Jonathan D. Kaunitz

Acid-sensing pathways of rat duodenum

We tested the hypothesis that the duodenal hyperemic response to acid occurs through activation of capsaicin-sensitive afferent nerves with subsequent release of vasodilatory substances such as calcitonin gene-related peptide (CGRP) and nitric oxide (NO). Laser-Doppler flowmetry was used to measure duodenal blood flow in urethan-anesthetized rats. Duodenal mucosa was superfused with pH 7. 0 buffer with capsaicin or bradykinin or was acid challenged with pH 2.2 solution, with or without vanilloid receptor antagonists, a CGRP receptor antagonist, an NO synthase (NOS) inhibitor, or a cyclooxygenase inhibitor. The selective vanilloid receptor antagonist capsazepine (CPZ) dose dependently inhibited the hyperemic response to acid and capsaicin but did not affect bradykinin-induced hyperemia. Ruthenium red was less inhibitory than capsazepine. Selective ablation of capsaicin-sensitive nerves, CGRP-(8-37), and N(G)-nitro-L-arginine methyl ester inhibited acid-induced hyperemia, but indomethacin did not. We conclude that luminal acid, but not bradykinin, stimulates CPZ-sensitive receptors on capsaicin-sensitive afferent nerves of rat duodenum. Activation of these receptors produces vasodilation via the CGRP-NO pathway but not via the cyclooxygenase pathway. Acid appears to be the endogenous ligand for duodenal vanilloid receptors.We tested the hypothesis that the duodenal hyperemic response to acid occurs through activation of capsaicin-sensitive afferent nerves with subsequent release of vasodilatory substances such as calcitonin gene-related peptide (CGRP) and nitric oxide (NO). Laser-Doppler flowmetry was used to measure duodenal blood flow in urethan-anesthetized rats. Duodenal mucosa was superfused with pH 7.0 buffer with capsaicin or bradykinin or was acid challenged with pH 2.2 solution, with or without vanilloid receptor antagonists, a CGRP receptor antagonist, an NO synthase (NOS) inhibitor, or a cyclooxygenase inhibitor. The selective vanilloid receptor antagonist capsazepine (CPZ) dose dependently inhibited the hyperemic response to acid and capsaicin but did not affect bradykinin-induced hyperemia. Ruthenium red was less inhibitory than capsazepine. Selective ablation of capsaicin-sensitive nerves, CGRP-(8-37), and N G-nitro-l-arginine methyl ester inhibited acid-induced hyperemia, but indomethacin did not. We conclude that luminal acid, but not bradykinin, stimulates CPZ-sensitive receptors on capsaicin-sensitive afferent nerves of rat duodenum. Activation of these receptors produces vasodilation via the CGRP-NO pathway but not via the cyclooxygenase pathway. Acid appears to be the endogenous ligand for duodenal vanilloid receptors.

Luminal Chemosensing and Mucosal Defenses in the Upper GI Tract

Abstract Recent discoveries of taste receptors in the lingual taste buds and the de-orphanization of G protein-coupled receptors (GPCRs), including nutrient receptors and olfactory receptors, in addition to the previously cloned ligand-gated cation channels such as the transient receptor potential (TRP) families and acid-sensing ion channels (ASICs), provide an understanding of luminal chemosensing in that most nutrient or nonnutrient chemical substances are sensed by membrane surface receptors or channels on the GI epithelium or on the surface subepithelial afferent nerves. Furthermore, recent technological advances have facilitated the purification of specific enteroendocrine cell types in which a fluorescent protein-tagged target hormone is expressed, including proglucagon-expressing L cells and cholecystokinin (CCK)-expressing I cells, enabling access to chemosensors that trigger the release of corresponding gut hormones. Our laboratory has studied mucosal defense mechanisms in the upper GI tract, especially in the duodenum, where the mucosa is regularly exposed to H+/CO2, bile acids, and nutrients originating from endogenous secretions and from ingested foodstuffs. The presence of physiological responses to luminal chemical substances implies that one of the physiological functions of luminal chemosensing is to initiate postprandial responses. Due to their location caudad to the stomach and the most proximal intestinal segment, the abundant expression of gut hormones and the close communication with the stomach and pancreas, the duodenum appears to be a master control center for postprandial chemosensory pathways in the upper GI tract. In this chapter, we will show how the duodenal mucosa senses luminal chemical substances under physiological conditions, focusing on nutrient sensors. Understanding how the GI mucosa “tastes” luminal chemical substances may help identify novel molecular targets in the treatment of mucosal injury, nutrient metabolism, and functional disorders.

Introduction to the “GRG Scholars Invited Reviews”

The editors of Digestive Diseases and Sciences (DDS) and the leadership of the Gastroenterology Research Group (GRG) wish to welcome the readership of our journal to a new section entitled “GRG Scholars Invited Reviews.” n nIn 1955, the GRG was founded by Drs. Joseph B. Kirsner, Basil I. Hirschowitz, and E. Clinton Texter in order to provide a forum for young investigators to discuss basic research problems in gastroenterology, and to focus on exchanging information and generating new ideas. In the 58 years since its inception, the GRG has maintained these goals as its primary mission. Today’s GRG promotes GI research through its support of the annual GRG Spring Symposium held during Digestive Disease Week, which features forward-looking basic research on gastrointestinal (GI) diseases. Through the sponsorship of the American Gastroenterological Association (AGA), the GRG Young Investigator awards are presented to outstanding young investigators involved in clinical and basic science GI research. The goal for the new section of DDS is to provide our readership with up-to-date reviews on research topics of special interest to all GI investigators, but in particular to young investigators engaged in basic science investigation. The invited reviews will be authored by the GRG Spring Symposium invited speakers and by our AGA/GRG young investigator awardees, who will provide scholarly and current summaries of their fields of research. n nTo kick off this new section, we have invited Jason R. Spence, PhD, Assistant Professor of Medicine at the University of Michigan, who will deliver one of our 2013 GRG Spring Symposium lectures entitled “Directed Differentiation of Human iPS Cells into Intestine.” This excellent review addresses the latest science in the field of stem cell engineering. To promote the GRG’s mission of fostering productive interactions between senior and young investigators, we are encouraging joint submission of up–to-date and learned research reviews. We are delighted that Dr. Spence has taken us up on that offer by co-authoring his review with his research fellow, Stacey R. Finkbeiner, PhD. n nWe look forward to publishing more learned reviews authored by the GRG symposium speakers and young investigators, and hope that you, the reader, will benefit from their outstanding content.

Correlation of surface pH versus mucus gel thickness by in vivo confocal microscopy of rat gastric mucosa

and HM-CAP, but the FLEX PACK assay failed to detect two (33%). Conclusions: (1) The Chiron lysate and HM-CAP are equally sensitive in detecting HP antibody but the lysate assay is twice as specific; (2) the FLEX PACK assay is significantly less sensitive than the other two assays; (3) 29% of pediatric patients with abdominal pain have antibodies to CagA or VacA. These patients are accurately detected by Chiron lysate or HM-CAP assays, but not by FLEX PACK. This study was funded in part by a grant from EPI.

Cellular mechanism of adaptive cytoprotection to luminal acid in rat duodenal mucosa

Possibly or probably drug-related adverse event reported by > 3% of patients in any treatment group was diarrhea. There were no reports of gastric ulcer hemorrhage. Conclusions: Lansoprazole 15 mg daily and 30 mg daily were significantly better than ranitidine 150 mg twice daily in healing NSAID-induced GU in patients continuing to take NSAIDs. All regimens were well-tolerated. This research was funded by TAP Holdings Inc., Deerfield, IL.