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Biomedical subjects

A D Stevens

Publications and source records attributed to A D Stevens.

At least 19 recordsLinked to original sources

Effects of intravenous infusions of noradrenaline into the pregnant ewe on uterine blood flow, fetal renal function, and lung liquid flow.

To determine the effects on the fetus of high maternal levels of noradrenaline, experiments were carried out in 17 pregnant ewes (123-137 days gestation). Intravenous infusion of 40 mg/min of norepinephrine to the ewe for 1.5 h increased maternal arterial pressure and significantly decreased maternal placental blood flow (p < 0.05). Fetal arterial pressure did not change, but fetal arterial PO2 fell (p < 0.01) and PCO2 rose (p < 0.01). Fetal urine flow fell and osmolality rose (p < 0.01), fetal lung liquid flow and osmolar excretion fell (p < 0.01, p < 0.05, respectively), and the lung sodium:potassium ratio changed. These effects of high levels of maternal noradrenaline were transient, i.e., 2.5 h after the infusion of noradrenaline had finished, fetal urine flow and lung liquid flow had both returned to control values and fetal PCO2 was significantly depressed relative to control values (p < 0.01). It is concluded that high levels of maternal catecholamines reduce placental blood flow and cause small changes in fetal oxygenation. These changes are sufficient to transiently affect fetal water excretion and to reduce lung liquid flow.

Animals

The effect of fetal lung inflation on fetal heart rate.

The effect on the fetal heart by inflating the fetal lungs with liquid or air while the animal was being maintained in utero by its normal placental circulation was investigated in 10 healthy, chronically catheterized fetal sheep of gestational age 126-137 days. It was found that initial attempts to inflate the lungs with volumes of air as small as 10 ml (i.e., with less than a predicted normal tidal volume) caused abrupt, powerful slowing of the fetal heart with, usually, an associated hypotension. Inflations with similarly small volumes of saline were ineffective. Atropine pretreatment abolished the cardiac slowing caused by the air inflations, indicating the operation of a neural reflex. An analysis of the pressure changes induced by the air and liquid inflations in airway, intrathoracic and intra-amniotic pressures showed that the cardiac slowing was primarily related to the level of mechanical stress applied across the fetal airway.

Air

Reconstruction of images from radiofrequency electron paramagnetic resonance spectra.

This paper discusses methods for obtaining image reconstructions from electron paramagnetic resonance (EPR) spectra which constitute object projections. An automatic baselining technique is described which treats each spectrum consistently; rotating the non-horizontal baselines which are caused by stray magnetic effects onto the horizontal axis. The convolved backprojection method is described for both two- and three-dimensional reconstruction and the effect of cut-off frequency on the reconstruction is illustrated. A slower, indirect, iterative method, which does a non-linear fit to the projection data, is shown to give a far smoother reconstructed image when the method of maximum entropy is used to determine the value of the final residual sum of squares. Although this requires more computing time than the convolved backprojection method, it is more flexible and overcomes the problem of numerical instability encountered in deconvolution. Images from phantom samples in vitro are discussed. The spectral data for these have been accumulated quickly and have a low signal-to-noise ratio. The results show that as few as 16 spectra can still be processed to give an image. Artifacts in the image due to a small number of projections using the convolved backprojection reconstruction method can be removed by applying a threshold, i.e. only plotting contours higher than a given value. These artifacts are not present in an image which has been reconstructed by the maximum entropy technique. At present these techniques are being applied directly to in vivo studies.

Electron Spin Resonance Spectroscopy

Technical note: a moderately sized resonator/surface coil for radiofrequency electron paramagnetic resonance spectroscopy and imaging in vivo.

A resonator for the radiofrequency (250 MHz) electron paramagnetic resonance spectroscopy (EPRS) and imaging (EPRI) of biological samples is described. It has been designed for use with a 0.5 m bore EPR spectrometer. It is of the double split-ring type, 65 mm in diameter and 100 mm in length, and is equipped with a tuning-lock mechanism for fixed frequency operation. It can be used in the whole-body mode for small animals and as a surface coil for larger samples. The extent of sensitivity in the latter mode is ca. 20 mm. Larger resonators are being developed for whole-body human studies. A phase-locked crystal oscillator frequency source with high spectral purity is used to minimize noise demodulation and automatic tuning; coupling and phase controls have been included to compensate for motional artefacts. For purely aqueous nitroxides, the minimum detectable concentration is ca. 4 x 10(-7) M using an internal sample 100 ml in volume. Sensitivity in the surface coil mode is discussed and spectra from phantoms using both physiological saline and a human volunteer to induce realistic conduction losses are shown.

