adrenal cortex and corticosteroids
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ADRENAL CORTEX AND CORTICOSTEROIDS. Zona glomerulosa. Regulation Angiotensin II, K+ Impt enz = P450 aldo Produces mineralocorticoids Functions: Stim’s Na+ reabs’n  incr’d ECF vol, Decr’d plasma K+, Incr’d plasma pH . Zona fasciculata . Regulation ACTH Impt enz’s

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slide5
Zona glomerulosa
  • Regulation
    • Angiotensin II, K+
  • Impt enz = P450 aldo
  • Produces mineralocorticoids
  • Functions:
    • Stim’s Na+ reabs’n
      •  incr’d ECF vol,
    • Decr’d plasma K+,
      • Incr’d plasma pH
slide6
Zona fasciculata
  • Regulation
    • ACTH
  • Impt enz’s
    • P450c17, P450c11
  • Produces
    • Glucocorticoids
    • Androgens (androstenedione, DHEA)
  • Functions
    • Stress response
    • Metabolism
    • Blood pressure
    • Immune function impacts
slide7
Zona reticularis
  • Regulation, enz’s, products same as zona fasciculata
  • Functions:
    • Main androgen source in females
corticosteroids
Corticosteroids
  • C21 pregnane deriv’s
    • C19 – androstane deriv’s; C18 – estrane deriv’s
    • Progesterone, mineralocorticoids, glucocorticoids
    • Lipophilic
    • Assoc w/ blood proteins
slide9
Pregnenolone: produced directly from cholesterol, the precusor molecule for all C-18, C-19 and C-21 steroids 

Cortisol:dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system

Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake 

slide10
Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstral cycle, differentiation factor for mammary glands

Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone 

Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics 

biosynthesis
Biosynthesis
  • Cell specific
  • Cholesterol precursor from cytoplasmic and membr pools
  • Rate-limiting: cholesterol  mitoch matrix
    • StAR incorporated into inner mitoch membr
    • Varied mol’s stim synth de novo
      • ACTH, LH, hCG
      •  cAMP    StAR
slide12
PBR – cholesterol channel
      • Ubiquitous; act’d by StAR
      • Assoc’d w/ “mitoch porin”
  • Cyt P450 enzymes coded by CYP genes
  • P450 scc catalyzes cholesterol  pregnenolone
    • Integral to inner mitoch membr
    • Active site faces matrix
adrenal cortex steroidogenic enzymes
Adrenal Cortex Steroidogenic Enzymes
  • P450c17 catalyzes rxns:
    • Pregnenolone  17a hydroxypregnenolone or DHEA
    • Not found in zona glomerulosa
      • So no glucocorticoids prod’d
    • DHEA impt to androgen synth
  • 3bHSD catalyzes rxns:
    • Pregnenolone  progesterone and
    • 17a hydroxypregnenolone  17a hydroxyprogesterone
slide16
P450c21
    • Catalyzes rxns:
      • Pregnenolone  11-deoxycorticosterone (DOC) and
      • 17a pregnenolone  11-deoxycortisol
    • Specific to adrenal cortex
    • DOC only in zona glomerulosa
      • Only progesterone available
    • 11-deoxycortisol in other zonae
slide17
P450 aldo (18 hydroxylase)
    • Catalyzes 3 rxns:
      • DOC    aldosterone
    • In inner mitoch membrane
    • Introduces C18 aldehyde grp
    • Expression specific for zona glomerulosa
    • Induced by
      • Angiotensin II
      • Elevated plasma K+
slide18
P450c11
    • Catalyzes rxn:
      • Deoxycortisol  cortisol (=hydrocortisone)
    • In inner mitoch membr
    • Expression specific for zonae fasciculata, reticularis
    • Induced by ACTH
mineralocorticoids
Mineralocorticoids
  • DOC secr’d by zonae fasciculata, reticularis
    • ACTH dependent
    • Potent in vitro
  • Zona glomerulosa secretes aldosterone
  • Plasma levels influenced by postural changes
  • CBG binds 20%
    • 40% bound to albumin
slide21
Free aldosterone cleared through kidneys
  • Inact’n in liver
    • Reduction, conjugation
    •  incr’d hydrophilicity, excrn
  • Stim’s renal Na+ reabs’n, K+ secr’n
  •  regulation ECF volume, electrolyte composition
renal na reabsorption
Renal Na+ Reabsorption
  • All Na filtered at glomerulus
  • Approx 1% plasma Na+ excr’d to urine
    • Reabs’n 65% by proximal tubule
    • Reabs’n 20-25% by distal tubule
    • Reabs’n 9% by cortical collecting duct
  • BUT cortical collecting duct sensitive to hormones
    • AVP
    • Aldosterone
aldosterone at cortical collecting duct
Aldosterone at Cortical Collecting Duct
  • Mineralocorticoid receptor
    • Related to glucocort, progesterone, androgen receptors
    • Ligand specific hormone-binding domain
    • Sequence specific DNA-binding domain
  • Several activities w/ ligand binding:
apical membr na channels
Apical Membr Na+ Channels
  • Aldosterone receptor occupation  stim’n de novo synth, activity of Na+ channels
  • Allows Na+ into cell w/ electrochem gradient
    • Conserves Na+ in body
  •  Depol’n luminal membr
  • Dietary Na+ intake 6-8 g/day
    • Aldosterone stim’d reabs’n max 30 g/day
adh regulated ad cyclase
ADH-Regulated Ad Cyclase
  • Aldosterone receptor occupation  induction expression ad cyclase sensitive to ADH
  • Impt to aquaporin synth, activation
  • So concerted reabs’n both water, Na+
  • Get isosomotic expansion ECF volume
  •  Incr’d bp
atpase activity
ATPase Activity
  • Aldosterone receptor occupation  stim’n ATPase
  • ATP needed to close electrolyte channels in luminal membr
    • Usually closed, high ATP
    • When open, K+ out of cells
  • When aldosterone, ATPase active  decr’d ATP  channel open  K+ out of cell
renin angiotensin system
Renin-Angiotensin System
  • Regulates zona glomerulosa
  • Angiotensinogen
    • Glycoprot
      • Sim to CBG, TBG
    • Secr’d by liver
    • Cleaved by proteinase (renin)
slide34
Renin catalyzes rxn angiotensinogen  angiotensin I
    • Rate limiting step of pathway
    • In liver, kidney
    • Secr’d by cells of juxtaglomerular apparatus
    • Incr’d renin secr’n w/
      • Conditions  decr’d renal blood flow
      • So w/ decr’d pressure at glomerular afferent arteriole
  • Angiotensin I cleaved by Angiotensin Converting Enzyme (ACE)  angiotensin II
    • ACE inhibitors lower bp
  • Angiotensin II
    • Biologically active
slide35
At zona glomerulosa
    • Angio II receptor heptahelical, G protein-coupled
    • Receptor occupation w/ angio II  stim’n PLC
    •  incr’d intracell Ca
    •  aldosterone synth
    • Also get act’n PKC, MAP kinase, maybe tyr kinases
    •  prolif’n zona glomerulosa, vasc sm muscle
  • Also acts as potent vasoconstrictor by same pathway in vasc smooth muscle
regulation of renin secr n
Regulation of Renin Secr’n
  • By feedback mech’s at kidney JGA
  • Incr’d renin secr’n w/
    • Conditions  decr’d renal blood flow
    • So w/ decr’d pressure at glomerular afferent arteriole
  • Macula densa = Na+ sensor
slide40
Tubuloglomerular feedback
    • Neg feedback between between macula densa NaCl concent and GFR
    • If NaCl in lumen incr’d, macula densa secr’s adenosine
      •  afferent arteriole  constriction  decr’d GFR
