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Adrenal Gland and its secretions

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Adrenal Gland and its secretions Powered By Docstoc
					Adrenal Glands
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Adrenal glands are located above each kidney.
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Each gland composed of inner portion (adrenal medulla) and outer layer (adrenal cortex).

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Adrenal medulla
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receives neural input from axons of sympathetic division of the autonomic nervous system, and secretes epinephrine and norepinephrine in response

Adrenal Glands
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Adrenal cortex
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Hormones from adrenal cortex are collectively referred to as corticosteroids.
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Cortisol maintains glucose homeostasis, and modulates some aspects of the immune response. Aldosterone stimulates the kidneys to reabsorb Na+ and secrete K+ into the urine.

Adrenal Glands

Adrenal gland
~3 cm

Adrenal cortex (corticosteroids)

Adrenal medulla

(catecholamine - adrenaline)

Adrenal gland
~3 cm

Adrenal cortex (corticosteroids)

Adrenal medulla

(catecholamine - adrenaline)

THE ADRENAL GLANDS
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CORTEX: STEROID HORMONES SECRETED MEDULLA: CATECHOLAMINES (EPINEPHRIN AND NOR-EPINEPHRIN) SECRETED. IT IS A MODIFIED SYMPATHETIC GANGLION

Adrenal cortex

zona glomerulosa mineralocorticoids zona fasiculata glucocorticoids zona reticularis androgens adrenal cortex (corticosteroids)

CORTEX: STEROID HORMONES SECRETED
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MINERALOCORTICOIDS

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GLUCOCORTICOIDS
SEX HOMONES

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MINERALOCORTICOIDS
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ALDOSTERONE ELECTROLYTE BALANCE BLOOD PRESSURE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM ALDOSTERONE SECRETION REGULATED BY RENIN SECRETION IN THE KIDNEY VIA ANGIOTENSIN II NEGATIVE FEEDBACK CONTROL VIA MONITORING BLOOD VOLUME

Mineralocorticoids
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Mineralocorticoids ���� Acutely critical for maintenance of life ���� Removal of the adrenal glands leads to death within few days.

Loss of mineralocorticoid activity
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���� ���� Elevated concentration of potassium in extracellular fluid High urinary excretion of sodium ���� Decreased concentration of sodium in extracellular fluid ���� Decreased volume of extracellular fluid and blood ���� Decline of cardiac output and shock

Good news
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���� All those symptoms can largely be prevented by replacement of salts and mineralocorticoids Principal mineralocorticoids

aldosterone
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���� The principal steroid with mineralocorticoid activity is aldosterone ���� Cortisol has weak mineralocorticoid activity Source ���� Cholesterol derivative ���� Synthesized in zona glomerulosa ���� Under control of renin/angiotensin system Z. glomerulosa Z. fasciculata

aldosterone

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Synthesis Transport ���� 20% bound to cortisol-binding protein ���� 40% albumin-bound ���� 40% free ���� Plasma levels compared to glucocorticoids Metabolism ���� Half-life 20 min ���� Liver (glucuronid conjugate) ���� Free hormone filtered by kidneys

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Receptors ���� Intracellular receptors ���� The mineralocorticoid receptor binds both aldosterone and cortisol with equal affinity Molecular recognition ���� In aldosterone-responsive cells, cortisol is effectively destroyed ���� Target cells for aldosterone express 11betahydroxysteroid dehydrogenase ���� This enzyme "protects" the cell from cortisol and allows aldosterone to bind its receptor without competition

Physiological effects
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���� Mineralocorticoids play a critical role in regulating concentrations of sodium and potassium in extracellular fluids ���� Increased resorption of sodium ���� Increased resorption of water ���� Direct effect of increased resorption of sodium ���� Increased renal excretion of potassium

Target tissues
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���� The major target of aldosterone is the distal tubule and collecting duct of the kidney ���� Sweat – salivary – gastrointestinal glands Kidney effects ���� Stimulates transcription of the sodiumpotassium ATPase ���� increased numbers of sodium pumps in the basolateral membranes of tubular epithelial cells ���� Stimulates expression of a sodium channel ���� facilitates uptake of sodium from the tubular lumen

Did you know?
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���� 92% of the filtered sodium is always reabsorbed from the tubular fluid (obligatory reabsorption) ���� 8% of sodium may also be reabsorbed (regulated by aldosterone) in the distal tubule and collecting duct Effects ���� Saves sodium for the body at the expense of potassium → total body sodium level↑↑ and potassium ↓↓

