Gastric Motility and Integrity of Interstital Cells of Cajal in Early Postoperative Ileus in Mice: A Pilot Study

Postoperative ileus (POI) is a surgically-induced decrease in gastric and/or intestinal motility. It is a common and expected consequence of surgical procedures consisting of abdominal wall lesioning with or without gastrointestinal tract perturbation, but remains poorly understood and difficult to attenuate. Research has traditionally focused on postoperative changes in intestinal motility; few studies have investigated POI within the context of changes in postoperative, non- surgically intervened gastric function. In addition, the integrity of the interstitial cells of Cajal (ICC), essential to the generation of slow waves and enteric neurotransmission, have not been previously examined for their potential as a contributing factor in impaired postsurgical gastric motility in after abdominal surgery. To date, no scientifically approved tests or methods have been implemented into clinical use for assessment, prevention, or treatment of postsurgical changes in gastrointestinal dysmotility. Patients with POI experience overall disturbance in gastric motility presenting as nausea, vomiting, early satiety, bloating and inability to tolerate oral intake. POI slows patient recovery and increases the cost of care significantly. The primary focus of this study was to better understand, from cellular to organ level, the alterations in gastric motility during this period of initial recovery. The use of ultrasound was explored as an easily-available, non-invasive, and economical method of studying gastric motility. Several other recording and analyzing techniques were used to study gastric motility patterns, the integrity of the ICC network, and the expression of inflammatory mediators involved in the acute inflammatory process. In summary, this research revealed changes in the distribution of contents after surgery, evidenced by a significantly enlarged fundus. Postoperative gastric contractions were significantly more frequent in the sham group undergoing laparatomy (n=5) and in the experimental group (n=5) with laparatomy followed by 15 minute jejunal manipulation compared to the control group (n=10). However, the gastric contractions remained regular and rhythmic in all study groups. The structure of the ICC network (ICC-IM and ICC-MY) appeared intact in all groups. Interestingly, a significant increase in the number of nNOS positive cell bodies in the greater curvature region was observed. This region is considered the "pacemaker region" where gastric slow waves initiate and pace the smooth muscle to produce the rhythmic peristaltic gastric contractions. One of the most intriguing findings was increased mRNA expression of acute phase inflammatory mediators, for which testing and analytical methods did not correlate with increased levels of physiologically active proteins. The ultrasound was an easy and noninvasive method for imaging gastric contractions, which was able to detect the movement of the gastric antrum. We observed a "skipping phenomenon" consisting of a missing gastric contraction among postsurgical groups that was not detected or measurable with the other methods used in this study. The missing gastric contraction in otherwise regular gastric contractile patterns is most likely a physiological phenomenon, but suggests that ultrasonography is sensitive enough to distinguish altered gastric motility patterns. In conclusion these findings suggest that even in the presence of significant postsurgical gastric distention and increased frequency of gastric contractions, profound damage to the ICC network or overall motility patterns does not occur. While this study was performed in mice, it suggests that directly observing gastric movements may be beneficial to improve the initiation of postoperative oral intake to shorten POI

Prostaglandin regulation of gastric slow waves and peristalsis

Gastric emptying depends on functional coupling of slow waves between the corpus and antrum, to allow slow waves initiated in the gastric corpus to propagate to the pyloric sphincter and generate gastric peristalsis. Functional coupling depends on a frequency gradient where slow waves are generated at higher frequency in the corpus and drive the activity of distal pacemakers. Simultaneous intracellular recording from corpus and antrum was used to characterize the effects of PGE2 on slow waves in the murine stomach. PGE2 increased slow-wave frequency, and this effect was mimicked by EP3, but not by EP2, receptor agonists. Chronotropic effects were due to EP3 receptors expressed by intramuscular interstitial cells of Cajal because these effects were not observed in W/WV mice. Although the integrated chronotropic effects of EP3 receptor agonists were deduced from electrophysiological experiments, no clear evidence of functional uncoupling was observed with two-point electrical recording. Gastric peristalsis was also monitored by video imaging and spatiotemporal maps to study the impact of chronotropic agonists on propagating contractions. EP3 receptor agonists increased the frequency of peristaltic contractions and caused ectopic sites of origin and collisions of peristaltic waves. The impact of selective regional application of chronotropic agonists was investigated by use of a partitioned bath. Antral slow waves followed enhanced frequencies induced by stimulation of the corpus, and corpus slow waves followed when slow-wave frequency was elevated in the antrum. This demonstrated reversal of slow-wave propagation with selective antral chronotropic stimulation. These studies demonstrate the impact of chronotropic agonists on regional intrinsic pacemaker frequency and integrated gastric peristalsis