Role of Progesterone in Colonic Muscle Dysfunction

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DESCRIPTION (provided by applicant): Chronic constipation due to colonic inertia is common in females of reproductive age with a 20% prevalence in Western countries and a female: male ratio of 9:1. Its pathogenesis at the cellular level, however, is unknown. Constipation is a frequent complication of pregnancy and correlates with rising serum levels of progesterone (PC). PG affects the motility of the gastrointestinal smooth muscle primarily through genomic actions. Our preliminary studies have shown signal transduction abnormalities in muscle cells from female patients with colonic inertia similar to those induced by PG in human colonic muscle cells in vitro and in muscle cells from guinea pigs treated with PG in vivo and in vitro. The proposed studies are therefore aimed at extending these investigations on the mechanisms whereby PG impairs contraction and increases relaxation in normal colonic muscle from guinea pigs and humans and to test the hypothesis that female colonic inertia is due to a greater muscle response to PG due to an over expression of PG receptors. This hypothesis is based on an abnormal G protein pattern that affects the signal transduction that contributes to the genesis of basal colonic motility [MI] and mediates the actions of G protein coupled receptor (GPCR) dependent agonists and impairs their binding to receptors as well as an increased mRNA levels of PG receptors. We therefore propose to determine that: a) PG's genomic actions alter the signal transduction due to changes in heterotrimeric and monomeric G proteins, b) These G protein changes have significant functional consequences impairing the basal and agonist induced colonic motility and whether this abnormal motor response is confined to agonists that are G protein dependent, c) Prostaglandin's (PGF2a) contribute to the genesis of basal MI and its actions and synthesis inhibited by PC. d) PG treatment causes signal transduction abnormalities in normal human colonic muscle that appear to be similar to those present in females with colonic inertia, e) The muscle abnormalities in females with colonic inertia could be explained by an over expression of PG receptors. These studies will be conducted in muscle cells and strips from control, PG treated and pregnant guinea pigs, and in normal and PG treated human colonic muscle cells from free margins of the sigmoid colon of patients with adenocarcinoma and from female patients with colonic inertia and chronic constipation.