Fatty acids inhibit anion secretion in rat colon: apical and basolateral action sites.
Ca2+-dependent secretagogues evoke only a transient Cl- secretion in intestinal epithelia, although they induce a prolonged increase in the intracellular Ca2+ concentration, suggesting that they may exert an additional antisecretory action. In order to study the mechanism of this antisecretory effect, Cl- secretion, measured as the increase in short-circuit current (Isc), was evoked by carbachol in the absence and presence of different inhibitors. Neither a calmodulin antagonist, calmidazolium, nor different inhibitors of the nitric oxide (NO) pathway, i.e. Nomega-nitro-L-arginine (L-NNA) and Nomega-nitro-L-arginine methylester (L-NAME), affected the carbachol-induced Isc. However, inhibition of phospholipases A2 (PLA2) by quinacrine or arachidonyltrifluoromethyl ketone (AACOCF3) enhanced the Isc response evoked by carbachol, suggesting a role of fatty acids in the downregulation of anion secretion. Neither econazole, a cytochrome P450 inhibitor, nor nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenases, mimicked the action of the PLA2 blockers. Conversely, short- or medium-chain fatty acids inhibited the carbachol- and forskolin-induced Isc with caprate (C10:0) being the most efficient water-soluble fatty acid. This fatty acid inhibited a Cl- current, which was driven across the apical membrane by a serosally to mucosally directed Cl- gradient after depolarization of the basolateral membrane. A second action site of fatty acids seems to be the basolateral membrane. After permeabilization of the apical membrane with the ionophore nystatin, a mucosally to serosally directed K+ gradient induced a K+ current, which was also inhibited by caprate. These results indicate that carbachol not only acts as a secretagogue but at the same time initializes downregulation by increasing the intracellular concentration of fatty acids, a mechanism limiting the resulting Cl- secretion.
Schultheiss
G
G
Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Germany. gerhard.schultheiss@vetmed.uni-giessen.de
Ribeiro
R
R
Diener
M
M
D000818:Animals; D000838:Anions / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002147:Calmodulin / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D016764:Cell Polarity / Q000502:physiology; D002712:Chlorides / Q000378:metabolism*; D018679:Cholinergic Agonists / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000166:cytology / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054467:Phospholipases A2; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000838:Anions; D001095:Arachidonic Acids; D002147:Calmodulin; D002712:Chlorides; D018679:Cholinergic Agonists; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D005227:Fatty Acids; C081565:arachidonyltrifluoromethane; D005576:Colforsin; D009569:Nitric Oxide; C031071:decanoic acid; D002217:Carbachol; D010741:Phospholipases A; D054467:Phospholipases A2; D011188:Potassium