Abstract
Background and purpose : Mutations in the CFTR chloride channel results in intestinal obstructive episodes in cystic fibrosis (CF) patients and in CF animal models. This study explores the possibility of reducing the frequency of obstructive episodes in theCftr -/- mice by the oral application of a gut selective NHE3 inhibitor tenapanor and searches for the underlying mechanisms involved.
Experimental approach: Sex and age-matchedCftr +/+ and Cftr -/-mice were orally gavaged twice daily with 30mg kg-1tenapanor or vehicle for a period of 21 days. Body weight and stool water content was assessed daily and gastrointestinal transit time (GTT) once weekly. The mice were sacrificed when an intestinal obstruction was suspected or after 21 days, and stool and tissues were collected for further analysis.
Key results: 21 day tenapanor application resulted in a significant increase in stool water content, stool alkalinity, and a significant decrease in GTT in Cftr +/+ andCftr -/- mice. Tenapanor significantly reduced obstructive episodes to 8% compared to 46% in vehicle treatedCftr -/- mice and prevented mucosal inflammation. A decrease in cryptal hyperproliferation, mucus accumulation and mucosal mast cell number was also observed in tenapanor compared to vehicle treated unobstructedCftr -/- mice.
Conclusion and implications: Oral tenapanor application prevented obstructive episodes in CFTR deficient mice and was safe inCftr +/+ and Cftr -/-mice. These results suggest that tenapanor may be a safe and affordable adjunctive therapy in cystic fibrosis patients to alleviate constipation and prevent recurrent DIOS.
Key words: mucoviscidosis, DIOS, mucus, intestinal fluid absorption, sodium hydrogen exchange, chloride channel