Cyclic N-Oxides

The effects of a converting enzyme inhibitor (captopril) and angiotensin II on fetal renal function.

1. Renal function was studied in chronically catheterized fetal sheep (119-128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) inhibitor, captopril, which crosses the placenta and blocks the fetal renin angiotensin system. 2. An i.v. dose of 15 mg (about 319 micrograms kg-1) of captopril to salt-replete ewes followed by an infusion to the ewe of 6 mg h-1 (about 128 micrograms kg-1 h-1) caused a fall in fetal arterial pressure (P < 0.01), and a rise in fetal renal blood flow (RBF) from 67.9 +/- 5.6 to 84.9 +/- 8.3 ml min-1 (mean +/- s.e. mean) (P < 0.05). Renal vascular resistance and glomerular filtration rate (GFR) fell (P < 0.01); fetal urine flow (P < 0.01); fetal urine flow (P < 0.01) and sodium excretion declined (P < 0.05). 3. Ewes were treated for the next 2 days with 15 mg captopril twice daily. On the 4th day, 15 mg was given to the ewe and fetal renal function studied for 2 h during the infusion of captopril (6 mg h-1) to the ewe. Of the 9 surviving fetuses, 3 were anuric and 3 had low urine flow rates. When 6 micrograms kg-1 h-1 of angiotensin II was infused directly into the fetus RBF fell from 69 +/- 10.1 ml min-1 to 31 +/- 13.9 ml min-1, GFR rose (P < 0.05) and urine flow (P < 0.01) and sodium excretion increased in all fetuses. 4. It is concluded that the small fall in fetal arterial pressure partly contributed to the fall in fetal GFR but in addition, efferent arteriolar tone fell so that the filtration pressure fell further. Thus maintenance of fetal renal function depends on the integrity of the fetal renin angiotensin system. These findings explain why use of ACE inhibitors in human pregnancy is associated with neonatal anuria.

Angiotensin II

Acute effects of captopril, an angiotensin-converting enzyme inhibitor, on the pregnant ewe and fetus.

After control measurements had been made, 15 chronically catheterized pregnant ewes (gestational age 123-141 days) were given 15 mg of captopril intravenously followed by an infusion of 6 mg/h. These doses blocked the pressor responses of both ewes and fetuses to 5 micrograms of angiotensin I. After captopril, maternal mean arterial pressure fell from 94 +/- 3.5 to 88 +/- 3.6 (SE) mmHg (P less than 0.0001) and pulse interval fell (P = 0.008). Maternal flow to the cotyledons fell from 766 +/- 118 to 525 +/- 77 ml/min (P = 0.002), as did flow to the remainder of the maternal placenta, i.e., the caruncles and their underlying myoendometrium (control flow 188 +/- 35 ml/min, flow 10-15 min after captopril 166 +/- 36.1 ml/min; P = 0.021). Flow to the rest of the myometrium did not change. Fetal arterial pressure fell from 46.9 +/- 1.6 to 44.1 +/- 1.6 mmHg (P less than 0.009), and fetal placental blood flow fell from 639.9 +/- 93.2 to 413.1 +/- 53.9 ml/min (P = 0.025). Flow to the fetal membranes declined also, from 53.2 +/- 6.5 to 35.6 +/- 3.3 ml/min (P less than 0.005). Maternal and fetal renal blood flows and fetal adrenal blood flows were unchanged. Fetal arterial PO2 was initially 19.5 +/- 0.8 mmHg; after captopril, it was 17.7 +/- 0.9 mmHg (P = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors

Changes in fetal and maternal plasma protein concentration and colloid osmotic pressure with gestation.

In pregnant ewes, plasma protein levels over the gestation age range of 58-141 days fell progressively (r = -0.332, P less than 0.05, n = 36) but colloid osmotic pressure (COP, mmHg) did not change significantly. In fetal sheep carried by these ewes, plasma protein levels increased with age (r = 0.85, P less than 0.00001, n = 32). COP also rose (r = 0.8, P less than 0.00001, n = 23). Since maternal COP did not change and fetal COP increased, the net transplacental COP gradient between mother and fetus decreased with increasing age (r = -0.589, P less than 0.004, n = 22). Fetal plasma protein levels can be used to calculate fetal COP while maternal plasma protein levels cannot be used to calculate maternal COP.

Animals

Effects of reduced uterine blood flow on fetal cardiovascular, renal, and lung function.

