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Susceptibility to postoperative ileus following abdominal surgery increases with advancing age. The mechanisms underlying this phenomenon are unknown. This study compares functional and molecular endpoints between young-adult (2 mo old), middle-aged (15 mo old), and elderly mice (26-30 mo old) to identify potential mechanisms. Susceptibility to ileus was assessed by measuring gastrointestinal transit (geometric center) 24 h after anesthesia, laparotomy, and light manipulation (LM) of the small bowel. Proinflammatory (IL-6, COX-2, inducible nitric oxide synthase) and anti-inflammatory (IL-10, heme oxygenase-1) gene and protein expressions were determined by real time RT-PCR, Western blot, and ELISA. LM did not alter gastrointestinal transit in young animals (geometric center = 8.8 [+ or -] 0.9), but transit was increasingly delayed in middle-aged (6.9 [+ or -] 0.8, P = 0.03) and elderly animals (4.7 [+ or -] 0.6, P = 0.013). Despite the lack of LM effect on transit in young mice, IL-6 and COX-2 mRNA expressions were significantly increased postoperatively (165 [+ or -] 24-fold and 2.9 [+ or -] 0.3-fold, respectively). Expressions were increased further in middleaged mice (1,103 [+ or -] 187-fold; 4.4 [+ or -] 0.7-fold) and further still in elderly mice (1,218 [+ or -] 168-fold; 6.9 [+ or -] 0.3-fold). IL-10 and heme oxygenase-1 gene expressions were also elevated postoperatively in young mice (4.8 [+ or -] 0.5-fold and 13.0 [+ or -] 1.3-fold, respectively) and were further increased in middle-aged mice (7.5 [+ or -] 0.6-fold; 21.8 [+ or -] 3.2-fold). However, inductions in elderly mice were significantly blunted (5.8 [+ or -] 0.9-fold; 16.9 [+ or -] 0.8-fold). There is both an age-dependent increase in the proinflammatory mediator expression and an age-dependent decrease in anti-inflammatory mediator expressions following minor insult to the bowel. Such imbalances between pro- and anti-inflammatory mechanisms may form the basis for increased susceptibility to ileus and for the increased severity and duration of ileus observed in the elderly. inflammation; interleukin-10; beme oxygenase-1 doi:10.1152/ajpgi.00570.2006

Highly inducible heme oxygenase (HO)-1 is protective against acute and chronic inflammation. HO-1 generates carbon monoxide (CO), ferrous iron, and biliverdin. The aim of this study was to investigate the protective effects of biliverdin against sepsis-induced inflammation and intestinal dysmotility. Cecal ligation and puncture (CLP) was performed on Sprague-Dawley rats under isoflurane anesthesia with and without intraperitoneal biliverdin injections, which were done before, at the time of CLP, and after CLP. In vivo gastrointestinal transit was carried out with fluorescein-labeled dextran. Jejunal circular muscle contractility was quantified in vitro using organ bath-generated bethanechol dose-response curves. Neutrophilic infiltration into the muscularis externa was quantified. The jejunal muscularis was studied for cytokine mRNA expressions [interleukin (IL)-6, monocyte chemoattractant protein (MCP)-I, inducible nitric oxide synthase, cyclooxygenase-2, biliverdin, IL-10, and HO-1] using real-time RT-PCR. Biliverdin treatment prevented the sepsis-induced suppression of gastrointestinal muscle contractility in vivo and in vitro and significantly decreased neutrophilic infiltration into the jejunal muscularis. Inflammatory mRNA expressions for small bowel IL-6 and MCP-1 were significantly reduced after biliverdin treatment in CLP-induced septic animals compared with untreated septic animals. The anti-inflammatory mediator expression of small bowel IL-10 was significantly augmented after CLP at 3 h compared with untreated septic animals. These findings demonstrate that biliverdin attenuates sepsis-induced morbidity to the intestine by selectively modulating the inflammatory cascade and its subsequent sequelae on intestinal muscularis function. cytokines; ileus; heine oxygenase-1

This study examined the role of outward [K.sup.+] currents in the acinar cells underlying secretion from Brunner's glands in guinea pig duodenum. Intracellular recordings were made from single acinar cells in intact acini in in vitro submucosal preparations, and videomicroscopy was employed in the same preparation to correlate these measures with secretion. Mean resting membrane potential was -74 mV and was depolarized by high external [K.sup.+] (20 mM) and the [K.sup.+] channel blockers 4-aminopyridine (4-AP), quinine, and clotrimazole. The cholinergic agonist carbachol (60-2,000 nM; E[C.sub.50] = 200 nM) caused a concentration-dependent initial hyperpolarization of the membrane and an associated decrease in input resistance. This hyperpolarization was significantly decreased by 20 mM external [K.sup.+] or membrane hyperpolarization and increased by 1 mM external [K.sup.+] or membrane depolarization. It was blocked by the [K.sup.+] channel blockers tetraethylammonium (TEA), 4-AP, quinine, and clotrimazole but not iberiotoxin. When videomicroscopy was employed to measure dilation of acinar lumen in the same preparation, carbachol-evoked dilations were altered in a parallel fashion when external [K.sup.+] was altered. The dilations were also blocked by the [K.sup.+] channel blockers TEA, 4-AP, quinine, and clotrimazole but not iberiotoxin. These findings suggest that activation of outward [K.sup.+] currents is fundamental to the initiation of secretion from these glands, consistent with the model of [K.sup.+] efflux from the basolateral membrane providing the driving force for secretion. The pharmacological profile suggests that these [K.sup.+] channels belong to the intermediate conductance group. exocytosis; cholinergic; secretion

