydration. (Blood. 2001;97:3976-3983)
Joiner
C H
CH
Cincinnati Comprehensive Sickle Cell Center, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA. clint.joiner@chmcc.org
Jiang
M
M
Claussen
W J
WJ
Roszell
N J
NJ
Yasin
Z
Z
Franco
R S
RS
D000755:Anemia, Sickle Cell / Q000097:blood*; D002118:Calcium / Q000378:metabolism; D002412:Cations / Q000378:metabolism*; D002478:Cells, Cultured; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013050:Spectrometry, Fluorescence
D002412:Cations; D004176:Dipyridamole; D012964:Sodium; D011188:Potassium; D002118:Calcium