Endothelin: a potent stimulator of intestinal ion secretion in vitro.
Effects of endothelin (ET) on electrical properties and Na+ and Cl- fluxes in stripped rabbit ileal mucosa were investigated in vitro in Ussing chambers. Results demonstrate that serosal addition of ET-1, ET-2, ET-3 or the precursor 38 amino acid 'big endothelin' produce dose-dependent increases in short-circuit current (Isc) with maximal effects at approx. 100 nM, 100 nM, 10 nM and 100 nM, respectively and half-maximal effects at 1.4 nM, 5 nM, 1.4 nM and 20 nM, respectively. Mucosal addition of ET-3 failed to elicit a response. Changes in Isc elicited by ET-3 are accompanied by decreases in net fluxes of both Na+ and Cl-. The cyclooxygenase inhibitors, indomethacin and piroxicam, inhibited the increase in Isc produced by ET-3 and indomethacin also abolished the changes in Na+ and Cl- fluxes produced by ET-3. However, no changes in the release of PGE2, thromboxane B2 or 6-keto-prostaglandin F1 alpha could be detected up to 20 min after the addition of ET-3. Preincubation of tissues with neuronal agonists or antagonists, antihistamines or an LTD4/LTE4 receptor antagonist, SKF 104353, failed to alter the response to ET-3. Furthermore, removal of serosal Ca2+ also failed to inhibit the change in Isc produced by ET-3. These results indicate that endothelin is a potent intestinal secretagogue which does not appear to elicit its response through stimulation of PGE2, thromboxane A2 or prostacyclin.
Department of Drug Delivery, SmithKline Beecham, King of Prussia, PA 19406-0939.
M A
MA
Brown
P L
PL
Smith
D000818:Animals; D001693:Biological Transport, Active; D002118:Calcium / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004553:Electric Conductivity / Q000502:physiology; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D011498:Protein Precursors / Q000494:pharmacology; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D013931:Thromboxanes / Q000378:metabolism
D002712:Chlorides; D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D016232:Endothelins; D015289:Leukotrienes; D018377:Neurotransmitter Agents; D011453:Prostaglandins; D011498:Protein Precursors; D013931:Thromboxanes; D012964:Sodium; D002118:Calcium; D007213:Indomethacin