This study examines whether intestinal inflammation leads to changes in the properties of ion channels in dorsal root ganglia (DRG) neurons. Ileitis was induced by injection of trinitrobenzene sulfonic acid (TNBS), and DRG neurons innervating the ileum were labeled using fast blue. Intracellular recording techniques were used to measure electrophysiological properties of acutely dissociated neurons 12-24 h after dissection. Nociceptive neurons were identified by sensitivity to capsaicin, tetrodotoxin resistance, and size (70% compared with controls (P < 0.001), but the resting membrane potential was unchanged. Cell diameter, input resistance (67%), and action potential upstroke velocity (22%) increased in the TNBS group (P < 0.05). The number of action potentials discharged increased in the TNBS group (P < 0.001), whereas application of 4-aminopyridine to control cells mimicked this effect. This study demonstrates that ileitis induces hyperexcitability in nociceptive DRG neurons and changes in the properties of [Na.sup.+] and [K.sup.+] channels at the soma, which persist after removal from the inflamed environment. sensory neurons; small intestine; abdominal pain; inflammation; peripheral sensitization; trinitrobenzene sulfonic acid; dorsal root ganglia

The activation of a 5-hydroxytryptamine(sub 4)-like (5-HT) receptors controls the cholera toxin-induced mucin secretion in the proximal and distal parts of the rat small intestine. Mucin secretion induced by 5-HT-administration follows two processes based on differences in sensitivities to capsaicin and tetrodotoxin. Both processes meet at a cholinergic pathway. The 5-HT(sub 2) receptor antagonist ketanserin and the cyclooxygenase inhibitor indomethacin are incapable of inhibiting the secretion. Partial blocking is affected by the mixed 5-HT(sub 3/4) receptor antagonist tropisetron.

An analysis of the function of enteric nerves during activation of mucin release by cholera toxin in rat small intestine reveals the correlation between capsaicin-responsive neurogenic mechanism, featuring a local sensory nerve-induction, and choleric mucin release. Local sensory nerve stimulation may associate with cholinergic nerves to potentiate mucin release. Administration of atropine inhibited mucin release in the proximal and distal small intestine of control animals.

Moore, Beverley A., David Kim, and Stephen Vanner. Neural pathways regulating Brunner's gland secretion in guinea pig duodenum in vitro. Am J Physiol Gastrointest Liver Physiol 279: G910-G917, 2000.--This study examined the neural pathways innervating Brunner's glands using a novel in vitro model of acinar secretion from Brunner's glands in submucosal preparations from the guinea pig duodenum. Neural pathways were activated by focal electrical stimulation and excitatory agonists, and videomicroscopy was used to monitor dilation of acinar lumen. Electrical stimulation of perivascular nerves evoked large dilations that were blocked by TTX (1 [micro] M) or the muscarinic receptor antagonist 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (1 [micro] M). The nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (100 [micro] M) had no effect, and the nerve-evoked responses were not inhibited by hexamethonium (200 [micro] M). Dilations were abolished in preparations from chronically vagotomized animals. Activation of submucosal ganglia significantly dilated submucosal arterioles but not Brunner's glands. Effects of electrical stimulation of perivascular and submucosal nerves were not altered by guanethidine. Capsaicin and substance P also dilated arterioles but had no effect on Brunner's glands. Cholinergic (choline acetyltransferase-immunoreactive) nerve fibers were found in Brunner's glands. These findings demonstrate that Brunner's glands are innervated by cholinergic vagal fibers but not by capsaicin-sensitive or intrinsic enteric nerves. cholinergic innervation; submucosal plexus; vagus; capsaicin-sensitive nerves

Moore, Beverley A., Gerald P. Morris, and Stephen Vanner. A novel in vitro model of Brunner's gland secretion in the guinea pig duodenum. Am. J. Physiol. Gastrointest. Liver Physiol. 278: G477-G485, 2000.--A novel in vitro model that combined functional and morphological techniques was employed to directly examine pathways regulating Brunner's gland secretion in isolation from epithelium. In vitro submucosal preparations were dissected from guinea pig duodenum. A videomicroscopy technique was used to measure changes in luminal diameter of glandular acini as an index of activation of secretion. Carbachol elicited concentration-dependent dilations of the lumen ([EC.sub.50] = 2 [micro]M) by activating muscarinic receptors on acinar cells. Ultrastructural and histological analyses demonstrated that dilation was accompanied by single and compound exocytosis of mucin-containing granules and the accumulation of mucoid material within the lumen. Inflammatory mediators (histamine, [PGE.sub.1], [PGE.sub.2]) and intestinal hormones (CCK, gastrin, vasoactive intestinal polypeptide, secretin) also stimulated glandular secretion, whereas activation of submucosal secretomotor neurons by 5-hydroxytryptamine did not. This study directly demonstrates that multiple hormonal, inflammatory, and neurocrine agents activate Brunner's glands, whereas many have dissimilar effects on the epithelium. This suggests that Brunner's glands are regulated by pathways that act both in parallel to and in isolation from those controlling epithelial secretion. videomicroscopy; hormones; inflammatory mediators; mucin