NITRIC OXIDE CONTROL OF UTERINE CONTRACTILITY

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Uterine quiescence during pregnancy, until term, is required for successful completion of gestation by providing a tranquil environment for the growing fetus. Failure to maintain uterine relaxation until term results in preterm delivery, which is the leading cause of infant mortality and morbidity. Recent evidence suggests that nitric oxide (NO) is a potent mediator of smooth muscle relaxation. We initiated studies to examine if an L-arginine-NO-cGMP-relaxation system is present in the rat uterus and if it inhibits contractility. Our preliminary studies provide strong evidence for the presence of a NO-relaxation pathway in the rat uterus and suggest that this system might play a role in maintaining uterine quiescence during pregnancy. To extend these studies we propose to test the following hypotheses: a. A L-arginine NO-cGMP-pathway is present in the uterus and that it specifically inhibits uterine contractility. b. The NO-cGMP-relaxation pathway is upregulated during pregnancy. c. The generation of NO-cGMP and relaxation effects of NO-cGMP are hormonally regulated. The specific aims of this study are: 1. To further establish the existence of a NO-cGMP-relaxation system in the uterus and determine if NO is produced in the uterus. For this we will use various agents to modulate the pathway and measure uterine contractility in vitro. 2. To localize nitric oxide synthase (NOS) activity in the uterine tissues and to ascertain which isoform(s) of NOS are present in this tissue. 3. To investigate whether the NO-cGMP-relaxation system is upregulated during pregnancy and if it is hormone regulated. 4. To examine the mechanisms involved in the NO-cGMP regulation of uterine contractility. 5. To ascertain whether manipulation of the NO-cGMP cascade during pregnancy will affect the pregnancy outcome. 6. To investigate the existence of NO-cGMP system in the human uterus and determine if the uterus reacts to this system differently in pregnant delivering, nondelivering and nonpregnant women. To accomplish these studies, we will use pharmacological studies of in vitro contractility measurement, biochemical assays for NO and cGMP production, arginine to citrulline conversion, histochemical localization and determine the isoform(s) of the NOS in the uterus. These studies will provide important information on the mechanisms through which uterine contractility is regulated during gestation and initiation of labor. Knowledge from these studies may provide the basis for designing appropriate therapeutic strategies to reduce preterm labor.