section 32.2
Adrenal Medulla
chronic, intense cholinergic stimulation increases the
/5-hydroxylase by increased protein synthesis.
Epinephrine production is catalyzed by PNMT, which
is induced by glucocorticoids (cortisol). The venous
drainage of the adrenal cortex, which contains very high
concentrations of newly released cortisol, bathes the
adrenal medulla before entering the general circulation.
Regulation o f Release
The major regulator of catecholamine release from the
adrenal medulla is cholinergic stimulation, which causes
calcium-dependent exocytosis of the contents of the secre-
tory granules. Exocytosis of the granular content releases
epinephrine (E), NE, DA, dopamine /1-hydroxylase, ATP,
peptides, and chromaffin-specific proteins that are biolog-
ically inert. The amounts of DA and NE released are minor
in comparison with that of E. Of the total catecholamine
content in the granules, approximately 80% is E, 16% is
NE, and the remainder is mostly DA.
Transport and Metabolism of Catecholamines
Under basal (unstimulated) conditions in the average adult,
NE enters plasma at an average rate of ~5.8 ng/kg/min,
almost entirely from adrenergic nerve endings that inner-
vate peripheral tissues (liver, kidney, intestines, pancreas,
skeletal muscle, heart, etc.), and with only negligible con-
tribution by the adrenal medulla; E enters plasma at an
average rate of ~3.6 ng/kg/min, entirely derived from the
adrenal medulla. Under stimulated conditions, however,
the degree to which plasma NE and E levels increase may
differ, depending on the nature of the stimulus. For ex-
ample, whereas physical exercise increases the level of
both catecholamines similarly, acute hypoglycemia causes
E levels to increase 5- to 10-fold without affecting the lev-
els of NE significantly. As discussed below, the adrenal
contribution to NE is physiologically important because it
can elevate the plasma level of NE to what is required for
a biological effect in peripheral tissues.
Circulating catecholamines have an estimated half-life
of about one circulation time (20 seconds). They are
rapidly taken up by various tissues (notably the liver),
where they may exert their effects before they are inac-
tivated. DA may be converted to NE after uptake by nerve
endings, kidney, heart, and other tissues. Two enzymes
responsible for inactivation of catecholamines are present
in most tissues but are particularly abundant in the liver.
(COMT) is a cytosolic,
Mg2+-dependent enzyme that catalyzes méthoxylation of
catecholamines at the hydroxyl group at position 3. COMT
utilizes S-adenosylmethionine as the methyl donor and
usually initiates inactivation (Figure 32-7).
(MAO), a mitochondrial enzyme that oxidizes
the amino side chain of catecholamines, acts gener-
ally (but not invariably) on methoxylated catecholamines
(Figure 32-7). About 70% of the total output of urinary
catecholamines is 3-methoxy-4-hydroxymandelic acid
(also called vanillylmandelic acid, VMA) (Figure 32-7).
Unmodified catecholamines represent 0.1-0.4% of the
Biological Actions of Catecholamines
Catecholamines exert their effects through specific recep-
tors on the target cell surface. However, the effects elicited
depend on the type or subtype of receptor with which they
interact. There are three types of catecholamine receptor:
dopamine, cc-adrenergic, and /i-adrcnergic. Each of these
consists of at least two or more subtypes, which differ with
respect to ligand affinity, tissue distribution, postreceptor
events, and drug antagonists (Table 32-3).
Mechanism of Action
Dopamine Receptors
Dopamine receptors (Dj and D2) have a greater affin-
ity for DA than for NE or E (Table 32-3). Both subtypes
exert effects by altering the activity of adenylate cyci-
ase via a G-protein. Di receptors coupled to Gsu activate
the enzyme and cause a rise in intracellular cyclic AMP.
receptors are coupled to
and inhibit the enzyme
(Table 32-3). At very high concentrations, however,
dopamine is capable of activating a-adrenergic receptors,
which results in an effect resembling that of NE (vaso-
constriction) instead of the characteristic vasodilatation
elicited by low concentrations of DA.
Adrenergic Receptors
There are two types of adrenergic receptors, designated
f .
Two subtypes of a-adrenergic receptors
\, a 2)
and three subtypes of
adrenergic receptors
(Jf, fi2,
have been identified according to their differing affinities
or susceptibilities to synthetic ligands with agonist or an-
tagonist biological activity.
Table 32-3 shows the five subtypes of adrenergic recep-
tors, their relative affinities for E and NE, their subtype-
specific agonists and antagonists, their tissue distribu-
tion, and the biological effects they mediate. Although
both E and NE are capable of binding to and activating
any of the adrenergic receptor subtypes (albeit to differ-
ing extents), the receptor subtypes may not be equally
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