Evidence that nitric oxide participates in non-adrenergic inhibitory transmission to intestinal muscle in the guinea-pig

doi:10.1016/0304-3940(91)90231-H

Neuroscience Letters

Volume 130, Issue 1, 2 September 1991, Pages 77-80

https://doi.org/10.1016/0304-3940(91)90231-H Get rights and content

Abstract

The possible involvement of nitric oxide (NO) in non-adrenergic nerve-mediated relaxations of guinea-pig gastrointestinal smooth muscle was investigated using longitudinal muscle that lies between the taenia of the caecum. Relaxations induced by electrical field stimulation in this preparation are similar to those described in other preparations of guinea-pig intestinal muscle when enteric inhibitory neurons are stimulated; they were blocked by tetrodotoxin (10⁻⁶ M) but were unaffected by guanethidine (10⁻⁶ M). $N- Nitro- l -arginine$ (NOLA) (5 × 10⁻⁵ to 10⁻⁴ M), an inhibitor of NO synthase, and haemoglobin (10⁻⁵ M), which reduces bioavailability of NO, both reduced the amplitude of nerve-mediated relaxations to less than 50%, without affecting the ability of the muscle to relax. These results suggest that NO may play a role in inhibitory neurotransmission to this preparation.

References (23)

A. Bowman et al.
Oxyhaemoglobin blocks non-adrenergic non-cholinergic inhibition in the bovine retractor penis muscle
Eur. J. Pharmacol.
(1982)
J.R. Grider et al.
Vasoactive intestinal peptide (VIP)
Relaxant neurotransmitter in the taenia coli of the guinea-pig
Gastroenterology
(1985)
S. Moncada et al.
Biosynthesis of nitric oxide from L-arginine
A pathway for the regulation of cell function and communication
Biochem. Pharmacol.
(1989)
J.P. Niel et al.
Apamin resistant poststimulus hyperpolarization in the circular muscle of the guineapig ileum
J. Auton. Nerv. Syst.
(1983)
N. Toda et al.
Role of nitric oxide in non-adrenergic, non-cholinergic nerve-mediated relaxation in dog duodenal longitudinal muscle strips
Jpn. J. Pharmacol.
(1990)
S. Will et al.
NO: possible role in TTX-sensitive field-stimulated relaxations of the rat oesophageal tunica muscularis mucosae?
Eur. J. Pharmacol.
(1990)
D.S. Bredt et al.
Localization of nitric oxide synthase indicating a neural role for nitric oxide
Nature
(1990)
H. Bult et al.
Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter
Nature
(1990)
G. Burnstock et al.
Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic nerves in the gut
Br. J. Pharmacol.
(1970)
R.A.R. Bywater et al.
Non-cholinergic excitatory and inhibitory junction potentials in the circular smooth muscle of the guinea-pig ileum
J. Physiol.
(1986)

M. Costa et al.

Apamin distinguishes two types of relaxation mediated by enteric nerves in the guinea-pig gastrointestinal tract

Naunyn-Schmiedebergs Arch. Pharmacol.

(1986)

