Inhibition Of Na+/H+ Exchanger Isoform 3 Improves Gut Fluidity And Alkalinity In Cystic Fibrosis Transmembrane Conductance Regulator-Deficient And F508del Mutant Mice

Background and Purpose: Constipation and intestinal obstructive episodes are major health problems in cystic fibrosis (CF) patients. Three FDA-approved drugs against constipation-prone irritable bowel syndrome were tested for their ability to increase luminal fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator (CFTR) null (cftr(-/-)) and F508del mutant (F508del(mut/mut)) murine intestine.Experimental Approach: Guanylate cyclase C agonist linaclotide, PGE(1) analogue lubiprostone and intestine-specific NHE3 inhibitor tenapanor were perfused through a similar to 3 cm jejunal, proximal or mid-distal colonic segment in anaesthetized cftr(-/-), F508del(mut/mut) and WT mice. Net fluid balance was determined gravimetrically and alkaline output by pH-stat back titration.Key Results: Basal jejunal fluid absorptive rates were significantly higher and basal HCO3- output was significantly lower in cftr(-/-) and F508del(mut/mut) compared to WT mice. In cftr(-/-) and F508del(mut/mut) mice, all three drugs significantly inhibited the fluid absorptive rate and increased alkaline output in the jejunum and tenapanor and lubiprostone, but not linaclotide, in the colon. After tenapanor pre-incubation, linaclotide elicited a robust fluid secretory response in WT jejunum, while no further change in absorptive rates was observed in cftr(-/-) and F508del(mut/mut) jejunum, suggesting that the increase in gut fluidity and alkalinity by linaclotide in CF gut is mediated via NHE3 inhibition. Lubiprostone also inhibited fluid absorption in cftr(-/-) and F508del(mut/mut) jejunum via NHE3 inhibition but had a residual NHE3-independent effect.Conclusion and Implications: Linaclotide, lubiprostone and tenapanor reduced fluid absorption and increased alkaline output in the CF gut. Their application may ameliorate constipation and reduce obstructive episodes in CF patients.