Eugenie R. Lumbers

Inhibition by angiotensin II of baroreceptor‐evoked activity in cardiac vagal efferent nerves in the dog.

1. Action potentials were recorded in single baroreceptor fibres dissected from the carotid sinus nerves in dogs during increases in blood pressure caused by I.V. injection of angiotensin II, and by I.V. injection of phenylephrine or inflation of an aortic balloon. Action potentials were recorded in single cardiac efferent fibres dissected from the right cervical vagus nerve in other dogs during increases in blood pressure caused by angiotensin II, and by phenylephrine or by inflation of an aortic balloon. 2. There was no difference in the discharge frequency of single carotid sinus baroreceptor fibres at any blood pressure when phenylephrine, balloon inflation, or angiotensin II were used to raise the pressure. 3. Activity in single cardiac vagal efferent fibres was increased when blood pressure was increased by phenylephrine or by inflation of an aortic balloon. However, when blood pressure rose by a comparable amount in response to angiotensin II, vagal firing decreased (three fibres), was little changed from control levels (four fibres), or increased less than it did in response to phenylephrine (one fibre). 4. It is concluded that while angiotensin II has no effect on baroreceptor sensitivity, it does inhibit vagal discharge which is evoked by stimulation of arterial baroreceptors.

Effect of cortisol on blood pressure and vascular reactivity in the ovine fetus

The aim of this study was to investigate the cardiovascular effects of exogenous cortisol in fetal sheep, (a) between 100 and 120 days of gestation when cortisol production is minimal and (b) after 130 days when endogenous plasma cortisol starts to rise. Chronically cannulated ovine fetuses (103–120 days, n = 9; 130–137 days, n = 7), received sequentially a 24 h infusion of vehicle (0.9% sodium chloride) and a 24 h infusion of cortisol at 100 micrograms/h. Blood pressure and heart rate changes to bolus injections each of angiotensin II and noradrenaline (0.2, 0.5, 1.0, 2.0 micrograms) were measured before and after the saline and cortisol infusions. Fetuses in each age group, served as additional controls receiving 48 h saline infusions. In both immature and mature age groups, the cortisol infusion increased basal fetal blood cortisol concentrations by 33.7 and 35.4 nmol/l respectively. In the immature group, cortisol, but not saline, caused significant 14.3 and 15.3% increases in basal systolic and diastolic pressures respectively. Basal blood pressure was higher in the mature group, but did not increase further despite the increase in cortisol levels. Furthermore, vascular responsiveness to angiotensin II but not to noradrenaline was significantly enhanced following the cortisol infusion, at both ages. Fetal heart rate did not change following the cortisol infusion. Exogenous cortisol contributes to the regulation of fetal blood pressure in the immature fetus, when other mechanisms have not developed. Cortisol might achieve this, in part, by enhancing vascular sensitivity to angiotensin II.

Renin concentration in human fetal and maternal tissues

Abstract Expressed as relative concentration per wet weight, chorion consistently displayed the highest renin content outside of kidney among the tissues and fluids examined. Renin in postmortem kidney was twelvefold more concentrated than in chorion. Mean concentration in chorion (4,420 units per gram) was fourfold that in either amniotic fluid, amnion and decidua; concentration in myometrium (47 units per gram) and maternal surface of placenta (51 units per gram) was much lower at approximately twofold that of fetal and maternal plasma. Renin concentration in chorion from the fetal surface of placenta (473 units per gram) was less than in peripheral chorion but greater than in the maternal surface of placenta. Following artificial rupture of the membranes, renin concentration in freely draining liquor did not alter during 2 to 7 hour periods. These findings suggest that chorion is the source of renin in human amniotic fluid and that decidua, by limiting outward diffusion effectively, promotes intra-amniotic accumulation.

The activation of renin in human amniotic fluid by proteolytic enzymes

Abstract Renin (EC 3.4.4.15) in human amniotic fluid can be activated by the proteolytic enzymes pepsin (EC 3.4.4.1) and trypsin (EC 3.4.4.4). Furthermore, activation of renin at pH 3.3–3.6 is due to an acid-stable factor which is inactive at physiological pH, and has properties similar to the enzyme pepsin. The possible relationship between these findings and the secretion of renin by the kidney is discussed.

Mechanisms by which angiotensin II affects the heart rate of the conscious sheep.

Intravenous infusions of angiotensin II were given to conscious sheep. During these infusions, the pressor action of angiotensin was antagonized by concomitant infusion of sodium nitroprusside. Under these conditions, angiotensin produced a dose-dependent tachycardia. This dose-dependent tachycardia was not affected by propranolol and therefore it was not due to an action of angiotensin on sympathoadrenal mechanisms. The dose-dependent tachycardia was reduced by atro-pine, and abolished by increases in systolic pressure. We conclude that iv infusions of angiotensin cause a central, dose-dependent reduction in vagal tone. This action is normally antagonized by the barore-ceptor reflex response to the hypertensive action of angiotensin. Therefore, in those conditions in which endogenous angiotensin production is increased and blood pressure is not elevated (e.g., sodium deficiency and pregnancy), angiotensin may influence heart rate. Circ Res 47: 286-292, 1980

Angiotensin and aldosterone.

The object of this review is to describe the role of the renin-angiotensin system in control of aldosterone secretion. The review focuses on the roles of the circulating renin-angiotensin (RAS) system, the activity of which is determined predominantly by control of renin secretion from the kidney and on the role of the intra-adrenal RAS. Angiotensin can bind to two types of G protein coupled receptors, the AT1 and AT2 receptors. Both receptors are found on cells from the zona glomerulosa, the site of aldosterone synthesis. Angiotensin II acting via the AT1 receptor stimulates the synthesis of aldosterone at early and late steps in the pathway. Its effect on aldosterone is influenced by a number of other factors such as plasma potassium levels, sodium status, other peptides such as ANP and adrenomedullin and proadrenomedullin N-terminal peptide. All components of the RAS are found in the adrenal gland. The activity of this intra-adrenal RAS is unmasked and amplified in nephrectomised animals. Aldosterone controls sodium transport across epithelial cells, but recently novel effects on the heart have been described.

FUNCTIONS OF THE RENIN-ANGIOTENSIN SYSTEM DURING DEVELOPMENT

1. From studies in chronically catheterized fetal sheep and other species, it can be shown that the renin‐angiotensin system (RAS) is active during intra‐uterine life. Levels of angiotensin II (AII) in fetal sheep are similar to maternal.

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.

Factors influencing plasma renin and angiotensin II in the conscious pregnant ewe and its foetus

1. Plasma renin (measured in the presence of additional substrate) was significantly higher (10·7 ± 1·1 S.E. of mean ng/ml.hr) in foetal lambs of 111–144 days gestation age (full term 147 days) than in their mothers (1·5 ± 0·2 ng/ml.hr S.E. of mean, P < 0·001) but plasma angiotensin II concentrations were in the same range (ewe 47·3 ± 6·6 S.E. of mean, foetus 47·4 ± 14·1 S.E. of mean pg/ml.). The endogenous velocity of renin production by foetal plasma was also greater than that of maternal plasma.

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.