Induction of glutamate dehydrogenase in the ovine fetal liver by dexamethasone infusion during late gestation

Glucocorticoids near term are known to upregulate many important enzyme systems prior to birth. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme that catalyzes both the reversible conversion of ammonium nitrogen into organic nitrogen (glutamate production) and the oxidative deamination of glutamate resulting in 2-oxoglutarate. The activity of this enzyme is considered to be of major importance in the development of catabolic conditions leading to gluconeogenesis prior to birth. Ovine hepatic GDH mRNA expression and activity were determined in near-term (130 days of gestation, term 147 +/- 4 days) control and acutely dexamethasone-treated (0.07 mg(-1) hr(-1) for 26 hr) fetuses. Dexamethasone infusion had no effect on placental or fetal liver weights. Dexamethasone infusion for 26 hr significantly increased hepatic GDH mRNA expression. This increased GDH mRNA expression was accompanied by an increase in hepatic mitochondrial GDH activity, from 30.0 +/- 7.4 to 58.2 +/- 8.1 U GDH/U CS (citrate synthase), and there was a significant correlation between GDH mRNA expression and GDH activity. The generated ovine GDH sequence displayed significant similarity with published human, rat, and murine GDH sequence. These data are consistent with the in vivo studies that have shown a redirection of glutamine carbon away from net hepatic glutamate release and into the citric acid cycle through the forward reaction catalyzed by GDH, i.e., glutamate to oxoglutarate

Fetal hypertension and abnormal Doppler velocimetry in an ovine model of intrauterine growth restriction

Our objective was to test the hypothesis that systemic blood pressure (BP) is increased above normal in intrauterine growth restricted (IUGR) fetal lambs with elevated umbilical artery (UmA) Doppler indices. Five pregnant ewes were exposed to hyperthermic conditions for 80 days beginning at 40 days' gestation (dGA) to induce IUGR. They were then placed in ambient conditions with 6 additional ewes that served as controls. Doppler indices were calculated from UmA Doppler flow velocity waveforms. At 128 dGA, fetal catheters were placed for measurement of umbilical blood flow (UBF) by an ethyl alcohol steady-state diffusion technique and for aortic BP measurements. At 132 dGA, fetal mean systemic BP and blood flow were determined. At necropsy the placental and fetal weights were recorded. UBF was normalized for fetal weight. Linear regression, F tests and t tests were performed as appropriate. P <. 05 was considered significant. Compared with control pregnancies, the IUGR pregnancies showed: (1) reduced fetal and placental weights, (2) elevated systemic BP, (3) reduced UBF, (4) elevated UmA and aortic Doppler velocimetry indices, (5) increased resistance per 100 g placenta, and (6) decreased UmA oxygenation and increased lactic academia. The UmA Doppler index of resistance (systolic/diastolic ratio) correlated strongly with calculated resistance (R 2 = 0.7). Doppler indices also correlated with systemic BP (R 2 = 0.5). Ovine IUGR fetuses with high UmA Doppler indices have elevated systemic BPs. UmA Doppler indices of resistance correlate well with (1) fetal systemic BPs and (2) resistance as calculated by pressure/flow. This whole animal study shows that IUGR fetuses are hypertensive and that increased UmA Doppler resistance indices are consistent with a fetal-placental hypertensive state

Improving pregnancy outcomes in humans through studies in sheep

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental and fetal health and to provide an evidence base for translation of interventions into the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.Janna L. Morrison, Mary J. Berry, Kimberley J. Botting, Jack R. T. Darby ... Kathryn L. Gatford ... Claire T. Roberts ... et al