Neuronal nitric oxide inhibits intestinal smooth muscle growth

作者：Pelletier Anne Marie; Venkataramana Shriram; Miller Kurtis G; Bennett Brian M; Nair Dileep G; Lourenssen Sandra; Blennerhassett Michael G^*

来源：American Journal of Physiology - Gastrointestinal and Liver Physiology, 2010, 298(6): G896-G907.

DOI：10.1152/ajpgi.00259.2009

• colitis
• growth inhibition
• intestine nitric oxide
• neuronal nitric oxide synthase
• cGMP
• cAMP

Pelletier A, Venkataramana S, Miller KG, Bennett BM, Nair DG, Lourenssen S, Blennerhassett MG. Neuronal nitric oxide inhibits intestinal smooth muscle growth. Am J Physiol Gastrointest Liver Physiol 298: G896-G907, 2010. First published March 25, 2010; 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-BrcAMP 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.

• 出版日期2010-6