THE ROLE OF VOLUME-SENSITIVE CL- CHANNELS IN THE STIMULATION OF CHLORIDE ABSORPTION BY SHORT-CHAIN FATTY-ACIDS IN THE RAT COLON

The short-chain fatty acids acetate, propionate and butyrate induced a concentration-dependent decrease in short-circuit current (I-sc) of the rat colon in vitro. The decrease in I-sc, being more pronounced in the distal than in the proximal colon, was dependent on the presence of Cl- ions and partly on the presence of HCO3-. In the distal colon, the fall in I-sc could be inhibited by amiloride, indicating that the activity of the Na+/H+ exchanger is necessary for the induction of this response. The decrease in I-sc was diminished by the Cl- channel blocker, 5-nitro-2-(3-phenylpropylamino)-benzoate and the lipoxygenase inhibitor, nordihydroguaiaretic acid. In contrast, inhibitors of the leukotriene pathway or a Cl- channel blocker did not affect the I-sc response in the proximal colon. Measurements of unidirectional fluxes revealed that butyrate caused a stimulation of the mucosa to serosa fluxes (F-ms) of Na+ and Cl- in the distal, but only of F-ms(Na) in the proximal colon. Unidirectional Rb+ fluxes were not altered. The stimulation of F-ms(cl), correlated with the degree of metabolism of the short-chain fatty acid. The increase in F-ms(Cl) was most pronounced for butyrate, smaller for acetate and not observed with the poorly metabolizable short-chain fatty acid, isobutyrate. Consequently, two factors seem to be responsible for the stimulation of Cl- absorption by short-chain fatty acids in the distal colon: (1) the intracellular production of HCO3- during the oxidation of short-chain fatty acids as substrate for the apical Cl-/HCO3-, exchanger, and (2) the activation of volume-sensitive basolateral Cl- channels.