The central theme of the proposal is to examine the cardiovascular responses to stress during fetal and neonatal life. We plan to examine the mechanisms by which the circulation responds to acute stress of hypoxia, asphyxia, or hemorrhage. Also we will assess the effects of chronic fetal stress resulting from reduction of uterine blood or from induced congenital cardiac lesions, on morphological and functional development of the circulation and on cardiovascular adaptations after birth. The studies, to be conducted in fetal and newborn lambs, include: 1) Observations on the normal patterns of umbilical venous and superior and inferior vena cava blood returning to the fetal heart, and their respective distributions to the fetal body, and the changes resulting from stress; 2) The effects of acute reduction of uterine blood flow on fetal heart rate patterns and on fetal cardiac output and its distributions; 3) The effects of chronic reduction of uterine blood flow on development of autonomic nervous regulation of the circulation, development of the adrenal cortex and the fetal pulmonary circulation and surfactant; 4) Factors determining the changes in cardiac output after birth and the ability to increase cardiac output in response to stress; 5) The pre- and postnatal effects of simulated congenital heart lesions producing ventricular outflow obstruction, on myocardial morphology and function; 6) The role of polyadenosine diphosphoribose in normal myocardial growth before and after birth, and the influence of chronic prenatal and postnatal stress of ventricular outflow obstruction on the NAD ion - polyadenosine diphosphoribose relationships; 7) The effects of the stress of premature birth on postnatal myocardial cell growth and achievement of myocardial performance; 8) The ontogeny of myocardial adrenergic receptors and the effects of chronic stress; 9) Myocardial blood flow and oxygen substrate uptake before and after birth and the effects of acute and chronic stress; 10) The effects of prenatal circulatory adjustments; 11) The factors affecting fluid accumulation and removal in the lungs before and after birth and the effects of hypoxia and other acute and chronic stress; 12) The role of prostaglandins in regulation of ductus arteriosus responses before and after birth and the effects of acute and chronic stress on prostaglandin metabolism and ductus arteriosus responses.