Knock out of neuronal nitric oxide synthase exacerbates intestinal ischemia/reperfusion injury in mice

Leni R. Rivera, Louise Pontell, Hyun Jung Cho, Patricia Castelucci, Michelle Thacker, Daniel P. Poole, Tony Frugier, John B. Furness

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30 Citations (Scopus)


Recent investigation of the intestine following ischemia and reperfusion (I/R) has revealed that nitric oxide synthase (NOS) neurons are more strongly affected than other neuron types. This implies that NO originating from NOS neurons contributes to neuronal damage. However, there is also evidence of the neuroprotective effects of NO. In this study, we compared the effects of I/R on the intestines of neuronal NOS knockout (nNOS-/-) mice and wildtype mice. I/R caused histological damage to the mucosa and muscle and infiltration of neutrophils into the external muscle layers. Damage to the mucosa and muscle was more severe and greater infiltration by neutrophils occurred in the first 24 h in nNOS-/- mice. Immunohistochemistry for the contractile protein, α-smooth muscle actin, was used to evaluate muscle damage. Smooth muscle actin occurred in the majority of smooth muscle cells in the external musculature of normal mice but was absent from most cells and was reduced in the cytoplasm of other cells following I/R. The loss was greater in nNOS-/- mice. Basal contractile activity of the longitudinal muscle and contractile responses to nerve stimulation or a muscarinic agonist were reduced in regions subjected to I/R and the effects were greater in nNOS-/- mice. Reductions in responsiveness also occurred in regions of operated mice not subjected to I/R. This is attributed to post-operative ileus that is not significantly affected by knockout of nNOS. The results indicate that deleterious effects are greater in regions subjected to I/R in mice lacking nNOS compared with normal mice, implying that NO produced by nNOS has protective effects that outweigh any damaging effect of this free radical produced by enteric neurons.

Original languageEnglish
Pages (from-to)565-576
Number of pages12
JournalCell and Tissue Research
Issue number2
Publication statusPublished - 2012
Externally publishedYes


  • Enteric nervous system
  • Intestine
  • Ischemia
  • Mouse
  • Nitric oxide synthase

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