Neuronal nitric oxide inhibits intestinal smooth muscle growth.

Authors: Pelletier, AM  Venkataramana, S  Miller, KG  Bennett, BM  Nair, DG  Lourenssen, S  Blennerhassett, MG 
Citation: Pelletier AM, etal., Am J Physiol Gastrointest Liver Physiol. 2010 Jun;298(6):G896-907. Epub 2010 Mar 25.
Pubmed: (View Article at PubMed) PMID:20338922
DOI: Full-text: DOI:10.1152/ajpgi.00259.2009

Hyperplasia of smooth muscle contributes to the thickening of the intestinal wall that is characteristic of inflammation, but the mechanisms of growth control are unknown. Nitric oxide (NO) from enteric neurons expressing neuronal NO synthase (nNOS) might normally inhibit intestinal smooth muscle cell (ISMC) growth, and this was tested in vitro. In ISMC from the circular smooth muscle of the adult rat colon, chemical NO donors inhibited [(3)H]thymidine uptake in response to FCS, reducing this to baseline without toxicity. This effect was inhibited by the guanylyl cyclase inhibitor ODQ and potentiated by the phosphodiesterase-5 inhibitor zaprinast. Inhibition was mimicked by 8-bromo (8-Br)-cGMP, and ELISA measurements showed increased levels of cGMP but not cAMP in response to sodium nitroprusside. However, 8-Br-cAMP and cilostamide also showed inhibitory actions, suggesting an additional role for cAMP. Via a coculture model of ISMC and myenteric neurons, immunocytochemistry and image analysis showed that innervation reduced bromodeoxyuridine uptake by ISMC. Specific blockers of nNOS (7-NI, NAAN) significantly increased [(3)H]thymidine uptake in response to a standard stimulus, showing that nNOS activity normally inhibits ISMC growth. In vivo, nNOS axon number was reduced threefold by day 1 of trinitrobenzene sulfonic acid-induced rat colitis, preceding the hyperplasia of ISMC described earlier in this model. We conclude that NO can inhibit ISMC growth primarily via a cGMP-dependent mechanism. Functional evidence that NO derived from nNOS causes inhibition of ISMC growth in vitro predicts that the loss of nNOS expression in colitis contributes to ISMC hyperplasia in vivo.


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CRRD ID: 5131958
Created: 2011-05-17
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Last Modified: 2011-05-17
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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.