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 N
a+, K+, and Ca++ in vitro. At 2% hematocrit, 10 muM dipyridamole inhibited
65% of the increase in net fluxes of Na+ and K+ produced by deoxygenation o
f SS RBCs, Sickle-induced Ca++ influx, assayed as Ca-45(++) uptake in quin-
2-loaded SS RBCs, was also partially blocked by dipyridamole, with a dose r
esponse similar to that of Na+ and K+ fluxes, In addition, dipyridamole inh
ibited the Ca++-activated K+ flux (via the Gardos pathway) in SS RBCs, meas
ured as net K+ efflux in oxygenated cells exposed to ionophore A23187 in th
e presence of external Ca++, but this effect resulted from reduced anion co
nductance, rather than from a direct effect on the K+ channel. The degree o
f inhibition of sickling-induced fluxes was dependent on hematocrit, and up
to 30% of dipyridamole was bound to RBC membranes at 2% hematocrit, RBC me
mbrane content of dipyridamole was measured fluoro- metrically and correlat
ed with sickling-induced flux inhibition at various concentrations of drug.
Membrane drug content in patients taking dipyridamole for other clinical i
ndications was similar to that producing inhibition of sickling-induced flu
xes in vitro. These data suggest that dipyridamole might inhibit sickling-i
nduced fluxes of Na+, K+, and Ca++ in vivo and therefore have potential as
a pharmacological agent to reduce SS RBC dehydration.