The mechanisms underlying the generation of the colonic migrating motor complex in both wild-type and nNOS knockout mice

Eamonn J Dickson, Dante J. Heredia, Conor J. McCann, Grant W. Hennig, Terence K. Smith

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Colonic migrating motor complexes (CMMCs) propel fecal contents and are altered in diseased states, including slow-transit constipation. However, the mechanisms underlying the CMMCs are controversial because it has been proposed that disinhibition (turning off of inhibitory neurotransmission) or excitatory nerve activity generate the CMMC. Therefore, our aims were to reexamine the mechanisms underlying the CMMC in the colon of wild-type and neuronal nitric oxide synthase (nNOS)-/- mice. CMMCs were recorded from the isolated murine large bowel using intracellular recordings of electrical activity from circular muscle (CM) combined with tension recording. Spontaneous CMMCs occurred in both wild-type (frequency: 0.3 cycles/min) and nNOS-/- mice (frequency: 0.4 cycles/min). CMMCs consisted of a hyperpolarization, followed by fast oscillations (slow waves) with action potentials superimposed on a slow depolarization (wild-type: 14.0 ± 0.6 mV; nNOS-/-: 11.2 ± 1.5 mV). Both atropine (1 μM) and MEN 10,376 [neurokinin 2 (NK2) antagonist; 0.5 μM] added successively reduced the slow depolarization and the number of action potentials but did not abolish the fast oscillations. The further addition of RP 67580 (NK1 antagonist; 0.5 μM) blocked the fast oscillations and the CMMC. Importantly, none of the antagonists affected the resting membrane potential, suggesting that ongoing tonic inhibition of the CM was maintained. Fecal pellet propulsion, which was blocked by the NK2 or the NK1 antagonist, was slower down the longer, more constricted nNOS-/- mouse colon (wild-type: 47.9 ± 2.4 mm; nNOS-/-: 57.8 ± 1.4 mm). These observations suggest that excitatory neurotransmission enhances pacemaker activity during the CMMC. Therefore, the CMMC is likely generated by a synergistic interaction between neural and interstitial cells of Cajal networks.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume298
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

Fingerprint

Migrating Myoelectric Complexes
Nitric Oxide Synthase Type I
Knockout Mice
Synaptic Transmission
Action Potentials
Colon
Interstitial Cells of Cajal
Muscles
Constipation
Atropine
Membrane Potentials

Keywords

  • Cholinergic transmission
  • Circular muscle
  • Interstitial cells of Cajal
  • Longitudinal muscle
  • Neuronal nitric oxide synthase
  • NK1 receptors
  • NK2 receptors
  • Slow waves
  • Smooth muscle
  • Tachykinins

ASJC Scopus subject areas

  • Physiology
  • Gastroenterology
  • Hepatology
  • Physiology (medical)

Cite this

The mechanisms underlying the generation of the colonic migrating motor complex in both wild-type and nNOS knockout mice. / Dickson, Eamonn J; Heredia, Dante J.; McCann, Conor J.; Hennig, Grant W.; Smith, Terence K.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 298, No. 2, 02.2010.

Research output: Contribution to journalArticle

@article{835e615d69d140b4a7003452d4970495,
title = "The mechanisms underlying the generation of the colonic migrating motor complex in both wild-type and nNOS knockout mice",
abstract = "Colonic migrating motor complexes (CMMCs) propel fecal contents and are altered in diseased states, including slow-transit constipation. However, the mechanisms underlying the CMMCs are controversial because it has been proposed that disinhibition (turning off of inhibitory neurotransmission) or excitatory nerve activity generate the CMMC. Therefore, our aims were to reexamine the mechanisms underlying the CMMC in the colon of wild-type and neuronal nitric oxide synthase (nNOS)-/- mice. CMMCs were recorded from the isolated murine large bowel using intracellular recordings of electrical activity from circular muscle (CM) combined with tension recording. Spontaneous CMMCs occurred in both wild-type (frequency: 0.3 cycles/min) and nNOS-/- mice (frequency: 0.4 cycles/min). CMMCs consisted of a hyperpolarization, followed by fast oscillations (slow waves) with action potentials superimposed on a slow depolarization (wild-type: 14.0 ± 0.6 mV; nNOS-/-: 11.2 ± 1.5 mV). Both atropine (1 μM) and MEN 10,376 [neurokinin 2 (NK2) antagonist; 0.5 μM] added successively reduced the slow depolarization and the number of action potentials but did not abolish the fast oscillations. The further addition of RP 67580 (NK1 antagonist; 0.5 μM) blocked the fast oscillations and the CMMC. Importantly, none of the antagonists affected the resting membrane potential, suggesting that ongoing tonic inhibition of the CM was maintained. Fecal pellet propulsion, which was blocked by the NK2 or the NK1 antagonist, was slower down the longer, more constricted nNOS-/- mouse colon (wild-type: 47.9 ± 2.4 mm; nNOS-/-: 57.8 ± 1.4 mm). These observations suggest that excitatory neurotransmission enhances pacemaker activity during the CMMC. Therefore, the CMMC is likely generated by a synergistic interaction between neural and interstitial cells of Cajal networks.",
keywords = "Cholinergic transmission, Circular muscle, Interstitial cells of Cajal, Longitudinal muscle, Neuronal nitric oxide synthase, NK1 receptors, NK2 receptors, Slow waves, Smooth muscle, Tachykinins",
author = "Dickson, {Eamonn J} and Heredia, {Dante J.} and McCann, {Conor J.} and Hennig, {Grant W.} and Smith, {Terence K.}",
year = "2010",
month = "2",
doi = "10.1152/ajpgi.00399.2009",
language = "English (US)",
volume = "298",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - The mechanisms underlying the generation of the colonic migrating motor complex in both wild-type and nNOS knockout mice

AU - Dickson, Eamonn J

AU - Heredia, Dante J.

