On the effects of propionate and other short-chain fatty acids on sodium transport by the toad bladder.

1. Propionate and other unbranched short-chain fatty acids, butyrate, pentanoate, hexanoate and octanoate were found to both stimulate and inhibit active sodium transport by the toad bladder, as measured by the short-circuit current (s.c.c.). 2. Stimulation alone followed addition of low concentrations of fatty acids (0.1-1.0 mM) to either the serosal or mucosal bathing medium; stimulation was also seen after an initial period of inhibition in response to higher concentrations (approx. 5 mM) of some compounds. 3. Inhibition alone followed addition of high concentrations (5-20 mM) of these compounds. The duration and magnitude of the inhibition varied with increasing concentration and chain length of the fatty acid, and was greater following mucosal addition than serosal addition. 4. The inhibitory effect of mucosal propionate increased with decreasing pH of the mucosal bathing medium. 5. Inhibition by the fatty acids was completely reversed upon removing the compound from the bathing medium, and stimulation characteristically followed. 6. In studies designed to evaluate the role of metabolism of the fatty acids in their mucosal inhibitory effects it was found that 14-c-labelled propionate, when added to the mucosal surface of the bladder, was converted to 14-CO2, and mucosal succinate and alpha-oxoglutaric acid at 20 mM inhibited the s.c.c. slightly. However, malonate did not interfere with inhibition by mucosal propionate and two non-metabolizable acids, dimethylpropionate and benzoate, induced inhibition (and no stimulation) of the s.c.c. 7. In the presence of an inhibitory concentration of fatty acid, the ability of the bladder to respond to added pyruvate was reduced in proportion to the reduction in the level of the s.c.c., whereas the natriferic response to vasopressin was largely intact. 8. We conclude that stimulation of sodium transport by propionate and other short-chain fatty acids is due to metabolism of the compounds and provision of energy to the sodium transport mechanism. The basis of the inhibition appears complex. It may in part depend on metabolism of the fatty acids and/or uncoupling of oxidative phosphorylation, with resultant reduction in net ATP production for the sodium transport mechanism. However, the inhibition may also be caused in part by a direct effect on the mucosal entry of sodium into the transporting epithelial cells.