Stress And Metabolism: Epinephrine Flashcards
Synthesis of catecholamines
. 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
Phenyl-ethanolamine-N-methyltransferase
. 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
Catecholamine storage
. 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
Adrenal gland activation
. 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
Concentrations of NE and E during adrenal medulla activation
. 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
Catecholamine mechanism of action
. 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
Alpha-1 adrenergic receptor
. Vasoconstriction
. Liver glycogenolysis/gluconeogenesis
. Intestinal smooth m. Relaxation
. E high affinity than NE
Alpha-2 adrenergic receptor
. Vasoconstriction
. Postganglionic sympathetic n. Terminals (dec. NE release)
. Dec. insulin release from pancreas
. E has higher affinity than NE
Beta-1 adrenergic receptor
. Heart: inc. HR, conduction velocity, and contractility)
. Inc. renin secretion from juxtaglomerular cells
. Equal E and NE affinity
Beta-2 adrenergic receptor
. 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
Beta-3 adrenergic receptor
. Inc. lipolysis in adipocytes
. NE higher affinity than E
What hormone is crucial and released during stressful situations bc it provides fuel for body in form of glucose and FAs
Epinephrine
Epinephrine and glucose metabolism
. 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)
epinephrine and fat metabolism
. 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
Regulation of catecholamines
. 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
Autocrine control of catecholamines
. 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
Half-life of catecholamines
1 and 3 min
Primary mechanism for catecholamine metabolism
. Enzymatic degradation
Enzymatic degradation
. 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
Catecholamine uptake1 system
. 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
Catecholamine uptake2 system
. 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
Catecholamine excretion
. Small amts of unmetabolized E and NE are excreted in urine
. Metabolites from COMT methylation, VMA, and MOPEG are excreted in urine
Pheochromocytoma
. 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
Pheochromocytoma symptoms
. 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
