Role of Na+ in the asymmetric paracellular transport of 4- phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg across rabbit colonic segments and Caco-2 cell monolayers

WC Yen and VH Lee

University of Southern California, School of Pharmacy, Department of Pharmaceutical Sciences, Los Angeles.

This study was conducted to demonstrate that Na+ played a role in the paracellular transport of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly- L-Pro-D-Arg (Pz-peptide), a hydrophilic proline-containing pentapeptide, across the rabbit colonic mucosa and Caco-2 cell monolayers. Over the 1 to 5 mM concentration range, Pz-peptide transport was 25 to 180 times greater from the mucosal-to-serosal than from the opposite direction. This asymmetry in transport was consistent with the ability of Pz-peptide to lower the transepithelial electrical resistance of Caco-2 cell monolayers only from the mucosal side. Blockade of Na+ access to the apically located amiloride-sensitive Na+ channel in the lower intestinal segments by mucosal 10 microM amiloride, serosal 100 microM ouabain or removal of Na+ ions in the mucosal fluid dramatically reduced Pz-peptide transport to 5% of the control. Moreover, Pz-peptide transport across Caco-2 cell monolayers could be titrated against mucosal Na+ concentration. There was a small mucosal-to-serosal solvent drag effect induced by transepithelial Na+ flux stimulated by Pz-peptide in the colon, contributing in part to enhanced paracellular solute transport. Overall, the above findings are consistent with a scenario whereby Pz-peptide stimulates transepithelial Na+ flux across the colonic segments at the level of the amiloride-sensitive Na+ channel, thereby triggering yet to be identified intracellular biochemical changes that ultimately result in tight junctional opening and enhanced paracellular solute transport.

Volume 275, Issue 1, pp. 114-119, 10/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				T. Lindmark, Y. Kimura, and P. Artursson Absorption Enhancement through Intracellular Regulation of Tight Junction Permeability by Medium Chain Fatty Acids in Caco-2 Cells J. Pharmacol. Exp. Ther., January 1, 1998; 284(1): 362 - 369. [Abstract] [Full Text]

				J. R. Pappenheimer, M. L. Karnovsky, and J. E. Maggio Absorption and Excretion of Undegradable Peptides: Role of Lipid Solubility and Net Charge J. Pharmacol. Exp. Ther., January 1, 1997; 280(1): 292 - 300. [Abstract] [Full Text]