M2 Flashcards
PNMT
phentolamine N-methyltransferase
- converts NE ➔ EPI
- only expressed in chromaffin cells in adrenal medula
inflammatory response
- inflammation = results of 1st line of defense (innate)
- initiated on site of antigen contact
- clinical signs:
- tumor (swelling): ➔ edema from blood
- rubor: redness
- calor: heat ➔ tons of metabolic activity generates heat
- dolor: pain
- tumor ➔ enlarged site b/c extra cells migrate to area
- functio laesa: loss of fx ➔ tissue busy fighting injury
immune system
2 levels of immune defense:
-
innate - 1st line
- antigen presenting cells ➔ macrophages, dendritic cells, neutrophils
- phagocytosis of antigens at site of injury
- antigen processing & presentation
- production of pro-inflammatory cytokines: interleukins (IL) & tumor necrosis factors (TNF)
-
acquired - 2nd line
- attract other immune cells
- build immune memory
eicosanoids
signaling molecules made by oxidation of fatty acids
- cytokines: pro-inflammatory mol that attract other cells to mount stronger immune response
- IL: interleukins
- TNF: tumor necrosis factors
inflammation pathway
phospholipase A2 releases arachidonic acid from PM & converts them into eicosanoids
- CYTP450 epoxygenase converts arachidonic acid into epoxyeicosatrienoic acids (EETs)
-
cox 1 & cox 2 convert arachidonic acid into prostanoids:
- prostaglandins
- prostacylin (PGI2)
- thromboxane (TXA2)
-
lox converts arachidonic acid into HETEs:
- leukotrienes
- lipoxins
cortisol action on inflammatory pathway
cortisol blocks phospholipase A2 ➔ inhibits entire inflammation pathway
arachidonic acid
precursor of pro-inflammatory eicosanoids
- released from PM by phospholipase A2
NSAID action on inflammatory pathway
block cox 2 ezyme ➞ inhibit prostanoids
- EETs & HETEs still synthesized
- minimize inflammatory response
glucocorticoid: innate immunity regulation
↓ pro-inflammatory mol
- ↓ prostaglandin synthesis
- ↓ cytokine production
↓ cell-mediated immune response
- ↓ vascular permeability
- ↓ mast cell #s
- ↓ antigen-presenting cell #s
glucocorticoid: acquired immunity regulation
↓ differentiation of antigen-fighting cells
- inhibits T & B lymphocytes in circulation
- inhibits synthesis of immunoglobulins
stimulates lymphocyte apoptosis ➔ removes antigen-fighting cells from circulation
embryonic origin of adrenal cortex
mesoderm
embryonic origin of adrenal medulla
neural ectoderm
adrenal medulla hormones
EPI, NE, dopamine
cells of the adrena medulla
chromaffin cells (pheochromocyte): synthesis & storage of catecholamines (NE, EPI)
- highly specialized neural system originating in neural crest that make up the adrenal medulla
- migrate to adrenal medulla & paraganglia during embryo/fetal development
epinephrine synthesis
tyrosine ➔ dopamine (dopamine β-hydroxylase - DBH) ➔ NE (PNMT) ➔ EPI
enzyme that converts NE to EPI
PNMT: phentolamine N-methyltransferase
epinephrine
- synthesized from NE
- precursor mol: tyrosine
-
produced exclusively by adrenal medulla cells (main product ~80%)
- NE present in CNS, adrenal medulla, & sympathetic neurons
adrenal medulla neurons innervated by:
SNS
- sympathetic cholinergic preganglionic neurons originate from thoracic & lumbar regions
- nerves synapse at ganglia outside of spinal cord
- stimulates adrenal medulla to secrete catecholamines
- directly stimulates CO: directs bf to muscles & diverts bf away from visceral organs
adrenal medulla glucocorticoid affinity
adrenal medulla has GCR ➞ able to immediately respond to newly synthesized cortisol
- cortisol acts locally on neighboring medulla cells
SNS input: normal vs adrenal medullary
normal:
- short cholinergic preganglionic neurons release ACh to paraganglion with nicotinic cholinergic receptors
- long adrenergic postganglionic neurons release NE to target organ/tissue with adrenergic receptors
adrenal:
- long cholinergic preganglionic neurons release ACh into nicotinic cholinergic receptors in adrenal medulla
- adrenal medulla secretes EPI
