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1 Department of pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
Fluid secretion across the blood–brain barrier, critical for maintaining the correct fluid balance in the brain, entails net secretion of HCO3–, which is brought about by the combined activities of ion transporters situated in brain microvessels. These same transporters will concomitantly influence intracellular pH (pHi). To analyse the transporters that may be involved in the maintenance of pHi and hence secretion of HCO3–, we have loaded primary cultured endothelial cells derived from rat brain microvessels with the pH indicator BCECF and suspended them in standard NaCl solutions buffered with Hepes or Hepes plus 5% CO2/HCO3–. pHi in the standard solutions showed a slow acidification over at least 30 min, the rate being less in the presence of HCO3– than in its absence. However, after accounting for the difference in buffering, the net rates of acid loading with and without HCO3– were similar. In the nominal absence of HCO3– the rate of acid loading was increased equally by removal of external Na+ or by inhibition of Na+/H+ exchange by ethylisopropylamiloride (EIPA). By contrast, in the presence of HCO3– the increase in the rate of acid loading when Na+ was removed was much larger and the rate was then also significantly greater than the rate observed in the absence of both Na+ and HCO3–. Removal of Cl– in the presence of HCO3– produced an alkalinization followed by a resumption of the slow acid gain. Removal of Na+ following removal of Cl– increased the rate of acid gain. In the presence of HCO3– and initial presence of Na+ and Cl–, DIDS inhibited the changes in pHi produced by removal of either Na+ or Cl–. These are the expected results if these cells possess an AE-like Cl–/HCO3– exchanger, a ‘channel-like’ permeability allowing slow influx of acid (or efflux of HCO3–), a NBC-like Cl–-independent Na+–HCO3– cotransporter, and a NHE-like Na+/H+ exchanger. The in vitro rates of HCO3– loading via the Na+–HCO3– cotransporter could, if the transporter is located on the apical, blood-facing side of the cells, account for the net secretion of HCO3– into the brain.
(Received 17 July 2006;
accepted after revision 15 August 2006;
first published online 17 August 2006)
Corresponding author S. B. Hladky: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. Email: sbh1{at}cam.ac.uk
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