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-mu-M 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 3070 1. 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.