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We examined this issue by investigating the effects of the oxidative stress inducer 6-anilino-5,8-quinolinedione (LY-83583) in basal as well as U-46619-stimulated tone, and nonadrenergic, noncholinergic (NANC) relaxation in rat IAS. LY-83583, which works via generation of reactive oxygen species in living cells, produced a bimodal effect in IAS tone: lower concentrations (0.1 nM to 10 \u03bcM) produced a concentration-dependent increase, while higher concentrations (50\u2013100 \u03bcM) produced a decrease in IAS tone. An increase in IAS tone by lower concentrations was associated with an increase in RhoA\/Rho kinase (ROCK) activity. This was evident by the increase in RhoA\/ROCK in the particulate fractions, in ROCK activity, and in the levels of phosphorylated (p)<jats:sup>Thr696<\/jats:sup>-myosin phosphatase target subunit 1 and p<jats:sup>Thr18\/Ser19<\/jats:sup>-20-kDa myosin light chain. Conversely, higher concentrations of LY-83583 produced inhibitory effects on RhoA\/ROCK. Interestingly, both the excitatory and inhibitory effects of LY-83583 in the IAS were reversed by superoxide dismutase. The excitatory effects of LY-83583 were found to resemble those with neuronal nitric oxide synthase (nNOS) inhibition by l-NNA, since it produced a significant increase in the IAS tone and attenuated NANC relaxation. These effects of LY-83583 and l-NNA were reversible by l-arginine. This suggests the role of nNOS inhibition and RhoA\/ROCK activation in the increase in IAS tone by LY-83583. These data have important implications in the pathophysiology and therapeutic targeting of rectoanal disorders, especially associated with IAS dysfunction.<\/jats:p>","DOI":"10.1152\/ajpgi.00125.2015","type":"journal-article","created":{"date-parts":[[2015,7,3]],"date-time":"2015-07-03T20:12:24Z","timestamp":1435954344000},"page":"G292-G300","source":"Crossref","is-referenced-by-count":10,"title":["Bimodal effect of oxidative stress in internal anal sphincter smooth muscle"],"prefix":"10.1152","volume":"309","author":[{"given":"Jagmohan","family":"Singh","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College of Thomas 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