BIO 5406 Notes, 2/16/08
ADRENAL MEDULLA
I. Anatomy of the Adrenal Gland. [Hadley, pp. 317-318, 338]
A. Cap above each kidney (fig. 15.1).
B. Adrenal cortex -- outer portion (fig. 15.2, figure).
1. Secretes steroid hormones.
C. Adrenal medulla -- central portion.
1. Neural crest origin.
2. Modified sympathetic ganglion.
3. Innervated by splanchnic nerve (sympathetic preganglionic neurons).
4. Secretes catecholamines.
D. Histology of adrenal medulla (figure).
1. Mostly chromaffin cells.
a. Large, oval shaped (fig. 14‑20, H & E).
b. Arranged in clumps.
c. Cytoplasmic granules stain yellowish‑brown in presence of
chromium salts -----> chromaffin reaction (fig. 14‑18).
d. Stain green with zinc chloride (fig. 14‑19).
2. A few ganglion cells (arrows, fig. 14‑21).
a. Sympathetic postganglionic cell bodies.
II. History. [pp. 315-316]
A. 1563 ‑‑ Adrenal glands first described by Bartholomeus Eustachius.
B. 1895 ‑‑ George Oliver and Edward Sharpey-Schafer found that
extracts of adrenal medulla produced a pressor effect.
C. 1899-1901 ‑‑ Isolation and purification of the pressor substance
independently by John Jacob Abel and Jokichi Takamine.
1. Named epinephrine (adrenalin).
2. First hormone to be isolated and purified.
D. 1929 ‑‑ Walter B. Cannon introduced the concept of the
"fight‑or‑flight" response.
E. 1948 ‑‑ Raymond Ahlquist introduced concept of alpha- and beta-
adrenergic receptors for catecholamines.
F. 1964 -- James Black developed first clinically useful beta-blocker,
propranolol.
III. Hormones of the Adrenal Medulla. [pg. 315, Carmichael and Winkler]
A. Epinephrine (80%) (fig. 14.1).
B. Norepinephrine (20%).
1. Lacks the methyl group on the nitrogen.
C. Enkephalins -- pentapeptides.
IV. Catecholamine Biosynthesis. [pp. 320-321, Carmichael and Winkler]
A. Four step biosynthetic pathway from tyrosine (fig. 14.3). MEMORIZE!
1. Ring hydroxylation of tyrosine (cytoplasm).
a. Enzyme -- tyrosine hydroxylase.
b. Rate‑limiting step.
c. Product -- dihydroxyphenylalanine (DOPA).
d. End-product inhibition by cytoplasmic EPI.
2. Side-chain decarboxylation (cytoplasm).
a. L-aromatic amino acid decarboxylase.
b. Dopamine is taken up into chromaffin granules.
3. Side-chain hydroxylation (chromaffin granule).
a. Dopamine b-hydroxylase.
b. Norepinephrine (NE) is a neurotransmitter in the sympathetic n.s.
and a product of the adrenal medulla.
4. N-methylation of norepinephrine (cytoplasm).
a. Phenylethanolamine N-methyltransferase (PNMT).
b. Epinephrine (EPI) is taken back up into chromaffin granules.
c. 10% of adrenal medullary cells lack PNMT ‑‑ produce NE.
B. Secreted by exocytosis.
V. Catecholamine Secretion, Transport, and Metabolism.
[pp. 254, 321-322, 332]
A. Contents of chromaffin granules are released by exocytosis.
B. Stimuli to catecholamine secretion.
1. Stress.
a. Activation of sympathetic n.s.
b. Stimulates release of catecholamines from vesicles.
c. Stimulates EPI synthesis -- activation of tyrosine hydroxylase.
2. Hypoglycemia.
3. Hypoxia.
4. Glucocorticoids and ACTH.
a. Glucocorticoids and ACTH stimulate activity of PNMT.
b. Blood flows through adrenal cortex to medulla.
C. Transport in blood -- dissolved in blood plasma.
D. Catecholamines are rapidly metabolized (half‑life = 5 min).
VI. Mechanisms of Catecholamine Action. [pp. 323-328]
A. Adrenoreceptor hypothesis.
1. Ahlquist (1948) recognized that some tissues differed in their
responses to a series of sympathetic amines.
