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MUCOSAL BIOLOGY

Duodenal brush border intestinal alkaline phosphatase activity affects bicarbonate secretion in rats

¹Greater Los Angles Veterans Affairs Healthcare System, Los Angeles; ²Department of Medicine, School of Medicine, and ³Department of Biomathematics, University of California, Los Angeles; and ⁴Brentwood Biomedical Research Institute, Los Angeles, California

Submitted 11 July 2007 ; accepted in final form 28 September 2007

We hypothesized that duodenal HCO₃^– secretion alkalinizes the microclimate surrounding intestinal alkaline phosphatase (IAP), increasing its activity. We measured AP activity in rat duodenum in situ in frozen sections with the fluorogenic substrate ELF-97 phosphate and measured duodenal HCO₃^– secretion with a pH-stat in perfused duodenal loops. We examined the effects of the IAP inhibitors L-cysteine or L-phenylalanine (0.1–10 mM) or the tissue nonspecific AP inhibitor levamisole (0.1–10 mM) on AP activity in vitro and on acid-induced duodenal HCO₃^– secretion in vivo. AP activity was the highest in the duodenal brush border, decreasing longitudinally to the large intestine with no activity in stomach. Villous surface AP activity measured in vivo was enhanced by PGE₂ intravenously and inhibited by luminal L-cysteine. Furthermore, incubation with a pH 2.2 solution reduced AP activity in vivo, whereas pretreatment with the cystic fibrosis transmembrane regulator (CFTR) inhibitor CFTR_inh-172 abolished AP activity at pH 2.2. L-Cysteine and L-phenylalanine enhanced acid-augmented duodenal HCO₃^– secretion. The nonselective P2 receptor antagonist suramin (1 mM) reduced acid-induced HCO₃^– secretion. Moreover, L-cysteine or the competitive AP inhibitor glycerol phosphate (10 mM) increased HCO₃^– secretion, inhibited by suramin. In conclusion, enhancement of the duodenal HCO₃^– secretory rate increased AP activity, whereas inhibition of AP activity increased the HCO₃^– secretory rate. These data support our hypothesis that HCO₃^– secretion increases AP activity by increasing local pH at its catalytic site and that AP hydrolyzes endogenous luminal phosphates, presumably ATP, which increases HCO₃^– secretion via activation of P2 receptors.

duodenum; brush-border membrane; ELF-97 phosphate