Mode of action and comparative efficacy of pharmacological agents that inhibit calcium‐dependent dehydration of sickle cells

1 Selected Ca‐channel antagonists were tested at 20 μm as inhibitors of Ca2+‐uptake in human sickle red cells. Nitrendipine, fendiline, and bepridil (and its stereoisomers), were found to be as effective as methoxyverapamil (D‐600) in inhibiting a fraction (25%) of Ca2+‐uptake. In contrast cetiedil and Org 30701 were ineffective. 2 The drugs were subsequently tested as inhibitors of Ca2+‐induced K+ efflux (Gardos) from sickle cells. They all showed inhibitory activity, with the order of efficacy nitrendipine > fendiline > bepridil > cetiedil > Org 30701. 3 With a 15 h programme of deoxygenation/reoxygenation cycles in a gas exchanger, it was shown that the inhibitors protected against cellular dehydration and loss of filterability in the order nitrendipine > fendiline > bepridil > cetiedil > Org 30701. However, significant stomatocytosis occurred at high concentrations of cetiedil, and bepridil (including its stereoisomers and analogues) impairing cell deformability. 4 It is concluded that Ca‐antagonists may partially block both Ca2+‐uptake and Ca2+‐induced K+ efflux. The latter pathway is significant in contributing to sickle cell dehydration and nitrendipine is the most effective inhibitor of this route.