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Article

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

Toyama Institute for Cardiovascular Pharmacology Research, Azuchi-machi, Chuo-ku, Osaka, Japan (N.T.); and Division of Pharmacology, University of Antwerp, Wilrijk, Belgium (A.G.H.)

Abstract

I. Introduction

II. Nitric Oxide as a Neurotransmitter

A. Discovery of Nitrergic Nerves

B. Mechanism of Nitric Oxide Actions

C. Is the Nitrergic Neurotransmitter Free Radical Nitric Oxide or a Stable Analog of Nitric Oxide?

D. Cotransmitters Responsible for Nonadrenergic Noncholinergic Inhibitory Responses

E. In Vivo Studies

III. Nitrergic Innervation in Various Regions

A. Esophagus

B. Stomach

C. Duodenum, Jejunum, Ileum, and Ileocolonic Junction

D. Colon, Rectum, and Internal Anal Sphincter

E. Sphincter of Oddi and Gall Bladder

F. Liver and Pancreas

1. Liver.

2. Pancreas.

IV. Secretion and Neurogenic Nitric Oxide

V. Species and Regional Differences in the Nitrergic Regulation

VI. Development and Aging

VII. Prejunctional Regulation

VIII. Gastrointestinal Blood Flow Regulation by Nitrergic Nerves

IX. Pathological Implications

X. Summary

Gastrointestinal (GI) smooth muscle responses to stimulation of the nonadrenergic noncholinergic inhibitory nerves have been suggested to be mediated by polypeptides, ATP, or another unidentified neurotransmitter. The discovery of nitric-oxide (NO) synthase inhibitors greatly contributed to our understanding of mechanisms involved in these responses, leading to the novel hypothesis that NO, an inorganic, gaseous molecule, acts as an inhibitory neurotransmitter. The nerves whose transmitter function depends on the NO release are called "nitrergic", and such nerves are recognized to play major roles in the control of smooth muscle tone and motility and of fluid secretion in the GI tract. Endothelium-derived relaxing factor, discovered by Furchgott and Zawadzki, has been identified to be NO that is biosynthesized from L-arginine by the constitutive NO synthase in endothelial cells and neurons. NO as a mediator or transmitter activates soluble guanylyl cyclase and produces cyclic GMP in smooth muscle cells, resulting in relaxation of the vasculature. On the other hand, NO-induced GI smooth muscle relaxation is mediated, not only by cyclic GMP directly or indirectly via hyperpolarization, but also by cyclic GMP-independent mechanisms. Numerous cotransmitters and cross talk of autonomic efferent nerves make the neural control of GI functions complicated. However, the findingsrelated to the nitrergic innervation may provide us a new way of understanding GI tract physiology and pathophysiology and might result in the development of new therapies of GI diseases. This review article covers the discovery of nitrergic nerves, their functional roles, and pathological implications in the GI tract.

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