Correction for the adverse influence of sodium–potassium cotransport on apparent sodium–lithium countertransport activity in human erythrocytes

Hardman, Timothy C.; Morrish, Z; Patel, Mayur B.; Chalkley, S; Noble, Mark I. M.

doi:10.1016/s1056-8719(02)00188-0

Cited by 2 publications

(3 citation statements)

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“…Bumetanide, a high-selective inhibitor of both NKCC1 and NKCC2 isoforms, clearly decreased Li + influx in hCMEC/D3 cells. Our results were consistent with one study showing that bumetanide decreased the sodium-stimulated Li + efflux from Li + -loaded erythrocytes . Although no studies confirmed directly the role of NKCCs in the Li + transport through the BBB, the involvement of NKCCs in the brain uptake of Na + was well-demonstrated , mainly via NKCC1, located in the luminal membrane of brain endothelial cells. , …”

Section: Discussionsupporting

confidence: 92%

“…Our results were consistent with one study showing that bumetanide decreased the sodiumstimulated Li + efflux from Li + -loaded erythrocytes. 38 Although no studies confirmed directly the role of NKCCs in the Li + transport through the BBB, the involvement of NKCCs in the brain uptake of Na + was well-demonstrated 39,40 mainly via NKCC1, located in the luminal membrane of brain endothelial cells. 39,41 Some limitations should be noted when interpreting the overall data of this study.…”

Section: ■ Discussionmentioning

confidence: 99%

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Sodium Transporters Are Involved in Lithium Influx in Brain Endothelial Cells

et al. 2018

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Variability in drug response to lithium (Li) is poorly understood and significant, as only 40% of patients with bipolar disorder highly respond to Li. Li can be transported by sodium (Na) transporters in kidney tubules or red blood cells, but its transport has not been investigated at the blood-brain barrier (BBB). Inhibition and/or transcriptomic strategies for Na transporters such as NHE (SLC9), NBC (SLC4), and NKCC (SLC12) were used to assess their role on Li transport in human brain endothelial cells. Na-free buffer was also used to examine Na/Li countertransport (NLCT) activity. The BBB permeability of Li evaluated in the rat was 2% that of diazepam, a high passive diffusion lipophilic compound. Gene expression of several Na transporters was determined in hCMEC/D3 cells, human hematopoietic stem-cell-derived BBB models (HBLEC), and human primary brain microvascular endothelial cells (hPBMECs) and showed the following rank order with close expression profile: NHE1 > NKCC1 > NHE5 > NBCn1, while NHE2-4, NBCn2, and NBCe1-2 were barely detected. Li influx in hCMEC/D3 cells was increased in Na-free buffer by 3.3-fold, while depletion of chloride or bicarbonate had no effect. DMA (NHE inhibitor), DIDS (anionic carriers inhibitor), and bumetanide (NKCC inhibitor) decreased Li uptake significantly in hCMEC/D3 by 52, 51, and 47%, respectively, while S0859 (NBC inhibitor) increased Li influx 2.3-fold. Zoniporide (NHE1 inhibitor) and siRNA against NHE1 had no effect on Li influx in hCMEC/D3 cells. Our study shows that NHE1 and/or NHE5, NBCn1, and NKCC1 may play a significant role in the transport of Li through the plasma membrane of brain endothelial cells.

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