Richard A. Wentworth

A comparative study of cardiovascular, endocrine and behavioural effects of betamethasone and dexamethasone administration to fetal sheep.

1. Chronically instrumented, late‐gestation fetal sheep were prepared to: (1) characterize cardiovascular, endocrine and behavioural effects of fetal treatment with clinical doses of betamethasone and dexamethasone; (2) define specific differences, if any, in the actions of betamethasone and dexamethasone of measured fetal responses; and (3) assess the contribution of changes in peripheral vascular resistance to the glucocorticoid‐induced hypertension. 2. Following baseline, either saline (n = 9), betamethasone (n = 9), or dexamethasone (n = 6) was infused for 48 h in fetal sheep commencing at 125 days of gestation. A pronounced increase in fetal blood pressure occurred following both betamethasone and dexamethasone treatment. The nature and magnitude of this increase was similar following treatment with either glucocorticoid. 3. To address possible mechanisms contributing to the glucocorticoid‐induced fetal hypertension, fetal plasma catecholamine levels and changes in fetal femoral haemodynamics were assessed following fetal glucocorticoid treatment. A fall in fetal plasma noradrenaline and adrenaline concentrations occurred during betamethasone and dexamethasone treatment. In contrast, a progressive femoral vasoconstriction occurred during betamethasone treatment. 4. A modest fall in the incidence of fetal breathing movements occurred during fetal treatment with either betamethasone or dexamethasone. The magnitude of this reduction was similar with treatment of either glucocorticoid. The fall in fetal breathing during betamethasone and dexamethasone treatment was not associated with a fall in the incidence of fetal low voltage electrocortical activity. 5. Our results indicate that prenatal betamethasone and dexamethasone treatment of late‐gestation fetal sheep, in doses similar to those employed clinically, is associated with fetal cardiovascular, endocrine and behavioural effects. Both betamethasone and dexamethasone induce similar increases in fetal blood pressure and similar falls in the incidence of fetal breathing movements. The pronounced betamethasone‐induced fetal hypertension is associated with an increase in fetal femoral vascular resistance.

Blood pressure and heart rate in the ovine fetus: ontogenic changes and effects of fetal adrenalectomy

Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109-114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120-126, 127-133, and 134-140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 μg/min) was infused intravenously in four ADX fetuses from day 7postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 ± 3.2 ng/ml (mean ± SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109-114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120-126, 127-133, and 134-140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 microgram/min) was infused intravenously in four ADX fetuses from day 7 postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 +/- 3.2 ng/ml (mean +/- SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.

Intrauterine asphyxia and the breakdown of physiologic circulatory compensation in fetal sheep

In response to acute hypoxemia, the fetus invokes physiologic compensatory mechanisms that cause a preferential redistribution of the circulation to sustain the brain, heart, and adrenal gland and maintain blood flow to the placenta. These mechanisms are available for a limited time and eventually the fetus is no longer able to maintain preferential perfusion and decompensation occurs. To identify the relationship between hypoxemia with severe acidemia and the breakdown of circulatory compensation, we decreased uterine blood flow in 10 chronically instrumented pregnant sheep. We measured fetal blood gases and pH, arterial and central venous pressures, heart rate, combined ventricular output, and regional blood flow distribution during hypoxemia with severe acidemia and when a fixed-baseline sustained bradycardia (agonal) heart rate pattern developed. Hypoxemia with severe acidemia was characterized by markedly decreased blood flow to most organs; however, the preferential perfusion of the brain, heart, adrenal gland, and placenta was still present. An agonal heart rate pattern was characterized by complete cardiovascular collapse. This study demonstrates that circulatory compensation is present in fetal sheep affected by deficiency of oxygen delivery despite hypoxemia with severe acidemia.

Power spectrum analysis of myometrial electromyogram and intrauterine pressure changes in the pregnant rhesus monkey in late gestation

Various methods have been used to quantify myometrial activity in the pregnant rhesus monkey during the last third of gestation. A precise definition of activity must retain the characteristics of epoch duration, amplitude, and the repetitive frequencies of active epochs. We used Fast Fourier Transform and power spectrum analysis to determine whether the patterns of myometrial contractility consist predominantly of contractions or contractures. This analysis allows quantification of activity represented by each of these patterns of activity. We applied these methods to myometrial electromyogram and intrauterine pressure recordings in pregnant rhesus monkeys to characterize the changes in myometrial activity that occur after surgery, after intravenous indomethacin administration, and when food is withdrawn for 48 hours. We conclude that changes in the frequency pattern of myometrial activity provide important information in relation to labor and delivery contractions.

