Bepridil protects sickle cells against the adverse rheological effects of cyclical deoxygenation

Johnston, M. N.; Ellory, J. Clive; Stuart, J.

doi:10.1111/j.1365-2141.1989.tb00291.x

Cited by 13 publications

(13 citation statements)

References 25 publications

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“…Quinidine HCO and cetiedil citrate were studied as reference Gardos channel inhibitors, causing 42-51% inhibition at 100 EM. As found previously (Johnston et al, 1989;Stuart et al, 1989), ( ± )-bepridil was a potent inhibitor of Ca2+-activated K+(86Rb) efflux, and its stereoisomers (+ and -) were nearly equipotent. This agrees with findings on coronary vascular muscle where bepridil has a low stereoselectivity factor (van Amsterdam & Zaagsma, 1988).…”

Section: Inhibition Of K+(6rb) Effluxsupporting

confidence: 71%

“…Any dehydration (decrease in cell K+ and loss of cell water, which crosses the erythrocyte membrane in ICHC). In the absence of CaCl2 these milliseconds (Sachs et al, 1975), therefore has a disproporuced (Johnston et al, 1989). tionate effect on polymerization and thus on cell deforient was also performed in the presence mability.…”

Section: Cyclical Deoxygenation-reoxygenationmentioning

confidence: 99%

“…Previous in vitro studies have substantial protection against loss of demonstrated the potential rheological benefit of Ca2+-entry [ion. Fendiline, which also inhibits Ca2+ blockade by nitrendipine (Nash et al, 1989) and of Gardos channel inhibition by bepridil (Johnston et al, 1989). We have now refined these methods by measuring the effect of (s. 13.26 ± 11.82 12.5 bility through pores of 5 plm diameter.…”

Section: Cyclical Deoxygenation-reoxygenationmentioning

confidence: 99%

“…The mode of action of classical Ca2t-entry blockers on the red cell membrane has been questioned by the demonstration that bepridil, a vascular smooth muscle relaxant that inhibits Ca2+ entry into excitable cells (Labrid et al, 1979;Vogel et al, 1979), causes inhibition of K+ efflux via the Gardos channel from normal erythrocytes ) and prevents dehydration of sickle cells (Johnston et al, 1989). Subsequently, the 1,4-dihydropyridine Ca2t-entry blockers nifedipine and nitrendipine have also been shown to inhibit the Gardos channel (Kaji, 1990;Ellory et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

“…These methods include measurement of Ca2t influx into and Ca2t-activated Kt efflux from sickle cells and cyclical deoxygenation-reoxygenation of sickle cells over 15 h in the presence of Ca2t. Repeated cycles of deoxygenation-reoxygenation cause repetitive sickling and unsickling with influx of Ca2t, efflux of Kt, cellular dehydration and loss of cell deformability (Johnston et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

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

Ellory¹,

Nash

Stone

et al. 1992

British J Pharmacology

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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. 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. 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. 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.

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Section: Inhibition Of K+(6rb) Effluxsupporting

confidence: 71%

Section: Cyclical Deoxygenation-reoxygenationmentioning

confidence: 99%

Section: Cyclical Deoxygenation-reoxygenationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ellory¹,

Nash

Stone

et al. 1992

British J Pharmacology

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Bepridil as an antisickling agent: Membrane internalization and cell rigidity

Johnson

Acquaye

Féo³

et al. 1994

American J Hematol

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The calcium channel antagonist, bepridil, beta-(2-methylpropoxy)methyl-N-phenyl-N-(phenylmethyl)-1-pyrrol idineethanamine monochloride monohydrate, inhibits the sickling of deoxygenated sickle (SS) erythrocytes, as determined by light microscopy. The anti-sickling effect was seen only in dilute suspensions of red cells. In concentrated erythrocyte suspensions, sickling was not inhibited and measurements of hematocrit and cell density were unchanged by bepridil. The determination of cell volume in dilute suspensions was complicated by bepridil's tendency to aggregate, but rapid measurements by electronic sizing also indicated no increase in cell volume, up to a bepridil concentration of 200 microM. Ektacytometry of dilute sickle cell suspensions suggested an explanation for the anti-sickling action of bepridil. Osmotic scan ektacytometry disclosed that bepridil initially increased the surface area of the red cell, as shown by a shift in the low osmolality minimum. This change was complete in 10 sec, the shortest time that could be measured. Subsequently, at concentrations that were observed to inhibit the sickling of deoxygenated sickle cells (100 microM or greater), red cells underwent a loss in surface area that was complete in 1 min. There was a concomitant loss of cell deformability. Light and scanning electron microscopy has previously shown that bepridil is a stomatocytic agent. Using transmission electron microscopy, we verified that the loss of surface area was a consequence of endocytosis, presumably as the end stage of the stomatocytic transformation induced by bepridil. Bepridil did not inhibit intracellular hemoglobin S polymerization even at 200 microM, as shown by oxygen scan ektacytometry. Bepridil thus appears to inhibit the sickling of deoxygenated SS cells by inducing endocytosis and lowering cell deformability. This mechanism may explain the anti-sickling effect of other basic amphiphiles, such as chlorpromazine.

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KCl Cotransport in HbAA and HbSS Red Cells: Activation by Intracellular Acidity and Disappearance During Maturation

Ellory¹,

Hall²,

Ody³

et al. 1991

Advances in Experimental Medicine and Biology

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Bepridil protects sickle cells against the adverse rheological effects of cyclical deoxygenation

Cited by 13 publications

References 25 publications

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

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

Bepridil as an antisickling agent: Membrane internalization and cell rigidity

KCl Cotransport in HbAA and HbSS Red Cells: Activation by Intracellular Acidity and Disappearance During Maturation

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