Uterine blood flow (UBF) was reduced for 1 h by partially occluding the maternal aorta below the renal arteries in seven pregnant ewes (gestation age 126-134 days). Fetuses became hypoxic, acidemic, and hypercapnic. They developed hypertension (P less than 0.005) and a bradycardia (P less than 0.05). During restricted UBF, fetal hematocrit (Hct) rose (P less than 0.005) and blood volume fell in five of seven fetuses. After release of constriction, fetal Hct fell, and blood volume rose by 7.5 +/- 3.26% (P less than 0.05) relative to control. During reduced UBF, lung liquid and urine flow rates fell (P less than 0.025 and P less than 0.05, respectively). After the occluder was released, Na excretion (which did not fall significantly during reduced UBF) increased (P less than 0.05), and fractional reabsorption of Na fell (P less than 0.05). Changes in fetal blood volume (FBV) were directly related to changes in maternal lower body flow (r = 0.47, P = 0.01, n = 33), and changes in fetal Hct were inversely related to maternal flow (r = -0.635, P = 0.001). Fetal urinary Na excretion per kilogram body weight was directly related to FBV per kilogram (r = 0.44, P = 0.005, n = 40), whereas fractional reabsorption of Na was inversely related to FBV per kilogram body wt (r = 0.48, P less than 0.002, n = 39). It is concluded that reductions in UBF cause fetal hypoxemia and acidemia, which lead to changes in fetal cardiovascular function and in FBV.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Effect of hypoxia and catecholamines on the habituation rates of chronically catheterized ovine fetuses.

Integrated electromyographic, electrocortical (ECoG) and electro-ocular activity were recorded in 13 chronically prepared fetal sheep (130-145 days). Fetal movements and the rate of habituation to repeated suffusions of cold saline against the fetal skin were recorded. Experiments were repeated during an intravenous infusion of noradrenaline to the fetus (0.4 microgram/kg estimated fetal weight/min) and during hypoxia induced by altering the oxygen content of the inspired air to the ewe to 9%. Repeated stimulation with cold saline resulted in an increase in fetal movements (p = 0.009). The number of stimuli for habituation was similar in high-voltage and in low-voltage ECoG activity. The rate of fetal habituation was significantly faster during the infusion of noradrenaline compared with control measurements (p = 0.009). During hypoxia, the number of spontaneous fetal movements prior to stimulation decreased (p = 0.002). Habituation rates were also faster during hypoxemia compared with control measurements (p = 0.003). These findings may help to explain the rapid habituation rates seen in some human fetuses in at 'at risk' pregnancies.

Acoustic Stimulation

Measurement of fetal responses to vibroacoustic stimuli. Habituation in fetal sheep.

Electrocortical (ECoG) and integrated electromyographic (EMG) activity was recorded in 6 chronically prepared fetal sheep (132-145 days). Recording were made in fetuses prior to and during repeated vibroacoustic stimulation. In the undisturbed fetus, two patterns of ECoG activity were apparent; high (HV) and low voltage (LV). The fetus responded to this broad spectrum stimulus during both LV and HV ECoG activity. In 18 of the 20 experiments, repeated stimulation was not associated with a change in the background ECoG activity. All fetuses responded at least once to the stimulus. Habituation of the EMG response was observed during both HV and LV ECoG activity. The rate of habituation was independent of the background ECoG activity and was unchanged when experiments were repeated at intervals of more than 3 days. These results show that fetal sheep also respond to vibroacoustic stimulation and with repetition habituation occurs.

Acoustic Stimulation

The effects of frusemide, saralasin and hypotension on fetal plasma renin activity and on fetal renal function.