Regulation of mineralocorticoid secretion
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���� Renin-angiotensin system ���� Direct effects of ions on z. glomerulosa ���� ACTH ���� Atrial Natriuretic Peptide Renin ���� Renin is an enzyme that cleaves angiotensinogen into angiotensin I ���� Proteinase ���� rate-limiting step in aldosterone responsse ���� kidney: juxtaglomerular apparatus

Angiotensin
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Angiotensin I ���� 10 aa peptide ���� Angiotensin I is inactive, but is quickly broken down into angiotensin II by angiotensin convertase (ACE) ���� ectoenzyme ���� somatic ACE (lung endothelial cells) ���� enzyme inhibitors used in blood pressure control Angiotensin II ���� 8 a.a biologically active hormone ���� half life < 1 min ���� Responsible for direct

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arteriolar vasoconstriction ���� Stimulus for aldosterone secretion ���� Maintains volume and pressure of arteriolar circulation through aldosterone Angiotensin receptors ���� G protein-coupled ���� AT1 ���� Gq coupled - PLC ↑ - calcium↑ -↑↑ aldosterone synthase↑↑ in z. glomerulosa → aldosterone↑↑

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���� Activation of tyrosine kinases
���� tyrosine phosphatase ↑ → Causes to release renin ���� The juxtaglomerular apparatus functions as a baroreceptor ���� Decrease in perfusion pressure of blood causes renin secretion ���� The concentration of sodium and chloride in the macula densa

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Concentration of plasma electrolytes ���� Concentration of circulating angiotensin II, a short feedback loop GI effects ���� Stimulates absorption of sodium from the intestinal lumen ���� Conservation of water follows conservation of sodium

Extrarenal effects
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���� During physical activity in hot climates, a lot of sodium is lost in the sweat, shrinks blood volume and thus activates the renin-angiotensinaldosterone mechanism

Aldosterone excess ���� Primary hyperaldosteronism (Conn’s syndrome) ���� due to benign adrenal tumor that secretes large amounts of aldosterone (renin ↓↓)
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•renovascular diseases or catecholamine hypersecretion → angiotensin ↑↑

���� Secondary hyperaldosteronism
Conn’s Syndrome  ���� Decreased proximal reabsorption, increases glomerular filtration,  suppression of the renin-angiotensin system. ���� Increase in blood pressure, hypertension and  hypokalemia
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Secondary Excess ���� High level of renin-angiotensin
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���� Continuous secretion of aldosterone due to increase in angiotensin II ���� Common effects include nephrotic syndrome, hypertension, heart failure and cirrhosis of liver with ascites.

Aldosterone excess
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���� Na+ retention → hypernatremia → EC volume↑↑ → BP↑↑ ���� K+ depletion → hypokalemia → damages kidneys and also muscle weakness ���� H+ depletion → alkalosis → plasma Ca++↓ → muscle cramps No leak

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Aldosterone excess
���� When there is no leak but the level still remains high  ���� In the administration of exogenous aldosterone and  aldosterone-secreting tumor  ���� Extra cellular volume expands by a few liters and then  Stops Leak effects due to Proximal sodium
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���� Proximal sodium
reabsorption is decreased, natriuretic factor that arises in the hypothalamus ���� Glomular filtration is increased, due to the actions of atrial natriuretic factor ���� Renin-angiotensin levels are suppressed by the rise in systemic pressure, renal perfusion pressure and sodium content in the macula densa

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���� Escape Normally the level of water replenishes the system and the volume increases thus shutting off the process ���� However a leak will cause aldosterone to never turn off, hyperaldosteronism ���� Seen in chronic edematous states ���� Cirrhosis of the liver and ascites

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Escape mechanism ���� if EC volume ↑ by more than 15%, then further increase in sodium reabsorption is prevented by ���� ANP↑↑ decreases in “obligatory” sodium reabsorption ���� increases in plasma ultrafiltration in the kidneys ���� But H+ and K+ loss continues

Chronic edematous diseases
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���� Heart failure ���� Cirrhosis of the liver with ascites ���� Nephrotic syndrome ���� Despite the high levels of reninangiotensin and the increased levels of aldosterone, blood volume remains shrunken and blood pressure is lownormal

nonmineralocorticoid steroidal
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Blocking aldosterone ���� Spironolactone, a compound that competes directly with aldosterone for the receptors in the renal tubule ���� But much more is needed because it is much weaker, 50-500mg/day are needed to compete with aldosterone ���� Aldosterone inhibition is successful against conditions such as heart failure and cirrhosis Adrenocortical insufficiency - etiology ���� Primary (Addison’s disease) - autoimmune disease or opportunistic infections in AIDS destroy adrenal cortex

