Inactivation of inducible nitric oxide synthase protects intestinal pacemaker cells from postoperative damage

Abdominal surgery causes postoperative gastrointestinal dysmotility which can progress to paralytic ileus. Surgery causes inflammatory responses leading to loss of interstitial cells of Cajal (ICC), which generate intestinal pacemaker activity. Here, we demonstrate that a deficiency in or pharmacological inhibition of inducible nitric oxide synthase (iNOS) before surgery protects ICC from postoperative damage. Ileal segments from wild-type, iNOS and cyclooxygenase-2 (COX-2) knockout mice were resected and reconstructions were performed by end-to-end anastomoses. Wild-type animals were exposed to iNOS inhibitors before surgery, and electrical activity and ICC were examined 5 h after surgery. Intestinal surgery on wild-type mice caused a significant reduction in ICC and pacemaking at distances up to 5 cm from the anastomosis site. ICC networks and pacemaking were protected in iNOS(-/-) mice. In animals treated preoperatively with iNOS inhibitors, pacemaker activity was depressed only at the anastomosis site. COX-2 deficiency also muted postoperative disruption in pacemaker activity. Postoperative surgical damage consists of a local response and a more widespread response in which ICC and pacemaker activity are disrupted. Damage to ICC and pacemaking was greatly attenuated in the absence of NO derived from iNOS. Thus, management of iNOS expression or activity prior to intestinal surgery protects against postsurgical dysmotility and reduces the severity of postoperative ileus.