Endothelin-1 potently stimulates chloride secretion and inhibits Na+-glucose absorption in human intestine in vitro

1. Serosally added synthetic endothelin-1 (ET-1) increased short-circuit current (I-SC) across isolated muscle-stripped human colonic mucosa in vitro. Bumetanide inhibited I-sc responses, indicating that ET-1 stimulates electrogenic Cl- secretion. 2. In isolated human jejunal mucosa, ET-1 exhibited a concentration-dependent dual action. At low concentrations it induced rapid increases in I-sc and these were inhibited by bumetanide. At a higher concentration (0.1 mu M), ET-1 provoked a drastic and progressive decrease in I-sc below the baseline value. 3. Pretreatment with phlorizin or omission of glucose from the Krebs-Ringer solution at the apical (luminal) side of the jejunal mucosa prevented the decreases in I-sc evoked by ET-1, suggesting that the peptide inhibits the glucose-coupled electrogenic Naf absorption. Indeed, flux experiments with D-[C-14]glucose demonstrated that ET-1. decreases jejunal glucose absorption by similar to 80% within 30 min. 4. Electron microprobe analyses of cryosections of human jejunum showed that ET-1 (0.1 mu M) evokes a significant decrease in intracellular Na+ concentrations of villus (not crypt) epithelial cells, suggesting that the peptide attenuates apical Na+-glucose entry by reducing the activity or the Na+-glucose cotransporter, SGLT1. 5. In the presence of tetrodotoxin (TTX), ET-1-induced Cl- secretion was significantly reduced, in both human jejunal and colonic mucosa. However, the inhibitory effect on jejunal Na+-glucose absorption was not affected by TTX. 6. ET-1 increases electrogenic Cl- secretion across human intestinal mucosa in vitro. This effect is mediated in part via the activation of enteric nerves. Responses of the human jejunal mucosa to high ET-1 concentrations exhibit a second component, namely the rapid inhibition of electrogenic Na+-glucose absorption, which might be mediated by an inhibition of the transport activity of SGLT1. This effect is independent from neuronal mediators. Our results suggest different cellular action sites for ET-1 in human small and large intestine.