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There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preeclampsia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy.

The effects of high salt intake on blood pressure and renal function were studied in nine subtotally nephrectomized pregnant ewes (STNxP) and seven intact pregnant ewes (IntP) in late gestation and in eight subtotally nephrectomized nonpregnant ewes (STNxNP) and seven intact nonpregnant ewes (IntNP). STNxP had higher mean arterial pressures (P < 0.02) and plasma creatinine levels (P < 0.001) than IntP. High salt (0.17 M NaCl as drinking water for 5 days) did not change blood pressure in either STNxP or IntP. STNxNP had higher mean arterial pressures (P = 0.03) and plasma creatinine levels (P < 0.001) than IntNP. In STNxNP, blood pressure increased with high salt intake and there was a positive relationship between diastolic pressure and sodium balance (r = 0.497, P = 0.05). This relationship was not present in IntNP, STNxP, or IntP. Because high salt intake did not cause an increase in blood pressure in STNxP, it is concluded that they were protected by pregnancy from further rises in blood pressure. The observed increase in glomerular filtration rate (P < 0.03) and depression of fractional proximal sodium reabsorption (P = 0.003) that occurred in STNxP, but not in STNxNP, in response to high salt may have contributed to this protection. As well, the increased production of vasorelaxants in pregnancy may selectively protect against the occurrence of salt-sensitive hypertension in pregnancy.

Fetal behavior, renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were studied 1-3 days after surgery in seven fetal sheep (aged 127-136 days). Five behavioral states were defined from chart recordings of electrocortical (electrocorticographic; ECoG) activity and eye, limb, and breathing movements. Most records were of high-voltage ECoG (HV) or low-voltage (LV) ECoG with breathing (LVB); 6.7 +/- 1.7% were LV ECoG with no breathing (LV0). RSNA was lower in LV0 (P < 0.001) and greater in LVB than in HV (P < 0.05). MAP was lower in both LV states than in HV and when the fetuses went from LV to HV (P < 0.001 to P < 0.03). HR was highest in HV (P < 0.001). In HV and LVB and when the fetus went from LV to HV, MAP and HR were inversely related (P = 0.012-0.003). In LVB and from LV to HV there were direct relationships between MAP and RSNA (P = 0.0014, P = 0.08), and when the fetus went from LV to HV there was also an inverse relationship between HR and RSNA (P = 0.02). Thus fetal RSNA, MAP, and HR are affected by behavioral state as is fetal cardiovascular control. The increase in RSNA during fetal breathing showed that there was an altered level of fetal RSNA associated with fetal breathing activity.

1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125-132 days gestation). Losartan reduced the fetal systolic (P <0.01) and diastolic (P <0.01) pressor response to 5 microg angiotensin II (AngII) i.v. from 27.4 +/- 1.5 to 7.4+/-0.9 and from 17.5 +/- 1.3 to 5.4 +/- 0.6 mmHg, respectively, after 1 h and to 6.1 +/- 0.5 and 4.4 +/- 0.5 mmHg, respectively, after 2 h. Maternal pressor responses to 5 microg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P <0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P <0.05), fetal PO2 decreased (P <0.01), PCO2 did not change and pH decreased (P <0.01), as did plasma bicarbonate levels (P <0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P <0.01) and an increase in blood flow (P <0.05). Glomerular filtration rate decreased (P <0.05); thus, filtration fraction decreased (P <0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P <0.01) and became negative. Urine flow decreased (P <0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium: potassium ratio decreased (P <0.05). There was a decrease in lung liquid flow (P <0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.

