A vasopressin antagonist blocks the norepinephrine and epinephrine responses to hemorrhage in the fetus.

In 8 chronically cannulated fetal lambs between 119 and 127 days gestation the resting plasma norepinephrine concentration was 528 +/- 77 pg X ml-1 and the resting plasma epinephrine concentration 159 +/- 42 pg X ml-1. Hemorrhage of 20% of estimated blood volume at 2% per min produced a 2.1-fold increase in plasma norepinephrine levels and a 3.4-fold increase in plasma epinephrine levels when the animals were pretreated with an injection of saline (1 ml). Plasma catecholamine levels returned toward control values following return of the shed blood. In contrast, hemorrhage of these animals following pretreatment with an antagonist of the pressor effect of vasopressin did not cause an increase in fetal plasma catecholamine levels. Thus, vasopressin may mediate the sympathetic responses to volume depletion in the fetus.

Effects of phenylephrine induced increase in arterial pressure and closure of the ductus arteriosus on the secretion of atrial natriuretic peptide (ANP) and renin in the ovine fetus.

Although atrial natriuretic peptide (ANP) has been detected in the plasma of late gestation fetal sheep, stimuli that control its secretion and its function in regulating fluid volume are unclear. To determine stimuli that increase ANP secretion and to ascertain whether the response is a function of gestation we studied 20 chronically cannulated fetal sheep. The fetuses were divided into 3 groups; Group I (age range 118-129 days), Group II (age range 129-141 days) and Group III (age range 127-137 days) gestation. Arterial pressure was increased to within a physiologic range by infusing phenylephrine at 6 micrograms/min at 0.1 ml/min into the inferior vena cava of the fetus (Groups I and II). Corrected for body weight fetuses in Group I received 2 micrograms/kg/min whereas fetuses in Group II received 1.66 micrograms/kg/min. In the fetuses in Group III preload to the right side of the heart was increased by inflating an occluder cuff was placed around the ductus arteriosus. Systemic mean arterial pressure (MAP) increased significantly in fetuses in Groups I and II. Plasma ANP concentrations increased significantly in all fetuses. Plasma Renin Activity (PRA) decreased significantly in the fetuses in Group II. These results suggest that phenylephrine infusion and closure of the ductus arteriosus in utero increase circulating ANP in fetal sheep.

By 95 days of gestation CRF increases plasma ACTH and cortisol in ovine fetuses.

Plasma adrenocorticotropin (ACTH) and cortisol (F) responses to 15-min intravenous infusions of synthetic ovine corticotropin-releasing factor (CRF) were measured by radioimmunoassay in three groups of chronically cannulated ovine fetuses. Fetuses (n = 7) in group I were 107 +/- 2 days gestation (0.72 G) and fetuses (n = 7) in group II were 126 +/- 2 days gestation (0.86 G). Group III fetuses (n = 5) were studied at 5-day intervals during the last 2 wk of gestation. Resting fetal plasma ACTH levels were not significantly different among the three experimental groups. Infusions of CRF (50 ng X kg-1 X min-1) provided similar, significant increases in fetal plasma ACTH concentrations in the three groups. In the young fetuses (group I) the ACTH responses to 500 ng X kg-1 X min-1 infusions of CRF were greater than responses to 50 ng X kg-1 X min-1 infusions P less than 0.001. In group II both doses of CRF produced equivalent increases in ACTH that were comparable with the responses to 50 ng X kg-1 X min-1 infusions in Group I. This suggests that fetal ACTH responsiveness to large doses of CRF decreases between 0.72 and 0.86 G. Resting fetal plasma F levels increased during gestation (P less than 0.01). There was an F response (P less than 0.001) to CRF in all groups with greater responses observed in the older fetuses. This suggests that fetal adrenal responsiveness to ACTH or other peptides released by CRF increases during gestation.

By 94 days of gestation plasma cortisol increases block ACTH response to hypotension in lamb fetuses.

