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

Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G222-32. doi: 10.1152/ajpgi.00399.2009. Epub 2009 Dec 3.


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 microM) and MEN 10,376 [neurokinin 2 (NK2) antagonist; 0.5 microM] 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 microM) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Analgesics / pharmacology
  • Animals
  • Atropine / pharmacology
  • Colon / innervation*
  • Colon / physiology*
  • Enzyme Inhibitors / pharmacology
  • Intestinal Mucosa / innervation
  • Intestinal Mucosa / physiology
  • Isoindoles / pharmacology
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Muscarinic Antagonists / pharmacology
  • Muscle, Smooth / innervation
  • Muscle, Smooth / physiology
  • Myoelectric Complex, Migrating / drug effects
  • Myoelectric Complex, Migrating / physiology*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Nitric Oxide Synthase Type I / genetics*
  • Nitric Oxide Synthase Type I / metabolism*
  • Nitroarginine / pharmacology


  • Analgesics
  • Enzyme Inhibitors
  • Isoindoles
  • Muscarinic Antagonists
  • 7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one
  • Nitroarginine
  • Nitric Oxide
  • Atropine
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse