Mineralocorticoids

Biochemical and
Physiological Actions…

Dr. Aseem Bhattarai, M.D.

 Introduction

Broad features of Mineralocorticoid Hormone (Aldosterone)

resemble those of other steroid hormones.
Receptors that bind aldosterone with high affinity occur in
the cytoplasm and nuclei of target cells. These cells include
those in the kidney, parotid and colon and also other organs
not normally thought to be targets of aldosterone action (like
the hippocampus and the heart).
These receptors have equal affinity for aldosterone, cortisol
and corticosterone and are called type I receptors to
distinguish them from the classic glucocorticoid receptor
(type II).
 Introduction
Despite the much lower levels of aldosterone in the plasma,
given the fact that there are no carrier proteins for the
molecule of aldosterone unlike corticosteroids, the effective
concentration of aldosterone is (i.e. free aldosterone) is much
higher, and hence it can bind to the type I receptors in spite
of circulating steroid hormones.
An additional fail safe mechanism is also present for the
action of aldosterone. The mineralocorticoid receptor in target
tissue has absolute selectivity for aldosterone because of the
presence of the enzyme 11β hydrosteroid dehydrogenase
which converts cortisol and corticosterone to its inactive 11β
metabolites giving aldosterone unimpeded access.
 Actions
Na+ from the luminal fluid bathing the apical surface of renal
cells enters passively through Na+ channels. Na+ is then
transported to the interstitial fluids through the serosal side
by the ATP dependent Na+ / K+ ATPase pump.
Aldosterone increases the number of apical membrane
pumps as well as increases the activity of several
mitochondrial enzymes leading to generation of more ATPs.
Other mechanisms, involving different aldosterone regulated
proteins are thought responsible for handling of K+ and H+.
 Renin / Angiotensin
Renin is a proteolytic enzyme that is produced and stored in
the granules of the juxtaglomerular cells surrounding the
afferent arterioles of glomeruli in the kidneys.
Renin acts on the basic substrate angiotensinogen (a
circulating α2 globulin made in the liver) to form the
decapeptide angiotensin I.
Angiotensin I is then then enzymatically transformed by the
converting enzyme (ACE), present in many tissues,
particularly in the pulmonary vascular endothelium, to the
octapeptide angiotensin II by splitting off the two C-terminal
amino acids.
 Renin / Angiotensin
Angiotensin II is a potent pressor agent and exerts its action
by a direct effect on arteriolar smooth muscle. In addition,
Angiotensin II also stimulates production of aldosterone by
the zona glomerulosa of the adrenal cortex. The nonapeptide,
seen in occurrence, angiotensin III, may also stimulate
aldosterone production.
Renal Renin Release is governed by four interdependent
factors:
1. The juxaglomerular cells, which are specialized
myoepithelial cells cuffing the afferent arterioles act as
miniature pressure transducers, sensing renal perfusion
pressure.
 Renin / Angiotensin
For example, under conditions of a reduction in circulating
blood volume, there is a corresponding reduction in renal
perfusion pressure and therefore, in afferent arteriolar
pressure.
This is perceived by the JG cells as a decreased stretch on
afferent arteriolar walls, leading to secretion of renin within
the kidney circulation.
This results in formation of angiotensin I which is converted
to angiotensin II by the converting enzyme.
 Renin / Angiotensin

Angiotensin II influences sodium homeostasis by two major

mechanisms:
1. It changes renal blood flow so as to maintain a constant
glomerular filtration rate, thereby changing the filtration
fraction of sodium and it stimulates the adrenal cortex to
release aldosterone.
2. Increasing plasma levels of aldosterone lead to increasing
renal sodium retention and thus result in expansion of
extracellular fluid volume, which, in turn, dampens the
initiating signal for renin release.
 Renin Release
2. A second control mechanism for renin release centers in
the macula densa cells, a group of distal convoluted
tubular epithelial cells in direct apposition to the
juxtaglomerular cells.
• They may function as chemoreceptors, monitoring the
sodium or chloride load presented to the distal tubule,
and such information may be conveyed to the
juxtaglomerular cells, where appropriate modifications
to renin release may occur.
• Under conditions of increased delivery of filtered
sodium to the macula densa, increasing release of
renin is capable of decreasing the glomerular filtration
rate, thereby reducing the filtered load of sodium.
 Renin Release