To determine the cause of the transient natriuresis in lambs within 1-2 h of birth, renal function and blood volume (BV) were measured in nine chronically catheterized fetal sheep aged 139-145 d before and after delivery by cesarean section. After delivery, sodium excretion increased 8-fold. This was due to a transient rise in glomerular filtration rate (by 39 +/- 21%, p < 0.02) and a fall in fractional reabsorption of sodium by the proximal tubule from 63.4 +/- 2.5% to 53.4 +/- 3.4% (p < 0.01). The distal tubule failed to compensate fully for this fall, because fractional reabsorption by the distal tubule rose from 35.5 +/- 2.4% to only 41.6 +/- 2.2% (p < 0.05). The extent of the natriuresis did not depend on the lamb's initial BV per kg at birth. However, the amount of fluid excreted and the clearance of sodium during a 45-min period within the first 1-1.25 h after birth were approximately equal to the fall in BV that occurred during this time. Thus, most of the fall in BV that occurs after delivery is due to renal salt and water losses. Because the natriuresis was greater if the lamb's arterial pressure rose after birth, it is possible that a high arterial pressure in the immediate newborn period could result in salt and volume depletion.

Fetal cardiovascular (CVS) changes, forelimb movements (FM) and rates of habituation to repeated stimulation, with suffusions of cold saline over the skin, were measured in 12 chronically catheterized fetal sheep aged 130-145 days. Stimulation of the fetuses caused a significant rise in heart rate (HR) (p less than 0.01) and blood pressure (BP) (p less than 0.001) and FM (p less than 0.01). When the ewe was given an intravenous (i.v.) infusion of ethanol which produced fetal ethanol levels of 87 +/- 1.1 mg/100 ml, the number of spontaneous FM decreased (p less than 0.05). After i.v. ethanol, repeated stimulation of the fetuses still caused an increase in FM (p less than 0.01) and a rise in HR (p less than 0.05) and BP (p less than 0.02) but the fetuses habituated more rapidly (7.25 +/- 1.28 stimuli) compared to control experiments performed prior to (21.5 +/- 3.57 stimuli) or after the ethanol (17.75 +/- 5.83, p less than 0.01). Fetal exposure to low concentrations of ethanol does affect the patterns of response and habituation of the developing fetal central nervous system.

1. Angiotensin II (AII, 0.22 microgram/min) infused for 7-14 days, into adult unanaesthetized wethers, caused a rise in blood pressure of 7 +/- 3/7 +/- 3 mmHg (mean +/- s.e.m.) from control values of 90 +/- 5/54 +/- 3 mmHg (P less than 0.05, n = 11). Cardiac output and pulse interval were not affected. A high salt intake had no effect on blood pressure, cardiac output and pulse interval, nor did it potentiate the action of AII. 2. Ethinyl oestradiol (EE, 20 mg/week) caused a small fall in systolic and diastolic pressure of 6 +/- 3/6 +/- 5 mmHg (n = 7, P less than 0.1, P less than 0.05). When AII (0.22 microgram/min) was given with EE, it still caused a significant rise in blood pressure (P less than 0.01). The synthetic progestin (1 mg of norethisterone [NE] for 8-18 days) plus a high salt diet had no effect on arterial pressure and cardiac output but pulse interval rose significantly (P less than 0.05). 3. Therefore the reduction in vascular reactivity to angiotensin seen in human pregnancy is probably not related to high levels of oestrogen. Further, NE combined with a high salt diet does not cause hypertension in sheep.

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)

1. Infusions of hyperosmotic mannitol to the ewe caused a rise in fetal arterial pressure in 17 chronically catheterized fetal sheep aged 120-140 days. The fetal heart slowed in 13 out of 17 of these fetuses. The rise in pressure occurred before there was any rise in fetal urinary osmolality. 2. In seven fetal sheep combined alpha- and beta-adrenoceptor and muscarinic blockade delayed the onset of the rise in blood pressure and no bradycardia was observed. It is concluded that the hypertension was due in part to increased activity of the sympatho-adrenal system, and that any reflex bradycardia that occurred was mediated by the vagus. 3. In three other fetal sheep aged 125-131 days, the cardiovascular responses elicited by infusion of hyperosmotic mannitol to the ewe were not blocked by a specific vasopressin antagonist. Thus vasopressin could not be responsible for either the initial rise in pressure nor the delayed hypertensive response that was not blocked by alpha- and beta-adrenoceptor blockade. 4. Fetal blood volume was maintained even though the changes in plasma osmolality and electrolytes were indicative of a fall in blood volume. Thus changes that threaten maintenance of fetal blood volume seem to induce increased solute and water transport across the placenta or from the extracorporeal fluid compartments.