2. Proposed two different adrenergic receptor subtypes.
a. EPI > NE > isoproterenol -----> α-adrenergic receptors.
b. Isoproterenol > EPI > NE -----> β-adrenergic receptors.
3. Subtypes often have antagonistic actions.
a. Stimulation of α-receptors causes smooth muscle contraction;
β causes relaxation.
4. Specificity of sympathetic amines.
a. NE has high affinity for α‑receptors.
b. Isoproterenol has high affinity for β-receptors.
c. Epinephrine acts on both α‑ and ß‑receptors.
1. Where both α‑ and ß‑receptors are present, α‑receptors
dominate.
5. Selective adrenergic blocking drugs.
a. Selective a-adrenergic antagonist unmasks "silent" b-receptors in
some tissues (fig. 14.6).
b. Propranolol -- first clinically useful b-blocker.
1. Developed by James Black in 1964.
2. Antihypertensive.
3. Research tool.
B. Structure.
1. Four different adrenergic receptor subtypes have been cloned and
sequenced.
2. Seven membrane-spanning regions (fig. 14.9, figure).
3. Linked to a G protein.
C. Beta‑adrenergic receptors.
1. Always involves activation of adenylyl cyclase (figure).
a. Example: Glycogenolysis.
D. Alpha‑adrenergic receptors.
1. Inhibit adenylyl cyclase (fig. 14.10, fig. 3.7, figure).
2. Activation of phospholipase C stimulates formation of IP3 and
diacylglycerol.
3. Increase cytoplasmic Ca++ levels (fig. 3.12).
E. Summary of alpha- and beta-receptors.
VII. Actions of Catecholamines. [pp. 329-332, Lagercrantz and Slotkin]
A. Arousal.
1. General CNS excitation.
2. Pupillary dilation.
3. Piloerection.
4. Sweating.
B. Cardiovascular.
1. Cardiac muscle cells have mostly b‑receptors.
a. EPI increases heart rate and stroke volume.
b. Increased systolic BP due to cardiostimulant action.
2. Blood vessels.
a. Arterioles in skin and internal organs have mostly a-receptors.
1. NE and EPI cause vasoconstriction.
b. Arterioles in myocardium and skeletal muscle have mostly
b-receptors.
1. EPI causes vasodilation.
c. Blood flow is shunted away from skin and internal organs (a)
to heart and skeletal muscle (b).
C. Respiratory.
1. Bronchodilation (b).
2. Increased rate and depth of breathing.
D. Metabolic (b).
1. Increases BMR.
2. Glycogenolysis (liver) -----> increased plasma glucose.
3. Lipolysis (adipose tissue) -----> increased plasma free fatty acids.
VIII. Comparative Aspects. [pp. 334-335, Lagercrantz and Slotkin]
A. Diversity in anatomical arrangement of adrenal glands (figure).
1. Close anatomical relationship between cortical and chromaffin cells.
2. Interrenal glands in fishes and amphibians.
a. Islands of steroid‑producing cells between kidneys or within renal
tissue.
b. Chromaffin cells lie nearby.
3. Reptiles, birds, mammals -----> suprarenal position.
4. Only mammals have distinct central medulla; others have steroid and
chromaffin cells mixed.
B. Secretions of adrenal medulla.
1. Close anatomical relationship between adrenal steroid and
chromaffin cells is required to produce EPI.
a. Adrenal steroids required for expression of PNMT.
2. Lower vertebrates secrete more NE than EPI.
3. Progressive reliance on EPI through evolution.
4. Exception -- diving mammals produce mostly NE
(ex. whale produces 83% NE).
IX. The "Stress" of Being Born. [Lagercrantz and Slotkin]
A. Birth is a stressful event.
B. Fetal adrenal medulla.
C. Effects of NE.
D. Block catecholamine secretion in newborn rat ----->
E. Cesarian section.
F. Benefits of increased catecholamine secretion at birth (figure).