        • Short-term adaptation to Na balance
      • Also  decr’d renin secr’n by JGA
        • Long-term adaptation to Na balance
    • If decr’d ECF vol or decr’d NaCl at JGA, get incr’d renin secr’n
      •  Incr’d angiotensin II, so
        • Vasc sm muscle constriction
        • Aldosterone  Na reabs’n  incr’d ECF vol
slide41
Short-loop feedback
    • Angiotensin II inhibits renin secr’n from JGA
  • Long-loop feedback
    • Aldosterone secr’n regulates Na concent  renin regulation
  • Plasma renin activity assoc’d w/ sleep rhythms
    • Impt to bp during sleep cycles
atrial natriuretic peptide factor
Atrial Natriuretic Peptide (Factor)
  • Opposes action of aldosterone
    • Decr’s Na+ retention
    • Decr’s bp
  • Prod’d by cardiac muscle cells (esp RA)
    • In response to stretch w/ incr’d venous P
  • ANP receptor is single-membrane span
slide43
In kidney, ANP:
    • Acts at afferent, efferent arterioles
      •  incr’d bhp  incr’d GFR
    • Acts at collecting duct
      • Inhibits Na+ reabs’n
      •  prod’n autocrine prot
        • Binds ANP receptor  cGMP  inhib’n Na channel
        •  diuresis, natriuresis
      • Inhibits renin secr’n
  • At adrenal, inhibits aldosterone secr’n
  • At brain, decr’s salt appetite, ADH secr’n
  • At vasculature, incr’s permeability of vessels  fluid from IVF  ISF/ICF
    • Also dilates vessels
glucocorticoids
Glucocorticoids
  • Cortisol most widely studied
  • Bound to CBG
    • Free 4-10%
  • Liver metab
    • Reduced, conjugated
    • Cortisone  cortisol
cortisol
Cortisol
  • Aid in adaptation to adverse situations
    • Widespread activities
      • Receptor widely expressed
    • Coordinated
  • Lipophilic
    • Passes through plasma membranes
    • Penetrates BBB
glucocorticoid receptor
Glucocorticoid Receptor
  • Classical action
    • Homodimer
    • Glucocort response elements at promoter regions
    • Act’n or suppression of transcription
  • Also, transcriptional cross talk
    • Prot-prot interactions of act’d receptor + other transcr’n factor
    • So other receptor/transduction pathways impacted
  • Act’n w/out ligand
    • Stim’n b2 adr receptor agonists
cortisol activities
Cortisol Activities
  • Direct
    • Ex: Induces enz’s involved in metab pathways
  • Indirect
    • Ex: Maintains vasc reactivity to catecholamines
  • Nongenomic
    • Ex: Induction PNMT in adrenal medulla
stress response
Stress Response
  • First: adrenaline incr’s liver glycogenolysis
    •  Free glucose
    • BUT liver glycogen rapidly depleted
  • Largest energy store: triglycerides in adipose tissue
    • Catecholamines, other hormones activate lipases  free fatty acids + glycerol
slide53
FFA  cells
    •  b oxidation  acetyl CoA
    •  Kreb’s cycle  ATP
    • Incr’d ATP allosterically inhibits glycolysis enz’s  incr’d plasma glucose
  • Glucocorts facilitate lipolysis at adipose
    • Permissive (Fig 15.17)
    • Provides FFA for liver: induct’n lipolysis @ adipose
      •  ATP, so incr’d plasma glucose
    • Induce liver gluconeogenic enz’s
      •  Stim’n liver gluconeogenesis
    • Mobilizes aa’s from muscle
      • Used for gluconeogenesis
cortisol regulates immune inflamm responses
Cortisol Regulates Immune, Inflamm Responses
  • Suppresses prod’n cytokines
    • Proinflammatory prot’s
  • Suppresses transcr’n COX2 (PG synthetase)
    • Suppresses PG/leukotriene synth
    • Also inhibits PLA2 so suppresses PG’s
  • Induces lipocortins
    • Autocrine inhibitors of wbc’s
  • Suppresses/causes apoptosis of immune cells
cortisol direct cns effects
Cortisol Direct CNS Effects
  • Overprod’n or exogenous glucocort’s  memory impairment
  • Hippocampal atrophy may be impt to posttraumatic stress disorder
  • Limbic system impact  impact on mood
    • Normal cortisol req’d for normal mood
    • Linkage to sleep cycles?
  • Stimulates appetite
stress signals
Stress Signals
  • Emotional (anxiety)
  • Hypoxia, hypercapnia
  • Hypoglycemia
  • Decr’d bp or ECF vol
  • Infections
  • Env tempt changes
  • Ethanol consumption
  • Long-term normocortisolemia req’d for acute responsiveness to other stress hormones
circadian rhythm
Circadian Rhythm
  • Environmental cues  suprachiasmatic nucleus
    •  Paraventricular neurons  CRH
    • Lowest cortisol 6-8 a.m.
    • Highest cortisol 6-10 p.m.
glucocorticoid regulation
Glucocorticoid Regulation
  • Hypothal CRH
    •  ant pit corticotrophs  ACTH release
    • Neg feedback control by cortisol
    • Pulsatile secr’n
  • In other brain areas
    • Synth b endorphins
  • Outside CNS
    • Stim synth PGs (proinflammatory)
slide60
CRH-BP
    • Secr’d by liver, placenta
    • CRH sink
  • CRH receptors in ant pit
    • CRH1R suppressed by cortisol
      • Impt to neg feedback control
      • Expressed in other brain areas where related to stress response
      • Impt to parturition initiation
    • CRH2R impt to vasodilation
slide62
ACTH
    • POMC derivative
      • Also b-LPH, a-MSH, b-endorphins
    • Pulsatile secr’n (CRH)
    • Secr’n stim’d by AVP
    • Secr’n inhib’d by glucocorticoids (cortisol)
  • ACTH receptor
    • G-prot coupled heptahelical
    • Stim’s adrenocortical steroidogenesis
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