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This document discusses mineralocorticoids and aldosterone. It describes how aldosterone receptors occur in target tissues like the kidney and bind aldosterone with high affinity. It also discusses how aldosterone increases sodium reabsorption in the kidney by increasing sodium pumps and mitochondrial enzymes. The renin-angiotensin system and its role in stimulating aldosterone production is also summarized. Primary aldosteronism or Conn's syndrome is caused by aldosterone-secreting adrenal adenomas and results in hypertension, hypokalemia, and metabolic alkalosis. Diagnosis involves low renin levels and failure of aldosterone to suppress with saline infusion.
This document discusses mineralocorticoids and aldosterone. It describes how aldosterone receptors occur in target tissues like the kidney and bind aldosterone with high affinity. It also discusses how aldosterone increases sodium reabsorption in the kidney by increasing sodium pumps and mitochondrial enzymes. The renin-angiotensin system and its role in stimulating aldosterone production is also summarized. Primary aldosteronism or Conn's syndrome is caused by aldosterone-secreting adrenal adenomas and results in hypertension, hypokalemia, and metabolic alkalosis. Diagnosis involves low renin levels and failure of aldosterone to suppress with saline infusion.
This document discusses mineralocorticoids and aldosterone. It describes how aldosterone receptors occur in target tissues like the kidney and bind aldosterone with high affinity. It also discusses how aldosterone increases sodium reabsorption in the kidney by increasing sodium pumps and mitochondrial enzymes. The renin-angiotensin system and its role in stimulating aldosterone production is also summarized. Primary aldosteronism or Conn's syndrome is caused by aldosterone-secreting adrenal adenomas and results in hypertension, hypokalemia, and metabolic alkalosis. Diagnosis involves low renin levels and failure of aldosterone to suppress with saline infusion.
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.