neurons release NE, medulla secretes EPI
effects of EPI
fight or flight response: extremely fast response mediated by nervous reflex, EPI release from adrenal medulla, & NE release in adrenergic synapses
- lipolysis
- ↑ breakdown of hepatic glycogen
- ↑HR (tachycardia) ➞ chronotropic effect: effects ↑ (speed up) time
- ↑SV ➞ strength of contraction ➞ inotropic effect: effects ↑ efficiency (strength of contraction)
- peripheral vasoconstriction ➞ blood redirected where it’s needed
- ↑BP
- dilation of coronary arteries (↑ perfusion to heart)
- dilation of muscle vessels (↑ perfusion to muscles)
catecholamines
DA: dopamine
EPI: epinephrine
NE: norepinephrine
catecholamine biosynthesis
- tyrosine = precursor
- from food or liver synthesis from phenylalanine
- DBH = dopamine β-hydroxylase: converts dopamine ➔ NE
- PNMT = phentolamine N-methyltransferase: converts NE ➔ EPI
- 10:1 EPI:NE
- cortisol stimulates PNMT synthesis ➞ can convert more (still possible w/out cortisol)
epinephrine response to hypoglycemia
- stimulates HSL enzyme to ↑ lipolysis
- stimulates glycogen phosphorylase to break down glycogen
- inhibits glycogen synthesis
- 2 & 3 oppose cortisol: EPI is breaking glycogen that cortisol is making
EPI & NE effects
- NE fxs primarily as a neurotransmitter for cardiac effects
- both NE & EPI influence vascular tone
- EPI affects metabolic processes (e.g carbohydrate metabolism)
- ↑ RR
- ↑ bf to skeletal muscles
- intestinal muscles relax
- pupils dilate
- ↑BP
- ↑BG
- ↑HR
catecholamines & adrenergic receptors
- 5 types of adrenergic receptors: ⍺1, ⍺2, β1, β2, β3
- located in diff parts of body
- extent of action depends on how much of the hormone is present
- at higher levels: catecholamines can also bind to receptors with lower affinity
- GPCRs
- at ↓[plasma]: EPI predominantly stimulates β-adrenergic receptors causing vasodilation
- at ↑[plasma]: EPI stimulates ⍺-adrenergic receptors sufficiently to override vasodilation & cause vasoconstriction
- each adrenergic receptor subtype is encoded by a diff gene
main receptor type for EPI at low concentrations
β2-adrenergic receptor
main receptor for EPI during high concentrations (during fight-or-flight)
⍺2-adrenergic
⍺1-adrenergic receptor pathway
Gq alpha subunit using phospholipase C to convert PIP2 to IP3 & DAG
⍺2 adrenergic receptor pathway
Gi ⍺ subunit inhibiting adenylyl cyclase
β adrenergic receptor pathway
Gs ⍺ subunit using adenylyl cyclase to convert ATP to cAMP
Gi alpha subunit GPCR
inhibitory: blocks adenylyl cyclase
⍺1-adrenergic affinity
NE > EPI
⍺1-adrenergic agonist
phenylephrine
⍺2-adrenergic G protein, linked enzyme, &
second messenger
Gi ⍺ subunit inhibits adenylyl cyclase to ↓ cAMP
β1-adrenergic tissue & action
- ↑ force & rate of contraction in myocardium
- ↑ renin secretion in JGC cells of kidney
β2-adrenergic G protein, linked enzyme, & second messenger
Gs protein using adenylyl cyclase to ↑ cAMP
β3-adrenergic G protein, linked enzyme, & second messenger
Gs protein using adenylyl cyclase to ↑ cAMP
β3-adrenergic agonist
BRL37344
β3-adrenergic affinity
NE > EPI
β2-adrenergic agonist
isoproterenol
β2-adrenergic affinity
EPI > > > NE
β1-adrenergic G protein, linked enzyme, & second messenger
Gs alpha subunit using adenylyl cyclase to ↑ cAMP
β1-adrenergic agonist
dobutamine or isoproterenol
β1-adrenergic affinity
EPI =NE
⍺2-adrenergic agonist
xylazine
⍺2-adrenergic affinity
NE > EPI
⍺1-adrenergic tissue & action
- vasoconstriction (↑ BP)
- contracts spleen expelling blood
⍺1-adrenergic G protein, linked enzyme, & second messenger
Gq using phospholipase C to↑ IP3, DAG, & Ca
⍺2-adrenergic tissue & action
↓ neurotransmitter release in preganglionic neurons
β2-adrenergic tissue & action
- vasodilation (↑ bf)
- bronchial dilation
- ↑ glycogenolysis & gluconeogenesis in liver
dopamine receptors
- not adrenergic receptors
- GPCRs
- subcategories: D1-like & D2-like
dopamine-2 receptor tissue & action
inhibits prolactin release in pituitary lactotrophs