Simultaneous maternal indirect blood pressure measurements, electronic fetal heart rate monitoring, and ultrasonographic biophysical profile testing were used to assess maternal-fetal homeostasis in gravid ewes during gestational days 127 to 134 (term 146), during a 72-hour fast, and during treatment with thromboxane synthetase inhibitors CGS13080 and CGS12970. Seventy-five percent of the ewes (12 of 16) developed clinical signs of ovine pregnancy-induced hypertension, including maternal hypertension and fetal depression. In three untreated hypertensive ewes, pregnancy was terminated by spontaneous premature delivery, and one maternal death occurred after an eclamptic seizure. All nine ewes treated with one of the two thromboxane synthetase inhibitors responded to therapy with decreases in blood pressure and resolution of fetal depression. These nine ewes completed gestation, and were delivered at term. These data indicate that therapy with thromboxane synthetase inhibitors in this animal model of preeclampsia results in profoundly beneficial effects and suggest that further studies of thromboxane synthetase inhibitors are warranted in preeclampsia.

Ovine placental lactogen (oPL) is postulated to be involved in the repartitioning of maternal nutrients during pregnancy, through its effect on insulin metabolism. Ovine pancreatic insulin responses to exogenous glucose are depressed during pregnancy and this depression becomes more pronounced as gestation advances. In addition, under the hormonal environment of rising oPL and growth hormone (oGH) concentrations, maternal whole body glucose irreversible loss (GIL) increases. The percentage of GIL accounted for by uterine glucose uptake also increases with advancing gestation and increasing litter size. Regression analysis of oPL concentration with glucose uterine uptake as a percentage of GIL, accounts for 39% of variation. Maternal oPL concentrations which increase with gestational age, were significantly greater in multiple bearing ewes and ewes subjected to reduced metabolisable energy (ME) intakes. It is postulated that through actions on pancreatic sensitivity, oPL plays a major role as a homeorhetic control during pregnancy. Elevated oPL concentrations were strongly associated with continually depressed pancreatic insulin secretory ability. The reduction in pancreatic sensitivity to glucose was not as a result of elevation in GH or non-esterified fatty acid (NEFA) concentrations. Muscle insulin receptor number and affinity were found to increase with increasing litter size, suggesting that pregnancy associated insulin resistance occurs predominantly in adipose tissue. During ovine pregnancy there is a specific stimulation of maternal gluconeogenesis. As gestation advances, an increasingly greater proportion of this glucose is partitioned to the gravid uterus. The development of insulin resistance, together with the suppression of pancreatic activity, ensures the preferential uptake of glucose by non-insulin dependent tissues over insulin dependent tissues. These activities favour uterine glucose uptake, decrease adipose glucose uptake, and also promote adipose mobilisation and hepatic gluconeogenesis, so as to meet the increasing energy requirement of pregnancy. It is postulated that through these effects on insulin secretion and associated adipose tissue mobilisation factors, oPL plays a major role in homeorhesis during pregnancy. / Doctor of Philosophy (PhD)