Stevens Ad

The action of angiotensin II on the baroreflex response of the conscious ewe and the conscious fetus.

1. In conscious non‐pregnant and pregnant ewes and in chronic fetal lamb preparations, the beat by beat relationship between pulse interval and systolic pressure was studied during acute elevations in arterial pressure induced by phenylephrine. Baroreflex sensitivity, which was defined as the slope of the pressure‐pulse interval relationship when phenylephrine was used to raise pressure, was abolished by atropine and increased by propranolol. Baroreflex sensitivity was less in pregnant ewes and in foetal lambs compared with non‐pregnant ewes. 2. These findings suggest that the vagus nerve is responsible for the reflex bradycardia that occurs in the foetus and the ewe when arterial pressure is increased. 3. In both fetal and adult sheep, actue hypertension due to I.V. injection of angiotensin II was not associated with a consistent and progressive bradycardia, such as was seen with acute hypertension caused by phenylephrine. Angiotensin II has no direct chronotropic effect on heart rate in either the adult or the fetus. 4. No linear relationship between arterial pressure and pulse interval was seen when angiotensin II was used to raise pressure in sheep which were treated with propranolol. Therefore the lack of cardiac slowing with pressor doses of angiotensin II was not due to concomitant activation of the sympathoadrenal system. 5. It is concluded that in both fetal and adult sheep angiotensin II reduces the increase in vagal tone which is responsible for slowing of heart rate in response to acute rises in arterial pressure.

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 μg kg−1) of Captopril to salt‐replete ewes followed by an infusion to the ewe of 6 mg h−1 (about 128 μg 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) 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 μg 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.

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.

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.

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)

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.

Effects of one-clip, one-kidney hypertension in chronically catheterized pregnant ewes.

1. Hypertension secondary to renal disease was studied in non‐pregnant and pregnant ewes to determine whether there were any changes in arterial pressure and the distribution of cardiac output and, in particular, whether uteroplacental blood flow was affected.

The effects of long-term infusions of angiotensin II into the pregnant ewe on uterine blood flow and on the fetus.

The effects of intravenous (i.v.) infusions of 62.5 microg/h of angiotensin II (Ang II) on maternal arterial pressure (MMAP), cardiac output (CO), and uteroplacental blood flow (UPF) were studied in 11 chronically catheterized pregnant ewes and their fetuses. Over the first 4 h of infusion, MMAP (p < 0.01) increased and CO decreased (p < 0.05). UPF and fetal PO2, PCO2, and pH were unchanged. After 16-24 h, MMAP increased further (p < 0.05-p < 0.005); UPF decreased (p < 0.05), and vascular resistance increased (p < 0.05). Fetal arterial PO2 decreased and PCO2 increased (p < 0.001; p < 0.05). There were correlations between fetal arterial PO2 and UPF (r = 0.6; p < 0.00005; n = 81), pH and UPF (r = 0.39; p < 0.0003; n = 81) and a negative correlation between PCO2 and UPF (r = -0.5; p < 0.00005; n = 81). Infusions of 33 microg/h of noradrenaline initially caused a decrease in UPF. In the longer term, UPF was unchanged, as was UVR. There were no changes in fetal blood gases or pH, but there was a correlation between fetal arterial PO2 and UPF (r = 0.48; p < 0.01; n = 27). The short-term effects of Ang II and noradrenaline on UPF and UVR are similar to effects reported previously. The finding that long-term infusions of Ang II caused a reduction in UPF and compromised fetal gas exchange was unexpected. Thus the protective effect of reduced vascular reactivity of the uteroplacental circulation to Ang II is only a transient phenomenon.

The Effects of Intravenous Angiotensin II on the Cardiac Baroreceptor Reflex

In their original studies in man, Smyth et al. (1) found that when i.v. phenylephrine [an alpha- agonist with no direct cardiac effects (2)] was used to increase arterial pressure, there was a linear relationship between systolic pressure and the pulse interval. However, when they used i.v. angiotensin II to increase arterial pressure, they observed an initial increase in pulse interval as arterial pressure increased, but “later points in the response…tended to depart from the regularly linear relation.”