By use of a crossover design, we studied the effects of increasing plasma cortisol concentration on ACTH responses to a standardized stress in 14 lamb fetuses between 94 and 108 days gestation. On a random basis we assigned the animals into two groups of seven. Animals in groups I and II received infusions of cortisol (5 and 1 microgram/min, respectively) or saline for 4 h. After the cortisol or saline pretreatment, we reduced arterial pressure approximately 40-50% in both groups of animals with nitroprusside. After saline pretreatment, hypotension in the group I animals produced an increase in the fetal plasma ACTH from 15 +/- 3 to 200 +/- 20 pg/ml (P less than 0.001), and in the group II animals pretreated with saline plasma ACTH increased from 21 +/- 4 to 141 +/- 19 pg/ml (P less than 0.001) with hypotension. Cortisol pretreatment elevated fetal plasma cortisol levels from 7 +/- 3 to 36 +/- 5 ng/ml in group I and from 8 +/- 4 to 20 +/- 2 ng/ml in group II. The ACTH response to hypotension in both groups was abolished by the cortisol pretreatment. We conclude that by 94 days gestation increases in plasma cortisol within a physiological range block ACTH responses to hypotension in lamb fetuses.

Renal and cardiovascular effects of atrial natriuretic peptide in fetal sheep.

In the adult, atrial natriuretic peptide (ANP) has been postulated to regulate renal and cardiovascular function both when blood volume is expanded and when atrial pressure is increased. In late gestation fetal sheep, ANP has been detected in plasma concentrations higher than in pregnant adults; however, its function in the fetus is unclear. To assess the role of ANP in mediating changes in combined ventricular output and organ blood flow, GFR, urine flow rate, and urinary sodium excretion, we studied 11 chronically cannulated fetal sheep at 126 to 131 d gestation (term 145 d). We infused ANP in doses of 27 +/- 4 and 55 +/- 8 ng/kg/min into nine of the 11 fetuses and vehicle only into the remaining two fetuses. ANP increased hematocrit, Hb, and plasma protein concentrations, which suggests that blood volume decreased. Combined ventricular output and umbilical-placental blood flow, measured by the radionuclide-labeled microsphere technique, decreased from 458 +/- 158 to 344 +/- 59 ml/min/kg and 210 +/- 85 to 144 +/- 31 ml/min/kg, respectively and the calculated umbilical-placental vascular resistance increased from 0.20 +/- 0.10 to 0.32 +/- 0.09 mm Hg/ml/min/kg during the infusion of the high ANP dose. Blood flow to the gastrointestinal tract decreased with the high dose of ANP but blood flow to all other organs, mean arterial blood pressure, and heart rate did not change significantly. The effects of ANP on fetal renal function were minimal. Thus, ANP may play a role in maintaining fluid homeostasis in the fetus through its ability to decrease blood volume and to decrease combined ventricular output and umbilical-placental blood flow.

Catecholamine responses in fetal lambs subjected to hemorrhage.

We monitored plasma epinephrine and norepinephrine responses to hemorrhage of 20% of estimated blood volume in 11 chronically instrumented, unanesthetized fetal lambs. In addition, we performed control experiments--blood sampling but no hemorrhage--in five fetuses. Arterial blood gases, pH, mean arterial pressures, heart rates, and plasma norepinephrine and epinephrine levels were similar in both groups in the resting state. Arterial blood gases and pH did not change significantly during the experimental period in either group. Mean arterial pressure, heart rate, and plasma norepinephrine and epinephrine levels did not change in the control group during the experimental period. Hemorrhage was associated with a significant decrease in fetal mean arterial pressure, 39.8 +/- 1.2 to 29.6 +/- 2.1 mm Hg, and heart rate, 186 +/- 8 to 146 +/- 6 bpm (p less than 0.01 in both cases). There was a significant increase in plasma norepinephrine, 664.9 +/- 91.6 to 1384.8 +/- 216.7 pg/ml (p less than 0.02) and epinephrine, 224.6 +/- 43.6 to 681.7 +/- 199.0 pg/ml (p less than 0.01) with hemorrhage. These results demonstrate significant catecholamine responses to hypovolemia in the fetal lamb.

