Influence of Vagal Innervation On Motility and Afferent Sensitivity During Early Postoperative Ileus in Mice
Mario H. Mueller*1,3, Zhirong Gao3, Jorg Glatzle2, Michael S. Kasparek1,3, Sarah Mittler3, Mia Karpitschka3, Andrei Sibaev5,3, Martin E. Kreis1, Bernhard W. Renz1, Li Yongyu4
1Department of Surgery, Ludwig-Maximilians University, Munich-Grosshadern, Germany; 2Department of Surgery, Eberhard-Karls University, Tuebingen, Germany; 3Walter-Brendel Zentrum (WBex), Ludwig-Maximilians University, Munich-Grosshadern, Germany; 4Department of Pathophysiology, Tongji University, Medical School, Shanghai, China; 5Department of Gastroenterology (Med. II), Ludwig-Maximilians University, Munich-Grosshadern, Germany
Introduction: Postoperative ileus is characterized by early reflex inhibition of intestinal motility within hours and followed by an intestinal inflammatory response that involves efferent vagal modulation via the α7 subunit of acetylcholine receptors on intestinal macrophages. The role of the vagus nerve during early hours of postoperative ileus is unknown. We hypothesized that vagal innervation is irrelevant during early postoperative ileus.Methods: Postoperative ileus was induced by standardized small bowel manipulation in C57BL6 mice following laparotomy. Subgroups were vagotomized 3-4 days prior to experiments or received pharmacological inhibition of the acetylcholine α7 subunit with the inhibitor α-bungarotoxine (1μg/kg i.p. 1h, 3h, 9h prior to ileus induction each n=6), while control animals were sham operated and remained otherwise untreated. Three hours after small bowel manipulation a 2 cm jejunal segment was harvested with the mesentery attached. Mesenteric afferent nerve discharge was recorded in vitro generating a multi-unit signal with subsequent computerized analysis including recording of intestinal motility. Afferent nerve discharge at baseline, responses to chemical stimulation with bradykinin (0.5 µM), 5-HT (500 µM) and mechanical stimulation by continuous ramp distension to 60 mmHg were studied. Data are mean ± SEM. Results: Peak amplitudes of intestinal motor events were 0.70±0.02, 0.69±0.04, and 0.67±0.03 mmHg and afferent nerve discharge was 12±2, 11±1, 14±1 1 imp sec-1 following vagotomy, α-bungarotoxine, or sham operation, respectively with no difference between groups (all n.s.). Increase of afferent discharge to 5-HT was 6 ± 1 imp sec-1 above baseline following α-bungarotoxine which was similar compared to 8 ± 1 imp sec-1 in sham controls, while the response was reduced to 0.7±1.6 imp sec-1 in chronically vagotomized animals (p<0.05). Bradykinin was followed by 20±2, 19±1 and 22±1 imp sec-1 after vagotomy, α-bungarotoxine or sham operation respectively, while peak firing rate was 83±9, 95±12 and 80±8 imp sec-1 during intraluminal ramp distension at 60 mmHg (all n.s.). At luminal distension from 10 to 30 mmHg, afferent discharge was lower in vagotomized animals compared to sham controls (p<0.05), but unchanged after α-bungarotoxine.Conclusions: Sensitivity to 5-HT and low-threshold distension is mediated via vagal afferents during postoperative ileus, while sensitivity to high threshold distension and bradykinin is independent of intact vagal afferents. Inhibition of intestinal motility early, i.e. 3 hours after induction of postoperative ileus, does not appear to depend on vagal innervation.
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