Disruption of the pacemaker activity of interstitial cells of Cajal via nitric oxide contributes to postoperative ileus.

Interstitial cells of Cajal (ICC) serve as intestinal pacemakers. Postoperative ileus (POI) is a gastrointestinal motility disorder that occurs following abdominal surgery, which is caused by inflammation-induced dysfunction of smooth muscles and enteric neurons. However, the participation of ICC in POI is not well understood. In this study, we investigated the functional changes of ICC in a mouse model of POI. Intestinal manipulation (IM) was performed to induce POI. At 24 h or 48 h after IM, the field potential of the intestinal tunica muscularis was investigated. Tissues were also examined by immunohistochemistry and electron microscopic analysis. Gastrointestinal transit was significantly decreased with intestinal tunica muscularis inflammation at 24 h after IM, which was ameliorated at 48 h after IM. The generation and propagation of pacemaker potentials were disrupted at 24 h after IM and recovered to the control level at 48 h after IM. ICC networks, detected by c-Kit immunoreactivity, were remarkably disrupted at 24 h after IM. Electron microscopic analysis revealed abnormal vacuoles in the ICC cytoplasm. Interestingly, the ICC networks recovered at 48 h after IM. Administration of aminoguanidine, an inducible nitric oxide synthase inhibitor, suppressed the disruption of ICC networks. Ileal smooth muscle tissue cultured in the presence of nitric oxide donor, showed disrupted ICC networks. The generation and propagation of pacemaker potentials by ICC are disrupted via nitric oxide after IM, and this disruption may contribute to POI. When inflammation is ameliorated, ICC can recover their pacemaker function.