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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3976-3983
RED CELLS
Dipyridamole inhibits sickling-induced cation fluxes in sickle
red blood cells
Clinton H. Joiner,
Maorong Jiang,
William J. Claussen,
Nancy J. Roszell,
Zahida Yasin, and
Robert S. Franco
From the Cincinnati Comprehensive Sickle Cell Center
and the Divisions of Pediatric and Medical Hematology/Oncology,
University of Cincinnati College of Medicine, Cincinnati, OH.
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 µM 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 45Ca++
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.
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