AU - McCann, Conor J.

AU - Hennig, Grant W.

AU - Smith, Terence K.

PY - 2010/2

Y1 - 2010/2

N2 - Colonic migrating motor complexes (CMMCs) propel fecal contents and are altered in diseased states, including slow-transit constipation. However, the mechanisms underlying the CMMCs are controversial because it has been proposed that disinhibition (turning off of inhibitory neurotransmission) or excitatory nerve activity generate the CMMC. Therefore, our aims were to reexamine the mechanisms underlying the CMMC in the colon of wild-type and neuronal nitric oxide synthase (nNOS)-/- mice. CMMCs were recorded from the isolated murine large bowel using intracellular recordings of electrical activity from circular muscle (CM) combined with tension recording. Spontaneous CMMCs occurred in both wild-type (frequency: 0.3 cycles/min) and nNOS-/- mice (frequency: 0.4 cycles/min). CMMCs consisted of a hyperpolarization, followed by fast oscillations (slow waves) with action potentials superimposed on a slow depolarization (wild-type: 14.0 ± 0.6 mV; nNOS-/-: 11.2 ± 1.5 mV). Both atropine (1 μM) and MEN 10,376 [neurokinin 2 (NK2) antagonist; 0.5 μM] added successively reduced the slow depolarization and the number of action potentials but did not abolish the fast oscillations. The further addition of RP 67580 (NK1 antagonist; 0.5 μM) blocked the fast oscillations and the CMMC. Importantly, none of the antagonists affected the resting membrane potential, suggesting that ongoing tonic inhibition of the CM was maintained. Fecal pellet propulsion, which was blocked by the NK2 or the NK1 antagonist, was slower down the longer, more constricted nNOS-/- mouse colon (wild-type: 47.9 ± 2.4 mm; nNOS-/-: 57.8 ± 1.4 mm). These observations suggest that excitatory neurotransmission enhances pacemaker activity during the CMMC. Therefore, the CMMC is likely generated by a synergistic interaction between neural and interstitial cells of Cajal networks.

AB - Colonic migrating motor complexes (CMMCs) propel fecal contents and are altered in diseased states, including slow-transit constipation. However, the mechanisms underlying the CMMCs are controversial because it has been proposed that disinhibition (turning off of inhibitory neurotransmission) or excitatory nerve activity generate the CMMC. Therefore, our aims were to reexamine the mechanisms underlying the CMMC in the colon of wild-type and neuronal nitric oxide synthase (nNOS)-/- mice. CMMCs were recorded from the isolated murine large bowel using intracellular recordings of electrical activity from circular muscle (CM) combined with tension recording. Spontaneous CMMCs occurred in both wild-type (frequency: 0.3 cycles/min) and nNOS-/- mice (frequency: 0.4 cycles/min). CMMCs consisted of a hyperpolarization, followed by fast oscillations (slow waves) with action potentials superimposed on a slow depolarization (wild-type: 14.0 ± 0.6 mV; nNOS-/-: 11.2 ± 1.5 mV). Both atropine (1 μM) and MEN 10,376 [neurokinin 2 (NK2) antagonist; 0.5 μM] added successively reduced the slow depolarization and the number of action potentials but did not abolish the fast oscillations. The further addition of RP 67580 (NK1 antagonist; 0.5 μM) blocked the fast oscillations and the CMMC. Importantly, none of the antagonists affected the resting membrane potential, suggesting that ongoing tonic inhibition of the CM was maintained. Fecal pellet propulsion, which was blocked by the NK2 or the NK1 antagonist, was slower down the longer, more constricted nNOS-/- mouse colon (wild-type: 47.9 ± 2.4 mm; nNOS-/-: 57.8 ± 1.4 mm). These observations suggest that excitatory neurotransmission enhances pacemaker activity during the CMMC. Therefore, the CMMC is likely generated by a synergistic interaction between neural and interstitial cells of Cajal networks.

KW - Cholinergic transmission

KW - Circular muscle

KW - Interstitial cells of Cajal

KW - Longitudinal muscle

KW - Neuronal nitric oxide synthase

KW - NK1 receptors

KW - NK2 receptors

KW - Slow waves

KW - Smooth muscle

KW - Tachykinins

UR - http://www.scopus.com/inward/record.url?scp=76749168135&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76749168135&partnerID=8YFLogxK

U2 - 10.1152/ajpgi.00399.2009

DO - 10.1152/ajpgi.00399.2009

M3 - Article

C2 - 19959818

AN - SCOPUS:76749168135

VL - 298

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 2

ER -