Adrenal Gland Hormones PDF

The Adrenal Gland and Adrenal Hormones After this lecture the students should be able to: State the class of hormones to which aldosterone, epinephrine, and norepinephrine belong and the location of their synthesis; Describe the regulation of aldosterone secretion with particular em...

The Adrenal Gland and Adrenal Hormones After this lecture the students should be able to: State the class of hormones to which aldosterone, epinephrine, and norepinephrine belong and the location of their synthesis; Describe the regulation of aldosterone secretion with particular emphasis on the renin-angiotensin system; Explain where and how aldosterone exerts its effects; Distinguish the 5 adrenoceptor subtypes and explain the relative affinities of adrenaline and noradrenaline for these; List the actions of epinephrine and norepinephrine and predict the consequences of exposure to excessive amounts of these hormones; zona glomerulosa aldosterone: function Aldosterone governs the extracellular volume (ECV) due to its action on Na retention/absorption by the kidney. Arginine vasopressin (AVP) - also known as antidiuretic hormone (ADH) – regulates osmolality because of its effect on free water balance (and indirectly affects Na concentration) Osmolarity maintained at 300 mOs/L 28 L 3.5 L 10.5 L Two integrated systems for regulating salt/water balance  Synthesis of aldosterone As with cortisol, the adrenal cortex synthesizes aldosterone from cholesterol. Because glomerulosa cells are the only ones that contain aldosterone synthase, these cells are the exclusive site of aldosterone synthesis. As with cortisol, no storage pool of presynthesized aldosterone so secretion of aldosterone by the adrenal is limited by the rate at which the glomerulosa cells can synthesize the hormone. ACTH, extracellular [K+] [Na+], and the peptide hormone ANG II stimulate the production of aldosterone in the glomerulosa cell. They enhance secretion by increasing the activity of enzymes acting at rate-limiting steps in aldosterone synthesis. These include the SCC enzyme (common to all steroid-producing cells) and aldosterone synthase (unique to glomerulosa cells and involved in the final steps of formation). Once secreted, ∼37% of circulating aldosterone remains free in plasma. The rest weakly binds to CBG (∼21%) and albumin (∼42%).  Mechanism of action of aldosterone The major action of aldosterone is to stimulate the kidney to reabsorb Na+ and water and to enhance K+ secretion. Aldosterone has similar actions in the colon, salivary glands, and sweat glands. Mineralocorticoid receptors (MRs) are also present in the myocardium, liver, brain, and other tissues, but the physiological role in these tissues is unclear. Like all the other steroid hormones, it acts by modulating gene transcription after binding to the MR. Some of the molecular consequences of aldosterone in the target cells of the renal tubule are given in the next slide. Aldosterone regulates only that small fraction of renal Na+ reabsorption that occurs in the distal tubule and collecting duct. Most Na+ reabsorption occurs in the proximal tubule by aldosterone- independent mechanisms, but loss of aldosterone-mediated Na+ reabsorption can result in significant electrolyte abnormalities, including life-threatening hyperkalemia and hypotension. Conversely, excess aldosterone secretion produces hypokalemia and hypertension. 2% change in excretion of Na 3 L change in ECV  Mechanism of action of aldosterone In the target cells of the renal tubule, aldosterone increases the activity of several key proteins involved in Na+ transport. transcription of the Na-K pump, so augmenting distal Na+ reabsorption. expression of apical Na+ channels and an Na/K/Cl cotransporter so increasing Na+ reabsorption and K+ secretion. ROMK = renal outer medullary potassium channel ENaC = epithelial sodium channel blood urine SGK = Serine/threonine- protein kinase zona glomerulosa aldosterone: regulation Regulation of aldosterone synthesis Na and water levels feedback through the RAS Ang II binds to receptor Gaq to PLC to DAG and IP3 Ca increase, Ca-dependent enzymes increase Depolarizes glomerulosa cells, voltage-gated Ca channels open Ca rises, stimulates production of P450scc (desmolase, CYP11A1) delivery of cholesterol aldosterone synthase High extracellular K Depolarizes glomerulosa cells, voltage-gated Ca channels open Ca rises, stimulates production of P450scc (desmolase, CYP11A1) delivery of cholesterol aldosterone synthase ACTH Binding to MC2R stimulates Ca influx Regulation of aldosterone synthesis Feedback regulation of aldosterone synthesis Also, adjustment of circulating volume will feedback on aldosterone synthesis. homeostasis inhibition The Adrenal Medulla: Catecholamines  Development of the AG The adrenal cortex develops from mesodermal cells into steroidogenic cells that produce mineralocorticoids, glucocorticoids, and adrenal androgens but neural crest-derived chromaffin cells migrate into the cortical cells to form the medulla Influence of Cortisol: Chromaffin cells have the potential of developing into postganglionic sympathetic neurons and synthesize the norepinephrine from tyrosine, however, the cells of the adrenal medulla are exposed to high local concentrations of cortisol (from the cortex) which inhibits neuronal differentiation. Additionally, cortisol induces the expression of phenylethanolamine-N-methyl transferase (PNMT) in chromaffin cells, which converts norepinephrine to epinephrine - the primary hormonal product of the adrenal medulla. The Adrenal medulla (AM) bridges the endocrine and sympathetic NS; similar to a sympathetic ganglion without postganglionic processes. Instead of being secreted near a target organ, adrenomedullary catecholamines are secreted into the blood and act as hormones.  