Linaclotide Improves Gastrointestinal Transit in Cystic Fibrosis Mice by Inhibiting Sodium/Hydrogen Exchanger 3.

Linaclotide Improves Gastrointestinal Transit in Cystic Fibrosis Mice by Inhibiting Sodium/Hydrogen Exchanger 3. Am J Physiol Gastrointest Liver Physiol. 2018 Aug 17;: Authors: McHugh DR, Cotton CU, Moss FJ, Vitko M, Valerio DM, Kelley TJ, Hao S, Jafri A, Drumm ML, Boron WF, Stern RC, McBennett K, Hodges CA Abstract Gastrointestinal dysfunction in Cystic Fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a Guanylate Cyclase C (GCC) receptor agonist, is an FDA-approved drug prescribed for chronic constipation, but has not been widely utilized in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders utilizing CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity was assessed in wildtype and CF mouse models in response to linaclotide. CFTR and Sodium/Hydrogen Exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl- secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fl...
Source: American Journal of Physiology. Gastrointestinal and Liver Physiology - Category: Physiology Authors: Tags: Am J Physiol Gastrointest Liver Physiol Source Type: research