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Background:
Changes in peptidergic neurotransmission might participate in pathophysiology of postoperative ileus (POI), but have not been studied yet. We aimed to explore changes in neurotransmission with Vasoactive Intestinal Polypeptide (VIP; inhibitory) and Substance P (Sub P; excitatory) during POI.
Methods:
Mucosa free, circular, jejunal muscle strips (n=8/rat) were studied in organ chambers. Six male Sprague Dawley rats were studied per group: Naïve controls (NC), rats 12h (P12h) and 3d (P3d) after laparotomy and standardized small bowel manipulation to induce POI, and sham controls after 12h (SC12h) and 3d (SC3d) to study combined effects of anesthesia and sham laparotomy. Dose-responses to exogenous VIP (10^-10-10^-7M) and Sub P (3x10^-10-3x10^-7M) were studied without and with L-NNA (blocking nitric oxide (NO)-synthase; 10^-4M) or L-NIL (selective blocker of inducible NO-synthase; 3x10^-5M). Effects of endogenously released neurotransmitters were studied during electrical field stimulation (EFS; 20V, 4ms, 3Hz) without and with L-NNA, VIP antagonist ([D-p-Cl-Phe⁶,Leu¹⁷]-VIP; 10^-6M), or Sub P antagonist ([D-Pro²,D-Trp^7,9]-Sub P; 10^-6M). Studies were performed under non-adrenergic, non-cholinergic conditions (propranolol 5x10^-7M, phentolamine 10^-5M, atropine 10^-7M). Intestinal transit was measured by charcoal gavage ([%] small bowel passed by marker). Histology for myeloperoxidase positive cells (MPO), macrophages, and mast cells was performed in whole mounts (cells/mm²). Data: mean±SEM.
Results:
VIP caused dose-dependent inhibition in all groups (p<0.05). Inhibition was more pronounced in P12h, P3d, and SC3d (p<0.05 vs NC). L-NNA reduced VIP-induced inhibition in NC and P12h (p<0.05), while L-NIL had no effect on VIP responses (p=NS). Sub P caused dose-dependent excitation in all groups (p<0.05), which was reduced in P12h and increased in P3d (both p<0.05 vs. NC), while it was unaffected in sham controls (p=NS). EFS induced inhibition was more pronounce in P12h (-67±8%) compared to NC (-33±8; p<0.05). VIP and Sub P antagonists had no effect on EFS responses (all p=NS), while L-NNA prevented EFS-induced inhibition in all groups (all p<0.05). Intestinal transit was delayed in POI groups and SC12h (P12h 27±2; P3d 40±3; SC12h 48±2%; all p<0.05 vs NC 60±3%). MPO positive cells and mast cells were increased in P12h and P3d, but not in sham controls (MPO: NC 9±2; P12h 551±86; P3d 579±45; mast cells: NC 21±3; P12h 694±73; P3d 460±10; all p<0.05 vs NC) and macrophages were increased only in P3d (NC 347±7; P3d 1163±31 p<0.05 vs NC).
Conclusion:
Induction of POI causes specific changes in neurotransmission with VIP and Sub P that are accompanied by intramural inflammatory response and delayed gastrointestinal transit. Therefore, changes in peptidergic neurotransmission with VIP and Sub P appear to participate in pathophysiology of POI in rat. DFG KA2329/5-1