Mechanisms of Red Cell Dehydration in Sickle Cell Anemia

Bookchin, Robert M.; Ortiz, Olga E.; Lew, Virgilio L.

doi:10.1007/978-1-4612-4500-1_19

Cited by 4 publications

(4 citation statements)

References 52 publications

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“…Pharmacologically, bepridil is used as an antianginal agent [27], because of its ability to block calcium channels. It is known that sickling allows the entry of calcium into the sickle cell [28,29], presumably as a consequence of cell deformation [30,31]. It has been suggested that bepridil could prevent irreversible sickle cell formation by inhibiting the calcium-activated potassium channel.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

Bepridil as an antisickling agent: Membrane internalization and cell rigidity

Johnson

Acquaye

Féo³

et al. 1994

American J Hematol

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“…Whereas with SS discocytes prolonged alternating oxygenation/deoxygenation protocols were necessary to elicit Ca2"-dependent net cation loss and dense cell formation (19)(20)(21)(22) (30,31). Ca2+-dependent dehydration may proceed by two pathways: directly, by activation of K+-and Cl--selective channels (29,32), and indirectly, by secondary acidification and activation of K:C1 transporters, as shown by model analysis (1).…”

Section: Discussionmentioning

confidence: 99%

“…By the time they attain the high density of ISCs, most would have lost the reticulum and the activity of all young cell transporters. Nonsusceptible reticulocytes and young cells, on the other hand, would mature further to discocytes, exposed to slow Ca2"-dependent dehydration by repeated deoxygenation in the circulation (19,39). This would generate the observed heterogeneity of cell densities, with a fraction of young cells dehydrating faster than the rest within each density fraction.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a direct reticulocyte origin of dense red cells in sickle cell anemia.

Bookchin¹,

Ortiz²,

Lew³

1991

J. Clin. Invest.

129

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“…This effect, due to the inhibition of net outward K+Cl-cotransport, prevented the density increase of HbS cells at pH 7.0. It is known that the K+Cl-cotransport system is activated in reticulocytes (13, 14); therefore, reticulocytes could account for the increased activity of the K+ efflux in sickle cells (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%