Inhibition of enterotoxin-induced porcine colonic secretion by diarylsulfonylureas in vitro.
Muscle-stripped piglet colon was used to evaluate changes in short-circuit current (I(sc)) as an indicator of anion secretion. Mucosal exposure to Escherichia coli heat-stable (STa) or heat-labile enterotoxins (LT) stimulated I(sc) by 32 +/- 5 and 42 +/- 7 microA/cm(2), respectively. Enterotoxin-stimulated I(sc) was not significantly affected by either 4,4'-diaminostilbene-2, 2'-disulfonic acid or CdCl(2), inhibitors of Ca(2+)-activated Cl(-) channels and ClC-2 channels, respectively. Alternatively, N-(4-methylphenylsulfonyl)-N'-(4-trifluoromethylphenyl)urea (DASU-02), a compound that inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl(-) secretion, reduced I(sc) by 29 +/- 7 and 34 +/- 11 microA/cm(2), respectively. Two additional diarylsulfonylurea (DASU)-based compounds were evaluated for their effects on enterotoxin-stimulated secretion. The rank order of potency for inhibition by these three closely related DASU structures was identical to that observed for human CFTR. The degree of inhibition by each of these compounds was similar for both STa and LT. The structure- and concentration-dependent inhibition shown indicates that CFTR mediates both STa- and LT-stimulated colonic secretion. Similar structure-dependent inhibitory effects were observed in forskolin-stimulated rat colonic epithelium. Thus DASUs compose a family of inhibitors that may be of therapeutic value for the symptomatic treatment of diarrhea resulting from a broad spectrum of causative agents across species.
O'Donnell
E K
EK
Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66506, USA.
Sedlacek
R L
RL
Singh
A K
AK
Schultz
B D
BD
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000838:Anions / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002034:Bumetanide / Q000494:pharmacology; D019256:Cadmium Chloride / Q000494:pharmacology; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D004232:Diuretics / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine; D013779:Tetrodotoxin / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D000838:Anions; D000970:Antineoplastic Agents; D001572:Benzofurans; D004232:Diuretics; D004768:Enterotoxins; C416188:N-(4-methylphenylsulfonyl)-N'-(4-trifluoromethylphenyl)urea; D010671:Phenylurea Compounds; D013267:Stilbenes; D013453:Sulfonylurea Compounds; D002034:Bumetanide; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C094382:N-(5-(2,3-dihydrobenzofuryl)sulfonyl)-N'-(3,4-dichlorophenyl)urea; D014660:Vasoactive Intestinal Peptide; D013779:Tetrodotoxin; C022306:4,4'-dinitro-2,2'-stilbenedisulfonic acid; D000584:Amiloride; D014508:Urea; D019256:Cadmium Chloride