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Inhibition of Na + /H + exchanger isoform 3 improves gut fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator‐deficient and F508del mutant mice
Author(s) -
Tan Qinghai,
Stefano Gabriella,
Tan Xinjie,
Renjie Xiu,
Römermann Dorothee,
Talbot Steven R.,
Seidler Ursula E.
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15323
Subject(s) - cystic fibrosis transmembrane conductance regulator , jejunum , chemistry , lubiprostone , medicine , endocrinology , cystic fibrosis , pharmacology , biochemistry , constipation , chronic constipation
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 ~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 HCO 3 − 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.