Stress And Metabolism: Epinephrine

Question 1

Synthesis of catecholamines

Answer 1

. Chromaffin cells in adrenal medulla start w/ Tyr/Phe converted to Tyr
. Tyr hydroxylated to DOPA via Tyr hydroxylase (rate-limiting step)
. DOPA to dopamine that is transported into chromaffin granule and dopamine hydroxylase converts dopamine to NE
. In come cells that make E the NE enters cytosol where enzyme PNMT catalyzes conversions to E
. E is transported back into chromaffin granule for storage

Question 2

Phenyl-ethanolamine-N-methyltransferase

Answer 2

. PNMT
. Only located in cytosol of E-producing cells
. Synthesis is stimulated by adrenal cortical hormone cortisol that during stress can reach high conc. In veins that perfume adrenal medulla

Question 3

Catecholamine storage

Answer 3

. Chromaffin cells store E and NE
. Granules concentrate catecholamines up to 25,000 times in cytosol
. Sequestration of catecholamines in granule complexes w/ ATP to protect them from oxidative degradation by cytosolic enzymes
. Interior of granules is acidic which stabilizes catecholamines and coincides w/ pH optimum of dopamine-beta-hydroxylase

Question 4

Adrenal gland activation

Answer 4

. Activates after intense SNS stimuli
. Sympathetic preganglionic fibers innervate adrenal medulla and release ACh
. ACh-receptor interaction on chromaffin cell membrane causes granules to move to and fuse w/ cell membrane so contents are released into extracellular space via exocytosis
. Ca is involved in process

Question 5

Concentrations of NE and E during adrenal medulla activation

Answer 5

. 80% cells synthesis E so plasma E inc. more then plasma NE
. Under resting conditions E conc. is 20-50 pg/ml and NE conc. Is 100-350 pg/ml
. NE at rest does not come from adrenal medulla but is a NT that escaped metabolism
. NE conc. Still well below threshold conc. Required to interact w/ adrenergic receptors of target cells

Question 6

Catecholamine mechanism of action

Answer 6

. Effect of NE and E dependent on predominant receptor subtype on cell membrane and the relative affinities
. Beta-1 in heart
. Alpha-1 in blood vessels
. Beta 2 and 3 in tissues crucial for intermediary metabolism, bronchial smooth m. And heart
. Affinity of E to beta-2 receptors exceeds that of NE
. Affinity of NE to beta-3 receptors is greater than E

Question 7

Alpha-1 adrenergic receptor

Answer 7

. Vasoconstriction
. Liver glycogenolysis/gluconeogenesis
. Intestinal smooth m. Relaxation
. E high affinity than NE

Question 8

Alpha-2 adrenergic receptor

Answer 8

. Vasoconstriction
. Postganglionic sympathetic n. Terminals (dec. NE release)
. Dec. insulin release from pancreas
. E has higher affinity than NE

Question 9

Beta-1 adrenergic receptor

Answer 9

. Heart: inc. HR, conduction velocity, and contractility)
. Inc. renin secretion from juxtaglomerular cells
. Equal E and NE affinity

Question 10

Beta-2 adrenergic receptor

Answer 10

. Liver: inc. glycogenolysis and gluconeogenesis 
. Bronchodilation 
. Intestinal smooth m. Relaxation 
. Inc. HR and contractility 
. Contracts sphincters 
. Adipose: inc. lipolysis
. Skeletal m.: inc. glycogenolysis
. Pancreas: inc. insulin (minor effect)
. E affinity higher

Question 11

Beta-3 adrenergic receptor

Answer 11

. Inc. lipolysis in adipocytes

. NE higher affinity than E

Question 12

What hormone is crucial and released during stressful situations bc it provides fuel for body in form of glucose and FAs

Answer 12

Epinephrine

Question 13

Epinephrine and glucose metabolism

Answer 13

. Counter-regulatory to insulin and stimulates glucagon
. Stimulates glycogenolysis and gluconeogenesis in liver to inc. plasma glucose
. Acts on skeletal mm. To stimulate glycogenolysis
. Inhibits insulin-dependent glucose entry into mm. And adipose to inc. plasma glucose (does not block transporters, just interfere’s w/ ability to stimulate glucose transport)

Question 14

epinephrine and fat metabolism

Answer 14

. Stimulates triglyceride lipase in adipose tissue releasing FAs that are then oxidized by tissues to generate ATP or converted to ketones in liver
. Cortisol and thyroid hormone are required as permissive hormones for this effect

Question 15

Regulation of catecholamines

Answer 15

. Secretion controlled by SNS input to the gland
. Conditions that activate the SNS also stimulate adrenal medullary secretion
. SNS receives a large part of its input from limbic system and hypothalamus

Question 16

Autocrine control of catecholamines

Answer 16

. Release of catecholamines from both n. Terminal sand chromaffin cells is controlled by inhibitory regulation
. When catecholamines released in large quantity, they can bind to alpha-2 adrenergic receptors located in pre-synaptic terminal (autoreceptors) that halt the exocytosis process, thereby inhibiting further release of catecholamines
.prevents excessive secretion of NE and E

Question 17

Half-life of catecholamines

Answer 17

1 and 3 min

Question 18

Primary mechanism for catecholamine metabolism

Answer 18

. Enzymatic degradation

Question 19

Enzymatic degradation

Answer 19

. Occurs in liver
. Deamination via monoamine oxidase (MAO) and aldehyde oxidase (AO)
. 3-O-methylation by catechol-O-methyltransferase (COMT)
. Major metabolites: VMA (small portion derived from NE that reflects SNS activity) and MOPEG
. COMT and MAO distributed in tissues but exist at highest conc. In liver and kidney
. Catecholamines are not taken up locally into target tissues and metabolized extracted out of plasma in liver or kidney

Question 20

Catecholamine uptake1 system

Answer 20

. Located in SNS n. Endings and removes NE from synapse
. Following neuronal uptake NE is stored in chromaffin granules or enzymatically degraded by MAO
. COMT not found in neuronal tissue, delaminates derivatives are metabolized to VMA by COMT in liver

Question 21

Catecholamine uptake2 system

Answer 21

. Extraneuronal
. Removes catecholamines in plasma
. Results in metabolism of catecholamines by MAO and/or COMT
. Predominance of this vs. uptake1 in particular tissue primarily depends on on extent of n. Innervation

Question 22

Catecholamine excretion

Answer 22

. Small amts of unmetabolized E and NE are excreted in urine
. Metabolites from COMT methylation, VMA, and MOPEG are excreted in urine

Question 23

Pheochromocytoma

Answer 23

. Uncommon tumor caused by hyperplasia of chromaffin cells
. Produce excessive amts of catecholamines
. Tumor may involve adrenal medullary tissue or extra-adrenal chromaffin tissue that failed to involve after birth
. Usually only involves 1 gland
.diagnosis based on clinical history, excessive adrenergic tone
. Treatment: removal of tumor that may involve whole gland
. Glucocorticoid and mineralcorticoid replacement after surgery

Question 24

Pheochromocytoma symptoms

Answer 24

. Paroxysmal hypertension
. Tachycardia 
. He ache
. Sweating and anxiousness
. Tumor
. Palpitations and chest pain
. Glucose intolerance 
. May show orthostatic hypotension: hypersecretion of catecholamines can dec. postsynaptic response to NE as result of down-regulation of adrenergic receptors 
. Baroreceptors response to blood shifts that occurs on standing is blunted