Adrenal Gland Phys (Parfenova) Flashcards by Jennifer Watson

What are the hormones produced in the adrenal gland and what part of the gland specifically makes them?

Cortex:
Z. glomerulosa: mineralcorticoids
Z. Fasciculata and reticularis: glucocorticoids, androgens, estrogens

Medulla: Catecholamines: Epi and NE

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provide sustained energy source by ↑ gluconeogenesis in liver, ↑ lipolysis, ↑ blood glc (↓glc utilization by tissues)

Cortisol (glucocorticoid)

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growth and developmental control mediated by…

sex hormones: androgens, estrogens

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↑ Na reabs and K and H+ secretion

aldosterone (mineralcorticoid)

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medites immediate response to stress: ↑glc and FA, ↑CV function and performance

catecholamines: epi and norepi

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describe the transport of adrenalcortical hormones in the blood

steroid hormones (i.e. not catecholamines) are about to serum proteins

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albumin has (low or high) affinity for adrenalcortical hormones

low

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90% of cortisol is bound to

transcortin (CBP)

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the other 10% of cortisol is bound to..

nothing! it is the free/active horomone

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in general, if you ↑ the % hormone bound to a plasma proteins, you ↑ ____ and ↓ _____

↑ t 1/2

↓biological activity

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adrenal cortocosteroids are derived from

cholesterol

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what is the main provider of cholesterol for corticosteroid prodction

LDL

*80% from LDL and 20% of cholesterol is synthesized in the adrenal gland

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Describe what happens to cholesterol in LDL when it arrives to the adrenal cells

LDL binds LDL receptor on adrenal cell surface → internalization via clatherin coated pits → endosome → lysosome → cholesterol is esterfied and stored in cytoplasmic vesicles and LDL receptors are recycled

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What are the key enzymes in the synthesis of mineralcorticoids? What steps do they mediate?

cholesterol desmolase (CYP11A1) 
-cholesterol → pregnenolone *rate limiting step

Aldosterone synthetase:
corticosterone → aldosterone

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activates cholesterol desmolase (CYP11A1)

ACTH

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activates Aldosterone synthetase:

Ang II

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synthetic, potent aldosterone analong (slightly more potent than aldosterone)

9alph-fluorocortisol (fludrocortisone)

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Effect of ACTH in adrenals

stimulates the activity of cholesterol desmolase (CYP11A1)
upregulates LDL receptors to inc cholesterol uptake

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(Cholesterol desmolase (CYP11A1) or Aldosterone synthetase) is located in the mitochondria

Aldosterone synthetase

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describe the regulation of aldosterone synthesis

decreased renal perfusion (low BP, vascular dz) → renin secretion → angiotensinogen to ang I (in liver) → ang I to ang II (by ACE) → ang II in adrenal cortex activates aldosterone synthetase → corticosterone to aldosterone

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aldosterone target tissues

“Aldosterone: Keeps Liquid Volume High (in our) Body”

Kidneys
Lungs
Vasculature 
Heart
Brain

i.e. where mineralcorticoid receptors are found

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What glucocorticoids have mineralcorticoid activity?

aldosterone (high receptor affinity)
cortisol (high affinity)
Cortisone (low affinity)

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How is the selectivity of MR shifted towards aldosterone (when cortisol is also present for binding and it has high affinity ofr MR as well)?

11beta hydroxysteroid dehydrogenase converts cortisol to cortisone, which has a lower affinity for MR ∴ aldo can displace it and bind

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where does aldo bind MR? (think on cellular level, not organ/tissue)

in cytoplasm

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describe the what happens when aldo binds MR: | delayed effects and immediate effects

aldo-receptor complex translocates to the nucleus → DELAYED: binds specific gene promotor → upregulation of... 1. Na/K ATPase 2. ENaC 3. ROMK 4. Sgk1**kinase that activates 1-3** **all of these ↓ intracell Na and ↑intracell K** IMMEDIATE: 1. ↑cAMP --IP3 mediated signaling → ↑Ca dept regulation 2. ↑ activity of kinases (ERK1/2 and JNK)

renal effects of aldosterone

↑Na reabs (∴ H2O too) -- via Na/K ATPase and ENaC ↑ K secretion -- via Na/K ATPase and ROMK ↑ H+ secretion -- via Carbonic Anahydrase ↑ bicarb production -- via CA

most potent glucocorticoid our body synthesizes

cortisol

cortisol precursor with moderate potency

corticosterone

cortisol metabolite with low potency

cortisone

key enzymes in cortisol biosynthesis and the steps they mediate

1. cholesterol desmolate (cholesterol → progenolone) 5. 11beta-hydroxylase (11deoxycortisol → cortisol) look at the slide for the others, its probable not worth memorizing 2. 17alpha hydroxylase 3. 3beta-hydroxysteroid dehydrogenase 4. 21beta-hydroxylase **numbered in order

