Infantile hypertrophic pyloric stenosis (IHPS) is a common disease of unknown etiology. The tetrahydrobiopterin (BH4) - deficient hph-1 newborn mouse has a similar phenotype to the human condition. 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, as well as, ROCK-2 expression and activity were evaluated. Primary pyloric smooth muscle cells from wild-type newborn animals were utilized to evaluate the effect of tetrahydrobiopterin (BH4) deficiency. One-week old hph-1 mice exhibited a 4-fold increase (P<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, while the rate of nNOS uncoupling increased (p<0.01) in one-week 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<0.05). At 1-3 days of age and during adulthood, the hph-1 mice's gastric emptying rate 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<0.01) and ROCK-2 activity (p<0.05). Oxidative stress upregulated ROCK-2 activity in pyloric, 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.
- smooth muscle
- Rho-associated protein kinase
- Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology