Mechanosensitive Ion Channels in the Development of Ileus

Abstract

IntroductionApproximately 30% of trauma patients develop ileus, a decrease or cessation of intestinal motility resulting in pathological distension of the intestinal wall. Mechanosensitive ion channels play a role in both the physiological and pathological response to mechanical stimuli.ObjectiveThe objective of this study was to determine if mechanosensitive ion channels play a role in the development of ileus and the response of the intestine to pathological stretch.MethodsIn a rodent model, we induced ileus by a combination of hemodilution and mesenteric venous hypertension. We measured intestinal function using an ex vivo organ bath system. We also measured smooth muscle myosin light chain phosphorylation and intestinal wall fluid content. We collected tissue for microarray analysis.ResultsIntestinal wall fluid content increased significantly, indicating the development of intestinal edema. Edema development resulted in distension of the intestinal wall, decreased intestinal smooth muscle contractile activity, and decreased smooth muscle myosin light chain phosphorylation. We used microarray analysis to compare normal (unstretched) intestinal smooth muscle to edematous (stretched) intestinal smooth muscle to characterize changes in ion channel expression. We identified hyperpolarization‐activated cyclic nucleotide‐gated 2 (HCN2), a cyclic nucleotide gated ion channel, which is also stretch‐activated. HCN2 gene expression decreased in edematous intestinal tissue. In the ex vivo organ bath system, we tested the effects of HCN2 inhibitors on intestinal function. In preliminary experiments, HCN2 inhibition with ZD7288 resulted in decreased response to carbachol, with little change in spontaneous contractile activity or frequency.ConclusionsOur data suggest that HCN2 downregulation/inhibition can suppress intestinal contractile activity. Thus, HCN2 is a potential therapeutic target for improving intestinal motility. In future experiments, we will determine the role of HCN2 in the intestinal response to stretch.Support or Funding InformationHungarian National Research Development and Innovation Office (K120669, EFOP‐3.6.2‐16‐2017‐00006)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.