Drug-induced shape change in erythrocytes correlates with membrane potential change and is independent of glycocalyx charge

Nwafor, A Paul; Wt, Coakley

doi:10.1016/0006-2952(85)90354-5

Cited by 18 publications

(5 citation statements)

References 16 publications

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“…This change in chloride distribution is likely the result of two factors: the competition of salicylate with Clfor coordination by the lipid headgroups (70) and the electrostatic repulsion of Clby the salicylate negative charge. This "competition" between chloride and salicylate in the molecular dynamics simulations is indirectly supported by experimental studies which demonstrated a linkage between chloride concentration and the distribution of salicylate across the erythrocyte membranes (71). Com-petition between salicylate and chloride has also been directly observed in OHC studies by Oliver et al (21).…”

Section: Resultsmentioning

confidence: 61%

Molecular Dynamics Simulations of Salicylate Effects on the Micro- and Mesoscopic Properties of a Dipalmitoylphosphatidylcholine Bilayer

2005

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Salicylate, an amphiphilic molecule and a popular member of non-steroidal antiinflammatory drug family, is known to affect hearing through reduction of the electromechanical coupling in the outer hair cells of the ear. This reduction of electromotility by salicylate has been widely studied but the molecular mechanism of the phenomenon is still unknown. In this study, we investigated one aspect of salicylate's action; namely, the perturbation of electrical and mechanical membrane properties by salicylate in the absence of cytoskeletal or membrane-bound motor proteins such as prestin. In particular, we simulated the interaction of salicylate with a dipalmitoylphosphatidylcholine (DPPC) bilayer via atomically-detailed molecular dynamics simulations to observe the effect of salicylate on the microscopic and mesoscopic properties of the bilayer. The results demonstrate that salicylate interacts with the bilayer by associating at the water-DPPC interface in a nearly perpendicular orientation and penetrating more deeply into the bilayer than either sodium or chloride. This association has several affects on the membrane properties. First, binding of salicylate to the membrane displaces chloride from the bilayer-water interface. Second, salicylate influences the electrostatic potential and dielectric properties of the bilayer, with significant changes at the waterlipid bilayer interface. Third, salicylate association results in structural changes including decreased head group area per lipid and increased lipid tail order. However, salicylate does not significantly alter the mechanical properties of the DPPC bilayer; bulk compressibility, area compressibility, and bending modulus were only perturbed by small, statistically-insignificant amounts, by the presence of salicylate. The observations from these simulations are in qualitative agreement with experimental data and support the conclusion that salicylate influences the electrical but not the mechanical properties of DPPC membranes. † This work was supported by NIH grant R01 GM069702 (NAB and YS) and an Alfred P. Sloan Research Fellowship (NAB).* To whom correspondence should be addressed. Dept. of Biochemistry and Molecular Biophysics, Center for Computational Biology, Washington Univ. St. Louis. 700 S. Euclid Ave., Campus Box 8036, St. Louis, MO 63110. Phone: (314) 362-2040, Fax: (314) 362-0234, E-mail: baker@biochem.wustl.edu, Web: http://agave.wustl.edu/. 1 Abbreviations: constant number-pressure-temperature (NpT), constant number-volume-temperature (NVT), dipalmitoylphosphatidylcholine (DPPC), giant unilamellar vesicle (GUV), human embryonic kidney (HEK), molecular dynamics (MD), outer hair cell (OHC), particle-mesh Ewald (PME), quantum mechanical/molecular mechanical (QM/MM), root mean squared (RMS), salicylate (SAL), solvent-accessible surface area (SASA), stearoyl-oleoylphosphatidylcholine (SOPC) Supporting Information Available Additional data, including figures of the QM/MM setup, time courses for system area, volume, and potential energy, select...