Glucocoticoids bind receptor on PM or intracell?

intracell

describe what happens once glucocorticoid binds receptor

GC-receptor complex translocates to nucleus → binds promoter of target genes → 1. transactivation (simultanous stimulation and repression) of gene expression 2. transrepression via NFkB → ↓proinflam cytokines

describe overall purpose/goal of glucocorticoids action on carbohydrate and protein metabolism

mobilize protein from peripherial tissues to provide glc supply to the brain and other tissues

effects of glucocorticoids in the liver

↑ gluconeogenesis (from aa) ↑ glycogenesis ↑ protein synthesis to make key enzymes

effect of gluconeogeneis in pancreas

↑ insulin production (to inc glc uptake)

glucocorticoids (activate or inhibit) insulin sensitive glucose transporters. effect of this?

inhibit: ↓ glc uptake by most cells (except brain) ∴ producing "insulin resistance" * recall, glucocorticoids also ↑insulin, so plasma levels of insulin will be high, yet tissues will not be able to utilize it = "insulin resistance"

What is the only organ that has enchanced glc uptake in the presence of glucocorticoids

brain | **insulin-indept process

in the presence of glucocorticoids, protein is broken down everywhere but the

liver | **protein synthesis is also inhibited everywhere but the liver

What happens to the thymus in the presence of glucocorticoids

involution

Describe the effect of fat metabolism by glucocorticoidsteroids

↑lipolysis (→FA → oxidation ) | paradoxically causes fat deposits, at high doses --think moonface

What immune cells are the main target of glucocorticoids?

macrophages and T lymphocytes

glucocorticoids effects on macrophages and T lymphocytes

↓ pro-inflammatory cytokines and ↑apoptosis *will eventually cuase atrophy of lymphoid tissue

glucocorticoids effects on immune function

1. lysosomal disruction to ↓ inital stages of infalmmation 2. prevents edema (↓permiability of capillaries) 3. ↓leukocyte migration to inflammed area 4. ↓ T lymphocytes 5. attenuates fever 6. prevents immunological rejection of transplant tissue

effect of glucocorticoids on skin

↓ collagen synthesis

effect of glucocorticoids on blood vessels

vasoconstriction → HTN

effect of glucocorticoids on stomach

↑ gastic acid secretion and enzyme production

effect of glucocorticoids on blood clotting

↓ clotting → bruising **bc ↓Ca abs and reabs → hypoCa, and Ca is needed in the blood for clotting factors

How do glucocorticoids suppress growth

↓ Ca abs in intestine and reabs in kidney → hypoCa → ↑PTH → bone demineralization/resorption

Cell composition in the adrenal medulla

granular chromaffin cells | ganglion cells

hormones of the adrenal medulla are dericed from

tyrosine *hormones = epi and NE

describe the synthesis of epi

tyrosine → DOPA → DA → NE → Epi

enzyme that converts NE to epi

PMNT (phenlethanolamine N-methyltransferase)

what activates PMNT

high levels of cortisol → ↑↑epi

targets of catecholamines

alpha and beta adrenergic receptors on... | heart, lungs, muscles, vessels

what controls the release of catecholamines

sympathetic nervous system

intracellular signaling of catecholamine binding alpha or beta adrenergic receptors

activate GPCR → AC active → ↑cAMP → pro kinases active

describe the steps/pathway of hypothalamic-pit-adrenal axis

stress → hypothalamus released CRH → Ant pit releases ACTH → adrenal cortex releases cortisol → metabolic and immune effects

describe the negative feedback of the hypothalamic-pit-adrenal axis

cortisol 1. ↓ inhibitory input of hippocampus 2. ↓ CRH release from hypothalamus 3. ↓ ACTH production from ant pit

consequences of long term dexamethasone treatment

↓cortisol production and functional atrophy of hypothalamus-pit-adrenal axis

What are the markers for stress in the blood

cortisol and ACTH

effects of sustained, severe stress

continuous stimulation of adrenal hormones → enlargement and adrenocortical hyperfusion → disease... - heart disease - immunosuppression - digestive problems - sleep disorders - anxiety and depression ...those poor monkeys...