Analysis of innervation of human mesenteric vessels in non-inflamed and inflamed bowel – a confocal and functional study (original) (raw)
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Novel Mechanism of Vasodilation in Inflammatory Bowel Disease
Arteriosclerosis, Thrombosis, and Vascular Biology, 2005
Objective-Endothelium-dependent dilation to acetylcholine (Ach) is reduced in mucosal arterioles from patients with inflammatory bowel disease (IBD). The contributions of both nitric oxide (NO) and endothelial-derived hyperpolarizing factor (EDHF) are decreased. We hypothesized that the remaining dilation results from products of cyclooxygenase. Methods and Results-High-performance liquid chromatography (HPLC) was used to isolate eicosanoid vasodilator products and videomicroscopy was used to examine vasomotor responses in human mucosal arterioles from subjects with or without IBD undergoing bowel resection surgeries. In subjects without IBD, Ach constricted (Ϫ52%Ϯ10%) arterioles devoid of endothelium. Indomethacin (INDO) (cyclooxygenase inhibitor) had no effect. In contrast, Ach dose-dependently dilated both intact and endothelial denuded arterioles from patients with IBD. The dilation was converted to constriction by INDO (Ϫ54%Ϯ9%; PϽ0.05 versus non-IBD) or by BWA868C (PGD 2 receptor antagonist). Only in arterioles from subjects with IBD did Ach produce an arachidonic acid metabolite that comigrated on HPLC with PG D 2 (PGD 2). Exogenous PGD 2 dilated (maxϭ66%Ϯ4%) IBD arterioles. Conclusion-In arterioles from IBD patients, Ach-mediated dilation shifts from endothelial production of NO and EDHF to nonendothelial generation of a PG, likely PGD 2. This is a novel dilator mechanism arising from nonendothelial vascular tissue that compensates for loss of endothelium-dependent dilation. PGD 2 appears to be important in regulating mucosal blood flow in patients with IBD, implicating potentially detrimental effects from nonsteroidal antiinflammatory drugs.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2008
Evidence from patients with inflammatory bowel disease (IBD) and animal models suggests that inflammation alters blood flow to the mucosa, which precipitates mucosal barrier dysfunction. Impaired purinergic sympathetic regulation of submucosal arterioles, the resistance vessels of the splanchnic vasculature, is one of the defects identified during IBD and in mouse models of IBD. We hypothesized that this may be a consequence of upregulated catabolism of ATP during colitis. In vivo and in vitro video microscopy techniques were employed to measure the effects of purinergic agonists and inhibitors of CD39, an enzyme responsible for extracellular ATP catabolism, on the diameter of colonic submucosal arterioles from control mice and mice with dextran sodium sulfate [DSS, 5% (wt/vol)] colitis. Using a luciferase-based ATP assay, we examined the degradation of ATP and utilized real-time PCR, Western blotting, and immunohistochemistry to examine the expression and localization of CD39 durin...
Sympathetic Innervation of Human Mesenteric Artery and Vein
Journal of Vascular Research, 2008
Background: Innervation of blood vessels shows inter-species variability. There are few studies on the innervation of human vessels; thus, healthy mesenteric vessels were studied to identify the expression of immunomarkers and the morphology of sympathetic innervation as the basis for a study of mesenteric vessels in inflammatory bowel disease. Methods and Results: Electron microscopy studies examined the relationships of nerves to smooth muscle cells. In veins, nerves were distributed throughout the medial smooth muscle coat, often in close apposition (50 nm) to smooth muscle cells. In arteries, nerves were located at the adventitial-medial border, few closer than 2,000 nm to smooth muscle cells, often with interposing connective tissue and Schwann cell processes. There was a significantly greater nerve density in veins than in arteries (227 vs. 41 mm 2 ; p = 0.03). Immunohistochemical studies revealed the presence of sympathetic and sensory-motor nerves in arteries and veins. Conclusions: It is suggested that in humans with an upright stance, the mesenteric venous system plays a particularly important role in controlling mesenteric capacitance, which is reflected by their dense innervation. It is speculated that transmitters released from perivascular nerves supplying the human mesenteric arteries may play a long-term (trophic) role in addition to short-term signalling roles.
British Journal of Pharmacology, 2003
1 The effect of chronic intestinal inflammation on the purinergic modulation of cholinergic neurotransmission was studied in the mouse ileum. Chronic intestinal inflammation was induced by infection of mice with the parasite Schistosoma mansoni during 16 weeks. 2 S. mansoni infection induced a chronic inflammatory response in the small intestine, which was characterised by intestinal granuloma formation, increased intestinal wall thickness, blunted mucosal villi and an enhanced activity of myeloperoxidase.
Colonic blood flow responses in experimental colitis: time course and underlying mechanisms
AJP: Gastrointestinal and Liver Physiology, 2005
Human inflammatory bowel diseases (IBD) are associated with significant alterations in intestinal blood flow, the direction and magnitude of which change with disease progression. The objectives of this study were to determine the time course of changes in colonic blood perfusion that occur during the development of dextran-sodium-sulfate (DSS)-induced colonic inflammation and to address the mechanisms that may underlie these changes in blood flow. Intravital microscopy was used to quantify blood flow (from measurements of vessel diameter and red blood cell velocity) in different-sized submucosal arterioles of control and inflamed colons in wild-type (WT) mice. A significant (18–30%) reduction in blood flow was noted in the smallest arterioles (<40 μm diameter) on days 4–6 of DSS colitis. The arteriolar responses to bradykinin in control and DSS-treated WT mice revealed an impaired endothelium-dependent, but not endothelium-independent, vasodilation in the inflamed colon. However...
