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Mode of action and comparative efficacy of pharmacological agents that inhibit calcium‐dependent dehydration of sickle cells
Author(s) -
Ellory J.C.,
Nash G.B.,
Stone P.C.W.,
Culliford S.J.,
Horwitz E.,
Stuart J.
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14444.x
Subject(s) - bepridil , nitrendipine , chemistry , pharmacology , calcium , efflux , biochemistry , verapamil , medicine , organic chemistry
1 Selected Ca‐channel antagonists were tested at 20 μ m as inhibitors of Ca 2+ ‐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 Ca 2+ ‐uptake. In contrast cetiedil and Org 30701 were ineffective. 2 The drugs were subsequently tested as inhibitors of Ca 2+ ‐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 Ca 2+ ‐uptake and Ca 2+ ‐induced K + efflux. The latter pathway is significant in contributing to sickle cell dehydration and nitrendipine is the most effective inhibitor of this route.