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.
Intravenous bombesin produced a dose-related stimulation of luminal gastric somatostatin output and a concomitant dose-dependent inhibition of food intake in the gastric fistula cat. Maximal food intake inhibition was observed at 1,280 pmol.kg-1.h-1 and corresponded to 65 +/- 7% (P less than 0.01). These effects of bombesin were dose dependently abolished by the specific bombesin-receptor antagonist, [Leu13-psi(CH2NH)-Leu14]bombesin. Furthermore, intragastric administration of somatostatin-14, at doses corresponding to those found in the gastric lumen in response to intravenously administered bombesin, significantly inhibited the first 30 min of food intake. This administration had however no effect on total (daily) food intake. We therefore suggest that luminal gastric somatostatin could at least account for bombesin-induced short-term satiety.
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