1. In eleven chronically catheterized fetal sheep aged 124-142 days, hypotension caused by infusion of sodium nitroprusside (1.6-3.3 mg/h) and competitive antagonism of angiotensin II by saralasin (3.3 mg/h) both caused a fall in fetal urine flow (P less than 0.02 and P less than 0.05, respectively), and in sodium excretion (P less than 0.05 and P less than 0.01) because they both caused a fall in glomerular filtration rate (G.F.R., P less than 0.02 and P less than 0.01). Neither hypotension nor saralasin had any significant effect on fractional sodium reabsorption. Saralasin only caused a significant fall in systolic pressure (P = 0.05) while infusion of sodium nitroprusside caused a fall in both systolic and diastolic pressure (P less than 0.005 and P less than 0.02). 2. Frusemide (6 mg I.V) caused a marked natriuresis and diuresis (F = 24.9, P less than 0.005 and F = 30.5, P less than 0.005). This effect was maximal within 30 min. There was no change in fetal G.F.R. and there was a significant decrease in the fraction of the filtered sodium load that was reabsorbed (F = 10.44, P less than 0.0025). Fetal mean plasma renin activity (p.r.a.) rose progressively throughout (F = 9.3, P less than 0.005). When frusemide was given to fetal sheep which were hypotensive because they were infused with sodium nitroprusside, it still caused a diuresis (F = 5.73, P less than 0.025) and the fraction of the filtered sodium load that was reabsorbed decreased (F = 4.06, P less than 0.05) to a similar extent to that seen in animals given frusemide alone. On the other hand, frusemide was ineffective as a diuretic i.e. it had no effect on fractional sodium reabsorption, when given to fetal sheep which were infused with saralasin. 3. Injection of frusemide was associated with a significant rise in the diastolic pressures of hypotensive fetuses (P less than 0.05). Furthermore, when the infusion of saralasin was terminated 1.5 h after frusemide injection, blood pressure rose significantly (F = 11.19, P less than 0.0005 for systolic pressure and F = 7.15, P less than 0.005 for diastolic pressure) and p.r.a. fell (F = 4.78, P less than 0.025). 4. It is concluded that the fetal renin-angiotensin system can play a significant role in regulation of fetal blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Effect on maternal and fetal renal function and plasma renin activity of a high salt intake by the ewe.

The effect on renal function of replacing maternal drinking water with a solution containing 0.17 M NaCl was studied in 9 ewes and their chronically catheterised fetuses over a period of 9 days. Maternal sodium intake increased from control values of 2.19 +/- 0.09 mmol/h to 44.3 +/- 7.4 (P less than 0.001) and 46.3 +/- 6.5 mmol/h (P less than 0.001) on the 3rd and 6th days of salt ingestion. Maternal plasma sodium levels were not affected, but the urinary sodium/potassium ratio increased from 0.15 +/- 0.07 to 2.26 +/- 0.34 (P less than 0.001) after 6 days and plasma renin activity fell from 2.87 +/- 0.76 to 1.00 +/- 0.25 ng/ml per h (P less than 0.05). The changes in maternal sodium intake had no effect on fetal plasma sodium levels nor on fetal plasma renin activity. Sodium excretion and fetal urinary sodium/potassium ratio did not change. However, 3 days after the ewes returned to drinking water fetal plasma renin activity was significantly higher than it was prior to maternal ingestion of 0.17 M NaCl. Fetal plasma renin activity was inversely related to fetal plasma sodium levels (P less than 0.01). The results show that changes in maternal sodium intake had no long term effect on fetal plasma sodium levels nor on fetal renal sodium excretion. The fall in maternal plasma renin activity in the absence of any change in the fetal renin activity, indicates that the fetal renin angiotensin system is controlled by factors other than those influencing the maternal renin angiotensin system. Since fetal urinary sodium/potassium ratios remained unchanged it would suggest that fetal sodium excretion is not influenced by maternal levels of aldosterone.

Animals

Measurement of net transplacental transfer of fluid to the fetal sheep.

If fetal drinking activity is prevented and it is assumed that in the latter third of gestation the fetus is capable of maintaining itself in fluid balance, then the net amount of fluid gained across the placenta by the fetus is equal to the amount of fluid lost from the fetus, by routes other than the placenta, plus fluid deposited in growing tissues minus the amount of water produced as a result of oxidative metabolism. Net transplacental transfer of fluid to the fetus over a 3 h period was measured in eight chronically catheterized fetal sheep in which drinking activity was prevented by ligating the oesophagus. Urine and lung liquid flow rates were measured. In the latter third of gestation, these are the only significant sources of fluid loss from these fetuses during the 3 h experimental period. Water produced as a result of oxidative metabolism was calculated, as was the amount of fluid deposited in growing tissues during the course of the experiment. The weight of the fetus at the beginning of the experiment and the change in weight that occurred during the experiment was calculated by measuring the weight of the fetus at death (within 30 h) and applying an equation which describes the body weight-gestation age relationship for merino sheep. Net transplacental fluid transfer was 0.40 +/- 0.09 ml min-1 kg-1 (range 0.30-0.54 ml min-1 kg-1). Fetal urine flow rate averaged 0.30 +/- 0.11 ml min-1 kg-1. It was 72.8 +/- 10.0% of the volumes used to calculate net transplacental fluid transfer to the fetus. Lung liquid flow rate was 0.079 +/- 0.039 ml min-1 kg-1. It was 20.2 +/- 9.2% of the volumes used to calculate net fluid intake. The amount of fluid deposited as a result of tissue growth was 0.023 +/- 0.001 ml min-1 kg-1; it was 5.94 +/- 1.1% of the volumes used in the equation, while the production of water as a result of metabolism was 3.9 X 10(-3) ml min-1 kg-1 (Conrad & Faber, 1977) and constituted 1.01 +/- 0.22% of the volumes used in the equation. This method of measuring net transplacental fluid transfer to the fetus can be used to measure fetal fluid intake over relatively short periods of time. It also means that the effects of disturbances in maternal fluid and electrolyte balance on fluid transfer to the fetus can be studied and quantitated.