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Numerous studies have revealed that NO affects many aspects of physiology including blood pressure, gut peristalsis, and feeding behavior in mammals (Aisaka et al., 1989; Rees et al., 1989; Kilbourn et al., 1990; Morley and Flood, 1991; De Luca et al., 1995; Konturek and Konturek, 1995; Förstermann and Sessa, 2012). In the digestive system, NO has a role in the relaxation of smooth muscles (Toda et al., 1990; Desai et al., 1991; Shuttleworth et al., 1991; Konturek and Konturek, 1995). Indeed, a NO donor induced the relaxation of the digestive tract (Dent et al., 1979) and affected gastric emptying in mammals (Konturek et al., 1995; Sun et al., 1998; Lucetti et al., 2017).
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Nitric oxide was identified as a biological intercellular messenger just over 20 years ago, and its presence and potential importance in the nervous system was immediately noted. With the cloning of NO synthase and the physiological NO receptor soluble guanylyl cyclase, a variety of histochemical methods quickly led to a rather complete picture of where NO is produced and acts in the nervous system. However, the details regarding the subcellular localization of NO synthase and the identity of its molecular binding partners require further clarification. Although the hypothesis that calcium influx via activation of NMDA receptors is a key trigger for NO production has proven very popular and led to suggested roles for NO in synaptic plasticity, there is little direct evidence to support this notion. Instead, studies from the peripheral nervous system indicate a key role for voltage-sensitive calcium channels in regulating NO synthase activity. A similar mechanism may also be important in central neurons, and it remains an important task to identify the precise sources of calcium regulating NO production in specific NO neurons. Also, although cGMP production appears to mediate the physiological signaling by NO, the specific roles of cGMP-dependent ion channels, protein kinases and phosphodiesterases in mediating NO action remain to be determined.
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This chapter provides an overview of the functions of nitric oxide (NO) in the gastrointestinal tract (GIT) in adult and developing animals and humans. NO is produced by nitric oxide synthase (NOS) and by nonenzymatic pathways. In the gastrointestinal tract (GIT) of adults, the majority of NO-producing neurons are localized in the myenteric plexus where they act as inhibitory inter and motoneurons. NO plays a role as a neurotransmitter in the enteric nervous system (ENS). NO is involved in non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmission in the GIT. The nitrergic innervation is important for the growth, maturation, and proper function of the GIT as the inhibition of cNOS causes severe impairment of gastrointestinal function. The occurrence of NOS-positive cells in a variety of organs (CNS, respiratory system, and GIT) is higher at the prenatal stage of development than at other times suggesting that NO is also important for the development of these organs in addition to its importance for foetal and postnatal development of the mammalian GIT. The distribution of nitrergic neurons in the GIT in fetuses, growing and adult animals, and humans is discussed. The chapter reviews interstitial cells of Cajal (ICC) that refer to the connection of ICC with nitrergic neurons, the involvement of ICC in NO production, and neurotransmission involving nitrergic neurons. The actions of NO and the distribution of nitrergic neurons in the GIT of growing animals is presented, and some other aspects of the role of NO in the development of the GIT are discussed.
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Since then, substantial evidence has emerged indicating that NO is the primary mediator of nonadrenergic, noncholinergic (NANC) neurotransmission in the gastrointestinal tract in various species.80-82 Numerous studies have shown the effectiveness of NO to evoke relaxation of the smooth muscle in different parts of the gastrointestinal tract.83,84 NO is released from bowel wall and stomach during nerve stimulation.85
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2001, Journal of Pharmacological and Toxicological Methods
Introduction: Human tissues are notoriously difficult to work with, giving results that are quantitatively variable within and between studies. Hence, previous investigations of nonadrenergic, noncholinergic (NANC) relaxation in human colon muscle report both partial and complete inhibitions of the NANC response by specific competitive inhibitors of nitric oxide (NO) production. We have established a robust and reproducible model to examine the contribution of NO during NANC relaxation assay in human sigmoid colon muscle strips. Methods: Complete control curves to long-train, stepwise, frequency-dependent, continuous electrical field stimulation (EFS) relaxation using vertical platinum electrodes connected to a biphasic pulse train stimulator generated NANC responses in fresh human sigmoid colon circular muscle strips set up in Bennett baths. A second complete curve was generated on the same strip in the presence of specific drugs to determine the contribution of NO to NANC relaxation. Responses to NO were also generated in muscle strips. Results were fitted to the Hill equation. Results: The first and second frequency–response curves without test drugs could be fitted to the Hill equation, resulting in similar midpoint locations ([f]₅₀), maximal asymptotes (α), and midpoint slope (n) parameters. l-N^G-nitro-arginine (l-NOARG), TTX, and haemoglobin produced a tonic contraction in the muscle strips. NANC relaxations to EFS were inhibited by l-NOARG (30–37%), TTX (56–62%), and haemoglobin (48–90%). NO relaxations were concentration dependently inhibited by haemoglobin. Haemoglobin was equipotent in mediating tonic contraction and inhibiting NO relaxation. Discussion: We established reproducible assays for human colon muscle strips by the generation of two complete dose–response curves to long-train EFS, thus enabling a “within-preparations” study. The results suggest that NO contributes but is not the sole mediator of relaxations to long-train EFS in human sigmoid colon muscle. Moreover, a basal production of NO may serve to regulate tone of human colonic muscle.

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Evidence that nitric oxide participates in non-adrenergic inhibitory transmission to intestinal muscle in the guinea-pig

Abstract

Eur. J. Pharmacol.

Gastroenterology

Biochem. Pharmacol.

J. Auton. Nerv. Syst.

Jpn. J. Pharmacol.

Eur. J. Pharmacol.

Localization of nitric oxide synthase indicating a neural role for nitric oxide

Nature

Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter

Nature

Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic nerves in the gut

Br. J. Pharmacol.

Non-cholinergic excitatory and inhibitory junction potentials in the circular smooth muscle of the guinea-pig ileum

J. Physiol.

Apamin distinguishes two types of relaxation mediated by enteric nerves in the guinea-pig gastrointestinal tract

Naunyn-Schmiedebergs Arch. Pharmacol.