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.     

Metoclopramide fails to stimulate aldosterone secretion and inhibits serotonin-mediated aldosterone secretion in the rat

The acute and chronic effects of metoclopramide on aldosterone secretion in the rat model were examined. Metoclopramide 50 micrograms iv in dexamethasone-treated rats did not increase plasma aldosterone concentration. Chronic infusion of metoclopramide (72 micrograms/hr) over 5 days also did not show any increase in the plasma or urinary aldosterone concentration when compared with control rats. Metoclopramide in vitro showed no effect on aldosterone secretion from rat adrenal capsular cells but it inhibited serotonin-mediated aldosterone secretion from the same cells significantly.     

Role of aldosterone availability in preeclampsia

Preeclampsia is a hypertensive disorder unique to pregnancy and remains the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiology of this disease remains still an enigma. There is increasing evidence that a combination of several factors is responsible for the development of preeclampsia. In this review, we discuss the role of aldosterone in the regulation of body fluid in pregnancy and preeclampsia. Aldosterone is produced by the enzyme aldosterone synthase and competes with cortisol and progesterone for the mineralocorticoid receptor, thus affecting sodium reabsorption and maternal volume expansion. Aldosterone seems to play a pivotal role in controlling blood pressure during pregnancy and to contribute to the well-being of the mother-to-be. Novel findings in understanding the underlying causes of preeclampsia provide a rationale for future novel prophylactic and therapeutic interventions in the treatment of this pregnancy-associated disease.     

Diurnal fluctuation in saliva aldosterone concentration

We have measured saliva aldosterone concentration (SA) at frequent intervals in subjects going about their normal daytime activities. Four hourly sampling sufficed to give a reasonable estimate of mean diurnal SA but hourly sampling is necessary if it is desired to study the temporal pattern of SA. In subjects with normal or elevated mean levels, SA fluctuated considerably suggestive of several distinct episodes of aldosterone secretion. Such fluctuations show little correlation with the concentrations in saliva of glucocorticoids (cortisol + cortisone) nor are they consistent with a circadian rhythm of aldosterone secretion. We suggest that they may represent responses to such stimuli as eating, drinking or physical activity, and possibly to other as yet unidentified factors. These observations show the importance of comprehensive diurnal assessment of aldosterone level in physiological and pathological investigations. Because of its non-invasive nature and the high productivity of the assay, measurement of SA is ideally suited for this purpose.     

Reduced urinary aldosterone excretion rates with normal plasma concentrations of aldosterone in the very elderly

Although aldosterone production declines with age, so does the aldosterone metabolic clearance rate (MCR), and the net effect of age on the circulating level of aldosterone may be less than can be predicted from production rates alone. The effect of age on aldosterone production and plasma levels was studied in a group of elderly individuals at a very advanced age when susceptibility to the impacts of age might be particularly pronounced. Seventeen nursing home patients, ages 75-99 (mean age 86 years), had aldosterone production assessed from the urinary excretion rate of the acid hydrolyzable 18-glucuronide conjugate of aldosterone. Aldosterone excretion was low in the elderly when compared to a group of healthy, young to middle-aged subjects: 123 +/- 19 (SEM) vs. 234 +/- 18 ng/h (P less than 0.001). However, plasma aldosterone concentrations in the elderly were well within a range observed in much younger and fully ambulatory subjects: 14.1 +/- 1.3 in the elderly vs. 15.9 +/- 1.8 ng/dL in the young. The plasma aldosterone concentration was apparently maintained at a normal level by a coincident decrease in both the metabolic clearance rate and the aldosterone production rate. In conclusion, an aldosterone deficiency state resulting from an age-correlated reduction in aldosterone production is probably uncommon in the elderly.     

Circadian rhythm of plasma aldosterone and time dependent alterations of aldosterone regulators

In order to investigate the relative contribution of ACTH, the renin angiotensin and dopaminergic system to the circadian rhythm of plasma aldosterone, hormone levels were determined at hourly intervals over a 24 h span in four supine healthy men. Blood was withdrawn under basal conditions (control), after either dexamethasone, captopril or bromocriptine++ (CB-154) administration. Plasma aldosterone rhythmicity was abolished in dexamethasone treated groups but not in captopril or CB treated groups. Time dependent alterations of aldosterone regulators were analyzed by multiple regression methods at 3 hourly intervals. These results indicate that plasma aldosterone rhythmicity is predominantly under the control of ACTH whereas the renin angiotensin or dopaminergic system plays a little role. In supine, sodium repleted states, ACTH is a potent stimulus of aldosterone at 000-0600 h and 1700-1900 h clocktime, whereas during daytime renin-angiotensin is an additional regulator.     

Regulation of aldosterone synthesis

The effects of angiotensin II and ACTH on cyclic AMP and aldosterone synthesis were studied in cells isolated from the bovine adrenal cortex. Angiotensin is a more potent stimulus of aldosterone synthesis than ACTH and the action of ACTH on aldosterone synthesis in cells from the glomerulosa is augmented by the presence of cells from the fasciculata. Angiotensin stimulates aldosterone synthesis in the absence of detectable changes in cyclic AMP, but the cells do respond to dibutyryl cyclic AMP leaving open the possibility that a cyclic nucleotide may play a role in the steroidogenic action of this hormone in the outer zone of the bovine adrenal cortex.     

Inhibitors of aldosterone secretion

Aldosterone secretion may be inhibited by potassium depletion, inhibitors of the renin-angiotensin system, dopamine and atrial natriuretic factor. The latter appears to be an important physiological regulator of aldosterone secretion. ANF inhibits basal, ACTH, Angiotensin II and potassium-stimulated aldosterone production in vitro by a direct action on the adrenal gland. In vivo data also support a direct inhibitions of aldosterone. The stimulation of aldosterone secretion by infusions of Angiotensin II and potassium is inhibited by simultaneous infusions of ANF. Infusions of ANF lower the basal aldosterone secretion in man. The mechanism by which ANF inhibits aldosterone is not known. No unifying first step has been identified to explain ANF's ability to inhibit all stimuli. In vivo, part of the lowering of aldosterone levels may be due to inhibition of renin secretion. This effect of ANF upon renin is inconsistent and appears to depend upon the experimental conditions.