Neurogastroenterology & Motility, 2013
Background-The purinergic component of enteric inhibitory neurotransmission is important for normal motility in the gastrointestinal (GI) tract. Controversies exist about the purine(s) responsible for inhibitory responses in GI muscles: adenosine 5′-triphosphate (ATP) has been assumed to be the purinergic neurotransmitter released from enteric inhibitory motor neurons, however recent studies demonstrate that β-nicotinamide adenine dinucleotide (β-NAD +) and ADP-ribose mimic the inhibitory neurotransmitter better than ATP in primate and murine colons. The study was designed to clarify the sources of purines in colons of Cynomolgus monkeys and C57BL/6 mice. Methods-HPLC with fluorescence detection was used to analyze purines released by stimulation of nicotinic acetylcholine receptors (nAChR) and serotonergic 5-HT 3 receptors (5-HT 3 R), known to be present on cell bodies and dendrites of neurons within the myenteric plexus. Key Results-nAChR or 5-HT 3 R agonists increased overflow of ATP and β-NAD + from tunica muscularis of monkey and murine colon. The agonists did not release purines from circular muscles of monkey colon lacking myenteric ganglia. Agonist-evoked overflow of β-NAD + , but not ATP, was inhibited by tetrodotoxin (0.5 μM) or ω-conotoxin GVIA (50 nM), suggesting that β-NAD + release requires nerve action potentials and junctional mechanisms known to be critical for neurotransmission. ATP was likely released from nerve cell bodies in myenteric ganglia and not from nerve terminals of motor neurons. Conclusions & Inferences-These results support the conclusion that ATP is not a motor neurotransmitter in the colon and are consistent with the hypothesis that β-NAD + , or its metabolites, serve as the purinergic inhibitory neurotransmitter.
Involvement of a purinergic pathway in the sympathetic regulation of motility in rat ileum
Autonomic Neuroscience, 2003
We investigated extrinsic neuronal regulation of intestinal motility. The mesenteric nerve stimulation (MNS; duration 0.5 ms, 10 Hz for 30 s) evoked relaxation in the longitudinal muscle direction of the isolated rat ileum. The MNS-induced relaxation was abolished by guanethidine (2 AM) or propranolol (10 AM), but was not affected by prazosin (10 AM), rauwolscine (10 AM), hexamethonium (100 AM) or capsaicin (1 AM). Exposure to a high concentration (100 AM) of ATP (ATP-desensitization) or ADP (ADP-desensitization) reduced the MNS-induced relaxation to 44.7% or 32.5% of the control ( P < 0.01), respectively. P2 purinoceptor antagonists [suramin (100 AM) and reactive blue-2 (RB-2, 50 AM)] or small conductance Ca 2 + -activated K + channel blocker, apamin (0.5 AM), significantly decreased the relaxation to 54.4% and 25.6% or 19.4% of the control ( P < 0.01), respectively, whereas selective P2Y 1 purinoceptor antagonist MRS2179 (10 AM) failed to affect the relaxation. Furthermore, exogenous ATP (1 AM) or ADP (1 AM) elicited relaxation in the rat ileum, which was almost abolished by reactive blue-2 (50 AM, 9.1% of control remained, P < 0.05). In contrast, relaxation induced by noradrenalin (10 AM) was not antagonized by ATPdesensitization, apamin (0.5 AM) or reactive blue-2 (50 AM). From the present results, we conclude that noradrenergic sympathetic nerves might regulate intestinal motility mediated through a purinergic inhibitory neuronal pathway in the rat small intestine. D 1566-0702/02/$ -see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 6 -0 7 0 2 ( 0 2 ) 0 0 2 5 7 -6
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2001
In anesthetized rats, the cyclooxygenase (COX) inhibitor indomethacin induces duodenal motility, increases duodenal mucosal alkaline secretion (DMAS), and evokes a transient increase in duodenal paracellular permeability (DPP). To examine whether enteric nerves influence these responses, the duodenum was perfused with lidocaine. Motility was assessed by measuring intraluminal pressure, and DPP was determined as blood-to-lumen clearance of 51 Cr-EDTA. DMAS was assessed by titration. In control animals, few contractions occurred during saline perfusion and lidocaine did not alter this condition. Perfusion with 0.03-0.1% lidocaine did not affect DMAS or DPP whereas 0.3-1% lidocaine reduced DMAS and increased DPP. Indomethacin induced motility and doubled DMAS. Application of 0.03% lidocaine on the duodenal serosa reduced motility and DMAS whereas 0.03% lidocaine applied luminally inhibited DMAS only. Higher concentrations of lidocaine abolished the increase in DMAS and changed the motility pattern to numerous lowamplitude contractions, the latter effect being blocked by iloprost. The lidocaine-induced increases in DPP were markedly higher than in controls. We conclude that indomethacin activates enteric nerves that induce motility, increase DMAS, and decrease DPP. anesthetized; blood flow; chromium-labeled ethylenediaminetetraacetic acid; iloprost; indomethacin PREVIOUS FINDINGS IN HUMANS (21), dogs (18), and rats (27) suggest a close relationship between duodenal motility and mucosal alkaline secretion. For example, in anesthetized rats basal duodenal mucosal alkaline secretion (DMAS) is higher in animals that exhibit spontaneous duodenal contractions compared with those that do not. Furthermore, administration of the cyclooxygenase inhibitor indomethacin induces duodenal contractions and increases DMAS (28), effects that are abolished by the nicotinic receptor antagonist hexamethonium (27) or the prostacyclin analog iloprost (26). These results may suggest that inhibition of cyclooxygenase activity increases HCO 3 Ϫ secretion via stimulation of secretomotor neurons, as part of a reflex, activated by induction of duodenal motility.