SummaryTo study the normal development of blood coagulation factor activities in a growing fetus while avoiding the effects of labor and delivery, a chronic fetal lamb model was developed in which serial blood samples from 10 fetuses were studied during the third trimester of pregnancy and 24 hr after birth. Under operating room conditions with sterile technique, a polyethylene catheter to which heparin had been bound to both internal and external surfaces was inserted into the femoral artery of the fetus. The catheter was brought out through a skin pouch to the side of the ewe and enclosed in a zip lock bag. Blood samples were withdrawn from the catheter three times each week for measurement of coagulation factor activities. Levels of coagulation factor activities at birth in noncatheterized animals were not different from those found in catheterized animals except for factor IX activity which was 12% higher in the catheterized animals (0.02 t P < 0.05). The patterns of development for each of the coagulation factors were similar in all 10 animals studied. Fibrinogen, prothrombin, and factor VII show a decrease in activity early in the last trimester of pregnancy whereas other factors V, VIII, IX, X, XI, XII, and XI11 show a gradual increase in activity throughout the last trimester of pregnancy. Both factors VIII and IX show a significant increase in activity (23% factor VIII and 12% factor IX) associated with the process of delivery. The levels of coagulation factor activities at birth in the lamb relative to adult sheep normals are similar to those found in humans with the exception of factor XIII. Factor XIII is at normal levels in the newborn lamb and is reported to be at levels approximately 50% of the adult level in human infants. SpeculationThe development of a chronic fetal lamb preparation has allowed the construction of developmental patterns for coagulation factor activities throughout the last trimester of pregnancy. Further studies into the biology of the changes in coagulation factor activities observed and the influences of such stresses as hypoxemia and premature delivery should enhance our understanding of the bleeding neonate.
ABSTRACT. The effect of glucocorticoids in regulating liver angiotensinogen gene expression was studied in chronically instrumented fetal sheep during the last trimester of gestation and was compared with the expression of other hepatic genes (prothrombin, factor IX, and albumin). Four sets of twins were studied at 118 d of gestation, and three sets were studied at 138 d of gestation (term, 145 d). One of each set of twins was infused intraperitoneally with cortisol (5 pmol.mL-'.h-') for 48 h, whereas the other twin received the same volume (1 mL/h) of normal saline. Plasma cortisol concentration increased from 0.32 f 0.12 and 2.7 f 0.12 nmo1/100 mL to 44.2 f 20.0 and 37.7 f 8.2 nmo1/100 mL in 118-and 138-d fetuses, respectively, during the cortisol infusion; no changes were observed in fetuses infused with saline alone. At the end of the infusion period, the animals were anesthetized, the fetal liver was removed, and total cellular RNA was isolated and probed for angiotensinogen, prothrombin, factor IX, and albumin. The results demonstrated that cortisol infusion decreased angiotensinogen mRNA by 61% in 138-d fetuses and albumin mRNA expression by 2.4-fold in 118-d fetuses and by 3.4-fold in 138-d fetuses. On the other hand, cortisol had no effect on fetal factor IX gene expression but increased prothrombin mRNA levels by 65% in 118-d fetuses and 62% in 138-d fetuses. Taken together, our results suggest that, during fetal life, angiotensinogen gene expression is negatively regulated by glucocorticoids. This effect is not universal because cortisol increases fetal prothrombin gene expression. (Pediatr Res 30: 256-260, 1991) Abbreviations SSPE, sodium chloride, sodium phosphate, EDTA creases during the last trimester of gestation but has been shown to decrease in the 1st wk after birth (5).Studies in mature rats have demonstrated that multiple factors, including glucocorticoids, can modulate liver angiotensinogen gene expression (6-9). Less is known about regulation of angiotensinogen mRNA levels in the fetus, but it has been suggested that glucocorticoid hormones play an important role in organ maturation and enzyme induction during fetal life (10, 11). In vitro studies with cultured rat fetal hepatocytes (12) have shown that addition of dexamethasone to culture media causes fetal hepatocytes to express adult levels of mRNA for albumin, tyrosine aminotransferase, and transfemn while decreasing the level of a-fetoprotein mRNA. Information about glucocorticoid effects on gene expression in fetal liver in vivo is more limited and differs from results obtained in vitro. Johnson et al. (13) have shown that tyrosine aminotransferase mRNA is not affected by glucocorticoids in near-term fetal rats but that hormone responsiveness develops postnatally.In an effort to determine if glucocorticoids play a role in the expression of liver angiotensinogen gene during fetal life, we studied the effect of cortisol on the hepatic expression of angiotensinogen gene in chronically instrumented fetal sheep. We also compared the e...
ABSTRACT. The renal hemodynamic response to renal arterial infusions of norepinephrine was compared to epinephrine infusions during renal a-adrenoceptor blockade in chronically instrumented and unanesthetized fetal (127-141 days gestation; term 145 days), newborn (6-10 days old), and nonpregnant adult sheep. Infusions of either catecholamines produced renal vasodilation which was of greater magnitude in fetal compared to newborn and adult sheep. Maximal increases in renal blood flow velocity during norepinephrine infusion were 64 f 5% in fetal, 23 f 4% in newborn, and 24 f 7% in adult sheep ( p < 0.001). Extremely high catecholamine levels are observed during fetal stress (1) and during birth (2,3), with the predominant circulating catecholamine being norepinephrine. In contrast, the sympathoadrenal response to stress in adults is associated with significantly lower plasma catecholamine values where epinephrine is the major circulating catecholamine (4). Because the sympathoadrenal system plays an important role in modulating renal hemodynamics ( 3 , knowledge about differences in sympathoadrenal activity during development and its functional role in determining RBF is of interest in perinatal medicine. Little is known about the ontogeny of sympathoadrenal stimulated renal vasodilation. Buckley et al. (6,7) have examined the postnatal development of renal vasodilatory mechanisms in anesthetized piglets (6, 7). Their studies have shown that the Padrenergic vasodilatory mechanism in the renal vascular bed of swine is absent at birth and appears postnatally at 2 wk. However, in chronically instrumented sheep, we have demonstrated during a-adrenoceptor blockade, enhanced renal P-adrenoceptor mediated vasodilator response to renal nerve stimulation (8) and to intrarenal infusions of epinephrine (unpublished observations) in fetal compared to newborn and adult sheep. In contrast, these results differ from dopamine-mediated vasodilator responses which are of considerably smaller magnitude in fetal, newborn, and adult sheep (9).Since levels of plasma catecholamines and of norepinephrine, the predominant circulating catecholamine found during stress, are age dependent, and because norepinephrine and epinephrine differ in their ability to stimulate the vascular P-adrenergic receptor (lo), the present protocol was designed to compare the renal hemodynamic response to renal arterial norepinephrine and epinephrine infusions during renal a-adrenoceptor blockade in chronically instrumented fetal, newborn, and adult sheep. METHODSAnimal preparation and surgical procedures. Fetuses of seven pregnant sheep of Dorset and Suffolk mixed breeding were studied between 127 and 141 days gestation (term was 145 days). Gestational ages were based on the induced ovulation technique as previously described (I 1).Ewes were fasted for 48 h prior to surgery. General anesthesia of the ewe and fetal surgery were performed as previously described (1 1). Briefly, when the ewe was receiving a mixture of 1% halothane. 33% oxvgen. and 66% nitrous oxi...
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