Upregulation of RhoA/Rho kinase pathway and downregulation of cGMP/PKG pathway in smooth muscle impair peristaltic reflex and pellet propulsion in the colon of diabetic mice (1110.5)

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Abnormalities in extrinsic and intrinsic innervation and in the distribution of interstitial cells of Cajal are known to contribute to altered gut motility in diabetes. Smooth muscle dysfunction in relation to diabetes has not been fully explored. Aim. To test the hypothesis that upregulation of RhoA/Rho kinase pathway and downregulation of cGMP/PKG pathway contribute to increased muscle tone in diabetes. Methods. Colonic smooth muscle cells from type 1 (NOD) or type 2 diabetes (db/db) mice were used to measure i) RhoA and PDE5 expression; 2) ACh‐induced Rho kinase activity and muscle contraction; 3) NO‐induced PDE5 activity, cGMP levels and muscle relaxation. Colonic segments were used to measure peristaltic reflex and pellet propulsion. Results. Smooth muscle cells isolated from the colon of NOD and db/db mice showed an increase in RhoA and PDE5 expression, Rho kinase and PDE5 activity, and muscle contraction, and a decrease in cGMP levels and muscle relaxation relative to control mice. Consistent with an increase in RhoA and PDE5 expression, orad contraction was increased by 20%, caudad relaxation decreased by 60%, and pellet propulsion decreased by 35% in db/db mice relative to control. Discussion. In diabetic colon upregulation of the RhoA/Rho kinase pathway and downregulation of the cGMP/PKG pathway causes an increase in muscle contraction and decrease in relaxation leading to a decrease in pellet propulsion.