Dynamics of cardiovascular responses to repeated partial umbilical cord compression in late-gestation sheep fetus

We characterized the detailed hemodynamics of fetal blood pressure, heart rate, common umbilical blood flow, and femoral blood flow responses to partial compression of the umbilical cord and tested the hypothesis that repeated cord compression modulates fetal cardiovascular responses in 10 chronically instrumented fetal sheep at approximately 130 days of gestation. In five fetuses (group I), partial compression of the umbilical cord was induced 12 times, each for 5 min at 15-min intervals. Each cord compression reduced common umbilical blood flow by 50% and produced modest falls in fetal pH (7.33 +/- 0 to 7.29 +/- 0) and arterial PO2 (21.1 +/- 0.2 to 16.8 +/- 0.2 mmHg) and a mild increase in arterial PCO2 (49.9 +/- 0.5 to 54.9 +/- 0.4 mmHg). Sham experiments were performed in five other fetuses (group II). Second-by-second analysis of group I fetal cardiovascular data revealed a clear biphasic response to partial cord compression. Phase I (1st min of cord compression) was characterized by a rapid bradycardia and a rapid femoral vasoconstriction (primary response); phase II (minutes 2-5 of cord compression) was characterized by a delayed bradycardia and a return of femoral vascular resistance toward baseline (secondary response). Repeated cord compression abolished the primary, but not the secondary, cardiovascular responses. These results demonstrate that fetal cardiovascular responses to stress may be modified by preexposure to repeated intrauterine challenges.We characterized the detailed hemodynamics of fetal blood pressure, heart rate, common umbilical blood flow, and femoral blood flow responses to partial compression of the umbilical cord and tested the hypothesis that repeated cord compression modulates fetal cardiovascular responses in 10 chronically instrumented fetal sheep at ∼130 days of gestation. In five fetuses ( group I), partial compression of the umbilical cord was induced 12 times, each for 5 min at 15-min intervals. Each cord compression reduced common umbilical blood flow by 50% and produced modest falls in fetal pH (7.33 ± 0 to 7.29 ± 0) and arterial [Formula: see text] (21.1 ± 0.2 to 16.8 ± 0.2 mmHg) and a mild increase in arterial[Formula: see text] (49.9 ± 0.5 to 54.9 ± 0.4 mmHg). Sham experiments were performed in five other fetuses ( group II). Second-by-second analysis of group I fetal cardiovascular data revealed a clear biphasic response to partial cord compression. Phase I (1st min of cord compression) was characterized by a rapid bradycardia and a rapid femoral vasoconstriction (primary response); phase II ( minutes 2-5of cord compression) was characterized by a delayed bradycardia and a return of femoral vascular resistance toward baseline (secondary response). Repeated cord compression abolished the primary, but not the secondary, cardiovascular responses. These results demonstrate that fetal cardiovascular responses to stress may be modified by preexposure to repeated intrauterine challenges.

Measurement of magnesium absorption in man using stable 26Mg as a tracer.

Abstract The stable isotope 26 Mg was compared to the radioisotope 28 Mg to estimate magnesium absorption in four healthy male subjects confined to a metabolic ward and consuming a constant diet for 146 days. Two isotopes tests were carried out in each subject on days 66 and 109 of the constant-diet period. In test 1, a solution containing 50 mg 26 Mg and 30 μC 28 Mg were taken orally during breakfast. In test 2, 50 mg 26 Mg were administered orally followed three hours later by an i.v. injection of 20 μC 28 Mg. True magnesium absorption was estimated by: (1) oral/i.v. ratios of 28 Mg in plasma and urine, or oral/i.v. 26 Mg/ 28 Mg ratios in urine; (2) the difference between intake and fecal excretion of total dietary magnesium over a period of 10 days, or of a single dose of either isotope, corrected for endogenous fecal magnesium. Estimates made in individual subjects by different procedures based on data derived solely by use of 28 Mg varied as much as estimates made by comparable procedures with data derived from either 26 Mg or 28 Mg. Measurements of 26 Mg enrichment in urine and feces were made by neutron activation analysis which loses precision at enrichment levels below 10% above natural abundance. With the doses used in this investigation only fecal samples collected within 3–4 days and urine samples taken wihin 2–24 h contained adequately detectable 26 Mg enrichment levels. Despite this limitation, 26 Mg significantly expands the scope of investigation of magnesium absorption in man beyond that possible with the short lived 28 Mg alone.

Intrauterine growth retardation and the circulatory responses to acute hypoxemia in fetal sheep

Intrauterine growth retardation has been produced experimentally by umbilical placental embolization for 9 days (early intrauterine growth retardation) in pregnant sheep. Fetuses with early intrauterine growth retardation had a 20% decrease in mean body weight and 33% decrease in placental blood flow. However, the regional blood flow distribution was not significantly different at rest between the embolized and normally grown fetuses despite the 39% decrease in fetal arterial oxygen content. The purpose of this study was to determine the circulatory responses to acute hypoxemic stress in the early development of intrauterine growth retardation. We found that the regional blood flow distribution was not significantly different during imposed acute hypoxemia between the seven fetuses with early intrauterine growth retardation and seven nonembolized normally grown fetuses. We conclude that growth-retarded fetuses are able to meet basal metabolic oxygen requirements and to respond normally to imposed acute hypoxemia until the placental circulatory reserve capacity is depleted.

Stable 26Mgin as an In Vivo Tracer Investigation of Magnesium Utilization

A procedure using 26Mg as an in vivo tracer has been developed. Enrichment of biological samples containing 26Mg was measured by neutron activation following acid digestion and solvent extraction to remove the interfering nuclides 37Cl, 55Mn and other heavy metals. Special counting procedures minimized interference by 41Ar and 28A1 during neutron activation analysis. Interference of 24Na was minimized by mathematical channel by channel spectrum stripping. With current techniques, the lower limit of enrichment with 26Mg measurable with precision is 20% above the natural abundance of 11·24%. Good agreement was obtained of 26Mg and 28Mg retentions and estimates of the biological half-life when the two isotopes were administered simultaneously to rats either orally or by intraperitoneal injection.