3. The sympathetic nervous system regulates the release of

renin in response to assuming the upright posture.
The mechanism is either a direct effect on the
juxtaglomerular cell to increase adenyl cyclase activity or
an indirect effect on either the juxtaglomerular or the
macula densa cells by way of a vasoconstrictive action on
the afferent arteriole.
 Renin Release
4. Finally, circulating factors also influence Renin release.
• Increasing dietary potassium directly decreases renin
release, decreasing potassium intake increases renin
release. The significance of this potassium effect is
unclear.
• Angiotensin II itself can exert a negative feedback
control on renin secretion.
• Atrial Natriuretic Peptide also inhibits renin secretion.
Thus, the secretion of renin is complex, consisting of both
intrarenal and extrarenal control mechanisms.
Hyperfunction of
Mineralocorticoids
Aldosteronism…
 Introduction

Aldosteronism is a syndrome associated with hypersecretion

of the major adrenal mineralocorticoid aldosterone. Primary
aldosteronism signifies that the stimulus for the excessive
aldosterone production resides within the adrenal gland; in
secondary aldosteronism, the stimulus is extra-adrenal.
Small adenomas of the glomerulosa cells can result in
primary aldosteronism (Conn’s Syndrome), the classic
manifestations of which include hypertension, hypokalemia,
hypernatremia and alkalosis. Patients with primary
aldosteronism do not have evidence of glucocorticoid
hormone excess, and plasma renin / angiotensin II levels are
typically suppressed.
 Introduction

Renal artery stenosis, with the attendant decrease in

perfusion pressure, can lead to hyperplasia and hyperfunction
of the juxtaglomerular cells and cause elevated levels of renin
and angiotensin II. This action leads to secondary
aldosteronism, which resembles the primary form, except for
the elevated renin and angiotensin II levels.
 Primary Aldosteronism

• Originally, the disease was a aldosterone producing adrenal

adenoma (Conn’s Syndrome).
• Majority of cases involve a small and unilateral (with no side
predilection) adenoma. Rarely, there is an association with
adrenal carcinoma.
• Twice more common in women, (median age 30-50 years)
and comprise of 1% of unselected hypertensive patients
overall.
• Some patients have a Bilateral Cortical Nodular Hyperplasia
as the root cause, often referred to as idiopathic
hyperaldosteronism.
 Signs / Symptoms
• The continual hypersecretion of aldosterone increases the
renal distal tubular exchange of intratubular sodium for the
secreted potassium and hydrogen ions, with progressive
depletion of body potassium and development of
hypokalemia.
• Most patients have diastolic hypertension, usually not of
marked severity and complain of headaches.
• Polyuria is present and associated with polydipsia.
• Muscle weakness and fatigue is related to the hypokalemia.
• Edema is characteristically absent in the absence of heart
failure or associated renal impairment.
 Lab Findings
An overnight urinary concentration test often reveals the
inability to concentrate the urine, probably secondary to the
hypokalemia. Urinary pH is neutral to alkaline to compensate
for the metabolic alkalosis.
Hypokalemia may be severe (<3mmol/L) and reflects
significant potassium depletion, usually in excess of 300
mmols. Hypernatremia is due to both sodium retention and a
concomitant water loss from the polyuria.
Metabolic alkalosis is a result of hydrogen loss in the urine and
migration of hydrogen into potassium depleted cells. If
hypokalemia is severe, serum magnesium levels are also
reduced.
Total body sodium and total exchangeable sodium are usually
increased, while total exchangeable potassium is reduced.
 Diagnosis

The diagnosis is suggested by a persistent hypokalemia in a

nonedematous patient on a normal sodium intake who is not
receiving potassium wasting diuretics.
The criteria for diagnosis of primary aldosteronism are:
1. Diastolic hypertension without edema
2. Hyposecretion of Renin that fail to rise despite volume loss
3. Hypersecretion of Aldosterone that fails to suppress
despite volume expansion (e.g. salt loading)
Patients with hypertension and hypokalemia may have primary
or secondary aldosteronism. The key to diagnosis is the plasma
renin activity.
 Differential Diagnosis

• Hypermineralocorticoid states due to bilateral nodular

hyperplasia of the adrenals.
• DOC (Deoxycorticosterone) secreting adenomas.
• Glucocorticoid remediable aldosteronism (Defect in cortisol
biosynthesis)
• 11β Hydroxysteroid Dehydrogenase Deficiency
 Treatment
• Primary aldosteronism due to an adenoma is treated by a
surgical excision. Dietary sodium restriction and
administration of an aldosterone antagonist like
spironolactone are also very effective.
• When idiopathic bilateral hyperplasia is suspected, surgery is
done only when hypokalemia is refractory. Hypertension
associated with idiopathic hyperplasia is not benefitted by
surgery.
• GRAs may be treated with glucocorticoids and
antimineralocorticoids. Patients with 11β hydroxysteroid
dehydrogenase deficiency are treated with low dose
dexamethasone.