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 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.