Gastroenterology

Gastroenterology

Volume 115, Issue 2, August 1998, Pages 314-329
Gastroenterology

Alimentary Tract
Interstitial cells of Cajal mediate enteric inhibitory neurotransmission in the lower esophageal and pyloric sphincters,☆☆

https://doi.org/10.1016/S0016-5085(98)70198-2Get rights and content

Abstract

Background & Aims: Previous studies have suggested that a specific class of interstitial cells of Cajal (ICC) act as mediators in nitrergic inhibitory neurotransmission. The aim of this investigation was to examine the role of intramuscular ICC (IC-IM) in neurotransmission in the murine lower esophageal (LES) and pyloric sphincters (PS). Methods: Immunohistochemistry and electrophysiology were used to study the distribution and role of IC-IM. Results: The LES and PS contain spindle-shaped IC-IM, which form close relationships with nitric oxide synthase–containing nerve fibers. The PS contains ICC within the myenteric plexus and c-Kit immunopositive cells along the submucosal surface of the circular muscle. IC-IM were absent in the LES and PS of c-kit (W/Wv) mutant mice. Using these mutants, we tested whether IC-IM mediate neural inputs in the LES and PS. Although the distribution of inhibitory nerves was normal in W/Wv animals, NO-dependent inhibitory neurotransmission was reduced. Hyperpolarizations to sodium nitroprusside were also attenuated in W/Wv animals. Conclusions: The data suggest that IC-IM play an important role in NO-dependent neurotransmission in the LES and PS. IC-IM may be the effectors that transduce NO signals into hyperpolarizing responses. Loss of IC-IM may interfere with relaxations and normal motility in these sphincters.

GASTROENTEROLOGY 1998;115:314-329

Section snippets

Materials and methods

Wild-type (+/+; black coats) and W/Wv (pure white coats) mice,18 between the ages of 20 and 30 days postpartum, were anesthesized by chloroform inhalation and exsanguinated by cervical dislocation followed by decapitation. The entire stomach, including portions of the esophagus and duodenum (Figure 1A), was removed and placed in Krebs–Ringer's buffer (KRB).

. Isolation of muscles of the pyloric sphincter and LES. (A) A stomach with segments of the esophagus (E) and duodenum (D) attached. (B) A

c-Kit–positive cells in the LES and pyloric sphincter and the consequences of W mutations on c-Kit–expressing cells

Antibodies to c-Kit were used to determine the distribution of cells with c-Kit–like immunoreactivity (c-Kit–LI). In six LES examined, cells with c-Kit–LI were distributed within the circular and longitudinal muscle layers (Figure 2A).

. Distribution of ICC in the murine LES. (A) A cryostat cross section through the circular (cm) and longitudinal (lm) muscle layers (section cut along the long axis of the longitudinal layer) of a wild-type (+/+) mouse. IC-IM are observed in both layers (arrows).

Discussion

The LES and pyloric sphincter of the mouse have spindle-shaped ICC similar to the gastric fundus.17 Similar cells have also been observed in the esophagus, LES, stomach, cecum, and internal anal sphincter of the guinea pig,21 but the physiological role of this class of ICC in sphincters has not been documented previously. Spindle-shaped ICC lie within the circular and longitudinal muscle layers in close apposition with smooth muscle cells and varicose processes of motor neurons. We have

Acknowledgements

The authors thank Julia Bayguinov for technical assistance and Piers Emson at the Molecular Neuroscience Group in Cambridge, England, for the gift of anti-nNOS antibody.

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      Neuromuscular transmission in gastrointestinal muscles involves communication between motor neurons and smooth muscle cells. However, there is evidence that this communication is mediated, in part, by ICC (distinguished with c-Kit antibodies) (Figure 2).7,9 ICC express receptors for enteric motor neurotransmitters, transduce neurotransmitter signals, and convey information to smooth muscle cells via gap junctions.

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    Address requests for reprints to: Kenton M. Sanders, Ph.D., Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557. e-mail: [email protected]; fax: (702) 784-6903.

    ☆☆

    Supported by grant DK 40569 from the National Institute of Diabetes and Digestive and Kidney Diseases. Morphology was provided by a core laboratory supported by PO1 DK 41315.

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