The exciting possibility that an exogenous Nitric Oxide (NO) donor might become an important pharmacological tool in the clinical management of preterm uterine contractions mandates a careful evaluation of the potential adverse effects the agent/agents might have, both on mother and fetus. We will evaluate the effects of several different NO donors, those currently appearing to hold most clinical promise, on the fetal-placental, fetal-neonatal transitional, uterine and maternal circulations and on fetal oxygen and substrate uptake and fetal growth. Since NO produces smooth muscle relaxation through cGMP production, we will also evaluate the combination of a NO donor and a cGMP phosphodiesterase inhibitor in order to inhibit cGMP breakdown, thereby prolonging the effects of NO and perhaps allowing for the administration of smaller amounts of the NO donor drug. We will use chronically instrumented fetal, neonatal and maternal sheep models and will study various hemodynamic variables using blood flow transducers and microspheres to evaluate cardiac output, uterine and umbilical flow and individual organ flows. We will evaluate fetal oxygen consumption and substrate uptake. Since the management of preterm labor may require not only the acute inhibition of contractions, but also the maintenance of uterine quiescence. for prolonged periods, up to many weeks, we will study both the effects of acute therapeutic regimens and also those of long-term maintenance therapy. In the latter we will examine the same hemodynamic variables throughout a 2 week infusion given at 2 different periods of gestation (smarting at 115 d and 13Od respectively) and we will also examine fetal organ growth and weight to examine the possible development of growth retardation. Following the prolonged period of infusion we will also examine the fetal responses to 2 levels of induced hypoxemia to determine whether stress induced compensatory mechanisms remain intact. Also, because normal delivery at term is the intent of this therapeutic approach, we will study the effects of treatment for several weeks on the transitional circulation, in particular the pulmonary circulation, and on the physiologic integrity of the NO cascade.
