section 32.1
Adrenal Cortex
result from ingestion of large amounts of licorice, which
contains glycyrrhetinic acid, an inhibitor of 11 /3HSD.
Physiological Effects o f Aldosterone
The major effect is on the distal tubules of nephrons,
where aldosterone promotes sodium retention and potas-
sium excretion. Under the influence of aldosterone,
sodium ions are actively transported out of the distal tubu-
lar cell into blood, and this transport is coupled to passive
potassium flux in the opposite direction. Consequently,
intracellular [Na+] is diminished and intracellular [K+]
is elevated. This intracellular diminution of [Na+] pro-
motes the diffusion of sodium from the filtrate into the cell,
and potassium diffuses into the filtrate. Aldosterone also
stimulates sodium reabsorption from salivary fluid in the
salivary gland and from luminal fluid in the intestines, but
these sodium-conserving actions are of minor importance.
Biological Actions of Cortisol
Mechanism o f Action
Cortisol and the synthetic glucocorticoids (GCs) bind to
the type II corticosteroid receptor (glucocorticoid receptor,
GR), and the resultant GC-GR homodimer activates glu-
cocorticoid response elements (GRE) in chromatin, which
ultimately leads to the genomic effects characteristic of
GCs (Chapter 30). However, not all of the biological ef-
fects of GCs can be explained by this mechanism. In exert-
ing its antimitogenic effects, GCs interfere with mitogen-
stimulated AP-1 transactivation of late response genes by
binding of c-jun by the GC-GR complex; thus, no induc-
tion of a GC-responsive gene is required for this effect.
Not all of the GC effects involve binding of GC to
the GR. Elevated levels of cortisol and synthetic GCs are
known to exert rapid-onset, nongenomic effects that are
seen within minutes and do not involve the GR or a change
in gene expression. Such nongenomic effects, which in-
clude the rapid suppression of ACTH release, the inhi-
bition of exocytosis in inflammatory cell types, and the
strong inhibition of GH release, are believed to involve
the direct binding of extracellular GC-CBG complex to
cell membrane receptors.
Physiological Effects o f Cortisol
Normal circulating levels of cortisol, including the cir-
cadian early-morning rise and the moderate elevations af-
ter meals and minor stresses, help sustain basic physio-
logical (vegetative) functions. Large amounts of cortisol
released in response to major stresses enable the individual
to withstand, or cope with, the metabolic, cardiovascular,
and psychological demands of the situation. Cortisol (and
other glucocorticoids) promotes the conservation of glu-
cose as an energy source in several ways:
1. Cortisol induces and maintains the activity of all of
the specifically gluconeogenic enzymes in the liver.
By increasing hepatic formation of glucose, cortisol
promotes its conversion to hepatic glycogen. Insulin
reduces cortisol-stimulated gluconeogenesis but
potentiates its effect on glycogenesis; glucagon, on
the other hand, augments the gluconeogenic action of
cortisol while inhibiting its effect on glycogen
2. Cortisol inhibits glucose utilization in peripheral
tissues, such as skeletal muscle, adipose tissue, bone
matrix, lymphoid tissue, and skin, by inhibiting
glycolysis and promoting the use of fatty acids. This
action is modulated by insulin and thyroid hormones
but is potentiated by GH.
3. Cortisol promotes the liberation of fatty acids from
adipose tissue by inducing and maintaining the
synthesis of hormone-sensitive lipase (HSL), an effect
supported by GH. The actual activity of HSL is
controlled by those hormones that trigger its
phosphorylation (glucagon, catecholamines) or
dephosphorylation (insulin, PGE).
4. Cortisol, by inhibiting glucose utilization in
peripheral tissues, exerts a mild antianabolic effect on
these tissues; this effect diminishes their rate of amino
acid incorporation, thus making available more amino
acids for metabolism by these tissues, but mainly for
hepatic protein synthesis and gluconeogenesis.
Cortisol has an important permissive influence on the
cardiovascular system by conditioning many components
of the system to respond maximally to regulatory sig-
nals. In the absence of GC, inadequacy of cardiovascu-
lar response can result in circulatory collapse and death,
whereas in GC excess, increased cardiovascular respon-
siveness may result in hypertension. Cortisol is required
for vascular smooth muscle to respond to the vasocon-
strictor effect of catecholamines (norepinephrine), but the
mechanism is incompletely understood. The hypotension
in GC deficiency is normalized by intravenous cortisol
treatment. Cortisol enhances the positive inotropic effect
of catecholamines on the heart, possibly by promoting
coupling of ^-adrenergic receptors to adenylate cyclase.
Elevated levels of cortisol increase both cardiac output
and stroke volume, whereas cortisol deficiency has the
opposite effect. Cortisol (GCs) increases the density of
yd2-adrenergic receptors in vascular smooth muscle and
promotes the vasodilating effect of epinephrine in some
vascular beds.
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