Animals

The effect of maternal fluid intake on the volume and composition of fetal urine.

The effects on fetal renal function of restricting maternal water intake to 1 l/day for 6 days was investigated in 7 chronically-catheterized fetuses (gestation age 118-131 days). Restriction of water intake caused a significant decrease in maternal urine flow rate and significant increases in maternal plasma and urinary osmolality. Fetal renal function was investigated on the third and sixth days of the period of restricted maternal intake of water. Urine flow rate from the fetus was depressed significantly, and urinary osmolality increased significantly. The glomerular filtration rate remained unchanged, and free water clearance was decreased. These changes indicate increased water reabsorption in the distal parts of the nephron, probably consequent upon increased circulating levels of antidiuretic hormone. In 3 fetuses whose mothers subsequently had free access to water, these changes in urine flow rate and free water clearance that occurred during water restriction were reversed. There was an inverse correlation between maternal plasma osmolality and fetal free water clearance corrected for glomerular filtration rate. It is concluded that when water intake by a pregnant animal is restricted, the availability of water to the fetus is reduced and fetal sheep respond by producing a concentrated urine.

Animals

Changes in fetal renal function in response to infusions of a hyperosmotic solution of mannitol to the ewe.

In six pregnant ewes a reduction in transplacental water transfer was produced by increasing maternal osmolality (by infusion of 180 g of mannitol in 500 ml of 0.15 M-sodium chloride) and the fetal renal responses to this reduction in water transfer were studied. These responses were compared with the renal responses of five other chronically catheterized fetal lambs whose mothers received I.V. infusions of 500 ml of 0.15 M-sodium chloride. Intravenous infusion of 500 ml of 0.15 M-sodium chloride to the ewe produced no changes in fetal plasma sodium, potassium or plasma renin activity and had no effect on fetal renal function. After I.V. infusion of mannitol to the ewe, fetal urinary flow rate fell from control levels of 0.69 +/- 0.12 ml/min to 0.32 +/- 0.04 ml/min (S.E. of mean, P less than 0.006). This fall in urinary flow rate was due to increased water reabsorption because there was no change in glomerular filtration rate and osmolar clearance. Fetal urinary sodium excretion increased from 16.2 +/- 2.0 mumol/min, to 34.2 +/- 6.9 mumol/min (S.E. of mean, P less than 0.04). This increase in fetal urinary sodium excretion was due to a fall in the fractional reabsorption of sodium which was related to this rise in fetal plasma sodium levels that occurred following infusion of mannitol to the ewe. The increases in fetal plasma sodium levels were also associated with reductions in fetal plasma renin activity.

Animals

The relationship between plasma renin activity and renal electrolyte excretion in the fetal sheep.

In eight fetal sheep the factors influencing renal sodium excretion were determined and related to the activity of the renin-angiotensin system. There was a direct relationship between glomerular filtration rate (GFR) and the amount of sodium reabsorbed (P less than 0.001) suggesting that glomerular tubular balance plays an important role in regulation of fetal sodium excretion. There was also a direct relationship between GFR and urinary sodium excretion (P less than 0.05). Since the percentage of the filtered sodium load that was reabsorbed was inversely related to the urinary Na/K ratio, (P less 0.001), the distal convoluted tubule is actively involved in the regulation of renal sodium excretion. There was no relationship between plasma renin activity and plasma sodium, and plasma osmolality or mean arterial pressure. There was however an inverse relationship between urinary sodium excretion and plasma renin activity, similar to that seen in adult animals (Vander & Miller, 1964) and between log plasma renin activity and GFR (P less than 0.001). These experiments do not distinguish between a possible effect of angiotensin on GFR and hence renal sodium excretion, and the possible effects of a variable GFR on distal tubular sodium delivery and hence renin secretion. However they do show that the fetal renin-angiotensin system like the adult renin-angiotensin system is closely linked to those renal factors that influence renal sodium excretion.

Animals