HORMONES OF THE
ADRENAL MEDULA (A.M.)
It is considered as a part of the sympathetic nervous system
whereby the splanchic preganglionic nerve fibers terminate in
the adrenal medulla where they innervate the chromaffin cells
that produce the catecholamine hrs.:
Dopamine, Nor-epinephrine, Epinephrine.
The A.M is thus a specialized ganglion without axonal
extensions, with its chromaffin cells synthesize, store, and
release products that act on distant sites, so that it also
functions as an endocrine organ.
*so the “sympathoadrenal system”
consists of the following:
[Link] NS with cholinergic pre-
and postganglionic nerves.
2. The sympathetic NS with cholinergic pre
– ganglionic and adrenergic post ganglionic
nerves.
3. The A.M.
The hrs. of the sympathoadrenal system are required
for adaptation to acute and chronic stress. They are
the major elements in the response to severe stress.
This response involves an acute integrated
adjustment of many complex processes in the organs
vital to the response (brain, muscles,
cardiopulmonary system, liver) at the expense of
other organs that are less immediately involved
(skin,GIT, lymphoid tissue).
Biosynthesis of
Catecholamines
These amines are synthesized in the chromaffin cells
of the adrenal medulla, they are so named because
they contain granules that develop a red – brown
color when exposed to potassium dichromate stain.
Collections of these cells are also found in (heart,
liver, kidney, gonads, adrenergic neurons of the
postganglionic sympathetic system, and CNS).
Catecholamines are 3,4 dihydroxyderivatives of
phenylethylamine. The major product of adrenal
medulla is epinephrine-which constitutes about
80% of the catecholamines in the medulla and its
not made in the extra medullary tissue.
However, most of the nor-epinephrine present in
organs innervated by sympathetic nerves is made
insitu and most of the rest is made in other nerve
endings and reaches the target tissue via the
circulation.
In other wards; in the extra-adrenal
chromaffin cell catecholamines synthesis ends
u p w i t h t h e f o r m a t i o n o f N E P, w h i l e c e l l s o f
adrenal medulla can convert NEP to EP which
is the major catecholamine product by the
adrenal medulla.
In addition, the chromaffin cells of extra-
adrenal tissues have the property of the
synthesis, storage and re-uptake of the
discharged catecholamine, while the adrenal
medullary cells can synthesize, store, and
secrete but not uptake the discharged
catecholamine.
Catecholamine are usually derived from
TYROSINE, the conversion of tyrosine
to EPN. requires 4- sequential steps :
1. Ring hydroxylation.
2. Decarboxylation.
3. Side-chain hydroxylation.
4.N- methylation.
1-RING H Y D R O X Y L AT I O N
Ty r o s i n e i s t h e i m m e d i a t e p r e c u r s o r o f
catecholamines, and “tyrosine hydroxylase” is
the rate-limiting enzyme in catecholamines
biosynthesis. This enzyme is found in both
soluble and particle- bound forms only in
tissues that synthesize catecholamines. .
It functions as an oxidoreductase with
tetrahydropteridine as a co-factor to convert
L-tyrosine to L- dihydroxyphenyl alanine ( L-
dopa).
This step is regulated in variety of ways. The
most important mechanism involves feed back
inhibition by the catecholamine.
Its also inhibited by a series of tyrosine
derivatives including α-methyltyrosine (this
compound is occasionally used to treat
catecholamine excess in pheochromocytoma).
A third group that inhibits this enzyme is those
compounds that act by chelating iron and thus
removing the co-factor.
2-DOPA decarboxylation: This soluble
enzyme is present in all tissues of the body
requires pyridoxal phosphate for conversion of
L- dopa to 3,4 dihydroxyphenylethylamine
(dopamine). Compounds that resemble L-dopa
are competitive inhibitors of this reaction as
* α-Methyldopa, *3- hydroxytyramine,
metaraminol, *α-methyl -tyrosine. These
compounds are usually used in treatment of
hypertension.
3-SIDE CHAIN HYDROXYLATION :
This step is catalyzed by DBH (dopamine b-
hydroxylase) and needs ascorbate as an electron
donor, copper at the active side and fumarate as
modulator.
This enzyme is present in the particulate fraction
of the medullary cells probably in the secretion
granules, thus the conversion of dopamine to nor-
epinephrine occurs in these organelles.
4-N- METHYLATION:
It’s the addition of methyl group to nitrogen, it is catalyzed by
(PNMT) phenyl ethanol amine N- methyl transferase and so
converts NEP to EP in the epinephrine forming cells of
adrenal medulla.
Since PNMT is soluble its assumed that the conversion
occurs in the cytoplasim. The synthesis of PNMT is induced
by glucocorticoid hrs. that reach the medulla via the intra-
adrenal portal system.
The intra- adrenal portal system provides a 100 fold steroid
concentration gradient over systemic arterial blood, and this
high intra- adrenal concentration appears to be necessary for
induction of PNMT.
Following the formation of NE in the
secretory granules, these CA will leave the
secretion granules to the cytoplasm where
its conversion to Ep will take place,
however the newly formed EP. and NE.
can be retaken by new population of
secretion granules.
STORAGA AND SECRETION OF CA.
The secretory chromaffin granules are capable of
biosynthesis, uptake, storage and secretion of CA.
These granules contain a number of substances in
addition to the CA. including ATP,Mg+2,Ca+2 ,DBH
and the protein chromagranin A.
Neural stimulation of the adrenal medulla results in the
fusion of the membrane of the storage granules with the
plasma membrane and this leads to the exocytosic
release of NEP and EP .
This process is calcium dependent and is stimulated by
cholinergic and b-adrenergic agents. CA and ATP are
released in proportion to their intra-granular ratio as the
other contents including DBH, Ca+2, chromagranin A.
(the ratio is 4\1),this means that the CA is 4 and the ATP
is 1.
Storage granules
Neural reuptake of CA is an important mechanism
for conserving these hormones and for quickly
terminating their hormonal or neurotransmitter
activities .
The adrenal epinephrine goes to the liver and
skeletal muscles, but then rapidly metabolized
(half life is very short; 10-30 seconds.)
METABOLISM OF CATECHOLAMINES:
Less than 5% of CA. can be excreted unchanged in
the urine ,however 95% of CA. usually undergoes
conversions to metabolites that are excreted mainly
as conjugated derivatives (with glucoronide or
sulfate) in urine .
Two enzymes are involved in the metabolism of CA:
[Link] (catechol O- methyl transferase):
Is a cytosolic enzyme found in many tissues; it
catalyzes the addition of a methyl group usually at 3-
position on the benzene ring. The result of this
reaction -depending on the substrate- is the
production of (homovanillic acid , nor metanephrine,
and metanephrine.
[Link] (monoamine oxidase):
is an oxidoreductase that deaminates mono-
amines ,it is located in many tissues,but mainly in
liver ,stomach, kidneys and intestine.
It is of two types :
*MAO-A: is found in neural tissue and deaminates
serotonin, epinephrine, and nor epinephrine.
*MAO-B: is found in the extra-neural tissues and is
mostly active against 2- phenylethylamine and
benzylamine. Both forms metabolize dopamine and
tyramine.
VMA is the end product of NE and EP.
metabolism and usually increases if
there is a tumor of the adrenal medulla
(pheochromocytoma.)
