Digestive Diseases Division, Department of Medicine, Center for Ulcer Research and Education/Digestive Diseases Research Center and Brain Research Institute, University of California Los Angeles School of Medicine, 90095, USA.
To prevent the blood-borne interference and reflex actions via neighboring organs and the central nervous system, the study was conducted in an in vitro isolated stomach-gastric vagus nerve preparation obtained from overnight-fasted, urethan-anesthetized rats. Afferent unit action potentials were recorded from the gastric branch of the vagus nerve. The left gastric artery was catheterized for intra-arterial injection. In vitro we found that 1) 55/70 gastric vagal afferents (GVAs) were polymodal, responding to CCK-8 and mechanical stimuli, 13 were mechanoreceptive, and 2 were CCK-responsive; 2) sequential or randomized intra-arterial injections of CCK-8 (0.1-200 pmol) dose-dependently increased firing rate and reached the peak rate at 100 pmol; 3) the action was suppressed by CCK-A (Devazepide) but not by CCK-B (L-365,260) receptor antagonist; 4) neither antagonist blocked the mechanosensitivity of GVA fibers. These results are consistent with corresponding in vivo well-documented findings. Histological data indicate that the layered structure of the stomach wall was preserved in vitro for 6-8 h. Based on these results, it seems reasonable to use the in vitro preparation for conducting a study that is usually difficult to be performed in vivo. For instance, because there was no blood supply in vitro, the composition of the interstitial fluid, i.e., the ambient nerve terminals, can be better controlled and influenced by intra-arterial injection of a defined solution. Here we report that acutely changing the ambient CCK level by a conditioning stimulus (a preceding intra-arterial injection of increasing doses of CCK-8) reduced the CCK sensitivity of GVA terminals to a subsequent test stimulus (a constant dose of CCK-8 intra-arterial injection).
"In this study we have identified both a visceral organ, the duodenum, from which vagal afferent activity arises to potently modulate noxious stimulus-induced inhibition of bradykinin plasma extravasation, as well as a specific physiological stimulus, mechanical stimulation, which modulates the inflammatory response by activity in subdiaphragmatic vagal afferents. While it is not known whether other stimuli, alone or by interacting with mechanical stimuli, also contribute to this effect of vagal afferent activity on inflammation, it seems likely since most duodenal vagal afferents are polymodal, responding to nutrients, osmotic stimuli and inflammatory mediators, as well as to mechanical stimuli; in fact, some are silent to mechanical stimuli until exposed to inflammatory mediators (Cottrell & Iggo, 1984; Grundy, 1988; Grundy & Scratchard, 1989; Berthoud et al. 1992; Wei & Wang, 2000; Zhu et al. 2001). Our observed effects of a 48 h fast could be due to changes independent of physical removal of luminal contents (e.g. "
[Show abstract][Hide abstract] ABSTRACT: Noxious stimuli inhibit inflammation by activating neuroendocrine stress axes, an effect that is potently attenuated by ongoing activity in subdiaphragmatic vagal afferents. Because this vagal afferent activity is carried in the coeliac and coeliac accessory branches of the subdiaphragmatic vagus, we tested the hypothesis that the activity arises from vagal afferents that innervate a proximal segment of the gastrointestinal tract. Surgical removal of the duodenum, but not the stomach, produces a marked (six orders of magnitude) leftward shift in the dose-response curve for intraplantar capsaicin-induced inhibition of synovial plasma extravasation induced by the potent inflammatory mediator bradykinin, in the knee joint; this is similar in magnitude to the inhibition produced by subdiaphragmatic or by coeliac plus coeliac accessory branch vagotomy. Fasting, to unload mechanically sensitive polymodal afferents in the proximal gastrointestinal tract, produces a similar leftward shift in the dose-response curve for the inhibitory effect of capsaicin, an effect that is reversed by balloon distension in the duodenum in fasted rats, while balloon distension postvagotomy had no effect. These results suggest that activation of mechanically sensitive vagal afferents in the duodenum contributes vagal afferent activity that modulates neuroendocrine control of the inflammatory response.
The Journal of Physiology 02/2004; 554(Pt 1):227-35. DOI:10.1113/jphysiol.2003.056804 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ghrelin, a 28-amino acid acylated peptide predominantly produced by the stomach, displays strong growth hormone (GH)-releasing activity mediated by the hypothalamus-pituitary GH secretagogue (GHS)-receptors specific for synthetic GHS. The discovery of ghrelin definitely changes our understanding of GH regulation but it is also already clear that ghrelin is much more than simply a natural GHS. Ghrelin acts also on other central and peripheral receptors and shows other actions including stimulation of lactotroph and corticotroph secretion, orexia, influence on gastro-entero-pancreatic functions, metabolic, cardiovascular and anti-proliferative effects. GHS were born more than 20 years ago as synthetic molecules suggesting the option that GH deficiency could be treated by orally active GHS as an alternative to recombinant human GH (rhGH). Up to now, this has not been the case and also their usefulness as anabolic anti-aging intervention restoring GH/insulin-like growth factor-I axis in somatopause is still unclear. We are now confronted with the theoretical possibility that GHS analogues could become candidate drugs for treatment of pathophysiological conditions in internal medicine totally unrelated to disorders of GH secretion. Particularly, GHS receptor agonists or antagonists acting on appetite could represent new drug intervention in eating disorders.
European Journal of Pharmacology 05/2002; 440(2-3):235-54. DOI:10.1016/S0014-2999(02)01432-2 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nutrients in the intestine initiate changes in secretory and motor function of the gastrointestinal (GI) tract. The nature of the 'sensors' in the intestinal wall is not well characterized. Intestinal lipid stimulates the release of cholecystokinin (CCK) from mucosal entero-endocrine cells, and it is proposed that CCK activates CCK A receptors on vagal afferent nerve terminals. There is evidence that chylomicron components are involved in this lipid transduction pathway. The aim of the present study was to determine (1) the pathway mediating reflex inhibition of gastric motility and (2) activation of duodenal vagal afferents in response to chylomicrons. Mesenteric lymph was obtained from awake rats fitted with lymph fistulas during intestinal perfusion of lipid (Intralipid, 170 micromol h(-1), chylous lymph) or a dextrose and/or electrolyte solution (control lymph). Inhibition of gastric motility was measured manometrically in urethane-anaesthetized recipient rats in response to intra-arterial injection of lymph close to the upper GI tract. Chylous lymph was significantly more potent than control lymph in inhibiting gastric motility. Functional vagal deafferentation by perineural capsaicin or CCK A receptor antagonist (devazepide, 1 mg kg(-1), i.v.) significantly reduced chylous lymph-induced inhibition of gastric motility. The discharge of duodenal vagal afferent fibres was recorded from the dorsal abdominal vagus nerve in an in vitro preparation of the duodenum. Duodenal vagal afferent nerve fibre discharge was significantly increased by close-arterial injection of CCK (1-100 pmol) in 43 of 83 units tested. The discharge of 88% of CCK-responsive fibres was increased by close-arterial injection of chylous lymph; devazepide (100 microg, i.a.) abolished the afferent response to chylous lymph in 83% of these units. These data suggest that in the intestinal mucosa, chylomicrons or their products release endogenous CCK which activates CCK A receptors on vagal afferent nerve fibre terminals, which in turn initiate a vago-vagal reflex inhibition of gastric motor function.
The Journal of Physiology 08/2003; 550(Pt 2):657-64. DOI:10.1113/jphysiol.2003.041673 · 5.04 Impact Factor
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