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Section: Resultsmentioning

confidence: 61%

Molecular Dynamics Simulations of Salicylate Effects on the Micro- and Mesoscopic Properties of a Dipalmitoylphosphatidylcholine Bilayer

2005

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“…A dose-dependent change in RBC morphology favoring the echinocyte rather than the discoid form was observed in accordance with NS3623 being an anionic compound. 26 In the same range of concentrations (24-hour incubation), NS3623 did not influence the amount of membraneassociated denatured hemoglobin in sickle cell ghosts, and it did not induce the formation of met-hemoglobin (data not shown). Figure 3A shows the valinomycin-induced hyperpolarizations from mouse RBCs isolated at various times after IV injection of NS3623 (50 mg/kg).…”

Section: In Vitro Effects On Human Ss Cellsmentioning

confidence: 87%

Treatment with NS3623, a novel Cl-conductance blocker, ameliorates erythrocyte dehydration in transgenic SAD mice: a possible new therapeutic approach for sickle cell disease

Bennekou

Franceschi

Pedersen

et al. 2001

Blood

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The dehydration of sickle red blood cells (RBCs) through the Ca-activated K channel depends on the parallel movement of Cl ions. To study whether Cl-conductance block might prevent dehydration of sickle RBCs, a novel Cl-conductance inhibitor (NS3623) was characterized in vitro using RBCs from healthy donors and sickle cell patients and in vivo using normal mice and a transgenic mouse model of sickle cell disease (SAD mice). In vitro, NS3623 reversibly blocked human RBC Cl-conductance (g Cl ) with an IC 50 value of 210 nmol/L and a maximal block of 95%. In vivo, NS3623 inhibited RBC g Cl after oral administration to normal mice (ED 50 ‫؍‬ 25 mg/kg). Although g Cl , at a single dose of 100 mg/kg, was still 70% inhibited 5 hours after dosing, the inhibition disappeared after 24 hours. Repeated administration of 100 mg/kg twice a day for 10 days caused no adverse effects; therefore, this regimen was chosen as the highest dosing for the SAD mice. SAD mice were treated for 3 weeks with 2 daily administrations of 10, 35, and 100 mg/kg NS3623, respectively. The hematocrit increased, and the mean corpuscular hemoglobin concentration decreased in all groups with a concomitant increase in the intracellular cation content. A loss of the densest red cell population was observed in conjunction with a shift from a high proportion of sickled to well-hydrated discoid erythrocytes, with some echinocytes present at the highest dosage. These data indicate feasibility for the potential use of Cl-conductance blockers to treat human sickle cell disease. (Blood.

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“…To assess the effect of membrane potential on shape, the potential had to be varied independently, without simultaneous shifts in cell pH, cell chloride, or cell water. By lowering external chloride in unbuffered, constant osmolality solutions (Nwafor and Coakley, 1985), this condition was well approximated. In each experiment, the membrane potential became more positive, and cell pH, chloride, and water were constant or changed to a minor extent.…”

Section: Independent Variation Of Membrane Potential and Effect On Shapementioning

confidence: 99%

Membrane potential and human erythrocyte shape

Gedde¹,

Huestis²

1997

Biophysical Journal

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Altered external pH transforms human erythrocytes from discocytes to stomatocytes (low pH) or echinocytes (high pH). The process is fast and reversible at room temperature, so it seems to involve shifts in weak inter- or intramolecular bonds. This shape change has been reported to depend on changes in membrane potential, but control experiments excluding roles for other simultaneously varying cell properties (cell pH, cell water, and cell chloride concentration) were not reported. The present study examined the effect of independent variation of membrane potential on red cell shape. Red cells were equilibrated in a set of solutions with graduated chloride concentrations, producing in them a wide range of membrane potentials at normal cell pH and cell water. By using assays that were rapid and accurate, cell pH, cell water, cell chloride, and membrane potential were measured in each sample. Cells remained discoid over the entire range of membrane potentials examined (-45 to +45 mV). It was concluded that membrane potential has no independent effect on red cell shape and does not mediate the membrane curvature changes known to occur in red cells equilibrated at altered pH.

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Drug-induced shape change in erythrocytes correlates with membrane potential change and is independent of glycocalyx charge

Cited by 18 publications

References 16 publications

Molecular Dynamics Simulations of Salicylate Effects on the Micro- and Mesoscopic Properties of a Dipalmitoylphosphatidylcholine Bilayer

Molecular Dynamics Simulations of Salicylate Effects on the Micro- and Mesoscopic Properties of a Dipalmitoylphosphatidylcholine Bilayer

Treatment with NS3623, a novel Cl-conductance blocker, ameliorates erythrocyte dehydration in transgenic SAD mice: a possible new therapeutic approach for sickle cell disease

Membrane potential and human erythrocyte shape

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