More than 99% of nearly all amino acids filtered by the kidneys of humans and other mammals are reabsorbed in the renal tubule and returned to plasma [1, 21. In man, glycine, histidine and taurine are exceptional in that they have urinary fractional excretions of 3.5%, 6% and 6%, respectively [2]. Considerable evidence exists that amino acids are reabsorbed predominantly in the pars convoluta of the proximal tubule and to a small extent in pars recta [1—4]. Micropuncture studies [2, 3] have shown that no significant reabsorption of amino acids occurs under normal conditions in nephron segments beyond the proximal tubule. However, as documented by Silbernagl [5], the loop of Henle may participate in amino acid resorption under conditions of an elevated filtered load. Micropuncture experiments [3, 5—7] and studies utilizing isolated perfused proximal tubules [8, 91 have clearly demonstrated that amino acids are primarily reabsorbed from tubular lumen by an active uphill transport across the apical membrane followed by a downhill efflux across the peritubular membrane. Fox et al [10] first showed that amino acid uptake by renal tissue was greatly diminished in the absence of Na in the incubation medium. A stop-flow micropuncture experiment by Ullrich and coworkers [61 showed that the transepithelial concentration difference of actively transported amino acids was abolished when Na4 was removed from the peritubular and luminal perfusates. Subsequently the Na dependence of amino acid transport across the renal tubular epithelium has been clearly established in multiple animal studies using isolated perfused tubules [8, 9], electrophysiological techniques [11—131, cultured renal epithelial cell lines [14, 151 and isolated brush border membrane vesicles [l&-25]. In the latter experiments the rate of accumulation of amino acids by vesicles and the magnitude of the" overshoot", which indicates active concentrative transport, were markedly augmented by a Na gradient across the vesicle membrane. Hence, it is widely accepted that uptake of most amino acids at the brush border surface occurs by sodium-amino acid cotransport driven by both the concentration and the voltage components [26], of the electrochemical Na gradient from tubular lumen to cell [4, 27—29]. The energy maintaining the Na gradient is established by the Na-K-ATPase which is located at the basolateral membrane and pumps Na out and K into the cell. In concert with this notion is the finding that ouabain, a specific inhibitor of Na-K-ATPase which dissipates the electrochemical Na gradient across the cell membrane, diminishes amino acid uptake by

© 1989 by the International Society of Nephrology renal epithelial cell line (LLC-PK1)[14]. Na-amino acid sym-port, like the cotransport of Na with other solutes, has been termed" secondary active transport" because its energy is derived from the electrochemical gradient of Na rather than from direct coupling to a metabolic process [27—29]. The dependence of tubular amino acid transport on Na gradient has been further demonstrated by the observation of decreased Na-linked accumulation of various amino acids into gramcidin-[22, 23, 25] and papain-[30] treated vesicles. Both com-pounds stimulate the entry of Na into vesicle, via pathways not coupled to uptake of amino acids, thereby rapidly collapsing the Na gradient necessary for amino acid transport. In the case of cystine, however, the findings that its Nat-dependent uptake by vesicles did not display an overshoot [311 and that its accumulation in papain exposed vesicles was enhanced, rather than diminished [32], has led Hsu, Corcoran and Segal [32] to speculate that tubular …