Role of brush border Na+/H+ exchange in canine ileal absorption

Na+/H+ exchanger isoforms have been identified in mammalian intestinal enterocytes and cloned: NHE1 on the basolateral membrane regulating intracellular pH; and NHE2 and NHE3 on the brush border serving transcellular absorption in Na+. NHE1 and NHE2 are much more sensitive to inhibition by amiloride than NHE3, their in vitro IC50s for amiloride being 1 microM, 1 microM and 39 microM, respectively. This study tested the hypothesis that the brush border NHE3 isoform plays the predominant role in basal and meal-stimulated ileal absorption. Absorption studies (N = 72) were performed in dogs with 25-cm ileal Thiry-Vella fistulae. Six groups were studied over 4 hr. Perfusion with [14C]PEG and 140 mM Na+ was used to calculate absorption of water, ions, and glucose. Luminal amiloride was administered from the second to the fourth hours at doses of 20 microM in groups 3 and 4 to inhibit NHE1 and NHE2, and 1mM in groups 5 and 6 to also inhibit NHE3. A 480-kcal canine meal was ingested after the second hour in groups, 2, 4, and 6. Meal ingestion was followed by significant increases in water and electrolyte absorption. Amiloride (1 mM) caused significant reductions in basal and meal-stimulated ileal absorption, while the 20 microM dose had no effect on either. These data are consistent with the hypothesis that NHE3, but not NHE2, is involved in basal and meal-stimulated ileal water and Na+ absorption.