It has been known for almost 50 years [152, 417] that influx and efflux of Na+ and Cl− across the blood–brain barrier are much larger than the net flux [4]. It was proposed by Crone [151, 418] that these apparently passive fluxes might well be paracellular, a suggestion that is still in agreement with all available data [4]. (The partial inhibitions seen in some studies with amiloride derivatives are discussed in Sections 4.3.3 and 4.3.4 of [4]).