A novel small molecule CFTR inhibitor attenuates HCO3- secretion and duodenal ulcer formation in rats.
The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) plays a crucial role in mediating duodenal bicarbonate (HCO(3)(-)) secretion (DBS). Although impaired DBS is observed in CF mutant mice and in CF patients, which would predict increased ulcer susceptibility, duodenal injury is rarely observed in CF patients and is reduced in CF mutant mice. To explain this apparent paradox, we hypothesized that CFTR dysfunction increases cellular [HCO(3)(-)] and buffering power. To further test this hypothesis, we examined the effect of a novel, potent, and highly selective CFTR inhibitor, CFTR(inh)-172, on DBS and duodenal ulceration in rats. DBS was measured in situ using a standard loop perfusion model with a pH stat under isoflurane anesthesia. Duodenal ulcers were induced in rats by cysteamine with or without CFTR(inh)-172 pretreatment 1 h before cysteamine. Superfusion of CFTR(inh)-172 (0.1-10 microM) over the duodenal mucosa had no effect on basal DBS but at 10 microM inhibited acid-induced DBS, suggesting that its effect was limited to CFTR activation. Acid-induced DBS was abolished at 1 and 3 h and was reduced 24 h after treatment with CFTR(inh)-172, although basal DBS was increased at 24 h. CFTR(inh)-172 treatment had no effect on gastric acid or HCO(3)(-) secretion. Duodenal ulcers were observed 24 h after cysteamine treatment but were reduced in CFTR(inh)-172-pretreated rats. CFTR(inh)-172 acutely produces CFTR dysfunction in rodents for up to 24 h. CFTR inhibition reduces acid-induced DBS but also prevents duodenal ulcer formation, supporting our hypothesis that intracellular HCO(3)(-) may be an important protective mechanism for duodenal epithelial cells.
Akiba
Yasutada
Y
Department of Medicine, University of California, Los Angeles, USA.
Jung
Michael
M
Ouk
Samedy
S
Kaunitz
Jonathan D
JD
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001639:Bicarbonates / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003538:Cystamine / Q000633:toxicity; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000517:prevention & control*; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013439:Sulfhydryl Reagents / Q000633:toxicity; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; D001639:Bicarbonates; D013439:Sulfhydryl Reagents; D013844:Thiazoles; D053778:Thiazolidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003538:Cystamine