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Adrenocortical insufficiency symptoms ���� hyperkalemia (arrhythmias) ���� hyponatremia (Na+ loss → water loss → blood volume↓ → circulatory shock) ���� blood pressure ↓ ���� fatigue, weakness, weight loss ���� salt craving

Genetic Disorders
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���� Peudoaldosteronism (Liddle’s Syndrome) ���� It is an activation mutation in the amiloride –sensitive Na+ channel. ���� Excessive sodium uptake ���� Can be treated with drugs that increase sodium excretion and potassium retention ( Amiloride and Triamterene) ���� An autosomal dominant disease.

ADRENAL INSUFFICIENY
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CORTEX: ADDISON’S DISEASE POOR RESPONSE TO STRESS LACK OF PERMISSIVE ACTION POTASSIUM RETENTION HYPOTENSION

Adrenal cortex pathophysiology

Over-secretion or under-secretion of cortisol.
Too much cortisol:  Cushing’s syndrome Not enough cortisol:  Addison’s disease  Pituitary problem (ACTH)  Adrenal problem (ACTH , also affects mineralocorticoids)  Congenital adrenal hyperplasia

Aldosterone

Aldosterone
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Mineralocorticoids • Aldosterone • 11-deoxycorticosterone (DOC) • Cortisol (blunted in local degradation by 11beta-hydroxysteroid dehydrogenase to cortisone in kidneys, colon, salivary glands)

Synthesis of aldosterone
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• Place of synthesis: zona glomerulosa • Synthesis control: • RA system • Potassium and sodium level • ACTH • dopamine

Aldosterone transport and metabolism
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• Binding to the (corticosteroid binding globulin) ,CBG • Free aldosterone: 30-50% • Relatively short half-live: 15-20 minutes • Inactivation in liver: tetrahydroaldosterone • Inactivation in kidney: aldosterone-18glucuronide • Free aldosterone in urine • Aldosterone secretion rates: 50-250 μg/d

DOC
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• Secreted as the same rate as aldosterone • Totally bound to the CBG • Free fraction less than 5% • Metabolism in liver: tetrahydrodeoxycorticosterone conjuncted with glucuronic acid and excreted with urine

Mechanisms of mineralocorticoid action
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• Binding to the receptor in the cytosol • Movement of the complex hormonereceptor into the nucleus • Alteration of the rate of transcription of mineralocorticoid-responsive genes • Changes in the level of mRNAs and their protein products

Biological effects of mineralocorticoids
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• Activation of Na influx into the cells (via apical membrane) – Increasing of the number of luminal Na channels (1 hour) – Activation of aldosterone-activated kinase that increases Na channels activity (6-24 hours) • Activation of Na,K-ATPase (basolateral membrane) and sodium and water transport to extracellular fluid

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– Indirect: by increased intracellular Na concentration – Direct activation of enzyme protein • Increasing of difference in electrical potential across the plasma membrane • Secretion of K+ and H+ • Places of action: part of the distal convoluted tubule, collecting tubule and other secretory systems (saliva, sweat, feces)

Renin angiotensinogen system

The renin • Proteolytic enzyme • Molecular weight: 40.000 • Secreted as prorenin or renin into the circulation • Liberates decapeptide angiotensin I from angiotensinogen

Control of renin secretion • Baroreceptors in the wall of the afferent arteriole, stimulated by deceased renal arterial perfusion pressure • Cardiac and systemic arterial receptors, that activate the sympathetic nervous system (via beta 1 receptors) • Cells of the macula densa detecting sodium and chloride concentration in tubular lumen

ADRENAL OVERSECRETION
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MINERALCORTICOIDS: SODIUM RETENTION, POTASSIUM DEPLETION CORTISOL:EXCESS GLUCONEOGENESISEXCESS GLUCOSE DEPOSITED AS FAT (CUSHING’S SYNDROME) ANDROGEN: MASCULINIZATION, PSEUDOHERMAPHODITISM, PRECOCIOUS PSEUDOPUBERTY, NO EFFECT IN ADULT MALES


				
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