Synthesis of Catecholamines epinephrine, some norepinephrine, are stored in the ACTH + chromaffin granule complexed with adenosine triphosphate (ATP), Ca2+, and proteins called chromogranins. Note: synergy between CRH/ACTH/cortisol and sympathetic epinephrine axis i.e., stress resulting in cortisol release sustains the epinephrine response About 70-80% of the cells of the Transported chromaffin granule adrenal medulla secrete epinephrine, VMAT (secretory vesicle) and the remaining 20-30% secrete ACTH + norepinephrine. Circulating epinephrine is derived entirely from the AM but only about 30% of the Diffuses out of granule circulating norepinephrine comes from it, the rest from postganglionic + sympathetic nerve terminals. Because the adrenal medulla is not the sole source of catecholamine production, Back to granule by vesicular this tissue is not essential for life. monoamine transporters (VMATs)  Regulation of catecholamines Secretion of epinephrine and norepinephrine from the adrenal medulla is regulated primarily by descending sympathetic signals in response to various forms of stress, including exercise, hypoglycemia, and surgery. The primary autonomic centers that initiate sympathetic responses reside in the hypothalamus and brainstem, and they receive inputs from the cerebral cortex, the limbic system, and other regions of the hypothalamus and brainstem. The chemical signal for catecholamine secretion from the adrenal medulla is acetylcholine (ACh), which is secreted from preganglionic sympathetic neurons and binds to nicotinic receptors on chromaffin cells. ACh increases the activity of the rate-limiting enzyme, tyrosine hydroxylase, and of dopamine β-hydroxylase and stimulates exocytosis of the chromaffin granules. Synthesis of epinephrine and norepinephrine is closely coupled to secretion so that the levels of intracellular catecholamines do not change significantly, even in the face of changing sympathetic activity. Cortisol regulates epinephrine production by maintaining adequate expression of the PNMT gene in chromaffin cells  Degradation of catecholamines The biological response of catecholamines is very brief ~ 10 sec, circulating catecholamines are degraded There are two primary enzymes involved in the degradation of catecholamines: monoamine oxidase (MAO) - the predominant enzyme in neuronal mitochondria catechol-O-methyltransferase (COMT)  Mechanism of action of catecholmines Catecholamines act through adrenergic GPCRs RECEPTOR TYPE PRIMARY MECHANISM OF ACTION EXAMPLES, TISSUE DISTRIBUTION AGONIST POTENCY α1 ↑IP3, DAG (PLC, Gas) Vascular smooth muscle Epinephrine < norepinephrine α2 ↓cAMP (AC, Gai) Pancreatic β cells Epinephrine < norepinephrine β1 ↑cAMP (AC, Gas) Heart Epinephrine = norepinephrine β2 ↑cAMP (AC, Gas) Liver Epinephrine >> norepinephrine β3 ↑cAMP (AC, Gas) Adipose Norepinephrine >> epinephrine The α receptors and β3 receptors respond better to norepinephrine than epinephrine. The β1 receptor responds equally to the two catecholamines, whereas epinephrine is more potent than norepinephrine for the β2 receptor. A large number of synthetic selective and nonselective adrenergic agonists and antagonists now exist. A single catecholamine may thus evoke multiple different responses as a consequence of circulating concentration e.g., epinephrine may evoke both vasodilation and vasoconstriction  Physiologic actions of catecholamines Because the adrenal medulla is directly innervated by the autonomic nervous system, adrenomedullary responses are very rapid. Because of the involvement of several centers in the CNS adrenomedullary responses can precede onset of the actual stress (i.e., responses can be anticipated). For example, consider the sympathoadrenal response to exercise. Exercise is similar to the fight-or-flight response, but without the subjective element of fear. It increases circulating levels of both norepinephrine and epinephrine. The overall goal of the sympathoadrenal system during exercise is to meet the increased energy demands of skeletal and cardiac muscle while maintaining sufficient oxygen and glucose supply to the brain. The response to exercise includes three of the following major physiologic actions of norepinephrine and epinephrine  Increased blood flow to the muscles Norepinephrine and epinephrine (β1) act on the heart to increase the rate (chronotropy) and strength (inotropy) of contractions, induce vasoconstriction (α) of veins and lymphatics. All these effects increase cardiac output. Increased glucose availability Epinephrine promotes glycogenolysis in muscle (β2). Exercising muscle can also use free fatty acids (FFAs), and epinephrine and norepinephrine (β2 and β3) promote lipolysis in adipose tissue. This increases circulating levels of lactate and glycerol, which can be used by the liver as gluconeogenic substrates to increase glucose. Epinephrine increases blood glucose by increasing hepatic glycogenolysis and gluconeogenesis (β2). decreased energy demand by visceral smooth muscle. In general, a sympathoadrenal response decreases overall motility of the smooth muscle in the GI tract and urinary tract, thereby conserving energy where it is not needed.  Pheochromocytoma An uncommon tumor caused by hyperplasia of adrenal medulla or other chromaffin tissue. Excessive, unregulated production of catecholamines Symptoms; Sudden outburst of hypertension, headaches, episodes of sweating, anxiousness, tremor and glucose intolerance Laboratory detection of urinary catecholamines and their metabolites is critical for diagnosis and treatment, adrenalectomy and subsequent glucocorticoid and mineralocorticoid replacement therapy may be necessary