Activation of Secretagogue Independent Gastric Acid Secretion via Endothelial Nitric Oxide Synthase Stimulation in Rats

Abstract

Background/Aims: L-arginine is an important mediator of cell division, wound healing, and immune function. It can be transformed by the nitric oxide synthase (NOS) to nitric oxide (NO), an important cell signaling molecule. Recent studies from our laboratory demonstrate specific effects of L-arginine (10mM) exposure on gastric acid secretion in rat parietal cells. Methods: Studies were performed with isolated gastric glands and the pH sensitive dye BCECF-AM +/- L-arginine to examine its effects on acid secretion. The direct NO-donor diethylamine NONOate sodium salt hydrate, was also used while monitoring intracellular pH. The specific inhibitor of the intracellular NO signal cascade ODQ was also used. Results: We found that gastric proton extrusion was activated with application of L-arginine (10mM), in a separate series when L-arginine (10mM) + L-NAME (30µM) were added there was no acid secretion. Addition of the NO-donor diethylamine NONOate sodium salt hydrate (10µM) also induced acid secretion. When the selective sGC-inhibitor ODQ was added with NONOate we did not observe acid secretion. Conclusion: We conclude that L-arginine is a novel secretagogue, which can mediate gastric acid secretion. Furthermore, the intake of L-arginine causes direct activation of the H⁺, K⁺ ATPase and increased proton extrusion from parietal cells resulting in the increased risk for acid-related diseases. The NO/sGC/cGMP pathway has never been described as a possible intracellular mechanism for H⁺, K⁺ ATPase activation before and presents a completely new scientific finding. Moreover, our studies demonstrate a novel role for L-NAME to effectively eliminate NOS induced acid secretion and thereby reducing the risk for L-arginine inducible ulcer disease.

Regulation of iNOS on Immune Cells and Its Role in Diseases

“…Transfer of naïve CD4 + T cells from iNOS −/− mice into Rag −/− mice induced more severe colitis, with an enhanced Th17 immune response. Furthermore, consistent with previous studies, iNOS −/− mice develop more severe experimental autoimmune encephalomyelitis (EAE) than do wild type (WT) mice [11,28], though iNOS −/− mice express significantly high levels of IL-17. This is consistent with the results of in vitro experiments in which iNOS transcripts are highly induced in T cells infiltrating the central nervous system (CNS) of WT mice, but not in iNOS −/− mice with EAE.…”

Induction of Secretagogue Independent Gastric Acid Secretion via a Novel Aspirin-Activated Pathway

“…Scheme of the parietal cell of a gastric gland. The scheme explains receptors, ion transporters, and the neuroendocrine regulation of gastric acid secretion (Kitay et al, 2017). The components of concentrated hydrochloric acid are secreted by proton pumps (H + , K + ATPases) and chloride channels.…”

Npom‐Protected NONOate Enables Light‐Triggered NO/cGMP Signalling in Primary Vascular Smooth Muscle Cells

“…NONOates are particularly useful NO‐releasing substances and have been used widely in NO and cGMP research . To study the mechanisms of NO‐dependent signalling, but also to generate smart drugs, potential means for the release of NO with high temporal and spatial control have been explored.…”

“…Diazeniumdiolates (also called NONOates) are a particularly interesting class of NO‐releasing substances widely used to study NO‐ and cGMP‐related processes . They are stable enough to have long shelf‐lives but can be designed to release NO with half‐lives ranging from 3 s to 20 h under physiological conditions .…”