Cortisol infusion blocks adrenocorticotropic hormone but not vasopressin responses to hypotension in fetal lambs.

In eight experiments in which a paired crossover design was used, we studied the ability of physiologic levels of cortisol to block adrenocorticotropic hormone (ACTH) and vasopressin responses to hypotension in fetal lambs. On different days, each fetus received a 4-hour infusion of cortisol or ethanol-saline solution vehicle, and then hypotension was induced with nitroprusside. Mean levels of ACTH before manipulation were 20 +/- 10 pg/ml and 18 +/- pg/ml in the saline solution- and cortisol-treated animals, respectively. Mean values of ACTH increased significantly to 70, 88, and 127 pg/ml at 2.5, 5, and 10 minutes of hypotension after pretreatment with saline solution. Cortisol pretreatment abolished the fetal ACTH response to hypotension. Mean levels of vasopressin during the control period were similar in the two groups of animals (5.7 +/- 1.5 pg/ml versus 5.9 +/- 1.3 pg/ml) and rose to comparable levels (69.4 +/- 15.6 pg/ml versus 65.2 +/- 7.7 pg/ml) during hypotension. Thus, increases in plasma cortisol levels within a physiologic range can suppress hypotension-induced ACTH but not vasopressin release in the fetus.

Vasopressin is important for restoring cardiovascular homeostasis in fetal lambs subjected to hemorrhage.

To determine if the posterior pituitary hormone vasopressin is important for maintaining fetal cardiovascular homeostasis during hypovolemic stress, in seven chronically catheterized fetal lambs we induced hemorrhage of 20% of estimated blood volume in the presence and in the absence of a potent antagonist to the pressor effects of vasopressin. The study was a paired crossover design with at least 48 hours separating experiments in the same animal. Injection of the vasopressin antagonist did not alter basal fetal heart rate or arterial blood pressure, but hemorrhage of 2% of estimated fetal blood volume per minute for 10 minutes produced a greater fall in blood pressure (13 +/- 2 versus 10 +/- 2 torr, p less than 0.05) when the blocker was present than when it was absent. Arterial blood pressure remained below control levels longer following hemorrhage when the fetuses were pretreated with the antagonist (49.7 +/- 6 versus 26.6 +/- 6 minutes, p less than 0.01), and the integrated fall in arterial blood pressure with hemorrhage was greatest (283 +/- 53 versus 169 +/- 57 mm Hg . min p less than 0.01) when the blocker was used. The fall in heart rate following hemorrhage was similar with and without blocker pretreatment. These results indicate that vasopressin plays a physiologic role in blood pressure regulation in fetal lambs during periods of hypovolemia.

Corticotropin-releasing factor--induced adrenocorticotropic hormone release in the sheep fetus: blockade by cortisol.

We administered intravenous injections of synthetic ovine corticotropin-releasing factor to chronically cannulated sheep fetuses and monitored fetal plasma adrenocorticotropic hormone and cortisol concentrations. The three doses of corticotropin-releasing factor used (10, 100, or 1000 ng X kg-1) increased fetal plasma adrenocorticotropic hormone; fetal plasma cortisol levels rose with the highest dose of corticotropin-releasing factor. Administration of corticotropin-releasing factor at these concentrations did not change fetal heart rate or blood pressure. Elevation of fetal plasma cortisol levels to 40 to 80 ng X ml-1 by infusions of the steroid blocked the adrenocorticotropic hormone responses to all three doses of corticotropin-releasing factor. These data indicate that corticotropin-releasing factor can increase plasma adrenocorticotropic hormone concentrations in the late-gestation fetus and that these increases can be blocked by elevations in fetal plasma cortisol levels within a physiologic range. This suggests that cortisol modulates adrenocorticotropic hormone release by the fetal pituitary gland late in gestation.