Gastrointestinal (GI) symptoms suggesting altered motility are modulated by ovarian hormone state, yet the physiological basis has not been explicated. There are indications that progesterone and estrogen alter functional variables (intestinal transit, gastric emptying, motility), however, experiments have not been performed to delineate the molecular basis for observed changes. The purpose of this study is to compare in 4 ovarian hormone groups (progesterone, estrogen, and vehicle treated ovariectomized rats; cycling rats in metestrus) the following characteristics of gastric, intestinal, and uterine smooth muscle: mechanical properties and composition of the contractile apparatus including myosin isoform composition, content of energy related phosphate compounds. Tension modulation by altered energy-related phosphate compound composition will be probed. The effect of hormone withdrawal on GI motility will be measured and interpreted in the context of altering hormone levels. Sprague-Dawley rats will be ovariectomized then implanted with slow-release hormone pellets for 26 days. Skinned fiber experiments will allow study o contractile machinery independent of changes in membrane properties. Gel electrophoresis will be used to identify myosin isoform composition. High performance liquid chromatography will be used to assay content of energy related phosphate compounds. It is hypothesized that estrogen treatment will be associated with increased maximum Ca2+-activated tension, increased maximum velocity of contraction, altered myosin heavy chain composition, and higher concentrations of creatine phosphate and adenosine triphosphate in the uterus but not in gut muscle, where actomyosin content may be diminished. Training objectives are to enhance the investigator's knowledge of biophysics, biochemistry, and regulation of smooth muscle, enhance technical capabilities in probing smooth muscle, enhance knowledge and skills in molecular biology, enhance linkages with clinical observations, and to develop a proposal. Training objectives will be achieved by consultation with experts, hands on experimentation under the guidance of skilled technicians, formal molecular biology coursework. The proposed study will contribute importantly to ongoing studies of ovarian hormone state and gut structure/function by expanding biotechnical capabilities in state-of- the-science measurements of smooth muscle contractile machinery and energetics. The information obtained will form a platform for launching inquiries into mechanisms underlying modulation of contraction, and for development of targeted therapeutic strategies for such disorders as irritable bowel syndrome. The training acquired will prepare the investigator to launch inquiries into mechanisms underlying modulation of smooth muscle contraction, and to participate in multidisciplinary efforts to design and evaluate therapies for GI symptoms.
| Bond, E F; Heitkemper, M M; Bailey, S L (1998) Estrogen suppresses gastric motility response to thyrotropin-releasing hormone and stress in awake rats. Res Nurs Health 21:221-8 |
| Bond, E F; Heitkemper, M M; Perigo, R (1996) Gastric emptying and gastric-intestinal transit in rats with varying ovarian hormone status. Nurs Res 45:218-24 |
