{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T22:33:28Z","timestamp":1773268408423,"version":"3.50.1"},"reference-count":47,"publisher":"American Physiological Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2014,12,15]]},"abstract":"<jats:p> Infantile hypertrophic pyloric stenosis (IHPS) is a common disease of unknown etiology. The tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia-1 ( hph-1) newborn mouse has a similar phenotype to the human condition. For hph-1 and wild-type control animals, pyloric tissue agonist-induced contractile properties, reactive oxygen species (ROS) generation, cGMP, neuronal nitric oxide synthase (nNOS) content, and Rho-associated protein kinase 2 (ROCK-2) expression and activity were evaluated. Primary pyloric smooth muscle cells from wild-type newborn animals were utilized to evaluate the effect of BH4 deficiency. One-week-old hph-1 mice exhibited a fourfold increase ( P &lt; 0.01) in the pyloric sphincter muscle contraction magnitude but similar relaxation values when compared with wild-type animals. The pyloric tissue nNOS expression and cGMP content were decreased, whereas the rate of nNOS uncoupling increased ( P &lt; 0.01) in 1-wk-old hph-1 mice when compared with wild-type animals. These changes were associated with increased pyloric tissue ROS generation and elevated ROCK-2 expression\/activity ( P &lt; 0.05). At 1\u20133 days of age and during adulthood, the gastric emptying rate of the hph-1 mice was not altered, and there were no genotype differences in pyloric tissue ROS generation, nNOS expression, or ROCK-2 activity. BH4 inhibition in pyloric smooth muscle cells resulted in increased ROS generation ( P &lt; 0.01) and ROCK-2 activity ( P &lt; 0.05). Oxidative stress upregulated ROCK-2 activity in pyloric tissue, but no changes were observed in newborn fundal tissue in vitro. We conclude that ROS-induced upregulation of ROCK-2 expression accounts for the increased pyloric sphincter tone and nNOS downregulation in the newborn hph-1 mice. The role of ROCK-2 activation in the pathogenesis of IHPS warrants further study. <\/jats:p>","DOI":"10.1152\/ajpgi.00221.2014","type":"journal-article","created":{"date-parts":[[2014,10,31]],"date-time":"2014-10-31T03:30:45Z","timestamp":1414726245000},"page":"G1198-G1206","source":"Crossref","is-referenced-by-count":10,"title":["Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn <i>hph-1<\/i> mouse model of the disease"],"prefix":"10.1152","volume":"307","author":[{"given":"Christopher","family":"Welsh","sequence":"first","affiliation":[{"name":"Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulia","family":"Shifrin","sequence":"additional","affiliation":[{"name":"Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, University of Toronto, 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