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Am J Physiol Gastrointest Liver Physiol 277: G521-G532, 1999;
0193-1857/99 $5.00
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Vol. 277, Issue 3, G521-G532, September 1999

Ammonia blockade of intestinal epithelial K+ conductance

Bruce J. Hrnjez, Jaekyung C. Song, Madhu Prasad, Julio M. Mayol, and Jeffrey B. Matthews

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, and the Harvard Digestive Diseases Center, Boston, Massachusetts 02215

Ammonia profoundly inhibits cAMP-dependent Cl- secretion in model T84 human intestinal crypt epithelia. Because colonic lumen concentrations of ammonia are high (10-70 mM), ammonia may be a novel regulator of secretory diarrheal responsiveness. We defined the target of ammonia action by structure-function analysis with a series of primary amines (ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, and octylamine) that vary principally in size and lipid solubilities. The amine concentrations required for 50% inhibition of Cl- secretion in intact monolayers and 50% inhibition of outward K+ current (IK) in apically permeabilized monolayers vs. the logs of the respective amine partition coefficients give two plots that are strikingly similar in character. Half-maximal inhibition of short-circuit current (Isc) by ammonia was seen at 6 mM and for IK at 4 mM; half-maximal inhibition for octylamine was 0.24 mM and 0.19 mM for Isc and IK, respectively. The preferentially water-soluble hydrophilic amines (ammonia, methylamine, ethylamine) increase in blocking ability with decreasing size and lipophilicity. Conversely, the preferentially lipid-soluble hydrophobic (propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine) amines increase in blocking ability with increasing size and lipophilicity. Ammonia does not affect isolated apical Cl- conductance; amine-induced changes in cytosolic and endosomal pH do not correlate with secretory inhibition. We propose that ammonia in its protonated ammonium form (NH+4) inhibits cAMP-dependent Cl- secretion in T84 monolayers by blocking basolateral K+ channels.

ammonia; chloride; diarrhea; T84 cells; pH


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